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Presented here is a system to standardize clinical studies of nutrient effects, using nutrient-specific physiological criteria. These guidelines are based mainly on analysis of the typical sigmoid curve of biological response to nutrients and are intended for design, interpretation, and pooling of studies of nutrient effects. Five rules have been articulated for individual studies of nutrients, and six for systematic reviews and/or meta-analyses.

Nutrient intake recommendations, unlike hormone replacement standards, are based empirically, rather than physiologically, i.e., they lack an a priori normal referent. Randomized controlled trials do not provide the needed referent and are unlikely to distinguish between fully normal and various suboptimal nutritional states. Several alternative approaches, each providing an a priori normal, are described and briefly discussed.

During the last decade, approaches to evidence-based medicine, with its heavy reliance on the randomized clinical trial (RCT), have been adapted to nutrition science and policy. However, there are distinct differences between the evidence that can be obtained for the testing of drugs using RCTs and those needed for the development of nutrient requirements or dietary guidelines. Although RCTs present one approach toward understanding the efficacy of nutrient interventions, the innate complexities of nutrient actions and interactions cannot always be adequately addressed through any single research design. Because of the limitations inherent in RCTs, particularly of nutrients, it is suggested that nutrient policy decisions will have to be made using the totality of the available evidence. This may mean action at a level of certainty that is different from what would be needed in the evaluation of drug efficacy. Similarly, it is judged that the level of confidence needed in defining nutrient requirements or dietary recommendations to prevent disease can be different from that needed to make recommendations to treat disease. In brief, advancing evidence-based nutrition will depend upon research approaches that include RCTs but go beyond them. Also necessary to this advance is the assessing, in future human studies, of covariates such as biomarkers of exposure and response, and the archiving of samples for future evaluation by emerging technologies.

Editor's Note: This paper is one of the first suggesting that idiapathic osteoporosis may be n disorder of calcium metabolism for which increased intakes calcium mas be preventative.

The bone remodeling transient is a temporary alteration in the balance between bone formation and bone resorption, brought about by any agency that affects bone remodeling. Ascertaining the steady state effect of an intervention requires factoring the component of the change due to the transient out of the total bony response. Since parathyroid hormone (PTH) is the principal regulator of the quantity of remodeling activity, and since calcium intake influences PTH secretion, it follows that altering calcium intake will always induce a remodeling transient. Worked examples from three published calcium intervention studies are presented, and the errors that can be made by ignoring the transient and simply measuring change in bone mass across treatment are described.

Meta-analysis is typically applied to studies developed in fairly mature fields, but may be ill-suited for younger fields in which most of the evidence comes from studies that were designed for other endpoints entirely and that are often significantly underpowered for the effect in question. Here, there are no generally accepted methods for getting a grasp on the preponderance of the evidence. In this review, one way of doing so is proposed and the recently emergent literature concerning calcium intake and body composition is used as an illustration of how such an approach might be used.

The functional status indicator for vitamin D, for both safety and efficacy, is serum 25-hydroxyvitamin D concentration. Efficacy for several health endpoints requires levels of 80 nmol/L or higher. Toxicity occurs at levels of 500 nmol/L or higher. The input needed for efficacy, in addition to typical food and cutaneous inputs, will usually be 1000-2000 IU/day of supplemental cholecalciferol. Toxicity is associated only with excessive supplemental intake (usually well above 20,000 IU/day).

The classic role of vitamin D has involved its function in calcium metabolism. However, a much broader perspective of the importance of vitamin D is now emerging. Therefore, a new approach is needed based on a combination of molecular biological, physiological, and clinical/epidemiological studies. The remarkable range of the effects of vitamin D relates to our new understanding of both the role of the vitamin D receptor and analyses of what might be considered an optimum vitamin D status in populations exposed to very different diets and levels of sun exposure. Assessing the breadth of the current approaches was the basis of the 22nd Marabou Symposium that took place in Stockholm in June 2007. The complete proceedings will be presented in this journal as a supplement to an upcoming issue.

When both calcium intake and calcium absorption are measured under controlled conditions, variation in absorption efficiency explains more of the interindividual differences in balance than does actual calcium intake (1). Small wonder, therefore, that interest in measuring absorption has remained high for nearly 40 years. True calcium absorption is defined as the quantitative, unidirectional flux of calcium from intestinal lumen into the blood. It is most accurately measured by a dual-tracer method, with one tracer labeling the oral calcium load and the other labeling the miscible calcium pool into which the absorbed calcium is introduced. This approach was first developed into a practicable human test by deGrazia et al. (2). As described, it is usually time-consuming and expensive. To reduce these barriers for widespread use, Heaney and Recker (3)(4) developed a single-tracer variant for women, requiring only a single blood sample, and calibrated it against a simultaneously performed double-tracer method. The single-tracer method has been used efficiently in thousands of women (5). However, because the calibration is empirical and based on body-size variables, it is not directly suitable for use in men who, with a typically higher proportion of fat-free mass than women, would be expected to distribute absorbed tracer in a larger mass of calcium. To fill this methodologic gap, we performed a small set of parallel measurements in adult men, using the female-based algorithm together wiketh a modified double-tracer approach. Participants in the study were 30 Caucasian men (age range, 20–60 years; weight range, 63.5–104 kg; height range, 1.67–1.93 m). All participants were free of known diseases affecting bone remodeling or calcium homeostasis, and tests were not performed if the individual had experienced any gastrointestinal disturbance in the preceding 5 days. Each gave informed consent after the procedures of the study were explained. Both the project …

We thank the Fentons for giving us the opportunity to emphasize and clarify certain points in our article titled “Evidence-based criteria in the nutritional context.”1 The Fentons recognize the distinction we made between the strength of the evidence and the confidence we might have in a particular nutrient intake recommendation. They reject the use of that distinction for nutrition, emphasizing that their results should be “consistent.” This is not the world in which we live and in which nutritional policy has to be forged and implemented. Across its full range, from micronutrients to protein, nutrition does not have the kind of evidence the Fentons advocate. This is not an indictment of nutrition as a science; it is simply recognition of the following facts: 1) we cannot get RCT-level evidence for many, and …

The connection between calcium intake and body weight was first described by McCarron et al.,1 who found an inverse relationship between these two variables in the National Health and Nutrition Examination Survey (NHANES) data. This observation was largely ignored for the next 16 years, until Zemel et al.2 described the weight-loss effect of calcium supplementation in a hypertension trial and suggested a cell biologic basis for the action of calcium in adipocytes. Since that time, there have been well over 100 reports of both experimental and observational studies evaluating the role of calcium intake in energy balance and body composition in humans. As summarized in 2009 in this journal,3 most of these studies found that increased calcium intake augmented the weight loss of energy-restricted diets, protected lean body mass, and reduced age-related weight gain, or that it had null effect. A very few reported negative findings (i.e., high calcium intakes were associated with weight gain), but the preponderance of the evidence tilted clearly toward the side of calcium intake favoring weight loss. In the present issue of this journal, Onakpoya et al.4 present yet another meta-analysis of this topic, with the results also favoring calcium. They report a highly significant, positive effect of calcium supplementation on total body weight loss and a somewhat larger effect on fat loss (suggesting some protection of lean tissue mass, which is a frequent casualty … [↵][1] RP Heaney , Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. E-mail: rheaney{at}creighton.edu [1]: #xref-corresp-1-1

I thank Dr. Martineau for his comments and for the opportunity to clarify some of the points he addresses.1 We both recognize that systematic reviews (SR) and meta-analyses (MA) have two major purposes: 1) to increase statistical power and get a better fix on whether an effect occurs and, if so, on its size; and 2) to use observed heterogeneity of response to clarify why some studies find an effect and others do not. The guidelines for SR and MA, to which Dr. Martineau responds,2 were pointed solely at …

In the rush to develop “peaceful uses of the atom” in the years following testing of the H-bomb, much interesting work was done with radioactive calcium isotopes (45Ca and 47Ca). Perhaps most important was the finding that the relatively huge quantities of calcium contained in mature bone exchanged only negligibly with calcium either in extracellular fluid (ECF) or in immediately adjacent bone (1). This meant that tracer uptake by bone could be used as a direct measure of new bone mineralization. Although various complicated kinetic models were developed(2)(3), the mathematics were actually quite straightforward. The tracer content of a sample of bone calcium obtained days or weeks after an injection of a calcium isotope into an animal, divided by the average tracer concentration in ECF calcium, directly yields the mass of calcium deposited by bone formation during the interval between tracer injection and the time of the bone sampling. What was missing from the picture was the ability to measure the other half of the bone remodeling/modeling process, i.e., bone resorption. How could one measure in a bone what was no longer there? Measuring the decrease in bone tracer content was not a feasible approach because the resorptive process removes mainly older bone, which contains little or no tracer. Despite this barrier and because so much of the interest in clinical bone biology was focused on bone resorption, there has for years been a search for a more “direct” quantification of the process. This quest was reinforced by the development of antiresorptive pharmacologic agents for the treatment of osteoporosis, as well as by the demonstration that resorption responds sensitively to environmental or physiologic signals, whereas bone formation tends to be relatively invariant over the short term (4). Moreover, the investigational focus shifted from in …