The discovery of Vitamins D 2 /D 3  happened exactly a century ago. Studies conducted over the past 50 years revealed that vitamin D has been found to have many effects on all human tissues and not only on bone health. Even though randomized controlled trials are commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, they often failed to provide supportive evidence for the expected health benefits of supplementation. A recent report published in ‘Endocrine Connections’ provide an overview of the evidence for a range of non-bony health benefits of vitamin D repletion and discusses specific aspects of vitamin D biology that can confound RCT design and how to allow for them. According to this published report, potential confounders of vitamin D RCTs include design defects, variations in 25(OH) D effect thresholds, non-supplemental vitamin D intakes during RCTs and varying absorption, and dietary factors modulating vitamin D efficacy.

The study highlighted that while conducting trials with Vitamin D, first and the foremost it should be noted that vitamin D is a nutrient, not a drug, and the graphs for changes in biological effects of vitamin D provision are not linear but S-shaped, both for rise in serum 25(OH) D with better vitamin D provision and for increase in the effects of increase in serum 25(OH) D. Thus, in RCTs, where identical doses are given to everyone in the treatment arm, the doses will be too small to normalize serum 25(OH) D in many deficient subjects and unable to induce significant changes in effects/outcomes in ‘replete’ subjects. For these reasons, the chances of observing measurable health benefits will be lost in significant proportions of study subjects in the treatment arm unless results can be picked out for those who were deficient at baseline, and, ideally, made replete during the RCT.

Variations in 25(OH)D effect thresholds is another potential confounder of RCT analyses. With pre-set thresholds, there may be chances of not concentrating on other values. Bone health, for instance, is generally accepted as being protected when serum 25(OH)D values are at least 50 nmol/L, as assessed from the available evidence. While this threshold for bone health continues to be used, higher thresholds of serum 25(OH) D concentration are emerging for non-skeletal health benefits. Thus, failure to ensure that the necessary thresholds are reached, and maintained, for the health outcome(s) of interest during RCTs is a likely confounder. This can be resolved by checking 25(OH) D values during RCTs so that individual dosages could be adjusted for maintenance of 25(OH) Ds at or above the appropriate thresholds.

Vitamin D is normally acquired through skin synthesis and from food, but these sources are rarely controlled for. Continued self-supplementation during RCTs can contribute to the confounding of RCT data analyses, but is often allowed. Absorption of supplemental vitamin D varies with how much fat it is taken with, but RCT subjects are not normally asked to take supplements in any specific way. It is also observed that the absorption of vitamin D becomes less efficient with age, and also the requirement varies in overweight and obese people. As a solution to the above mentioned problems which are common in vitamin D RCTs, the study urges to conduct RCTs organized by baseline and achieved 25(OH) D values, monitoring status and adjusting doses to ensure planned target vitamin D status is maintained throughout.