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 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

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