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Role of vitamin D deficiency
in non-skeletal disorders
Ravinder Goswami MD DM FASc FNASc
Additional Professor
Department of Endocrinology and Metabolism
All India Institute of Medical Sciences
New Delhi
25(OH)D amp absorption of dietary calcium
Vitamin D deficiency results in poor
absorption of calcium from our diet
from a maximum possible of 60 to 15
Reversed with Vitamin D
supplementation
Goswami et al
J Hum Nutr Dietetics 2009
Dietary calcium transporters in the intestine mucosa
VDRE Calbindin Calcium transporters
(+)
5rsquo 3rsquo
ndash100 bp
Nuclear hormone receptor binding
Translocation to nucleus
Positive regulation by vitamin D
Adapted from Chen RA Goodman WG Am J Physiol Renal Physiol 2004286F1005-F1011
Site of expression of vitamin D receptor protein
Normal tissue
Adrenal gland
Appendix
Bone marrow
Breast
Bronchus
Cerebellum
Cerebral cortex
Colon
Duodenum
Endometrium
Epididymis
Fallopian tube
Gall bladder
Hippocampus
Kidney
Lateral ventricle
Liver
Lung
Nasopharynx
Pancreas
Placenta
Prostrate
Rectum
Salivary gland
Seminal vesicle
Skin
Small intestine
Stomach
Testis
Thyroid
Tonsil
Urinary bladder
Utrine cervix
Vulva
Breast cancer
Cervical cancer
Colo-rectal cancer
Endometrial cancer
Head amp neck cancer
Liver cancer
Lung cancer
Malignant carcinoid
Malignant lymphoma
Malignant melanoma
Disease tissue
Ovarian cancer
Pancreatic cancer
Prostrate cancer
Renal cancer
Skin cancer
Stomach cancer
Testis cancer
Thyroid cancer
Urothelial cancer
Source Human proteinpedia
Renal and extrarenal 1α-hydroxylase
Current Opinion in Nephrology and
Hypertension 2008
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
25(OH)D amp absorption of dietary calcium
Vitamin D deficiency results in poor
absorption of calcium from our diet
from a maximum possible of 60 to 15
Reversed with Vitamin D
supplementation
Goswami et al
J Hum Nutr Dietetics 2009
Dietary calcium transporters in the intestine mucosa
VDRE Calbindin Calcium transporters
(+)
5rsquo 3rsquo
ndash100 bp
Nuclear hormone receptor binding
Translocation to nucleus
Positive regulation by vitamin D
Adapted from Chen RA Goodman WG Am J Physiol Renal Physiol 2004286F1005-F1011
Site of expression of vitamin D receptor protein
Normal tissue
Adrenal gland
Appendix
Bone marrow
Breast
Bronchus
Cerebellum
Cerebral cortex
Colon
Duodenum
Endometrium
Epididymis
Fallopian tube
Gall bladder
Hippocampus
Kidney
Lateral ventricle
Liver
Lung
Nasopharynx
Pancreas
Placenta
Prostrate
Rectum
Salivary gland
Seminal vesicle
Skin
Small intestine
Stomach
Testis
Thyroid
Tonsil
Urinary bladder
Utrine cervix
Vulva
Breast cancer
Cervical cancer
Colo-rectal cancer
Endometrial cancer
Head amp neck cancer
Liver cancer
Lung cancer
Malignant carcinoid
Malignant lymphoma
Malignant melanoma
Disease tissue
Ovarian cancer
Pancreatic cancer
Prostrate cancer
Renal cancer
Skin cancer
Stomach cancer
Testis cancer
Thyroid cancer
Urothelial cancer
Source Human proteinpedia
Renal and extrarenal 1α-hydroxylase
Current Opinion in Nephrology and
Hypertension 2008
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Dietary calcium transporters in the intestine mucosa
VDRE Calbindin Calcium transporters
(+)
5rsquo 3rsquo
ndash100 bp
Nuclear hormone receptor binding
Translocation to nucleus
Positive regulation by vitamin D
Adapted from Chen RA Goodman WG Am J Physiol Renal Physiol 2004286F1005-F1011
Site of expression of vitamin D receptor protein
Normal tissue
Adrenal gland
Appendix
Bone marrow
Breast
Bronchus
Cerebellum
Cerebral cortex
Colon
Duodenum
Endometrium
Epididymis
Fallopian tube
Gall bladder
Hippocampus
Kidney
Lateral ventricle
Liver
Lung
Nasopharynx
Pancreas
Placenta
Prostrate
Rectum
Salivary gland
Seminal vesicle
Skin
Small intestine
Stomach
Testis
Thyroid
Tonsil
Urinary bladder
Utrine cervix
Vulva
Breast cancer
Cervical cancer
Colo-rectal cancer
Endometrial cancer
Head amp neck cancer
Liver cancer
Lung cancer
Malignant carcinoid
Malignant lymphoma
Malignant melanoma
Disease tissue
Ovarian cancer
Pancreatic cancer
Prostrate cancer
Renal cancer
Skin cancer
Stomach cancer
Testis cancer
Thyroid cancer
Urothelial cancer
Source Human proteinpedia
Renal and extrarenal 1α-hydroxylase
Current Opinion in Nephrology and
Hypertension 2008
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Site of expression of vitamin D receptor protein
Normal tissue
Adrenal gland
Appendix
Bone marrow
Breast
Bronchus
Cerebellum
Cerebral cortex
Colon
Duodenum
Endometrium
Epididymis
Fallopian tube
Gall bladder
Hippocampus
Kidney
Lateral ventricle
Liver
Lung
Nasopharynx
Pancreas
Placenta
Prostrate
Rectum
Salivary gland
Seminal vesicle
Skin
Small intestine
Stomach
Testis
Thyroid
Tonsil
Urinary bladder
Utrine cervix
Vulva
Breast cancer
Cervical cancer
Colo-rectal cancer
Endometrial cancer
Head amp neck cancer
Liver cancer
Lung cancer
Malignant carcinoid
Malignant lymphoma
Malignant melanoma
Disease tissue
Ovarian cancer
Pancreatic cancer
Prostrate cancer
Renal cancer
Skin cancer
Stomach cancer
Testis cancer
Thyroid cancer
Urothelial cancer
Source Human proteinpedia
Renal and extrarenal 1α-hydroxylase
Current Opinion in Nephrology and
Hypertension 2008
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Renal and extrarenal 1α-hydroxylase
Current Opinion in Nephrology and
Hypertension 2008
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Goswami et al 2008
European Journal of Clinical Nutrition
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D amp cancer related
genes transcription
Vitamin D related signaling
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Potential significance of vitamin D deficiency
in disorders unrelated to bone health
Type 2- DIABETES MELLITUS
TUBERCULOSIS amp other immune disturbances
CARDIOVASCULAR DISEASE
MALIGNANCY
OSTEOARTHRITIS
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Mental health Schizophrenia
Type I-DM
Multiple Sclerosis
Crohnrsquos disease
Wheezing disorders
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Diabetes Metabolic Syndrome and Vitamin D
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and type 2 diabetes
Winters Blood glucose values are worse
Pancreatic β -cell function ndashDirect effect of vitamin D
VDR in islet cells 1 alpha hydroxylase VDRE in insulin gene
Thus VDD may interfere with normal insulin release especially in response to a glucose load
Insulin resistance ndash In VD deficiency Sarcopenia
Decreased insulin receptor expression
Dercreased Insulin receptor phosphyration (Ca dependent)
UP regulate NFkB and thus pro inflammatory cytokines
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Diabetes and Vitamin D Longitudinal Observational Cohort Studies
Seven studies
bull Liu et al - Womenrsquos Health Study (2005)
bull Pittas et al- Nurses health study (2006)
bull Knekt et al- Mini Finland health survey (2008)
bull Kirii et al- Japan Public Health Center-based Prospective Study (2009)
bull Liu et al- Framingham offspring study (2010)
bull Pittas et al- Nurses health study (2010)
bull Anderson et al- Intermountain healthcare system (2010)
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Risk of Type 2 DM Based on Ca amp D IntakesNurses Health Prospective Observational Study
0
02
04
06
08
1
12
D lt400 IUd D 401-800 IUd D gt800 IUd
Ca lt600mgd
Ca 601-1200 mgd
Ca gt1200 mgd
Rel
ati
ve
Ris
k o
f D
M
Pittas et al 2006
Daily intake of gt1200 mg Ca + gt800 iu vitamin D associated with
33 lower risk of DM cf lt600mg calcium and lt400 iu vitamin D
Cohort of 83779 women followed up for 20 yrs for new DM
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
bull Nested case-control study
bull 608 women with new T2 DM and 559 control subjects in
Nursesrsquo Health Study
bull OR for incident T2 DM in top (median 25-D 334
ngml) vs bottom (median 25-D 144 ngml) quartile
= 052 (95 CI 033ndash 083)
Pittas AG et al Diabetes Care 2010
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
bull 33951 postmenopausal women aged 50-79 years
bull Double-blind randomized controlled trial
bull 1000 mg elemental Ca plus 400 IU of vit D3 daily or
placebo
bull Median FU of 7 years
bull 2291 newly diagnosed DM
bull Hazard ratio for incident diabetes associated with
calciumvitamin D treatment 101 (95 CI 094 ndash110)
de Boer et al Diabetes Care 2008
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Association of vitamin D deficiency with incidence of type 2
diabetes in high-risk Asian subjects Soo Lim et al AJCN2013
105 lt10 ngmL 159
516 =100-199 ngmL FU for 32 months 102
380 ge20 ngmL 54
After adjustment for age sex blood pressure lifestyles family history
season parathyroid hormone and high-sensitivity C-reactive protein
the participants with 25(OH)D deficiency had an increased risk of T2D
independently of BMI HOMA2-IR
HRs 323 (95 CI 17-63) for 25(OH)D lt10 ngmL vs ge20 ngmL
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
OR 054 (95 CI 023ndash127) for the highest vs the lowest
25-OHD concentration (25ndash38 vs 10ndash23 ngml)
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Randomized trials of vitamin D and glycemic outcomes
11 RCTs
bull Nilas and Christiansen 1984
bull Pittas et al 2007
bull Sugden et al 2008
bull de Boer et al 2008- WHI study
bull Avenell et al 2009- RECORD trial
bull Nagpal et al 2009
bull Zittermann et al 2009
bull Witham et al 2010
bull von Hurst et al 2010
bull Jorde et al 2009
bull Jorde et al 2010
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D supplementation reduces insulin resistance in South
Asian women (23-68 yrs) living in New Zealand who are
insulin resistant and vitamin D deficient - a randomised
placebo-controlled trial
Von Hurst et al Br J Nutr 2009 Sep 281-7
Vitamin D3(4000 IU n 42) or placebo (n 39) daily for 6 months
Reducing in IR were observed with serum 25(OH)D = 80 nmolL
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Trials in participants with T2 DM
bull 3 small underpowered RCTs ndash Sugden et al 2008
ndash Jorde R et al 2010
ndash Witham et al 2010
bull High infrequent doses
bull No change in HBA1c FPG or insulin resistance
with vitamin D supplementation after a follow-up
period of 8ndash26 weeks
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Interventional trials assessing effect of Vit D on glycemic
improvement are limited (total 4)
Placebo controlled randomized trial of longest duration 3 yrs
92 subjects (gt65 yrs) with IGF
700 IU of vitamin D and 500 mg Ca day
Lower rise in FPG at 3 years compared with those on placebo
(04 mgdl vs 61 mgdl respectively P = 0042)
Net reduction in vitamin D supplemented 57mgdl P = 004)
(Pittas et al Diabetes care 2007)
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Meta-analysis Effect of vitamin D supplementation on type 2 DM
bull Evidence suggests that combined vitamin D amp calcium
supplementation may have a role in prevention of T2DM in
populations at risk such as those with glucose intolerance
bull It is difficult to draw definitive conclusions from available
intervention studies in Tye 2 DM because most studies were short
in duration had few subjects used variety dose and combinations
of vitamin D and calcium among various cohorts
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant glycemic outcomes
are needed
Pittas AG et al EJCN 2011
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
CVD and Vitamin D
Epidemiological Evidence
Higher mortality rates with increasing distance from equator (Fleck et al 1989)
IHD mortality inversely proportional to hrs of sun exposure in
UK (Grimes et al 1996)
uarr Prevalence of CAD in CRD
uarr CAD prevalence and associated mortality in winter
uarr CAD in Urban vs Rural linked to poor VD status
Framingham Cohort Inverse correlation between serum 125(OH)D and
coronary artery calcification
(Watson et al Circulation 1997)
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
NHANES
NHANES (1988-1994)
Participants with CVD had greater frequency of vitamin D
deficiency than those without (29 vs 21)
After multivariate analysis participants with vitamin D
deficiency had increased CVD (OR 120 [95(CI) 101-136) (Atherosclerosis 2009205255-60)
NHANES (2000-2004)
Burden of CVDs increased with lower 25(OH)D levels across
CHD HF stroke and PVD
Several CV risk factors such as DM HT raised TG elevated
BMI and microalbuminuria were associated with vitamin D
deficiency (Am J Cardiol 20081021540-4)
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
CVD and Vitamin DMechanism
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cardiovascular disease
(Core binding factor alpha)
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
ProspectiveCohort studies
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Health Professionals Follow-up Study
bull Health professionals without CVD
bull 18225 subjects 40-75 years of age
bull Two fold increase in MI in vitamin D deficient population(Giovannucchi et al 2008)
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Framingham Offspring Studybull 1739 subjects with no CVD 5 year FU
bull HR of 18 (95CI 105-308) in subjects with 25(OH)D
lt10ngdl for developing first CV event compared to subjects
with higher vitamin D levels
Wang et al 2008
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Journal American Geriatric Society 2009
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and CVD
Arch Intern Med 2008
3258 subjects 77 year FU
Mortality RR gt2 in lower quartiles of 25(OH)D cf highest
Low 25(OH)D correlated with CRP IL-6 oxidative burden adhesion molecules
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
9578 German subjects age 50-74 yr with 25(OH)D measured at
baseline Follow-up 95 yrs
Vitamin D deficiency associated with increased mortality
CVD 139 (95 CI 102 189)]
Cancer 142 (95 CI 108 188)
Respiratory 250 (95 CI 112 556)
The RR started to increase at 25(OH)D lt75 nmolL
Am J Clin Nutr 2013
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
CARDIOVASCULAR DISEASE and VDD
40 fall in CRP and IL-6 in CAD patients on three
monthly cholecalciferol (1250microg) injections for a years
Li YC JCI 2002
Significant improvement of EF after VD supplementation
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
RCTs
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D Research
Meta-analysis 8 RCT 57 311 individuals
Conclusions Intake of ordinary doses of Vitamin D supplements
(300-2000 IU mean 528 IU) seems to be associated with decrease
in mortality rates Arch Intern Med 2007
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Prescribing vitamin D reduces the risk of mortality in
CKD in 194932 patients (14 observational Studies )
Vitamin D Treatment and Mortality in Chronic Kidney
Disease Meta-Analysis
Duranton et al Am J Nephrol 2013
RR = 067 (95 CI 045-098) after 5 years
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cardiovascular disease
18 patients with untreated mild essential HT -
randomised to receive thrice weekly full-body
UVB or UVA at suberythematous doses over 6
weeks
Treatment caused a significant reduction in 24-h
ambulatory systolic and diastolic blood pressure
in the UVB but not in the UVA group
This fall in BP was evident both during daytime
and night-time
In the UVB group there was a 162 rise in
plasma concentrations of 25(OH)D (57middot6 [12middot0ndash
91middot2] to 151middot2 [100middot8ndash273middot6] nmolL plt0middot001)
Lancet 1998
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
CARDIOVASCULAR DISEASE and VDD
Inverse relationship between 25(OH)D and HT
(Higher intake of vitamin D led to 93 decrease in
systolic blood pressure in elderly women)
(Pfeifer et al JCEM 2001)
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D status and arterial hypertension a
systematic review Nat Rev Cardiol 2009 Oct6 Pilz et al
Observational data support the concept that vitamin D is
involved in the pathogenesis of cardiovascular diseases and
arterial hypertension
ldquoThe results of clinical studies largely favor the
hypothesis that vitamin D sufficiency promotes
lowering of arterial blood pressure Randomized
placebo-controlled trials are greatly needed to clarify
and definitively prove the effect of vitamin D on blood
pressurerdquo
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
CARDIOVASCULAR DISEASE
6-8 prevalence of overt CAD in urban Indians
Earlier presentation
Role of vitamin D supplementation
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
MALIGNANCY
uarr incidences amp mortality of Prostate colonic Breast and
pancreatic cancer in vitamin D deficiency
25 times increase in risk of colorectal Ca over a 8 year
in women health initiative study
Prevalence is linked to effect of VD and VDR
on p21 and p27 gene important in Carcinogenesis
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cancer
bull Inhibiting tumor angiogenesis
J Investig Dermatol Symp Proc 1996
bull Stimulating mutual adherence in cells - induction of E-cadherin and inhibit β catenin gene regulatory activity
J Cell Biol 2001
bull Stimulates the expression of cell cycle inhibitors p21 and p27 JCEM 2009
bull Protective mechanism against UV damage - uarr Nuclear p53 protein expression J Invest Dermatol 2007
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cancer
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cancer
bull Large geographic gradients in Cancer mortality rates in US
(twice as high in the northeast vs southwest)
bull Analysis of UV-B data exposure and cancer mortality rates
showed UV-B radiation was aw darr risk of cancer of the breast
colon ovary and prostate as well as non-Hodgkin lymphoma
bull
bull CANCER 2002
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and cancer NHANES-3
bull In 16818 participants ge 17 yrs were followed from 1988 ndashthrough 2000 with 25(OH)D measured at baseline
bull 536 cancer deaths Cancer mortality not related to 25(OH)D
bull Colorectal cancer mortality related to 25(OH)D
bull Levels gt 80 nmolL lead to a 72 risk reduction
bull (95CI =32- 89) vs lt 50 nmolL P = 002 JNatl Cancer Inst 2007
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Cancer Epidemiol Biomarkers Prev 2013 Mar 5
Serum 25-hydroxyvitamin D and cancer risk in older adults
Results from a large German prospective cohort study
CONCLUSIONS
25(OH)D concentrations were significantly associated with
overall cancer incidence
No significant association was observed with site-specific
cancers
Abstract (text)Abstractabstractabstractabstract20201false1
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and Cancer
RCTs Primary outcome - Incident cancer
Cohort studies Primary outcome ndash Cancer mortalityNo significant risk reduction
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Meta-Analysis
VDN and Cancer Risk(Gandini et al
Int J Cancer 2011 1281414-24)
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
ldquoDose-Responserdquo
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Meta-analysis Effect of vitamin D on Cancer
bull Evidence suggests a possible increased mortality related to
Cancer
bull It is difficult to draw definitive conclusions regarding sites specific
data and dose response with vitamin D
bull High-quality observational studies and RCTs that measure
blood 25-OH D and clinically relevant incident and mortality
outcomes are needed
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D amp Tuberculosis
In 1895 Niels Finsen exposed individuals with skin TB to high intensity light produced from an electric arc lamp
Phototherapy cured or substantially improved the disease in about 95 of affected people
By the 1920 sun exposure for the treatment of pulmonary TB had become routine
Finsen was awarded nobel prize for his work
Nature medicine 2006
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Potential significance of VDD other than Bone
TUBERCULOSIS
VDR receptor are there in PBMC
In in-vitro studies 125(OH)D2 favors Th2 rather than
Th1 Response
How to explain the paradox of improvement with VD
in TB which needs enhancement in Th1 response for
quick healing
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D amp Tuberculosis
Current Opinion in Nephrology and
Hypertension 2008
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D amp Tuberculosis
SCIENCE 2006
Monocyte respnse to 125(OH)2D3
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
S 25(OH)D levels amp Tuberculosis
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D treatment amp Tuberculosis J Steroid Biochemistry amp Molecular Biology 2007
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D treatment amp Tuberculosis
Results of RCT trial
Vitamin D (10000 IUday) or placebo in a double
blind method during the 6 initial wk of PTB Rx
Sputum AFB conversion VD vs placebo (100 vs 76)
Acta Med Indones 2006
24 newly diagnosed TB children (PTB amp EPTB)
After 8 wks clinical amp radiological improvement was
more in patients on vitamin D Boll Chim Farm 1998
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D supplementation and Cat-I PTB
A double-blind randomized placebo-controlled trial
Wejse c et al Am J Respir Crit Care Med (2009)
365 adult new smear +ve Categ-I PTB patients
100000 IU of cholecalciferol or placebo (oral)
at baseline 5th and 8th months (total 30 lacs) with ATT
Assessed TB score and sputum AFB examination at 2nd4th6th wks and at 2nd 5th and 8th months
Sputum AFB conversion rates was similar in 2 groups
2 month (8 vs 7)
5th month (40 vs 14)
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
High-dose vitamin D(3) during intensive-phase antimicrobial
treatment of pulmonary tuberculosis a double-blind
randomised controlled trial
Martineau AR Lancet 2011
NTERPRETATION Administration of four doses of 2middot5 mg vitamin
D(3) increased serum 25-hydroxyvitamin D concentrations in patients
receiving intensive-phase treatment for pulmonary tuberculosis Vitamin
D did not significantly affect time to sputum culture conversion in the
whole study population
Vitamin D amp Tuberculosis
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and autoimmune disease (Multiple
Sclerosis Type 1 DM Rheumatoid Arthritis
Crohnrsquos Disease)
Ann NY Acad Sci 2007
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and Type 1 DM (Observation)
12 055 Finnish women due to give birth in 1966 were enrolled
Data collected in first year of birth about vitamin D supplementation
Primary outcome diagnosis of type 1 diabetes by December 1997
Vitamin D supplementation led to decreased frequency of T1DM
RR adjusted for neonatal anthropometric and social characteristics was 0middot12 95 CI 0middot03ndash0middot51) for regular vs no supplementation Lancet 2001
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and Type 1 DM
Maternal intake of vitamin D via food was significantly
associated with a decreased risk of Insulin autoantibiodies
appearance in offspring which was independent of HLA
genotype family history of type 1 diabetes presence of
gestational diabetes mellitus and ethnicity
(adjusted HR - 037 95 CI 017ndash 078)
Diabetes Care 2003
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vit D intake in pregnant women and risk of
newborn to develop type 1 DM ndash Meta analysis
(MmMean pooled OR = 095)
Antonio et al Autoimmunity Reviews 2012
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Effect of vit D supplementation in infancy on
development of type 1 diabetes ndash Meta analysis
Arch Dis Child 2008
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
S 25(OH)D levels and Multiple Sclerosis
Epidemiologic data supports relationship
between Sun exposure and prevalence of MS
MS gt in 10 fold higher in Temperate than tropics
A negative correlation between UV exposure amp MS
European Journal of Clinical Nutrition (2004)
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
S 25(OH)D levels and Odd ratios for developing
Multiple Sclerosis
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Only 4 studies had Jadad scores of 5 or more
Three did not find vitamin D to be significantly
superior to placebo
Beatriz Pozuelo-Moyano Neuroepidemiology 201340147ndash153
A Systematic Review of Randomized Double-Blind
Placebo-Controlled Trials Examining the Clinical
Efficacy of Vitamin D in Multiple Sclerosis
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Goswami et al 2008
British Journal of Nutrition
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Potential significance of vitamin D deficiency in
disorders unrelated to bone health
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D and Muscle
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Fall prevention
by dose of
vitamin D
and threshold
serum 25OHD
levels
Bischoff-Ferrari
Arch Int Med
2009
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Grip Strength
gt25 nmoll 25OHD17 RCTs (5072 participants) Only 4 with baseline lt 25 nmolL
Hand Grip
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Grip Strengthgt25 nmoll 25OHD
Lower limb
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Other issues
Dose of vitamin D
Frequency of administration
Other co-morbid conditions
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Gupta et al 2010
First RCT in young showing significant effect of vitamin D
supplementation on muscle strength
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
No Change in Hand Grip Strength in females
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Vitamin D in Non-Skeletal Health
bull Diabetes
ndash Insulin secretion and insulin resistance
ndash Risk of developing T2DM
bull Cardiovascular
bull Cancer
ndash Breast Colon Lung Pancreas Leukemia etc
bull Autoimmunity
ndash T1DM Rheumatoid Arthritis MS Childhood allergy
Tuberculosis
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
Conclusionsbull We need to rethink ldquoone nutrient-one diseaserdquo concept
bull Vitamin D has pleomorphic effects far beyond it was originally assumed
bull Some benefit of vitmain D supplementation on muscle function ndash especially those with low VDN
bull However at present no data exist to recommend higher vitamin D intakes to prevent DM CV events or Cancer
THANK YOU
THANK YOU
