1. VITAMIN D: the latest and greatest Rachel Busse, MD Ray Teets, MD

2. Goals Understand the role of vitamin D in the body. Become familiar with the latest evidence for vitamin D deficiency, in areas including cancer, obesity, diabetes, autoimmune disease, pregnancy, cardiovascular risk, and osteoporosis.

3. Objectives Define vitamin D deficiency, insufficiency, and toxicity. Understand who is at risk for deficiency, associations with other medical conditions, and when and how you might test. Become familiar with over the counter, prescription, sun, and food sources of vitamin D.

4. Physiology Fat soluble vitamin Bone deposition Calcium absorption Immune function

5. Symptoms of deficiency  Usually asymptomatic until severe  Musculoskeletal pain  Fractures  Weakness

6. Case 48 year old black female presents with diffuse joint pain, worse over 1-2 years Exercises regularly at a gym, vegan diet Would you check a vitamin D level? How?

7. Case continued 25 OH Vitamin D is 7 ng/ml How would you replace?

8. Case continued Ergocalciferol 50,000 IU 1-2x/week x 8 weeks Repeat level is 24 ng/ml Diffuse pains have improved Consider repeat ergocalciferol vs daily D3

9. How to measure 25 OH vitamin D Don’t measure 1,25 vitamin D Calcium or PTH Consider in severe deficiency

11. Definition of deficiency Ng/ml vs Nmol/L Normal 75 nmol/L) Insufficiency 20-30 ng/ml (50-75 nmol/L) Deficiency <20 ng/ml (<50 nmol/L)

12. Prevalence of deficiency (<20 ng/ml) Infants 78% deficient during winter Children 9% deficient, 61% insufficient Hospitalized patients 57% deficient African-Americans 42-52% deficient PEDIATRICS Vol. 118 No. 2 August 2006, pp. 603-610 Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001–2004 Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. Mar 19 1998;338(12):777-83

13. Causes Decreased sun exposure/sunscreen SPF 15 decreases vitamin D3 synthesis by 99% Air pollution Decreased intake of foods rich in vitamin D Impaired absorption Chronic kidney disease Additional risk factors: premature birth skin pigmentation obesity advanced age immigrants

16. Associations

17. All-cause mortality Osteoporosis Falls Obesity Diabetes Autoimmune diseases Cancer risk Cardiovascular disease (including MI) Upper respiratory infections Pregnancy outcomes

18. All-cause mortality Meta-analysis 18 trials, 57,311 patients (4777 deaths) Average dose 528 IU (300-2000) Average length of follow up 5.7 years 7% reduction in any cause mortality Arch Intern Med. 2007 Sep 10;167(16):1730-7. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.

19. Osteoporosis Review of literature generally shows decrease in fractures with doses > 700-800 IU, but data still mixed Specific benefit seen in hospitalized patients and postmenopausal women Evid Rep Technol Assess (Full Rep). 2007 Aug;(158):1-235. Effectiveness and safety of vitamin D in relation to bone health. NEJM Vol 354:669-683 No 7. Calcium plus Vitamin D Supplementation and the Risk of Fractures NEJM Volume 327:1637-1642 December 3, 1992 Number 23,Vitamin D3 and calcium to prevent hip fractures in the elderly womenDecember 3, 1992

20. Falls Both meta-analyses show reduction in falls by 20% in elderly 2009 review of 8 RCTs, 2426 pts No reduction in low dose (200-600 IU subgroup) 19% reduction in mod dose (700-1000 IU) 2004 5 RCTs, 1237 pts NNT = 15 Independent of calcium supplementation BMJ. 2009 Oct 1;339:b3692. doi: 10.1136/bmj.b3692. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. Effect of Vitamin D on Falls A Meta-analysis. JAMA. 2004;291:1999-2006.

21. Obesity Obese subjects had lower vitamin D levels and higher PTH than age matched controls Treatment with irradiation or vitamin D2 was less effective than in non-obese patients Decreased bioavailability due to deposition in fat stores % body fat is inversely related to 25 OH vitamin D Body Fat Content and 25-Hydroxyvitamin D Levels in Healthy Women. The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 157-161 Decreased bioavailability of vitamin D in obesity. American Journal of Clinical Nutrition, Vol. 72, No. 3, 690-693, September 2000

22. Diabetes Reduction in DM1 Reduction in DM2 risk with 800 IU daily Increased insulin resistance and metabolic syndrome NHANES III study individuals with a 25(OH)D concentration of <21 ng/mL had twice the risk of DM compared to those with concentrations above 37 ng/mL Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167:1159-1165. Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006;29:650-656. Am J Clin Nutr. 2004 May;79(5):820-5. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.

23. Autoimmune diseases Lupus Multiple cohorts show low vitamin D with SLE Vitamin D inversely related to disease activity Multiple sclerosis Higher latitudes ages 0-10 Vitamin D supplementation 400 IU Living at higher latitudes increases risk of MS, DM1, Crohn’s disease Curr Opin Rheumatol. 2008 Sep;20(5):532-7. Vitamin D in systemic lupus erythematosus

24. Cancer Reduction in cancer rates, especially in digestive cancers Breast cancer risk did not decrease with 400 IU Similarly colon cancer risk did not decrease with 400 IU in postmenopausal women 7 year, 36,282 women Long lead time Portion of women were also on HRT, which can increase cancer risk Subanalysis shows benefit RCT in postmenopausal women Reduction in cancers of all types 4 years, 1179 women in Nebraska D3 1100 IU, 1400 mg Calcium, p<0.005 J Natl Cancer Inst. 2006 Apr 5;98(7):451-9. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Lappe JM, Travers-Gustafson D, Davies KM, et alLappe JMTravers-Gustafson DDavies KM J Natl Cancer Inst. 2008 Nov 19;100(22):1581-91. Epub 2008 Nov 11. Calcium plus vitamin D supplementation and the risk of breast cancer. Int J Cancer. 2008 Apr 15;122(8):1690-4. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial.

25. Cardiovascular disease Participants with CVD had a greater frequency of deficiency [serum 25(OH)D levels <20 ng/mL] than those without (29.3% vs. 21.4%; p<0.0001) Linear increase in CVD as vitamin D decreased Lack of RCTs Atherosclerosis. 2009 Jul;205(1):255-60. Epub 2008 Nov 11. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Circulation. 2008 Jan 29;117(4):503-11. Epub 2008 Jan 7. Vitamin D deficiency and risk of cardiovascular disease

26. Respiratory infections URI Vitamin D levels are inversely associated with recent URI RCT 162 adults received 2000 IU D3 or placebo -> no change in URI frequency Wheezing Influenza A prevention RCT: Flu occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group Arch Intern Med. 2009 Feb 23;169(4):384-90. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Epidemiol Infect. 2009 Oct;137(10):1396-404. Epub 2009 Mar 19. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections Am J Clin Nutr. 2010 May;91(5):1255-60. Epub 2010 Mar 10.Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.

27. Pregnancy outcomes 5-50% of pregnant women are vitamin D deficient Newborns of pre-eclamptic mothers were twice as likely as control newborns to have 25(OH)D less than 37.5 nmol/liter RCT 350 pts with 2000 IU or 4000 IU showed best outcomes with 4000 IU /d Poor health outcomes associated: Preeclampsia low birthweight neonatal hypocalcemia poor postnatal growth bone fragility autoimmune diseases J Clin Endocrinol Metab. 2007 Sep;92(9):3517-22. Epub 2007 May 29. Maternal vitamin D deficiency increases the risk of preeclampsia Am J Obstet Gynecol. 2010 May;202(5):429.e1-9. Epub 2009 Oct 20. Implications of vitamin D deficiency in pregnancy and lactation. Vitamin D Supplementation during Pregnancy Part 2 NICHD/CTSA Randomized Clinical Trial (RCT): Outcomes

28. Breastfeeding mothers Breastfeeding supplies about 25 IU/L 1 Liter = 33.8 ounces Formula has 258 (minimum by law)-666 IU/L Most rickets cases have had African-American breastfeeding mothers Pediatrics. 2006 Aug;118(2):603-10. Vitamin D deficiency in breastfed infants in Iowa. Kreiter SR, Schwartz RP, Kirkman HN Jr, Charlton PA, Calikoglu AS, Davenport ML. Nutritional rickets in African American breast-fed infants. J Pediatr.2000; 137 :153 –157

29. Rickets Occurs between ages 5-25 months Premature very low birth weight infants at higher risk African-american infants at increased risk 166 cases reported between 1986-2003 83% African-american 98% breastfed Am J Clin Nutr. 2004 Dec;80(6 Suppl):1697S-705S. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003.

31. Prevention and treatment

32. Prevention Sunlight Winter supplementation Supplement Pregnant mothers Breastfed infants Children Elderly Other high risk

33. Supplementation recommendations Adults 800-1000IU, max of 2000 IU daily AAP 400 IU unless adequate food sources Many multivitamin drops have appropriate vit D, including Poly vi sol, Gerber vitamin drops Vitamin D only drops – Carlson’s 400 IU/drop US current RDA Everyone under age 50: 200 IU Ages 50-70: 400 IU Ages 70+ 600 IU

34. Treatment of deficiency High dose: Ergocalciferol (D2) 50,000 IU rx weekly x 8 weeks D2 not as well-absorbed as D3 Maintenance: Cholecalciferol (D3) 800-2000 IU daily, higher in certain situations Sunlight 15-45 minutes nonburning midday sun (depending on skin pigment) several times per week UV radiation

35. Toxicity Impossible to become toxic from the sun Doses > 10,000 IU daily can be toxic 25 OH levels of >150 ng/ml Symptoms include Renal calculi Hypercalcemia Renal insufficiency Fatigue and weakness

36. VITAL study The VITamin D and OmegA-3 TriaL (VITAL) is a research study in 20,000 U.S. men and women investigating vitamin D (2000 IU) or fish oil (1g) Funded by NIH Conducted by Harvard med school Studying the risk of developing cancer, heart disease, and stroke in people. Recruitment for the study began in Jan 2010.

37. Questions? Mmm…. Vitamin D drops!