Limitations of vitamin D supplementation trials: Why observational studies will continue to help determine the role of vitamin D in health.

Observational studies have shown that low vitamin D status is associated with an increased risk of a wide range of diseases. The body of observational evidence now is so large, that there have been many calls for randomized controlled trials (RCT) of vitamin D supplementation to confirm once and for all whether increasing body vitamin D levels prevents these diseases. These calls have arisen because of concern that confounding and reverse causation may explain many of the results from observational studies. However, RCTs also are prone to limitations that compromise their validity. These include low response rates that affect their external validity; and biases that affect their internal validity, such as recruitment of vitamin D sufficient people which decreases the power to detect beneficial effects, studies of long-term outcomes requiring participation for many years which decreases compliance and retention, and easy access for participants to vitamin D supplements and blood testing which increase contamination and unblinding. Because of these potential limitations, it is possible that RCTs of vitamin D supplementation may not to give a clear answer by themselves. Future decisions about the role of vitamin D in health are likely to be based on the evidence from a range of study designs including RCTs, mendelian randomization studies and other observational designs.