1. Optimal Nutrition and Adaptive Potential: Function of Dietary Supplements Vitamin D: Health Benefits And Reduction Of Disease Risk Susan J. Whiting PhD University of Saskatchewan CANADA

2. What’s Important About Vitamin D METABOLISM New knowledge of vitamin D in past 10 years -Importance of intermediate 25- hydroxyvitamin D -Need to provide vitamin D to all tissues, not just for bone Dietary requirements need to be changed to meet the newly discovered health benefits

3. 3

4. 4 Importance of 25(OH)D Transport form of vitamin D Is directly correlated with vitamin D stores Not active metabolite Is the only substrate for 1,25D - 1,25D made in kidney for endocrine [calcium and phosphate] metabolism - 1,25D made in other cells for autocrine uses Serum 25(OH)D levels are measured for status

5. 5 Holick M. N Engl J Med 2007;357:266-281 25(OH)D is substrate for 1,25D in paracrine/autocrine and endocrine reactions

6. What’s Important About Vitamin D HEALTH BENEFITS Bone: ↓ fractures ↓ ricketic bones Muscle strength and balance: ↓ falls Pain: ↓ rickets and Osteomalacia Immunity: ↓ recent colds and flu; ↓ Tuberculosis Autoimmunity: ↓ Multiple sclerosis, Type 1 diabetes Cardiovascular and Diabetes: ↓ blood pressure; ↓ insulin resistance Cell growth: ↓ cancer (colorectal, breast)

7. 7 Figure illustrates multiple causes and multiple outcomes of deficiency: from head to toe. Holick 2008

8. Serum 25(OH)D EFFECT < 20 nmol/L (<8 ng/ml) Vitamin D deficiency (rickets or osteomalacia 30 nmol/L (< 12 ng.ml) Not at risk for classical clinical deficiency – “old” threshold to define deficiency 75 nmol/L (30 ng/ml) New threshold for vitamin D: maximal calcium absorption; improved balance and muscle strength  fracture and falls reduction 90-100 nmol/L (35-40 ng/ml) Further reduction in risk for many chronic conditions such as cancer >250 nmol/L (> 100 ng/ml) Potential adverse effects seen above this level (hypercalcemia) Vitamin D Status and Disease Vitamin D Status and Disease

9. 9 Vitamin D’s role in so many disease processes has biological plausibility Endocrine Pathway: vitamin D promotes calcium and phosphate absorption; each of these minerals is important for healthy bone, muscle, cardiovascular, brain tissues. Paracrine/autocrine Pathway: 1,25D is a transcription factor in cells - Cell differentiation, immunity

10. 10 Optimal Calcium Absorption A function of 25(OH)D level: Heaney 07

11. 11 Improvement of Physical Performance in Older Adults is Related to serum 25(OH)D = sum score walking test, chair stands, tandem stand => better balance, less falls Wicherts ‘07

12. What’s Important About Vitamin D HIGHER REQUIREMENT Revised requirements are needed New knowledge of vitamin D in past 10 years -↑ Intake to provide vitamin D to all tissues to satisfy need for higher levels of 25(OH)D Dietary requirements need to be changed -To meet the newly discovered health benefits -To acknowledge lack of adequate sun (UVB) exposure

13. 13 1100 IU Vitamin D per day reduces Relative Risk of any cancer 25(OH)D = 71 nmol/L Relative Risk of incident cancer 25(OH)D = 71 nmol/L 25(OH)D = 96 nmol/L P=0.01 P<0.005 NS Lappe et al., 2007

14. 14 Studies Corroborate Cancer Prevention with vitamin D Garland 2007: –Reduce breast cancer risk by 50% when 25(OH)D > 130 nmol/L –Reduce colon cancer risk by 50% if 25(OH)D > 85 nmol/L Freedman 2007: –Colon cancer risk reduced by 28% if 25(OH)D is 80 nmol/L or higher

15. 15 Vitamin D Effective at Reducing Fractures and Falls Cranney et al., 2007 performed meta- analysis of literature commissioned by NIH Findings significant in long-term care: Vitamin D and calcium ↓ risk of fracture Vitamin D and calcium ↓ risk of falls Most studies used 800-1000 IU Vitamin D and 500-1200 mg calcium and subjects were mainly white postmenopausal women

16. 16 Vitamin D Effective at Reducing Fractures and Falls Bischoff-Ferrari, 2009 re-analysed studies that Cranney and others had used, adjusting for received dose (i.e., removing those with low levels of supplementation or use of vitamin D 2 ) For studies where received dose was > 400IU, fracture risk in community and institutionalized adults showed Vitamin D ↓ risk of hip fractures and nonvertebral fractures.

17. Higher dose trials: Vertebral (top) and hip fracture reduction (bottom). Final Relative Risk (RR) show significant reduction in fractures.. Bischoff-Ferrari et al. Arch Int Med March23/09

18. What’s Important About Vitamin D DIETARY INTAKES Why dietary intakes are not keeping up with requirements: Loss of sun exposure: no longer our major source of D Lack of D in the diet: few natural sources Food fortification: risks and benefits; need to have staple foods Supplementation: now encouraged for all Canadians (2007)

19. Serum 25(OH)D Dietary Intakes needed for effect < 20 nmol/L (<8 ng/ml) Vitamin D deficiency (rickets or osteomalacia 30 nmol/L (< 12 ng.ml) Not at risk for classical clinical deficiency 200 IU 75 nmol/L (30 ng/ml) New threshold for vitamin D: maximal calcium absorption; improved balance and muscle strength > 400 IU (500 IU to maintain; 5000 IU to replete) 90-100 nmol/L (35-40 ng/ml) Further reduction in risk for many chronic conditions + 2000 IU >250 nmol/L (> 100 ng/ml) Potential adverse effects seen above this level (hypercalcemia) > 10,000 IU Vitamin D Status and Disease Vitamin D Status and Disease

20. 20 How Much Dietary Vitamin D will maintain 25(OH)D > 75 nmol/L? Need for vitamin D related to degree of sun exposure: Complete lack of sun exposure: = Determine need for vitamin D to replete then maintain 25(OH)D Seasonal lack of sun exposure: = Determine need for vitamin D to maintain 25(OH)D that was obtained in summer

21. 21 Meier et al., JBoneMinerRes 2004 Year 1Year 2 Vitamin D Intervention: 500 IU/ d 500 IU maintains 25(OH)D in winter – Germany 30 ng/ml =75 nmol/L

22. 22 Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration: Aloia et al. 2008 Gave doses of vitamin D to white and black American adults in winter, to determine how much D was needed to raise 25(OH)D above 75 nmol/L => a dose of 5000 IU needed to ensure all those entering study below 55 nmol/L; needed to be given for 9-18 weeks to replete.

23. Irish study of vitamin D supplementation for 22 weeks in older adults at latitude 51° ~600 IU enough to reach 75 nmol/L for half of population ~1600 IU to reach 75 nmol/L for 97.5% of population Cashman et al., AJCN 2008 25(OH)D nmol/L

24. 24 Physiological Factors Affecting Need for Vitamin D Age: –less skin synthesis; less ability to make 1,25D Body Size and /or body fatness –Need is relative to body size –Adipose may “hoard” D and make less accessible to blood Life stage: pregnancy and lactation Skin pigmentation –Melanin is natural sunscreen

25. 25 Yetley, E. A Am J Clin Nutr 2008;88:558S-564S Serum 25(OH)D concentration from the National Health and Nutrition Examination Survey (NHANES) 1988-1994 by body fat quartile (Q) for non- Hispanic white women aged 20-49 y. Serum 25(OH)D means are age-adjusted Persons with higher body fat have lower vitamin D status: is it metabolic or sun avoidance?

26. 26 Supplements improve intake of older Canadians from 200 to 400 IU (2004 survey data) micrograms

27. 27 Environmental Factors Affecting Need for Vitamin D Factors related to ↓ sun exposure Latitude > 40° gives a long “vitamin D winter” Clothing, sun screens block UVB Pollution, cloudy weather reduce UVB exposure Working or staying indoors from 10am-3pm It is now not possible to assume that sun exposure provides us with all the vitamin D we need in Canada

28. 28 Estimated Times to make 1000 IU if expose 25% of body surface Skin TypeTime (minutes) at noon June 21 At 62.5 ºN I - White burns easily7 II - White – mostly burns9 III - White - mostly tans11 IV - Mediterranean16 V - East Asian21 VI - African36 Webb & Engelsen 2006: assumes cloudless day

29. 29 Estimated Times to make 1000 IU if expose 25% of body surface Skin TypeTime (minutes) at noon March 21 At 62.5 ºN I - White burns easily44 II - White – mostly burns55 III - White - mostly tans67 IV - Mediterranean106 V - East Asian163 VI - Africann/a Webb & Engelsen 2006: assumes cloudless day

30. 30 Yetley, E. A. Am J Clin Nutr 2008;88:558S-564S Prevalence (%) of low serum 25(OH)D In USA 2000-2004

31. 31 Groups Recommending Vitamin D Supplements of 25 µg (1000 IU) USDA in 2005 Dietary Guidelines = those who are older or those who lack sun-exposure Canadian Dermatology Association –as this group promotes sun avoidance Canadian Cancer Society –in winter and all year for those at-risk National Osteoporosis Foundation 2008 –for adults who are at-risk for vitamin D deficiency

32. 32 Canada’s Food Guide (2007) recommends vitamin D supplementation Recommends all adults over 50 years take a supplement of 400 IU This document is “policy” for diet-based programs such as nursing homes and hospitals

33. 33 What’s Important About Vitamin D SAFETY In 1997, for USA and Canada, estimates of the highest safest amount was published (Upper Level = safe, but risk of adverse effects begins with intake about this amount) Since this time, many have criticized the value that was set for adults

34. 34 Upper Level (UL) for vitamin D ReferenceUpper Level (UL) DRI, 19971 y + 50 µg (2000 IU) 1 y + 20 µg (800 IU) Hathcock et al. 2007 review of evidence > 19 y 250 µg (10,000 IU)

35. 35 Safety of Vitamin D There is a UL for vitamin D of 50 µg (2000 IU) in USA/Canada –UL of 1000 IU for infants By definition a UL is safe Experts say intakes of ~10,000 IU/day, which can bring 25(OH)D up to 250 nmol/L, are safe For repletion, intakes above the UL are required and necessary

36. 36 Vitamin D Toxicity At 25(OH)D levels above > 375 nmol/L, hypercalciuria or hypercalcemia may occur All known cases are from labelling errors, faulty manufacturing, dosing errors or excessive dosing by health provider; none from accidental supplement use –With large repletion doses, monitoring is advised Overdoses: resolve with withdrawal of product and sun avoidance

37. 37 Vitamin D Hypersensitivity Tissues in autocrine/paracrine pathway overproduce 1,25D which is released into blood and acts to cause hypercalemia –Granulomatous disease (e.g., sarcoidosis) and lymphoma –Diagnosis: elevated serum calcium, elevated 1,25D –So-called Marshall Protocol not proven Treated by avoiding D in foods/supplements and avoiding sun exposure –Controversial as these patients become vitamin D deficient

38. 38 What’s Important About Vitamin D PUBLIC WELL-BEING Prevention of chronic conditions: Improved quality of life for the individual –Decrease risk of many chronic diseases –Immediate impact: colds and influenza risk Economic benefit to government

39. On the Epidemiology of Influenza Cannell et al. Virology J. 2008 5:29 Innate immunity: 1,25D ↑synthesis of AMPs that exhibit rapid and broad- spectrum antimicrobial activity against bacteria, viruses and fungi. Humans make beta-defensin 2 and cathelicidin that directly disable microorganisms (irreversible damage to lipoprotein membranes) and indirectly as chemo-attractants for macrophages and neutrophils.

40. Vitamin D status can affect innate immunity and therefore colds, flu, and other infectious diseases Cathelicidin also plays a role in epithelial repair by triggering epithelial growth and angiogenesis while beta-Defensin 3 inhibits influenza haemagglutinin A mediated fusion. In the macrophage, the presence of 1,25D may suppress the pro-inflammatory cytokines.

41. Incidence of reported cold/influenza symptoms according to season: northern USA The 104 subjects in the placebo group (light shade) reported cold and flu symptoms year around with the most symptoms in the winter. Vitamin D-treated subjects reported very few incidences. Aloia JF, Li-Ng M: Epidemic influenza and vitamin D. Epidemiol Infect 2007; 135: 1095–1096

42. Estimated benefit of improved vitamin D status in reducing economic burden of disease in western Europe Grant et al. 2009 Prog Biophys Mol Biol Raise 25(OH)D levels to 100 nmol/L, using a supplement: consider direct and indirect costs, plus cost of supplement, to find net saving.

43. Conclusions The amount of vitamin D needed to protect against bone loss, cancer, poor immunity, diabetes and cardiovascular disease exceeds what we can get from diet. Sun-induced synthesis of vitamin D is compromised during winter and with many factors (clothing, being indoors) that prevent UVB radiation reaching skin. The amount needed to maintain healthy levels year-round can be met only by supplementation