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

REVIEW Dermato-Endocrinology 4:2, 95–100; April/May/June 2012; G 2012 Landes Bioscience Why randomized controlled trials of calcium and vitamin D sometimes fail Joan M. Lappe and Robert P. Heaney* Creighton University; Osteoporosis Research Center; Omaha, NE USA . e nc Keywords: chronic disease, nutrient dose response, systematic reviews, meta-analyses, design flaws, evidence-based medicine 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. the risk of the diseases concerned. There are, however, reasons to reject that conclusion. There are well over 100 RCTs of vitamin D with respect to various health endpoints, and several times that number involving calcium as the principal intervention. For the most part, the results for both nutrients fall into just two categories: many of the trials are positive, many are null, but almost none is actually negative. And most of the effects, when positive, are small. If a particular intervention were, in fact, unrelated to a particular disease risk, one would expect a more symmetrical distribution of results,6 with the majority of the trials being null and a minority split roughly evenly between positive and negative. However, as noted, the preponderance of the evidence tilts strongly toward a positive result, and the purpose of this review is to examine why, if the agent is in fact efficacious, randomized controlled trials sometimes fail to find the underlying causal connection. When RCTs (or observational studies) produce this kind of mixed result, systematic reviews and meta-analyses can often help to discern an underlying pattern. By aggregating several trials they effectively increase sample size and narrow the range of uncertainty around estimates of effect. Accordingly we will also examine several of the larger reviews concerning these relationships. EBM, in its grading of the evidence in particular papers, focuses on certain methodological issues which can confound the results of even the best RCTs. These include such features as inadequate randomization and blinding, excessive losses of participants during the course of a trial, and other such issues of unquestioned importance. Typically, the analyses and reviews of EBM admit studies into review, and/or grade studies, mainly on these methodological grounds. They usually presume that all the trials so aggregated measured the same thing, under uniform exposure conditions, in participants of similar nutritional status. Unfortunately that is often not the case. If these reviews are conducted by individuals or teams with limited understanding of the biology concerned, what emerges in the process may be a set of studies that, while methodologically “pure” are nevertheless biologically mixed, if not actually invalid. In addition to biology-related issues, trials may fail for probabilistic reasons common to any clinical trial. The latter are generally well known and will be discussed only briefly. The biological issues that are the basis of the following criteria are less familiar but probably more important, at least for nutrients, and will be our principal focus. e i c s o i B . e s t e u d b i n r a t L s i 2 d 1 t 0 o 2 n o © D Introduction Enthusiasm for evidence-based medicine (EBM) has resulted in the extension of its methods to the evaluation of nutrient effects. However, as has become increasingly clear, EBM, as applied in the evaluation of drugs, is poorly suited to the study of nutrients. The reasons have been discussed in depth elsewhere1-5 and will not be revisited in detail here. Basically those methods call for the use of randomized controlled trials (RCTs) to establish nutrient effects. The reason is that this design is the only certain way to establish a causal connection between an intervention and the production of a particular endpoint. The experience has been that RCTs of calcium and vitamin D, while often positive, have sometimes failed to find the sought for causal link. The most obvious explanation for such failure is that the intervention concerned is not actually efficacious with respect to the endpoint being studied, i.e., calcium and vitamin D have little to do with *Correspondence to: Robert P. Heaney; Email: Submitted: 02/15/12; Revised: 02/20/12; Accepted: 02/22/12 http://dx.doi.org/10.4161/derm.19833 www.landesbioscience.com Dermato-Endocrinology 95 Nutrient-Specific Issues Before evaluating the major clinical trials and systematic reviews of calcium and vitamin D, we describe and illustrate certain features which are largely unique to nutrients and which must be factored into the design of nutrient efficacy studies. Examples of critical biological criteria needed for a RCT to be informative (and for inclusion into a systematic review) would include such features as: N Use of a single form of the nutrient N Use of a low exposure control group N Adequacy of dose in the treatment group N Demonstration/documentation of the altered intake/ exposure, i.e., was a “therapeutic” blood level achieved N Use of a uniform response measure N Optimization of co-nutrient status This is not an exhaustive list of relevant biological criteria, but it serves to focus attention on some of the reasons why, in a particular study, an effective agent may seem to be ineffective, and specifically why meta-analyses and systematic reviews of calcium and vitamin D, when they ignore these criteria, have sometimes been null. We then show, in actual RCTs, why these biological criteria are important and point out how ignoring them leads to erroneous conclusions. Sigmoid response vis-à-vis starting level. A unique feature of the physiological response to nutrients is the sigmoid character of the response. This relationship is depicted in Figure 1, which illustrates a phenomenon common to virtually all nutrients.4 At low intakes (or low nutri (...truncated)