Redefining Vitamin D Sufficiency

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

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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 (ngt31,000, 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 lt12 months.
• Level of 25-(OH)-D lt50 nmol/L has been linked
  to a high risk of frailty in men, less so in
  women
• Patients with 25-(OH)-D levels lt25 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 gt75 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 gt50 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 gt30 nmol/L
• Infants are born with 25-(OH)-D levels that
  are between 75 and 100 of maternal levels

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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 mothers 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

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What level of 25-(OH)-D is necessary to maintain
health?

• Deficient lt25 nmol/L
• Insufficient 25 and lt50 nmol/L
• Suboptimal 50 to lt75 nmol/L
• Considered sufficient are levels in the range of
  75 and lt300 nmol/L
• Presumed toxicity in levels gt300 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