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Dietary calcium, obesity and hypertension--the end of the road?

Obesity is recognized as one of the most significant public health burdens, and its prevalence continues to escalate in most industrialized nations. Over the past two decades, many pharmacological drugs have been developed to affect body weight through appetite suppression or by intestinal lipase inhibition. Several of these medications have fallen into disfavor due to limited efficacy and/or significant side effects. Continued efforts have been made to develop safe and effective therapies to induce and maintain weight loss. If proven to reduce fat mass, calcium would be one such safe and simple dietary supplement to accomplish this goal. Moreover, calcium supplementation may be beneficial in the treatment of hypertension because dietary calcium intake is also postulated to be an important determinant of blood pressure. The mechanism(s) by which calcium plays a pathogenetic role in weight control, energy balances, and hypertension is not fully understood. The negative clinical study published in this issue of the journal by Reid et al. (1) raises an interesting question as to whether we are at the crossroads, at the end of the road, or whether we should move to a new beginning. NHANES I (2), in a survey of over 10,000 subjects, was the first study to show an inverse relationship between dietary calcium intake and body weight. This study generated subsequent investigations as to whether the effect of calcium on body fat is causal, and a large body of supportive evidence has emerged over the past two decades (3–5). This has raised questions about the mechanisms through which calcium operates pathophysiologically in the control of body weight. Studies have provided evidence that calcium may act either systemically, through the alteration of calcitropic hormones (3), or directly through complexation of fat in the intestinal tract (6). In support of the mechanism mediated by calcitropic hormones, data from adipocyte culture studies indicate that alteration in intracellular calcium concentration may regulate fat metabolism. In vitro, the intracellular influx of calcium, mediated either by PTH or 1,25-dihydroxyvitamin D, was shown to inhibit lipolysis and increase lipogenesis in adipocytes (3). Conversely, the inhibition of PTH and/or calcitriol was proposed to explain fat loss associated with increased calcium intake. In accordance with this model, the intracellular calcium concentration in fat cells from obese individuals was higher than in adipocytes from lean subjects (7). Further support comes from clinical observations that patients with primary hyperparathyroidism, a condition in which both serum PTH and calcitriol concentrations are elevated, have increased body weight (8). However, three principal drawbacks with these experimental models limit their generalization to the normal physiological state. First, it is unclear whether the changes in intracellular calcium concentration induced by calcitropic hormones would apply to a steady-state condition in which calcium is supplemented chronically. Secondly, the concentrations of PTH and 1,25dihydroxyvitamin D used in the experimental model by Zemel et al. (3) exceed physiological serum concentrations by approximately 1000-fold. Thirdly, a short-term increase in calcium intake does not alter fat oxidation in healthy subjects (9). One may also question whether the complexation of intraluminal fat by calcium will lead to a clinically significant increase in fecal fat excretion and a quantifiable weight loss. Compared with placebo, provision of 2 g of elemental calcium daily has been demonstrated to cause a 0.6% increase in fecal fat excretion in one study (6). In an individual consuming 2000 kcal/d, with fat representing 35% of caloric intake, this change in fecal fat excretion would lead to a loss of 4.2 kcal/d. This would translate to a weight loss of less than 200 g/yr. However, in other studies, higher ranges of fecal fat excretion were reported with calcium supplementation. Jacobsen et al. (9) recently reported as much as an 8-g increment in fecal fat with short-term provision of dairy products supplying 1800 mg elemental calcium. If sustained, this fecal fat loss would lead to a 3.5-kg weight loss per year, assuming that energy intake and expenditure are otherwise kept constant. Whether the source of calcium provided is responsible for the variation in fecal fat excretion has not been fully explored. It is also plausible that increased dietary calcium intake may reduce body weight through additional mechanisms. In addition to the observation described in the NHANES I paper, a beneficial role of calcium supplementation in weight control has been detected in subsequent cross-sectional and observational studies. These studies confirmed the inverse relationship between calcium intake and body weight in various patient populations including pre-school children (10), young adults (11), and preand postmenopausal women (5). At first glance, the findings of these studies were attractive, as a difference of 1000 mg in dietary calcium intake was associated with an 8-kg difference in body weight (5). The results of these observational studies should be considered with caution because the presence of confounding factors such as lifestyle (“healthy user effect”) may have influenced the results. Moreover, the benefits found with the consumption of milk may be attributed to more limited intake of carbonated beverages, a source of “empty calories.” Alternatively, it is possible that those subjects consuming more milk were of higher socioeconomic status and hence had better access to healthcare, which in part accounted for weight loss. Although attempts to correct JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. 0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(7):4411–4413 Printed in U.S.A. Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2005-1004