Vitamin D

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VITAMIN D METABOLISM

Endocrine, paracrine and intracrine functions of Vitamin D

Vitamin D from sunlight exposure• Vitamin D is manufactured in your skin

following direct exposure to sun.

• Amount varies with time of day, season, latitude and skin pigmentation.

• 10–15 minutes exposure of hands, arms and face 2–3 times/week may be sufficient (depending on skin sensitivity).

• Clothing, sunscreen, window glass and pollution reduce amount produced.

Source: National Osteoporosis Foundation Web site; retrieved July 2005 at http://www.nof.org

Toxic >150 nmol/L (60 mcg/L)

Check calcium Stop treatment

(enough to suppress PTH)

Definition of vitamin D deficiency & sufficiency based on serum 25(OH)D concentrations

Vitamin D Deficiency & Insufficiency

Davies JH & Shaw NJ. Arch Dis Child. 2010 Jul 23. [Epub ahead of print]

System and Tissue Distribution of Nuclear Vitamin D Receptors (VDR) System Tissue

Immune Thymus, bone marrow, macrophages, B cells, T cellsGastrointestinal Esophagus, stomach, small intestine, colon, rectumCardiovascular Endothelial cells, smooth muscle cells, myocytesRespiratory Lung alveolar cellsHepatic Liver parenchyma cellsRenal Proximal and distal tubules, collecting ductEndocrine Parathyroid, thyroid, pancreatic beta cellsExocrine Parotid gland, sebaceous glandCNS Brain neurons, astrocytes, microgliaEpidermis/appendage Skin, breast, hair folliclesMusculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscleConnective Tissue Fibroblasts, stromaReproductive Testis, ovary, placenta, uterus, endometrium, yolk sac

Vitamin D Deficiency

Rickets, Osteomalacia

Influenza, Tuberculosis MS, RA, SLE, Type I diabetes Hypertension, CAD, PVD, CHF Syndrome X, Type 2 Diabetes Chronic Fatigue, SAD,

Depression Cataracts, Infertility Osteoporosis Cancer

Holick BMJ June 2008;336:1318-1319

Possible Consequences of Vitamin D Deficiency

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What May Vitamin D Improve?

-Improved bone health-Increased absorption of calcium-Reduced risk of falls and bone fractures-Reduced coronary artery disease-Improved muscular function-Lowering of high blood pressure-Improved blood sugar tolerance-Improved nerve function-Improved kidney function-Reduced risk of 17 cancers-Reduced influenza, cold infections, tuberculosis-Reduced risk of some types of dementia

Vitamin D & Innate Immunity

Adequate serum 25(OH)D

Innate immunity

Toll like receptors recognise pathogens

expression of VDR & CYP27B1 enzyme 25(OH)D 1,25(OH)2D

1,25(HO)2D leads to production of antimicrobial proteins (AMPs)

AMPs (e.g. Cathelcidin) important role in defence against bacterial & viral infections

Role of vitamin D in the pathogenesis of type 2 Diabetes Mellitus

Palomer et al, Diabetes, Obesity and Metabolism, 2008

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Inverse Relationship between Vitamin D and Morning Blood Glucose Levels in 1,614 Men and Women

5.96.06.16.26.36.46.56.66.76.86.9

0 20 40 60 80 100 120Median 25OHD (nmol/L)

Med

ian

Glu

cose

(mm

ol/L

)

Lu ZX et al, unpublished data

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1

2

1

2

1,25(OH)2 vitamin D sites of actionCalcium sites of action

Harrison’s On-line

Effects of Vitamin D and Calcium on Insulin Sensitivity

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Effects of Vitamin D and Calcium on Insulin Sensitivity

Entire Group(n=80)

Vitamin D3 2000 IU/d + Calcium Carbonate 1200

mg/d(n=40)

Placebo(n=40)

Randomisation* 8 weeks

* Randomisation in block and Stratification according to sex, age (< or >50 yo)and BMI (< or >30 kg/m2)

† If 25OHD < 75 nmol/L

Extra vitamin D3

2000 IU/d† or placebo

Extra placebo

Schematic representation of the multitude of other potential physiologic action of vitamin D for cardiovascular health, cancer prevention,

regulation of immune function and decreased risk of autoimmune diseases

Holick, Am J Clin Nutr, 2004

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Vitamin D Anti-microbial ActivityEndogenous Anti-microbial Peptides

MACROPHAGE

N

Cathelicidin Gene

Activation

25(OH)D

1,25-(OH)2D

1-hydroxylaseMicrobes

+

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Infectious Diseases - Colds

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Infectious Diseases - Epidemic Influenza

• Influenza outbreaks were inversely correlated

with solar UVB

• Epidemic influenza is seasonal in part due to

seasonal variations of solar UVB and vitamin D

Hope-Simpson RE. J Hyg (Lond). 1981; 8:35-47 Cannell JJ, et al. Epidemiol Infect. 2006; 134:1129-40

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Relationship of 25(OH)D and Activation of Latent Tuberculosis (n=155)

• Serum 25(OH)D lower in those with no TB (55 nmol/L), latent TB (37 nmol/L) & TB/pastTB (16 nmol/L) p<0.01

Any vs. no TB Infection

TB/past TB vs. latent TB Infection

Gibney K et al, Clin Inf Disease 2008

Tuberculosis Treated with Sunshine

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Vitamin D and Cancer

● Inverse correlation between incidence, mortality and or survival rates for many cancers including breast, colorectal, ovarian, and prostate cancers.

● Emerging evidence that more than 17 cancers are likely to be vitamin D sensitive.

● 1000 IU/day could reduce cancers 7% for men, 9% for women in US.

● 25(OH)D level of 52 ng/ml reduced breast cancer by 50%● 60-80 ng/ml may be optimal for most individuals● 25(OH)D level increase from 29 to 39 reduced cancer risk by

60% after 4 years.

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Vitamin D and Cancer

Apperly first demonstrated an association between latitude and cancer mortality in 1941

Cancers associated with low vitamin D include:

•Breast and Ovarian Cancer

•Prostate Cancer

•Digestive system cancer, including Colon Cancer

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Vitamin D and Calcium Supplementation Reduces Cancer Risk

• A 4-yr prospective, placebo-controlled study of 1100 IU vitamin D3 and/or 1400 mg calcium and

cancer risk in 1179 post-menopausal women

• Serum 25(OH)D rose from 71.8 to 96.0 nmol/L

• The all-cancer incidence for women over the age of 55 years at time of enrollment was reduced by 60% (p=0.01)

Lappe JM et al. Am J Clin Nutr 2007 85: 1586-91

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Vitamin D Deficiency is Associated with Increased Risk of Breast Cancer Recurrence and Death

• 512 women (mean age 50 yrs) with early stage breast cancer• After 11 yrs, 85% of women with sufficient levels survived

compared with 74% of deficient women• After 10 yrs, women with deficient levels were 94% more likely to

have distant metastasesGoodwin P et al. ASCO (abstract) 2008

Northern vs. Southern U.S.

1 – 2 extra skin cancer deaths (per 100,000)

30 – 40 extra deaths for other major cancers (per 100,000)

June, 2007 American Journal of Clinical Nutrition

Women who regularly took vitamin D3 and calcium had a 60% reduction in all-cancer incidence compared with a group taking placebo and a 77% reduction when the analysis was confined to cancers diagnosed after the first 12 months.

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Vitamin D and Mortality Rates• The risk of dying from any cause in subjects who

participated in randomized trials of vitamin D supplementation

• 18 independent randomized, controlled trials, including 57,311 participants

• 4777 deaths from any cause occurred• Mean daily vitamin D dose was 528 IU, 5.7 year

average follow-up• The relative risk for mortality from any cause was 0.93

(95% CI, 0.87-0.99)

Autier P, Gandini S Arch Intern Med 2007 167(16):1730-7

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Cardiovascular Disease

• A graded increase in cardiovascular risk across

categories of serum 25(OH)D, with hazard ratios of 1.53

for levels 25 to 38 nmol/L and 1.8 for levels < 25 nmol/L

• Highest risk was in those with hypertension and vitamin

D deficiency

Wang TJ et al, Circulation 2008;117: 503-11

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Vitamin D and the Heart

Low levels of vitamin D associated with increased risk of cardiovascular disease and mortality.One study: Low vitamin D risk increase of Coronary Artery Disease - 45%Stroke - 78%Heart attack - 50%Death – 77-100%25-57% USA adults may be deficient

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Vitamin D and Obesity

• Obese subjects vs. normal weight controls have– Lower serum 25OHD levels– Higher PTH and inconsistent results for 1,25(OH)2 vitamin D

• Two possible explanations– Less sunlight exposure– Decreased bioavailability of vitamin D due to sequestration in adipose tissue

Liel et al, Calcif Tissue Int, 1988

Wortsman et al, Am J Clin Nutr, 2000

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Vitamin D and MS

Multiple Sclerosis: Vitamin D levels of 40 ng/ml or higher may confer some protection against MS.

Patients receiving Magnesium, Calcium and 5000 IU vitamin D significantly reduced MS

exacerbations (14 vs 32).

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Vitamin D and Dementia● Vitamin D may be primarily associated with cognitive

domains other than memory , such as executive cognitive functions, depression, bipolar disorders, and schizophrenia.

● Low 25(OH)D may be a risk factor for cognitive impairment (41-60%).

● Receptors for Vitamin D are present in brain cells. Increased Vitamin D may improve cognitive function in patients with Alzheimer's

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Vitamin D and Falls

Low vitamin D may result in more falls and fractures since muscles contain vitamin D receptors.

Vitamin D activation increases protein synthesis in muscles.

13 studies using 800-1000 IU consistently demonstrated beneficial effects on muscle strength and balance with aged 60 or older.

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Vitamin D and the Lungs

Asthma: Early studies indicate may reduce severe exacerbations, exercise induced bronchoconstriction

Lower respiratory tract infections are more frequent in those with low 25(OH)D levels.

2000 IU Vitamin D abolished the seasonality of influenza and dramatically reduced the self-reported incidence.

Vitamin D reduces inflammation and viral pathogens.

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Vitamin D and the Lungs

One Vitamin D Influenza study showed:

334 children 6-15 years50% -1200 D3 4 months vs placeboFlu: 10.8% (with D) vs 18.6%Asthma children – 93% reduced attacksLow vitamin D adults: double risk of viral infections

Vitamin D Assessment Lab assays are available to measure both 25(OH)D and

1,25-D. 25(OH)D closely reflects total amount of vit D produced in

the skin and from diet D2 and D3: have similar biological activity Both D2 and D3 should be measured DO NOT USE - 1,25-D. This can often be normal with vit D

deficiency

Who is at greatest risk? Low dietary intake: BF infants, children who do not drink

fortified milk Malabsorption syndrome Severe liver disease Kidney disease Drugs Higher latitudes People who spend little time outside Older adults Decreased sun exposure due to cultural reasons Races with high skin melanin levels

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Malabsorption Drug Interactions and Storage

Patients who may require more vitamin D intake include those with:

● Intestinal fat-malabsorption syndromes● Anticonvulsive medications● Glucocorticoids and related medications● Less ability to absorb sunlight (elderly)● Excess fat (vitamin D stored in fat is not

available)

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Vitamin D Sources

The Sunshine VitaminFortified foods:

Typically supply 150 IU per day, but highly variable (100 - 400 IU per day).

Supplements:-Over-the-counter usually vitamin D3-Prescription versions are usually vitamin D2 (synthetic).-Vitamin D3 is more than three times powerful than D2.

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How Much Vitamin D is Needed?

Estimated body requirements per day are 3000-5000 IU.Obese and elderly may need the higher levels.

10,000 IU per day may be the new recommended upper limit.(10)

The only way to know how much is needed is to test 25(OH)D.

Everyone should be tested!

Goal: 25(OH)D between 60-80 ng/ml after a consistent intake

level over 2 months.

100 IU of vitamin D raises 25(OH)D about 1 ng/ml.

Vitamin D SupplementationDeficiency (<25 nmol/l or 10 mcg/l)Oral Therapy

– 1st line agent: Fultium-D3 ® (Cholecalciferol) 800 iu capsules x4/d (licensed product) - 3200 iu daily for 8-12 weeks. – 2nd line:

Dekristol® (Cholecalciferol) capsules 20,000 units (unlicensed import). Prescribe 1 capsule (20,000 units) once per week for 8-12 weeks.

Where oral therapy not appropriateErgocalciferol 300,000 (or 600,000) iu single dose by intramuscular injection. The injection is gelatin free and may be preferred for some populations.

Vitamin D SupplementationInsufficiency (25-50 nmol/l or 10-20 mcg/l) or for long-term maintenance following rx of deficiency1st line therapy

– Fultium-D3® 800iu capsules x2/d (licensed) - 1600iu per day (a dose between 1000 – 2000 units daily is appropriate).

2nd line:– Prescribe Dekristol® capsules 20 000 units [unlicensed

import]. Prescribe 1 capsule (20,000 units) once per fortnight.

Alternatively where oral therapy not appropriate– Ergocalciferol 300,000 international units single dose by

intramuscular injection once or twice a YEAR.

Alfacalcidol/CalcitriolAlfacalcidol (1 alpha- vitamin D) and Calcitriol

have no routine place in the management of primary vitamin D deficiency

Reserved for use in renal disease, liver disease and hypoparathyroidism.

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Who is at risk to overdose on Vitamin D?Anyone who takes Vitamin D supplements CAN take too much Vitamin D. But the majority of documented overdose on vitamin D are from:

• Children whose parents accidentally give them massive doses of vitamin D• Elderly people who incorrectly take massive vitamin D dosages• Adults who take more than 10,000 IU's per day for long periods of time.• 'Industrial Accidents' where massive quantities of vitamin D are put into fortified foods in error

These categories comprise nearly all people who have had an overdose on Vitamin D.

FAQ

Yes , any increase in BMD results in fructure

reduction Decrease BMD despite

adequate R/ , pt. should be reevaluated for

compliance or a 2ry cause of loss

No definite time limit to bisphosphonate use for osteoporosis.Maintenance or increase in BMD with use of Alendronate for up to 10

years, Risedronate for at least 5 years.Normalization of BMD on therapy reasonable to cosider stopping the

agent.

No , only some pt. with osteopenia need to be treated for example : h/o a law trauma fracture . Pts. deserve to be treated. Pts. At high risk of fracture due to , prior fracture ,T-score ≤

1.8, poor mobility or poor overall health status

It shouldn’t be used for more than 2 years , stop it and switch pt. to a bisphosphonate .

15 minutes between 10:00 am and 2:00 pm should provide adequate sunlight.

No , it needs massive doses of vit. D given chronically to induce toxicity (> 10,000 IU/day)

Don’t be afraid and give appropriate supplementation (some pt. on anticonvulsant therapy may need 4000 IU/day to achieve adequate vit. D level )

Fracture at time of menopause is less than at old age .

The incidence of spine and hip fractures begins to increase starting at the age of 60 or 65.

Women with several lifestyle risk factors (e.g. on steroid therapy or breast CA on R/) , should be screened earlier than age 65 to identify who would benefit from pharmacological R/.

Counsel all women on life style strategies (calcium,vit. D ,exercise, and nonsmoking.

Summary You are never too old or too young

to improve your bone health• Adults

– At least 30 minutes of moderate physical activity a day– Strength and balance training– Protect from falls– Eye exam to check for visual impairments– Bone density test with a fracture after age 50, and for everyone with risk factors– Bone density test for all women over age 65– Extra calcium and vitamin D over age 50– Medication, if indicated, to prevent

bone loss or build new bone

• Children & Teens– Teens are at greater risk for poor bone health because of rapidly growing bones

and poor diet– At least one hour of physical activity a day – Increase calcium during teens

• Babies– Bone health begins before birth

SummaryYou are never too old or too young

to improve your bone health

“Men grow old, pearls grow yellow, there is

no cure for it “Chinese proverb