1. Common Misconceptions about Vitamin D Bouchra Jandali, MD Noon Conference April 4, 2016

2. Outline o Introduction o Vitamin D deficiency guidelines o Vitamin D and musculoskeletal health o Vitamin D and extra-musculoskeletal diseases o Vitamin D and pregnancy

3. Vitamin D has been the focus of attention in the medical and lay literature in the past few years In fact, it is the nutrient du jour

4. Rosen, C. J. & Taylor, C. L. Nat. Rev. Endocrinol. 9, 434–438 (2013)

5. Misconceptions about Deficiency What is the definition of vitamin D deficiency? The blood level of 25(OH)D that is defined as vitamin D deficiency remains somewhat controversial < 75 nmol/L (30 ng/ml) Or <50 nmol/L (20 ng/ml) Or <25 nmol/L (10 ng/ml)

6. Vitamin D Deficiency Guidelines  Institute of Medicine (IOM): – Vit D level < 20 ng/ml or 50 nmol/L  European Society of Endocrinology (ESE): – Vit D level < 20 ng/ml (deficiency) – Vit D level < 30 ng/ml (insufficiency)  International Osteoporosis Foundation (IOF): – Vit D level < 30 ng/ml or 75 nmol/L Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D, 2011 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et a.l. J ClinEndocrinol Metab. 2011 Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P.2010 IOF position statement

7. Vitamin D Assays and Deficiency Barake M, Daher RT, Salti I, Cortas NK, Al-Shaar L,Habib RH, et al. J Clin Endocrinol Metab. 2012

9. El-Hajj Fuleihan G, Rahme M, Bassil D. Nutritional Influences on Bone Health.2013

10. Fuleihan, G. E. & Deeb, M. Hypovitaminosis D in a sunny country. N. Engl. J. Me(1999)

11. Should vitamin D screening be a part of primary care? There is no evidence demonstrating benefits of screening for vitamin D deficiency at a population level Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et a.l. J ClinEndocrinol Metab. 2011

12. High Risk Group Dark skinned Obese Institutionalized/ hospitalized Taking medications that accelerate vit D metabolism Patients with osteoporosis or malabsorption Patient with limited sun exposure

13. Misconceptions about Osteoporosis  Low serum 25-hydroxyvitamin D levels are associated with increased risk of osteoporosis  Serum 25-hydroxyvitamin D level does serve as a biomarker of Rickets/osteomalacia  Low serum vit D levels are associated with increased risk of fractures and falls Rosen, C. J. & Taylor, C. L. Nat. Rev. Endocrinol.2013

14. Low Serum Vitamin D Increases Osteoporosis, Osteomalacia and Rickets Risk 1.The biologically active form of vitamin D can directly stimulate osteoclastogenesis in vitro and in some models inhibits osteoblast mineralization in vivo 2.Prevalence of impaired mineralization in osteoporosis has not been established 3.Many cases of rickets disease have normal vitamin D levels 4.A lot of subjects with very low vitamin D levels do not have osteomalacia Rosen, C. J. & Taylor, C. L. Nat. Rev. Endocrinol.2013

15. Priemel, M. et al. J. Bone Miner. Res. 25, 305–312 (2010)

18. Lips P, van Schoor NM Best Pract Res Clin Endocrinol Metab. 2011.

19. Kuchuk NO.et al. J Clin Endocrinol Metab.2009

21. Vitamin D and Fractures In the absence of calcium supplementation, vitamin D alone does not reduce fracture risk Rosen, C. J. & Taylor, C. L. Nat. Rev. Endocrinol.2013

26. Vitamin D and Fractures Favorable Results Bicshoff-Ferrari et al., 2012 Bicshoff-Ferrari et al., 2005 Unfavorable Results Avenell et al., 2009 U.S. Preventive Services Task Force guidelines 2013

27. Vitamin D and Risk of Falls Should Older People Receive Vitamin D to Prevent Falls? The evidence is inconsistent, inconclusive as to causality, and insufficient to serve as a basis for DRI development Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D, 2011

28. In at least two RCTs of elderly individuals at risk of fractures, when high doses of vitamin D were administered intermittently the risk of fracture and falls was actually increased rather than reduced Sanders, K. M. et al. J. Am. Med. Assoc. 303, 1815–1822 (2010) Glendenning, P. et al. A randomized controlled trial. J. Bone Miner. Res

29. Vitamin D and Risk of Falls Favorable Pfeifer et al., 2000 Flicker et al., 2005 Broe et al., 2007 Pfeifer et al. (2008) Unfavorable Bischoff-Ferrari et al, 2006 Prince et al, 2008 Bischoff et al, 2003 Graafmans et al, 1996 Bischoff-Ferrari HA, et al. a meta-analysis of randomised controlled trials. BMJ.2009

31. Misconceptions about Diseases Arabi, A. et al. Nat. Rev. Endocrinol. 6, 550–561 (2010)

32. Misconceptions about Diseases  For extra-skeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements  Randomized clinical trial evidence for extra skeletal outcomes was limited and generally uninformative Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D, 2011

33. Misconceptions about Supplements Vitamin D supplementation is safe at any level A tendency exists to believe that if some of a nutrient is good, then more is better

34. The risk for deficiencies such as rickets and osteomalacia is expected to decline with increasing intake of vitamin D However, as intake continues to increase, the risk of excess intake and adverse effects begins to emerge Am. J. Clin. Nutr. 88, 578–581 (2008)

35. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D, 2011

36. IOF Recommendations  The estimated average vitamin D requirement for older adults to reach a serum 25OHD level of 75 nmol/L (30 ng/ml) is 20 to 25 μg/day (800 to 1,000 IU/day)  Intake may need to be adjusted upward to as much as 50 μg/day (2,000 IU/day) in individuals who are obese, and in those with osteoporosis, limited sun exposure (institutionalized, homebound), and malabsorption, and in non-European populations Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P.2010 IOF position statement

37. IOF Recommendations  Each 2.5 μg (100 IU) of added vitamin D will increase the serum 25OHD level by about 2.5 nmol/L (range 1.75– 2.75 nmol/L) or 1.0 ng/ml (range 0.7 to 1.1 ng/ml)  In high-risk individuals, the serum 25OHD levels should be retested after about 3 months of supplementation Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P.2010 IOF position statement

39. Misconceptions about Pregnancy

40. Calcium and vitamin D requirements are not increased during pregnancy or lactation. Nor does vitamin D supplementation alter the development of the fetal, infant, or maternal skeletal health outcomes Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D, 2011

41. However, the European Society of Endocrinology advocates Different Recommendations

42.  Pregnant women are at high risk for vitamin D deficiency, which increases the risk of preeclampsia and cesarean section  Pregnant and lactating women require at least 600 IU/d of vitamin D and recognize that at least 1500–2000 IU/d of vitamin D may be needed to maintain a blood level of 25(OH)D above 30 ng/ml Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et a.l. J ClinEndocrinol Metab. 2011

43.  Two observational studies reported an association between supplementation with vitamin D and a reduced incidence of pre-eclampsia  Two case–control studies, one in the USA and one in Denmark, found no significant difference in serum 25- hydroxyvitamin D concentrations between women with pre-eclampsia and those without Frolich, A. et al. Eur. J. Obstet. Gynecol. Reprod. Biol. 47, 25–29 (1992) Seely, E. et al. J. Clin. Enocrinol. Metab. 74, 1436–1440 (1992) Haugen, M. et al. Epidemiology 20, 720–726 (2009) Hypponen, E. et al. Eur. J. Clin. Nutr. 61, 1136–1139 (2007)

44. IOMIOFECE Vitamin D deficiency <20 ng/ml<30 ng/ml<20 ng/ml deficiency <30 ng/ml insufficiency Desirable level 50 nmol/L75 nmol/L (elderly) - Ca and vitamin D supp 51-70 male 51-70 female 1000 mg/d- 600 IU/d 1200 mg/d- 600 IU/d 800-1000 IU/d1500-2000 IU/d UL4000 IU/d to reach 20 ng/ml 2000 IU/d10,000 IU/d Vit D in pregnancy Pregnant ladies < 18 y Pregnant ladies > 18 y No increased needs Daily supp: 600 IU/d UL : 4000 IU/d Daily supp: 600 IU/d UL : 4000 IU/d -Increased needs 600-1000 IU/d 4000 IU/d 1500-2000 IU/d 10,000 IU/d

45.  Serum 25 (OH) Vitamin D level is the preferred indicator of vitamin D status  Hypovitaminosis D is prevalent worldwide  Risk factors are: dark skinned, hospitalized/ institutionalized, obese, OP, medications  The beneficial effect of vitamin D on musculoskeletal heath is unquestionable

46.  The relationship between vitamin D and the risk of common chronic disorders is a subject of continued controversy  Primary care is in great need of cut-off points for vitamin D status that are authoritative and evidence- based  A change in 25-OHD assays has a significant impact on results, patient classification, and treatment recommendations