To the Editor:
The narrative review by Allan and colleagues concluded that while vitamin D supplementation provides some benefit in fracture prevention, it has not been demonstrated to prevent cancer, respiratory tract infections or rheumatoid arthritis.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 dose-response 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 2001–20064 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 D3. 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 D3 by them significantly decreased the risk of total, breast and invasive breast cancers by 14–20 %.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 D3, 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 D3 had a baseline concentration of 17.5 nmol/l.
Thus, more progress could be achieved in the near term if clinical trials were designed to evaluate 25(OH)D concentration-health outcome relations trying to determine whether giving vitamin D3 supplements to the general public affects health outcomes.
Compliance with Ethical Standards
Disclosure
I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR) and the Vitamin D Society (Woodstock, ON, Canada) and the Vitamin D Council (San Luis Obispo, CA).
References
- 1.Allan GM, Cranston L, Lindblad A, McCormack J, Kolber MR, Garrison S, Korownyk C. Vitamin D: A narrative review examining the evidence for ten beliefs. J Gen Intern Med. doi: 10.1007/s11606-016-3645-y [DOI] [PMC free article] [PubMed]
- 2.Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48–54. doi: 10.1111/nure.12090. [DOI] [PubMed] [Google Scholar]
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