Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs

Allan, G. Michael; Cranston, Lynda; Lindblad, Adrienne J.; McCormack, James; Kolber, Michael R.; Garrison, Scott; Korownyk, Christina

doi:10.1007/s11606-016-3645-y

Cited by 37 publications

(32 citation statements)

References 76 publications

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“…1 However, we disagree with their conclusions that the current literature supports only a beneficial effect of vitamin D supplementation on fracture risk. As the authors correctly point out, observational studies of vitamin D are subject to important limitations since, in general, a decreased level of vitamin D is a marker of poor health.…”

Section: T O the Editorcontrasting

confidence: 63%

Vitamin D: Ten Beliefs

Mokry

Richards

2016

J GEN INTERN MED

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We commend the authors on their comprehensive review investigating the use of vitamin D supplementation across many clinical outcomes. 1 However, we disagree with their conclusions that the current literature supports only a beneficial effect of vitamin D supplementation on fracture risk. As the authors correctly point out, observational studies of vitamin D are subject to important limitations since, in general, a decreased level of vitamin D is a marker of poor health. Consequently, bias due to confounding is likely to be an important limitation of observational vitamin D studies. Further, since many diseases lead to a decrease in time outside and reduced sun exposure, reverse causation may likewise plague such studies. While randomized controlled trials (RCT) are usually less susceptible to these forms of bias, vitamin D is offpatent. Therefore RCTs of vitamin D supplementation are often small and limited to short follow-up periods, due to cost constraints.Given this lack of high-quality observational and RCT evidence, we elected to investigate whether vitamin D influences the risk of MS and coronary artery disease (CAD) using Mendelian randomization (MR). This approach allows for an assessment of lifelong exposure to decreased vitamin D on risk of disease that is uninfluenced by reverse causation and less susceptible to bias due to confounding. This is because MR uses the genetic determinants of vitamin D status as proxies for vitamin D level and since genetic variants are randomized at meiosis, MR retains many of the advantages of an RCT. While our MR analyses supported a causal role of vitamin D in the MS etiology (OR = 2.02, 95 % CI = 1.65-2.46, p = 7.72 × 10 −12 ), 2 they did not support an important effect of vitamin D on CAD risk (OR = 0.99, 95 % CI = 0.84-1.17, p = 0.93). 3 We concluded that vitamin D supplementation may be an important form of primary prevention for MS, which warrants further investigation by clinical trials. Restricting a systematic review of the effects of vitamin D to observational studies and RCTs ignores relevant information provided by MR. As this field progresses, we believe that a discussion of MR analyses in future reviews of vitamin D is worth consideration. Given the paucity of high-quality RCT data, MR may present the best evidence to support, or contradict, a role for vitaminD in disease susceptibility.

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Section: T O the Editorcontrasting

confidence: 63%

Vitamin D: Ten Beliefs

Mokry

Richards

2016

J GEN INTERN MED

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“…5 Regarding respiratory tract infection clinical trials (Belief 3 in Ref. 1), it is noted that in the trial from New Zealand finding no benefit for large-dose vitamin D 3 , the baseline 25(OH)D concentration was 72.5 nmol/l, which is in stark contrast to the trial from Mongolia finding significant benefits of 300 IU/day vitamin D 3 had a baseline concentration of 17.5 nmol/l.…”

Section: T O the Editormentioning

confidence: 97%

“…1 What the authors failed to realize is that many of the clinical trials were based on the guidelines for pharmaceutical drugs. Such trials have two main assumptions: (1) that the trial is the only source of the agent and (2) that there is a linear doseresponse relation.…”

Section: T O the Editormentioning

confidence: 99%

Vitamin D: Ten Beliefs

Grant

2016

J GEN INTERN MED

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What the authors failed to realize is that many of the clinical trials were based on the guidelines for pharmaceutical drugs. Such trials have two main assumptions: (1) that the trial is the only source of the agent and (2) that there is a linear doseresponse relation. Neither assumption is satisfied for vitamin D trials. Heaney recently outlined the guidelines for trials of nutrients such as vitamin D.2 They include that the baseline 25-hydroxyvitamin D [25(OH)D] concentration should be measured, only those with low concentrations should be enrolled in the study, sufficient vitamin D should be given to raise concentrations to achieve significant reductions in the risk of health outcomes, and the achieved concentration should be measured. In addition, meta-analyses should only compare trials with similar conditions. A typical 25(OH)D concentration-health outcome relation is given for breast cancer in Figure 2 in a recent paper.3 Risk decreases rapidly from 10 to 30 nmol/l, at a moderate rate from 30 to 60 nmol/l and slowly above 60 nmol/l. The percentile values of 25(OH)D concentrations for women aged over 50 years in the US for [2001][2002][2003][2004][2005][2006] 4 can be used with the 25(OH)D-breast cancer incidence relation to estimate the reduction in breast cancer rates if all women achieved 100 nmol/ l, which could take about 4000 IU/day vitamin D 3 . The result is a 35 % reduction. This value compares well with the results from the Women's Health Initiative for those women not taking vitamin D or calcium prior to enrollment: taking 1500 mg/day calcium plus 400 IU/day vitamin D 3 by them significantly decreased the risk of total, breast and invasive breast cancers by 14-20 %.

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“…2 Third, to support the belief that individuals with lower serum levels are more likely to reap benefits from vitamin supplementation, Dr. Grant references a single study that demonstrated infection prevention with supplementation for those with low Vitamin D levels. We too had raised this potential important linkage in our paper, 1 but noted the results cannot be applied to all developing countries. A large trial in Kabul Afghanistan did not see any reduction in pneumonia when infants were provided with vitamin D supplementation, despite vitamin D levels being roughly 50 nmol/L or higher in the treated arm, while levels in the untreated arm were lower by roughly 20 nmol/L or more at most time points (Vitamin D levels estimated from Fig.…”

mentioning

confidence: 88%

“…1 However, this evidence is observational and any potential benefits resulting from Vitamin D supplementation are only an extrapolation from this lower-level evidence. Unfortunately, a cancer benefit from Vitamin D supplements is not supported by the available higher-level evidence, which suggests future research on cancer mortality is unlikely to yield meaningful change in the estimate of no effect.…”

mentioning

confidence: 99%

Vitamin D: Ten Beliefs

2016

Self Cite

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However, this evidence is observational and any potential benefits resulting from Vitamin D supplementation are only an extrapolation from this lower-level evidence. Unfortunately, a cancer benefit from Vitamin D supplements is not supported by the available higher-level evidence, which suggests future research on cancer mortality is unlikely to yield meaningful change in the estimate of no effect.2 Third, to support the belief that individuals with lower serum levels are more likely to reap benefits from vitamin supplementation, Dr. Grant references a single study that demonstrated infection prevention with supplementation for those with low Vitamin D levels. We too had raised this potential important linkage in our paper, 1 but noted the results cannot be applied to all developing countries. A large trial in Kabul Afghanistan did not see any reduction in pneumonia when infants were provided with vitamin D supplementation, despite vitamin D levels being roughly 50 nmol/L or higher in the treated arm, while levels in the untreated arm were lower by roughly 20 nmol/L or more at most time points (Vitamin D levels estimated from Fig. 3). Overall, evidence for the health benefits of vitamin D supplementation is unconvincing. Further research is needed, but additional observational studies and small, low-quality trials will only muddy the waters. From here on in, Vitamin D research should emphasize high-quality randomized, controlled trials, particularly in individuals with lower serum concentrations.

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Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs

Cited by 37 publications

References 76 publications

Vitamin D: Ten Beliefs

Vitamin D: Ten Beliefs

Vitamin D: Ten Beliefs

Vitamin D: Ten Beliefs

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