1. Redefining Vitamin D Sufficiency Based on the Symposium “Shining Light on Vitamin D: What is the Evidence for Redefining Vitamin D Sufficiency?” Chairs: J. Christopher Gallagher, Francis Glorieux Speakers: Roger Bouillon, Chantal Mathieu, JoAnn Manson, Heike Bischoff-Ferrari, Christopher Kovacs Tuesday, October 19, 2010 ASBMR 2010 Toronto, Ontario

2. Immunomodulation and Vitamin D Vitamin D is an immune system modulator with multiple effects on different cells In inflammation, the immune system starts to produce 25-(OH)-D In the presence of 25-(OH)-D, the macrophages produce greater amounts of bactericidal substances 25-(OH)-D downregulates inflammatory cytokines and modifies the behaviour of dendritic cells such that they become less proficient at antigen presentation as well as T-lymphocyte activation In animal models: Vitamin D deficiency is associated with higher infection and autoimmunity rates, and possibly adverse transplant outcomes Intervention with high doses of 25-(OH)-D has been shown to prevent autoimmune disease, provided it is given before the immune system has been activated

3. Muscle, Bone Health and Vitamin D Human muscle tissue has vitamin D receptors (VDRs) that decrease in numbers with age, possibly linking the VDR to age-related sarcopenia Vitamin D: – Appears to stimulate muscle protein in postmenopausal women with OP – Deficiency causes osteomalacia, characterized by muscle weakness, pain and a waddling gait that is reversible with treatment – A meta-analysis of 12 RCTs (n>31,000, ≥65 years of age) showed that fracture risk was reduced by 14% for non-vertebral fractures and 30% for hip fractures only in the highest quartile levels of 792 to 2000 IU/day High doses of vitamin D 3 supplementation have been shown to significantly reduce fall-related injuries in seniors ≥65 years of age and the protective effect occurs in <12 months. Level of 25-(OH)-D <50 nmol/L has been linked to a high risk of frailty in men, less so in women Patients with 25-(OH)-D levels 75 nmol/L

4. Cancer Risk Reduction, CVD and Vitamin D Evidence of a protective association between vitamin D, cancer and CVD is inconsistent No RCTs have been done with cancer or CVD primary outcomes with vitamin D interventions Proposed biological mechanisms that support a promising role of vitamin D are still largely supported by laboratory evidence Laboratory evidence suggests that vitamin D has an important role in inhibiting cell proliferation, inducing apoptosis and causing cell differentiation Vitamin D may also inhibit angiogenesis along with inflammation and inflammatory cytokines Evidence for a protective effect is strongest for 25-(OH)-D and colorectal cancer risk The effect with other cancers is modest and inconsistent, and there is some concern that vitamin D may be causally related to pancreatic cancer

5. Cancer Risk Reduction, CVD and Vitamin D Vitamin D mechanisms that have the potential to protect patients from CVD include inhibition of inflammation, inhibition of vascular smooth muscle proliferation and vascular calcification Pooled data from epidemiologic studies suggest that the highest levels of serum 25-(OH)-D are protective against CVD compared to the lowest levels in individuals ± prevalent coronary heart disease (CHD) A large-scale randomized trial, VITAL, is currently underway. VITAL will involve 20,000 men and women who will receive vitamin D 3 2000 IU/day or placebo, then either omega-3 fatty acids or placebo The primary objective of VITAL is to evaluate whether vitamin D 3 has any effect on total and site-specific cancers and CV outcomes

6. Vitamin D in Pregnancy 25-(OH)-D readily crosses the placenta to the fetus Maternal 25-(OH)-D levels >50 nmol/L should ensure the fetus has adequate vitamin D levels Maternal 25-(OH)-D levels remain unchanged during pregnancy There is no evidence that women require more vitamin D during pregnancy to maintain levels of 25-(OH)-D No significant differences in femoral ash weight or calcium phosphorous or magnesium content of the ash and no sign of rickets were observed between fetuses born to mothers with significant vitamin D deficiency/osteomalacia and those born to healthy mothers because rickets develops weeks/months after birth and not in utero When calcium intake is adequate, no cases of rickets or neonatal hypocalcemia appear to develop when 25-(OH)-D >30 nmol/L Infants are born with 25-(OH)-D levels that are between 75 and 100% of maternal levels

7. Vitamin D in Lactation There is a 5-10% loss of BMD between end of pregnancy and end of lactation but it returns to baseline BMD within 3 to 12 months Maternal 25-(OH)-D levels do not change during lactation and there is no evidence that mothers require more vitamin D to maintain a given level Even very high doses of vitamin D during lactation have no effect on breast milk calcium content During lactation, the mother’s 25-(OH)-D levels do not affect the baby (unless very high) because little goes into the milk Breast-fed babies require supplemental vitamin D at a dose of 200 to 300 IU/day Formula-fed babies should be getting enough vitamin D in the formula

8. What level of 25-(OH)-D is necessary to maintain health? Deficient: <25 nmol/L Insufficient: ≥25 and <50 nmol/L Suboptimal: ≥50 to <75 nmol/L Considered sufficient are levels in the range of ≥75 and <300 nmol/L Presumed toxicity in levels >300 nmol/L Most adults need vitamin D supplements because sunlight exposure and diet alone are not sufficient to maintain a desirable serum 25-(OH)-D level ≥75 nmol/L throughout the year 800 IU/day of vitamin D 3 appears to be an appropriate dose for most adults For fall prevention and preservation of lower extremity function, serum 25-(OH)-D levels should be between 75 and 100 nmol/L