Why randomized controlled trials of calcium and vitamin D sometimes fail.

The importance of nutrients for promotion of health and prevention of disease has long been recognized. Nonetheless, scientists are still trying to delineate the optimal intakes of various nutrients and their potential benefits for different populations. To that end, evidence-based medicine (EBM) has been applied to the study of nutrition. EBM methods basically call for the use of randomized controlled trials (RCTs) to establish causal connection between the intervention and any particular endpoint. This paper focuses on problems that arise in the use of RCTS to establish a causal link between nutrients and various clinical endpoints. While many RCTS of calcium and vitamin D have been positive, many others have been null. In this paper, we discuss the reasons why effective nutrient agents may be found to be ineffective in particular studies, giving examples of such null results, and focusing on the nearly universal failure to consider biological criteria in designing RCTs. Our purpose is (1) to inform future study design so as to ensure that relevant biological facts are considered and (2) to aid in the interpretation of the abundant, but often inconsistent literature on this topic.