Why do so many trials of vitamin D supplementation fail?

Abstract

Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and prevented rickets. Vitamins D2/D3 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 affecting the actions of vitamin D at the cellular level are increasingly und erstood, but deficiency persists globally. 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 use d designs evolved for testing drugs while vitamin D is a nutrient; the appreciation o f this difference is critical to identifying health benefits from existing RCT data and for impro ving 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 spec ific aspects of vitamin D biology that can confound RCT design and how to allow for them.

Keywords

• vitamin d
• trials
• confounding
• nutrition
• health outcomes
• non-bony