Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations
The Journal of Steroid Biochemistry and Molecular Biology 2017 Aug 24. pii: S0960-0760(17)30223-6. doi: 10.1016/j.jsbmb.2017.08.009
William B. Grant,1 Barbara J. Boucher,2 Harjit P. Bhattoa,3 Henry Lahore 4
- 1 Sunlight, Nutrition, and Health Research Center, wbgrant at infionline.net, www.sunarc.org,
- 2 Honorary Professor, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London UK. bboucher at doctors.org.uk,
- 3 Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei Blvd 98, Debrecen H-4032, Hungary. harjit at med.unideb.hu.
- 4 2289 Highland Loop, Port Townsend, WA 98368. VitaminDWiki.com hlahore at VitaminDWiki.com
Many health benefits are attributed to vitamin D, with those findings supported mostly by observational outcome studies of relationships to serum 25-hydroxyvitamin D [25(OH)D]. However, many randomized controlled trials (RCTs) aiming to confirm those findings have failed, perhaps because serum 25(OH)D is an index of UVB exposure and non–vitamin D mechanisms or because disease reduces serum 25(OH)D content. But the most likely reason for that failure is inappropriate design, conduct, analysis, and interpretation of RCTs.
Most RCTs used principles designed to test pharmaceutical drugs; that design incorporates the assumptions that the RCT is the sole source of the agent and that dose–response relationships are linear.
However, neither assumption is true for vitamin D, since neither vitamin D dose–responses or health outcome–serum 25(OH)D concentration relationships are linear—larger changes being induced with low rather than high baseline 25(OH)D values.
Here, we propose a hybrid observational approach to vitamin D RCT design, based primarily on serum 25(OH)D concentration, requiring an understanding of serum 25(OH)D concentration–health outcome relationships, measuring baseline 25(OH)D values, recruiting non-replete subjects, measuring serum 25(OH)D during the trial for adjustment of supplemental doses for achievement of pretrial selection of target 25(OH)D values, where possible, and analyzing health outcomes in relation to those data rather than solely to vitamin D dosages.
Additional points to consider
- Seek participants with low baseline serum 25(OH)D values.
- Use vitamin D3, not vitamin D2 and at sufficiently high doses, 1000–4000 IU/d.
- Consider giving a modest loading dose of vitamin D3 to reach target 25(OH)D concentrations rapidly .
- Measure baseline serum 25(OH)D concentrations and repeat at suitable intervals to assess compliance and the achievement of target 25(OH)D values (e.g., using blood spot assays, where acceptable, affordable, convenient, and sufficiently accurate).
- If calcium and magnesium are given, give them in both RCT arms .
- Monitor participants’ UVB exposure as well as dietary and supplemental intakes of vitamin D3 and potential confounders, including obesity and genetic variants.
- Allow for the natural history of disease development in planning RCT duration and dosing, and for subject age.
- Analyze results in terms of 25(OH)D values at baseline, at completion, and at intervals before disease diagnosis, rather than solely with vitamin D3 dose.
- Carefully consider vitamin D3 dosing interval with respect to compliance and physiological effect.
- If, for ethical reasons, participants in the control are given 400 IU/d vitamin D3, the resulting increase in 25(OH)D concentration should be factored into the selection of participants and into outcome analyses.
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