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
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
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 supplementation have been shown to significantly
3 in seniors ≥65 years of age and the protective effect
reduce fall-related injuries
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
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
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
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
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
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