Vitamin D Update Dustin Sulak D.O.

Maine Osteopathic Association Midwinter Conference

February 8th, 2013

Overview �  Introduction

�  History of Vitamin D

�  Vitamin D Physiology

�  Review of Old News

�  Recent Vitamin D News �  Mortality �  Depression �  Pain

�  Hepatitis C �  Respiratory Infections �  Infant Heart Failure

�  SLE �  Atopic Dermatitis

Overview �  D2 (ergocalciferol) vs D3 (cholecalciferol)

�  Safety, Toxicity

�  Recommendations For Testing And Supplementation

�  Summary

Introduction �  Disclosure – I have no conflicts of interest or

financial relationships with vitamin D etc.

�  Integrative Medicine �  Assessing patients as individuals, taking into account

body, mind, spirit, family, and community.

�  Emphasis on prevention, education, natural and less-invasive treatments

�  Individualized treatment

�  Panacea?

Andrew  Taylor  S.ll  “Man  should  study  and  use  the  drugs  

compounded  in  his  own  body.”  

S.ll  AT.  Autobiography  of  Andrew  T.  S.ll.  Kirksville,  Mo:  AT  S.ll;  1897  

Vitamin D: Brief History Mid 1600s

�  Rickets identified as major health problem

�  People moving from rural to urban areas, lifestyles change, decreased sun exposure

Early 1800s

�  Rickets incidence escalates with Industrial Revolution, becoming epidemic in northern Europe and in industrialized northern regions of the United States.

Vitamin D: Brief History 1822

�  First published observation that lack of sun exposure could be the cause of rickets: children who lived in Poland had a higher incidence of rickets compared with children from the countryside who were disease-free.

Mozolowski W. Jedrzej Sniadecki (1768–1838) on the cure of rickets. Nature. 1939;143:121–124.

Vitamin D: Brief History 1824

�  First report on the use of cod liver oil to prevent rickets �  Schutte D. Beobachtungen Uber den Nutzen des Berger Leberthrans (Oleum

jecoris Aseli, von Gadus asellus L) Arch Med Erfahr. 1824;2:79–92.

1922

�  McCollum coined term “vitamin D” to describe antirachitic factor in cod liver oil �  McCollum EV, Simmonds N, Becker JE, Shipley PG. J Biol Chem. 1922;53:293–

312.

�  Antirachitic properties of UV light demonstrated in rats �  Hess AF. Lancet. 1922;ii:367. Reprinted in: Hess AF. Collected Writings. Vol 2.

Springfield, Ill: Charles C. Thomas; 1936:5–14.

Vitamin D: Brief History �  1927

�  Quaker Oats begins manufacturing vitamin D enriched cereals

�  Pharmaceutical companies begin to manufacture a product called Viosterol (irradiated ergosterol)

�  1934 and on… �  Irradiation used to produce vitamin D enriched milk �  Eradication of rickets

�  SOLAR Ultraviolet Radiation AND Vitamin D. Am J Public Health. 2007 October; 97(10): 1746–1754.

Heliotherapy for Tuberculosis – Late 1800s

Heliotherapy for Tuberculosis – Late 1800s

Heliotherapy for Tuberculosis – Early 1900s

Finsen Light Therapy for Lupus Vulgaris - 1900

Niels Ryberg Finsen – Nobel Prize 1903

Dec 1939 – The Osteopathic Profession

Daily Recommended Intake

Conflicting Evidence with DRI

�  28 Adults given 4000iu/d x 5 months �  25-OH-D levels averaged 40ng/ml

�  Vieth. Am J Clin Nutr 2001.73(2):288.

�  67 men given higher doses x 20 weeks �  5000iu/d – average 25-OH-D level 60ng/ml �  10,000iu/d – average level 90ng/ml

�  No toxicity seen �  Heany et al. Am J Clin Nutr. 2004;79(3):362.

Vitamin D Physiology

Physiology �  1 Minimal Erythema Dose (MED) of UV radiation is equivalent to

10,000-25,000iu oral intake D2

�  Factors affecting intensity of UVB exposure and D3 production: �  Solar zenith angle (latitude and season) �  Altitude �  Clouds, atmospheric aerosols �  Ozone �  Surface reflection �  Melanin (skin type) �  Age, Obesity

�  SPF 8 Sunblock prevents 92-95% vit D production

�  Holick, Michael F., et al. "Vitamin D and Skin Physiology: AD‐Lightful Story." Journal of Bone and Mineral Research 22.S2 (2007): V28-V33.

Sample Calculations �  Norwegan Institute for Air Research online calculator

�  http://nadir.nilu.no/~olaeng/fastrt/VitD_quartMEDandMED_v2.html

�  Portland, Maine (43.66N latitude)

�  Mid-day, moderate ozone

�  Fitzpatrick skin type 3 �  Medium, white to light brown, sometimes mild burn, gradually tans to a light

brown

�  Skin Exposure 25% (face, neck, hands, arms)

�  Altitude: Sea level

�  Cloudless Sky, Visibility 25Km

�  Surface type: Grass

Sample Calculations �  Exposure to produce 2,000iu vit D3 equivalent

�  Exposure to produce 5,000iu vit D3 equivalent

Feb 8 April 8 June 8

Time 57 min 14 min 9 min

% MED 48% 36% 33%

Feb 8 April 8 June 8

Time 2hrs 33min 36 min 23 min

%MED 122% 90% 86%

Vitamin D Physiology

Vitamin D Physiology

1,25(OH)2D = Calcitriol �  Most biologically active form of Vitamin D

�  Increases GI calcium and phosphorus absorption

�  Increases renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine

�  Induces osteoclast maturation for bone remodeling

�  Promotes calcium deposition in bone and reduction of parathyroid hormone

1,25(OH)2D – Not Just Kidneys

�  Circulating 25(OH)D levels are directly related to dietary vitamin D intake plus skin exposure to ultraviolet light.

�  Circulating 1,25(OH)2D is controlled largely by calcium homeostasis and is not directly related to one's nutritional vitamin D status.

�  Although the kidney supplies 1,25(OH)2D to the circulation, we are just beginning to understand the importance of the supply of 25(OH)D to various tissues that use 25(OH)D to produce, in a paracrine–intracrine fashion, 1,25(OH)2D for tissue-specific use.

�  The conversion of 25(OH)D to 1,25(OH)2D in these tissues appears not to be controlled by calcium, but rather to be directly linked to the substrate availability of 25(OH)D.

�  Hollis B W , Wagner C L CMAJ 2006;174:1287-1290

Fig. 2: The endocrine, paracrine and intracrine functions of vitamin D. Vitamin D is converted in the liver to 25(OH)D, which enters the systemic circulation and is converted to 1,25(OH)2D

in a variety of end-organ tissues.

Hollis B W , Wagner C L CMAJ 2006;174:1287-1290

©2006 by Canadian Medical Association

Vitamin D Receptor

�  VDR is a nuclear transcription factor

�  1,25-(OH)2D enters nucleus of cell, associates with the VDR and promotes its association with the retinoic acid X receptor (RXR).

�  VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs) and initiates a cascade of molecular interactions that modulate the transcription of specific genes.

�  More than 50 genes in tissues throughout the body are known to be regulated by 1,25-(OH)2D.

�  Guyton KZ, Kensler TW, Posner GH. Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev. 2003;61(7):227-238

Vitamin D Receptor �  Cells containing Nuclear VDR

�  pancreatic islet cells �  monocytes �  transformed B cells �  activated T cells �  neurons �  prostate �  ovaries �  pituitary �  aortic endothelium �  placenta �  skeletal muscle cells

�  Zittermann A. Br J Nutr. 2003;89(5):552. �  Bischoff HA, et al. Histochem J 2001;33:19.

Parathyroid Hormone �  Secondary HyperPTH can be due to

Hypovitaminosis D �  25OH-Vit D levels 30-40ng/ml

�  Zittermann A. Br J Nutr. 2003;89(5):552.

�  Suppression of PTH is important �  Low PTH promotes good health

�  High PTH associated with increased risk of MI, HTN, CVA

�  Kamycheva et al. Eur J Cardiovasc Prev Rehab. 2004;11(1).

�  Sato et al. Neurology. 2003;60(4):626.

Vitamin D Studies �  Beware:

�  D2 vs D3

�  25-OH-D: 1 ng/ml ≈ 2.5 nmol/L �  Cod liver oil and/or concurrent vit A supplementation

�  Baseline vitamin D status �  Dosage makes a big difference �  Association vs causality

�  Co-factors: Mg, vit K, Zn, Boron

Old News

Heart Disease �  1,739 individuals without cardiovascular disease

�  Baseline 25-OH-Vitamin D levels were assessed and participants were followed for a mean of 5.4 years.

�  Compared to having a level >15ng/ml �  25-(OH)D < 10 ng/mL - 80% increased risk of having a

cardiovascular incident

�  25 (OH)D of 10-15 ng/mL - 53% increased risk

�  The authors concluded vitamin D deficiency is positively correlated with incident cardiovascular disease.

�  Wang TJ, Pencina MJ, Booth Sl, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-511.

Cancer �  47,800 men in Health Professionals Follow-

Up Study over 14 years

�  10 ng/ml rise in Vitamin D level of associated with: �  17% reduction in cancer incidence

�  29% reduction in all cancer mortality

�  45% reduction in GI cancer mortality

�  Giovanucchi et al. J Natl Cancer Inst. 2006. 98(7):428.

Pain �  Study with 150 patients with persistent,

nonspecific musculoskeletal pain at Mayo clinic �  93% had Vit D deficiency

�  Plotnikoff, Quigley. Mayo Clin Proc. 2003;78(12):1463.

�  Idiopathic Low Back Pain �  83% of 299 LBP patients had Vit D deficiency

�  Supplementation with 5,000-10,000iu D3 daily �  Decreased use of pain medication in nearly 100% of

patients after 3 months �  Al Faraj, Al Mutairi. Spine 2003;28(2):177.

Diabetes Type 2 �  Metformin improves insulin sensitivity by 13%

�  Highest Vit D levels associated with 60% improvement in insulin sensitivity

�  Chiu. Am J Clin Nutr. 2004;79:820.

�  Small trial of 10 women with DM Type 2 �  Vit D 1332iu per day x 30 days �  21% increase in insulin sensitivity

�  Borrisova et al. Int J Clin Pract. 2003;57(4):258.

Maternal-Fetal Health: Caesarian

�  n=253, 2005-2007, urban teaching hospital in Boston

�  Women with levels <15 ng/ml were 4x as likely to have cesarean section compared to >15 ng/ml

�  Women with levels >50 ng/ml had 5% total cesarean section rate

Merewood A, et al. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab. 2009 Mar;94(3):940-5. Epub 2008 Dec 23.

Epilepsy �  Seizures can be first sign of Vit D def

�  Johnson, Willis. Med J Aust. 2003;178(9):467.

�  Hypovitaminosis D decreases seizure threshold

�  Several anticonvulsants (phenytoin, phenobarbital, carbamazepine, perhaps others) �  Interfere with renal calcitriol formation �  Induce hepatic clearance of calcitriol �  Impair calcium absorption from the intestine and

mobilization from the bone. �  May cause iatrogenic seizures via iatrogenic

hypovitaminosis D and hypocalcemia �  Ali et al. Ann Pharmacother. 2004;38(6):1002.

Longevity �  Meta-analysis of 18 RCTs – 57,311 patients

�  Range of 300-2000iu/day

�  Highest intake – 7% reduction in all-cause mortality

�  “Based on the total body of evidence of health conditions associated with vitamin D deficiency, abetted with the results from this meta-analysis, a more proactive attitude to identify, prevent and treat vitamin D deficiency should be part of standard medical care.”

�  Giovannuchi. Arch Intern Med. 2007;167:1709-1710.

Recent News

Fracture Prevention in Elderly

�  New England Journal of Medicine review of 11 double-blind RCTs �  n=31,022 �  Mean age 76yrs, 91% women

�  Highest intake level median 800iu daily

�  30% reduction in risk of hip fracture �  (hazard ratio, 0.70; 95% CI, 0.58 to 0.86)

�  14% reduction in risk of any non-vertebral fracture �  (hazard ratio, 0.86; 95% CI, 0.76 to 0.96).

�  Bischoff-Ferrari, Heike A., et al. "A pooled analysis of vitamin D dose requirements for fracture prevention." New England Journal of Medicine 367.1 (2012): 40-49.

Vitamin D and Mortality �  9,146 individuals

�  1993 to 2009 �  Frozen blood samples from the beginning of their enrollment

and assayed vitamin D levels �  Total of 832 deaths �  Median follow-up 10 years

�  Quartiles: �  1st: 9 ng/ml �  2nd: 16 ng/ml �  3rd: 22 ng/ml �  4th: 32 ng/ml

Skaaby T, Husemoen LLN, Pisinger C, Jørgensen T, Thuesen BH, et al. (2012) Vitamin D Status and Cause-Specific Mortality: A General Population Study. PLoS ONE 7(12): e52423. doi:10.1371/journal.pone.0052423

Vitamin D and Mortality �  Compare 4th Quartile (32ng/ml) to 1st Quartile (9ng/ml)

�  Respiratory system diseases (Hazard Ratio or HR=.26)

�  Digestive system diseases(HR=.28)

�  Endocrine, nutritional and metabolic diseases (HR=.21)

�  Unlike most other studies, they found no association between vitamin D status and death caused by cancer or cardiovascular disease.

Skaaby, Tea, et al. "Vitamin D Status and Cause-Specific Mortality: A General Population Study." PLOS ONE 7.12 (2012): e52423.

RCT: Vitamin D and Prozac �  42 patients with major depression

�  Half 20 mg fluoxetine daily

�  Half 20 mg fluoxetine plus 1,500 IU of vitamin D daily

�  95% participants had levels less than 30 ng/ml

�  Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) measured q 2 weeks.

�  The vitamin D + fluoxetine combination was significantly better than fluoxetine alone from the 4th week of treatment

�  Aust N Z J Psychiatry. 2012 Oct 23.

Persistent Nonspecific Musculoskeletal Pain

�  84 immigrants from Middle East, Turkey, northern Africa, and Somalia, and their offspring currently living in the Netherlands, aged 18-60 years

�  Baseline and 6 weeks administration of 150,000iu vitamin D3 or placebo

�  At week 6, the vitamin D group reported significant improvement in pain compared with the placebo group (34.9% vs 19.5% respectively, p=0.04)

�  At week 6, the vitamin D group reported significant improvement in their ability to walk stairs compared with the placebo group (21% vs 8.4% respectively, p=0.008)

�  Schreuder F, et al. Annals of Family Medicine. November 2012.

Hepatitis C �  72 patients with HCV genotype 1

�  Treatment group received Peg-α-2b interferon plus ribavirin and vitamin D3 2000 IU/d

�  Control group received identical therapy without vitamin D.

�  Abu-Mouch S, et al. World J Gastroenterol. 2011 Dec 21;17(47):5184-90.

Hepatitis C �  Week 4: 16 (44%) treated patients and 6 (17%) controls were

HCV-RNA negative (P < 0.001).

�  Week 12: 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001).

�  24 weeks post-treatment: 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001).

�  “Adding vitamin D to conventional Peg-α-2b/ribavirin therapy for treatment-naïve patients with chronic HCV genotype 1 infection significantly improves the viral response.”

�  Abu-Mouch S, et al. World J Gastroenterol. 2011 Dec 21;17(47):5184-90.

Hepatitis C

Abu-Mouch S, et al. World J Gastroenterol. 2011 Dec 21;17(47):5184-90.

Hepatitis C

Abu-Mouch S, et al. World J Gastroenterol. 2011 Dec 21;17(47):5184-90.

Hepatitis C �  Follow up study on 50 patients with HCV genotype 2-3

�  24 weeks after treatment (SVR), 19/20 (95%) treated patients and 23/30 (77%) controls were HCV RNA negative (P < 0.001)

�  Low vitamin D levels predicts negative treatment outcome, and adding vitamin D to conventional Peg/RBV therapy for patients with HCV genotype 2-3 significantly improves viral response.

�  Nimer A, Mouch A. World J Gastroenterol. 2012 Feb 28;18(8):800-5.

Respiratory Infections - RCT �  4,000 IU/day of vitamin D3 for one year in 140 patients

with: �  60%: immune deficiency (selective IgA subclass deficiency,

IgG subclass deficiency, common variable immune disorder) or a history of frequent infections

�  40%: history of frequent infections (>4 bacterial RTIs/year)

�  Treatment group: �  25% reduction in self-reported infections. �  64% reduction in antibiotic use

�  Bergman, et al. BMJ Open 2012;2:e001663

Respiratory Infections - RCT Conclusion:

“Our data indicate that vitamin D3 supplementation reduces the odds of taking antibiotics by approximately 60% in patients with frequent respiratory tract infections. Thus, supplementation with vitamin D3 could provide a novel strategy to reduce antibiotic use among high consumers and indirectly prevent the emerging epidemic of bacterial resistance.”

Bergman, et al. BMJ Open 2012;2:e001663

Vitamin D Levels Predict Pneumonia Death

�  Prospective study in 272 adults presenting to the emergency department with CAP

�  143 patients (53%) were vitamin D deficient (≤50 nmol/L), of which 65 patients were severe deficient (<30 nmol/L).

�  Severe vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality.

�  25-OH-D was an independent predictor of 30-day mortality. When combined with the Pneumonia Severity Index (PSI) score, the prognostic accuracy was superior to that of the PSI score alone.

�  H. Remmelts, et al. Vitamin D level predicts clinical outcome in community-acquired pneumonia. European Respiratory Society Annual Congress, Vienna 2012.

Infant Heart Failure �  Double-blind RCT: 80 infants with CHF

�  Treatment group: conventional treatment + D3 1,000iu daily �  Control group: conventional treatment + placebo

�  Treatment group ejection fraction went from 36% to 52% in 3 months, clinically and statistically significant compared to placebo plus standard treatment, which increased fraction from 37% to 43%.

�  Treatment group had decreased PTH, IL-6, and TNF-α compared with the placebo group (p < 0.001)

�  “Vitamin D supplementation has great benefits as an anti-inflammatory agent in infants with CHF. It helps acceleration of the clinical improvement and cytokine profile balance.”

�  Shedeed SA. Pediatr Cardiol. 2012 Jun;33(5):713-9.

Atopic Dermatitis �  60 patients with AD >14yo, no systemic disease

�  Treatment group: D3 1,600iu daily for 60 days

�  Control group: placebo �  Scoring Atopic Dermatitis (SCORAD) and Three Item

Severity (TIS) score evaluated by blinded physicians

�  Amestejani M, et al.J Drugs Dermatol. 2012 Mar;11(3):327-30.

SCORAD TIS 25-OH-D (ng/ml)

Before After Before After Before After

Vitamin D 24.8 15.3 3.5 1.9 9.1 22.15

Placebo 25.3 23.46 3.8 4.02 10.2 9.8

Systemic Lupus Erythematosis �  267 SLE patients randomized to receive 2,000 IU/day (n=178) vitamin

D3 or a placebo (n=89) for 1 year

�  Baseline 25-OH-D 19.8 ng/ml compared to 28.7 ng/ml in healthy controls.

�  After 12 months of therapy, the vitamin D group’s mean 25(OH)D level increased to 37.8 ng/ml, compared to no change in the placebo group.

�  10% of patients in the vitamin D group experienced a flare-up

�  24% of patients in the control group experienced a flare-up (p<0.05).

�  The authors noticed a significant reduction in SLE-related antibodies in the vitamin D group compared with the placebo group (p=0.05).

�  “Vitamin D, a safe, inexpensive, and widely available agent, may be as effective as a disease-suppressing intervention for patients with SLE.”

�  Abou-Raya, A, et al. "The Effect of Vitamin D Supplementation on Inflammatory and Hemostatic Markers and Disease Activity in Patients with Systemic Lupus Erythematosus: A Randomized Placebo-controlled Trial." The Journal of Rheumatology (2012).

D2 vs D3 �  D2 = ergocalciferol

�  Plant based from irradiated fungi ergosterol

�  Brand names: Drisdol, Calcidol, Deltalin

�  D3 = cholecalciferol �  Animal based, most supplements from

irradiated lanolin

�  Not FDA approved

�  Most resources suggest equivalent activity

�  Most insurance plans cover D2

D2 vs D3 �  3 groups, 10 healthy males in each

�  Single dose of 50,000iu D2, 50,000iu D3, or control

�  Equivalent absorption

�  Similar initial rise in 25-OH-D over 3 days

�  25-OH-D3 peaked at 14 days

�  25-OH-D2 returned to baseline at 14 days

�  Laura A. G. et al. J Clin Endocrinol Metab 89: 5387–5391, 2004

D2 vs D3

Laura A. G. et al. J Clin Endocrinol Metab 89: 5387–5391, 2004

Design

The project was conducted during the month of July, 2003. Subjectswere randomly assigned to receive 1) no supplement (the seasonal effect,control group), 2) one tablet labeled to contain 50,000 IU (1.25 mg)ergocalciferol (the vitamin D2 group), or 3) 10 tablets labeled to contain5,000 IU (125 !g)/tablet cholecalciferol (the vitamin D3 group). Becausethe vitamin D3 preparation was not a marketed product, we asked thesupplier to provide a certificate of analysis. [The 50,000-IU D2 tabletpreparation was supplied by Sidmak Laboratories, Inc. (High Point,NC). The 5,000-IU D3 tablet preparation was supplied by Tishcon Corp.(Salisbury, MD). The product was assayed on June 12, 2003, and foundto contain 5,513 IU/capsule.]

For the control group receiving no vitamin D supplement, serumsamples were obtained at d 0 and 28, so as to quantify the midsummerrise in 25OHD that would be expected in all groups. For the two groupsreceiving a vitamin D supplement, serum samples were obtained at d0, 1, 3, 5–7, 14, and 28. At the initial visit, each subject’s weight and heightwere measured. Height was measured using a Harpenden stadiometer(Seritex, Inc., Carlstadt, NJ). Blood was obtained for measurement ofserum vitamin D and 25OHD. After the baseline blood was obtained, thesubjects were observed while they took the assigned vitamin D sup-plement dose. At each subsequent visit, the subject’s weight was mea-sured and blood obtained for measurement of serum vitamin D and25OHD. The subjects were asked to recall their sun exposure since theprevious visit. The subjects were given supplies of sun block lotion, sunprotection factor (SPF) 15, to use during out-of-the-ordinary sunexposure.

Analytical methods

Serum ergo- and cholecalciferol concentrations were determined byreversed-phase HPLC, as described elsewhere (11). Serum 25OHD wasdetermined by RIA, using the IDS kit (Nichols Institute, San Clemente,CA). Because it has been reported (12) that the antibody in this kit reactspoorly with 25OHD2, we measured the samples from the vitamin D2-treated subjects using both the IDS and the DiaSorin kits (DiaSorin,Stillwater, MN). However, in this group of subjects, there were nosignificant differences in analyzed 25OHD increments above baselinebetween the values produced by the two antibodies. Hence, for thevalues in the D2-treated participants that we report here, we averagedthe results obtained with the two RIAs. Finally, to be certain that theRIAs were adequately detecting both 25OHD2 and 25OHD3, aliquots ofthe serum samples obtained at 0, 3, and 28 d were assayed by HPLC (10)for both 25OHD2 and 25OHD3. The mean increment in total 25OHD byHPLC at 3 and 28 d was virtually identical with the mean incrementmeasured by RIA.

Statistical methods

The 25OHD signal produced by the 50,000-IU calciferol dose wasanalyzed as the increment in total 25OHD concentration above baseline,adjusted for the mean rise in serum 25OHD observed in the untreatedcontrols (0.259 nmol/liter!d). Area under the curve (AUC) of serum25OHD increments at 14 and 28 d was calculated by the trapezoidalmethod individually for each subject. AUC! was calculated using phar-macokinetic, biexponential models (PK Solutions, Summit Research Ser-vices, Ashland, OH) fitted to the mean 25OHD values at each time point.Mean values for AUC14 and AUC28 for the two calciferols were com-pared by the usual t test for independent samples.

Results

Serum calciferol concentrations were measured at d 0, 1,and 3. The results are shown in Fig. 1. Baseline values of bothcalciferols were low, with the D3 concentration higher thanthe D2, as would be expected. However, the rise by d 1 wasessentially identical for both calciferols, and at d 3 the serumlevels of the two had fallen close to baseline and were vir-tually identical. This behavior indicates that absorption of thetwo calciferols was approximately equivalent.

The time course for the increment in serum 25OHD is

shown in Fig. 2, which presents the mean changes in valuesat each visit for total 25OHD (i.e. the sum of 25OHD2 and25OHD3). These values were corrected for the change wemeasured in 25OHD levels in our control population because

FIG. 2. Time course of the rise in serum 25OHD after a single oraldose of 50,000 IU of either cholecalciferol (vitamin D3) or ergocalciferol(vitamin D2) to two groups of 10 normal men each. Error bars are 1SEM. The zero-change line incorporates a correction for the seasonalrise in 25OHD occurring at the time this study was performed. (Toconvert from nmol/liter to ng/ml, multiply by 0.4.) [Copyright RobertP. Heaney, 2004. Used with permission.]

FIG. 1. Time course of serum concentrations of vitamin D after asingle oral dose of 50,000 IU of cholecalciferol (vitamin D3) or ergo-calciferol (vitamin D2,) in healthy male subjects (n " 10 for eachgroup). The error bars are 1 SEM. [Copyright Robert P. Heaney, 2004.Used with permission.]

5388 J Clin Endocrinol Metab, November 2004, 89(11):5387–5391 Armas et al. • Reduced Efficacy of Vitamin D2

by on September 30, 2009 jcem.endojournals.orgDownloaded from

•  Area under the curve (AUC) to day 28

•  D3:D2 = 3.4:1

•  Calculated AUC∞ D3:D2 = 9.5:1.

D2 vs D3 - Summary �  D2, if given in high enough doses, prevents infantile

rickets and is capable of healing osteomalacia.

�  D2 has 1/3 to 1/9 the potency of D3

�  25-OH-D2 has shorter duration of action, less binding to VDR

�  D2 has shorter shelf life

�  “D2 should no longer be regarded as a nutrient appropriate for supplementation or fortification of foods.”

�  Am J Clin Nutr October 2006 vol. 84 no. 4 694-697

Toxicity �  No credible evidence of toxicity at 25-OH-D <150ng/ml

�  No evidence for toxicity at doses of 10,000iu/d indefinitely

�  Vieth R. Am J Clin Nutr. 1999;69

�  Indicator of direct Vitamin D toxicity: �  Elevated serum calcium and 25-OH-D > 90ng/ml

�  Toxicity rare and requires long-term administration of at least 40,000iu/day in infants (or 100,000iu/d in adults) for several months

�  Berkow. Merck Manual. 1987:928.

Toxicity �  Toxicity sx’s appear with level >125ng/ml

�  Anorexia, nausea, vomiting, weakness, nervousness, pruritis, polyuria, polydipsia, renal impairment, soft tissue calcifications

�  Holick. Am J Clin Nutr. 2001;73(2):288.

�  Caution in Sarcoidosis �  Macrophages in sarcoid patients have

considerably increased rates of conversion of 25OHVitamin D to 1,25(OH)2Vitamin D.

Vit D Safety in Pregnancy �  A study in human subjects involved the administration of

100,000 IU vitamin D3/day throughout pregnancy to hypoparathyroid women to maintain serum calcium

�  (n= 15)

�  Infants were examined for signs of hypercalcemia at birth, 6 weeks, and several times in the first 4 years. None showed:

�  craniofacial stigmata micrognathia

�  Structural abnormality

�  pulmonary stenosis or other detectable cardiovascular anomalies.

Goodenday LS, Gordon GS. No risk from vitamin D in pregnancy. Ann Intern Med 1971; 75: 807– 8.

Prevalence of Vitamin D Deficiency

�  National Health and Nutrition Examination Survey 2005 to 2006 data were analyzed for vitamin D levels in adult participants (N = 4495).

�  Vitamin D deficiency = 25-OH-D ≤20 ng/mL

�  The overall prevalence rate of deficiency was 41.6%

�  Highest rate seen in blacks (82.1%), followed by Hispanics (69.2%).

�  Vitamin D deficiency was significantly more common among those who had no college education, were obese, with a poor health status, hypertension, low high-density lipoprotein cholesterol level, or not consuming milk daily (all P < .001).

�  Nutr Res. 2011 Jan;31(1):48-54.

Risks vs Benefits of Sun Exposure

�  Review article assessing relative risk for cutaneous malignant melanoma (CMM) and UV exposure

�  Increased sun exposure to the Norwegian population raising 25-OH-D by 25nmol/L (10ng/ml)

�  Estimated increase 200–300 CMM deaths per year

�  Estimated decrease of 4,000 internal cancers and 3,000 cancer deaths overall per year.

�  Moan, Johan, et al. "Vitamin D, sun, sunbeds and health." Public Health Nutrition 1.1 (2011): 1-5.

Rethinking Our Recommendations on Sun

Exposure �  Protect Face and Eyes with hat or sunblock

�  Expose skin to sun at angle when your shadow is shorter than your height (zenith angle >45 degrees)

�  Avoid sunburn

�  Avoid exposure through windows

�  Avoid washing skin with soap after exposure

�  Use more skin protection early in the outdoor season when vitamin D and melanin levels are low

Recommendations �  Screen patients for 25-OH-D annually

�  Goal: 50-100ng/ml

�  Testing in early winter makes most sense, but many patients are deficient year-round

�  Obese, pregnant, dark-skinned, home-bound patients are most likely to be deficient

�  Also check 1-25-OH-D in patients with kidney disease

�  Retest after 3-4 months of supplementation to determine if dosage is appropriate

�  Serum levels plateau after 3-4 months of daily supplementation

�  Heaney. Am J Clin Nutr. 2003;77(1):204

Recommendations �  Dosage:

�  1,000iu of D3 daily with meal per 30-50lbs body weight (depending body fat %)

�  Excessive adipose tissue absorbs Vitamin D and decreases bioavailability by 57%

�  Wortsman et al. Am J Clin Nutrition, 2000: 72 (3), 690-693

�  Empiric Tx of adults with D3 4,000iu daily is safe without monitoring

�  In severely deficient patients, consider a loading dose of 10,000-20,000iu daily for 1-2 weeks

�  Patients can take D3 once weekly for convenience

�  Sun-tanning: bulb must be UVB, avoid over-exposure

Recommendations Think of Vitamin D in

�  Pregnancy �  Breast-fed babies (1,000iu D3 daily is safe) �  Chronic Pain �  Autoimmune conditions �  Hepatitis C �  Recurrent and chronic infections �  Diabetes and metabolic syndrome �  Cancer �  Heart Disease �  Osteoporosis, osteopenia �  Depression, especially SAD

D3 – How to Prescribe? �  Prescription coverage not available

�  Consider selling vitamin D3 in your office or send patients to store for OTC preparations

�  The best deal I could find: �  www.emersonecologics.com �  Wholesale $10 �  Retail $20 �  1 drop = 2,000iu �  Contains 900 drops �  1 year supply for most adults

Vitamin D Cofactors �  Magnesium

�  Zinc

�  Boron

�  Vitamin K2

�  Required in enzymes that metabolize vitamin D �  Can limit production of 1-25-OH-D �  Required for vitamin D’s beneficial effect on bone, possibly

immune system, and more �  Vitamin D supplementation can increase requirements for

these nutrients

�  I recommend most patients take a multi-mineral supplement with vitamin D3

Summary �  Vitamin D has a wide spectrum of physiologic

activity in various tissues, and is associated with our most common health conditions.

�  Vitamin D has direct and short-term benefits on chronic pain, auto-immune diseases, depression, and much more.

�  Vitamin D3 supplementation is likely the most cost-effective preventative health measure for any person in the winter in Maine!

Thank You!

Dustin Sulak D.O.

dustin@maine-health.com

Maine Integrative Healthcare

964 Western Ave Suite #1 Manchester, ME 04351 www.maine-health.com

207-512-8633

Integr8 Health LLC 170 US Route 1

Falmouth, ME 04105 www.integr8health.com

207-482-0188