Redefining Vitamin D Sufficiency Based on the Symposium “Shining Light on Vitamin D:

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 D3 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 <25 nmol/L have a 3.5x greater risk of being admitted to a nursing home over a 6-year follow-up compared to those with >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 D3 2000 IU/day or placebo, then either omega-3 fatty acids or placebo • • The primary objective of VITAL is to evaluate whether vitamin D3 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 D3 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