Why do so many trials of vitamin D supplementation fail?

Abstract

Abstract. Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860-1890, that both sunlight and cod liver oil [a well-known folk remedy] cured and prevented rickets.1]Vitamins D2/3 were discovered exactly a hundred years ago and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms effecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally.2 Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them

Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment

“…Numerous observational epidemiological studies in humans have shown significant associations of low 25(OH)D concentrations with increased (current and future) health risks, in line with the various known actions of vitamin D. However, RCTs, the ‘gold standard’ for assessing the efficacy of treatments, and meta-analyses, have frequently failed to provide supportive evidence for the expected health benefits of vitamin D supplementation [ 73 , 74 ]. Such RCTs have used designs developed for testing drugs while vitamin D is a nutrient, in which a different rational should guide trial designs.…”

New Roles for Vitamin D Superagonists: From COVID to Cancer

“…Some, but not all, studies found positive effects for supplementation in respiratory infections including influenza ( 66 , 68 ). Interpretation in such studies, is complicated by disagreement concerning serum levels of calcidiol required for sufficiency ( 198 ), multiple confounding factors ( 18 , 120 , 121 ) and the application of methods designed for testing drugs rather than nutrients ( 140 , 141 ).…”

“…More recently, Boucher further explores Heaney’s ideas and additional factors complicating analysis of vitamin D supplementation studies ( 141 ); further confounding issues are also discussed elsewhere ( 18 , 120 , 121 ).…”

Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

“…There are of course other reasons for some of the negative trial results, including vitamin D being treated as a drug rather than a nutrient, often with inclusion of many participants with normal vitamin D status at baseline. 35…”