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

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

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

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

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

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

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

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 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 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 IU Vitamin D and mg calcium and subjects were mainly white postmenopausal women

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.

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

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)

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) nmol/L (35-40 ng/ml) Further reduction in risk for many chronic conditions 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 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 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 Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration: Aloia et al 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.

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 (OH)D nmol/L

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 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) by body fat quartile (Q) for non- Hispanic white women aged 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 Supplements improve intake of older Canadians from 200 to 400 IU (2004 survey data) micrograms

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

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

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 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 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 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

On the Epidemiology of Influenza Cannell et al. Virology J :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.

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.

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

Estimated benefit of improved vitamin D status in reducing economic burden of disease in western Europe Grant et al 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.

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