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Editorial |
The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research University of Texas Southwestern Medical Center Dallas, Texas 75390-8885
Address all correspondence and requests for reprints to: Khashayar Sakhaee, M.D., The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8885. E-mail: Khashayar.Sakhaee{at}utsouthwestern.edu.
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, 4, 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 1,25-dihydroxyvitamin 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 pre- and 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 for confounding bias have been made by controlling for factors such as caloric intake and activity level (3), no observational study can eliminate confounding.
Randomized blinded studies minimize many of the confounders that may influence the results of observational and cross-sectional epidemiological studies. Recently, Barr (12) summarized the results of 17 randomized placebo-controlled trials of calcium supplements and dairy products. In these studies, she found little support for an effect of dairy products or calcium supplementation on the reduction of body weight or fat mass. The primary endpoint for these studies was the bone-protective effect of calcium supplementation, and the effect on body mass was a post hoc analysis. Therefore, these results should be viewed with skepticism until confirmed by appropriately designed prospective studies.
A more recent study by Gunther et al. (13) added a major insight, as weight loss was the primary end point. This randomized, double-blinded study followed 155 young lean healthy females for 1 yr while they maintained an isocaloric diet. One group served as a control, whereas two other groups received medium-dairy and high-dairy intake, respectively. The results showed no significant differences in body weight and fat mass between the control and dairy groups. The investigators concluded that calcium in itself is ineffective for weight control. The young patient population and the source of calcium limit the generalization of the results. Because dairy products provide calories in addition to calcium, provision of calcium in the form of tablets may affect body weight differently. In addition, older individuals, in whom calcium intake and absorption are low, may respond differently to calcium supplementation.
The study of Reid et al. (1) in this issue of the JCEM provides some insights toward the influence of calcium supplementation on weight and blood pressure control in an older patient population. This prospective double-blinded, placebo-controlled study of 1471 postmenopausal women is the largest trial to date that evaluates whether calcium supplementation influences these parameters. In a post hoc analysis, the authors showed that calcium supplementation (1 g oral elemental calcium daily) for 30 months did not affect body weight or fat mass. The authors should be commended for thoroughly conducting this study. The drawback of their report is that body weight and body fat were not the prespecified primary endpoints. An intriguing observation was the marginal effect of calcium supplementation on body weight and blood pressure control in those subjects with baseline dietary calcium intake of less than 600 mg daily.
Because the effect of calcium intake on blood pressure control has been debated over the last 2 decades, Reid et al. also examined the impact of calcium intake on blood pressure in their study. The NHANES I study was the first epidemiological survey linking the inverse relationship between these two parameters (2). Calcium supplementation is suggested to lower blood pressure by different mechanisms. It may directly inhibit renal sodium reabsorption (14), lower the activity of the renin-angiotensin system (15), or inhibit vascular smooth muscle cell constriction via suppression of PTH secretion and/or calcitriol synthesis (16). Whether any of these factors is operative in a chronic steady-state remains to be proven.
Most of the clinical studies to date have shown a minimal effect of the role of calcium supplementation in lowering blood pressure (17, 18). A meta-analysis of over 4500 patients showed an average of 1.4-mm Hg reduction in systolic blood pressure with calcium supplementation (19). Overall, the degree of decline in blood pressure is so small that there is little clinical benefit. The study by Reid et al. (1) confirms this observation, showing a nonsignificant change in blood pressure.
The insights provided by published studies on the role of calcium in the pathogenesis of obesity and hypertension must be cautiously taken into consideration. Due to the discussed limitations and drawbacks of basic studies, the potential mechanism(s) of calcium on regulation of fat metabolism and blood pressure control needs further detailed investigation. To date, most published human studies suffer from the confounding factors inherent to observational reports and the limitations of post hoc analyses. Further clinical research on the effects of calcium on body weight, fat mass, and blood pressure must be pursued with prospective randomized double-blinded clinical trials. The difference in the response to calcium supplementation in subjects with low calcium intake at baseline may suggest a target population to be considered for future investigations. We believe we are at the crossroads and have yet to reach the end of the road.
Received May 5, 2005.
Accepted May 13, 2005.
References
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