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Calcium Modulation of Hypertension and Obesity: Mechanisms and Implications

Departments of Nutrition and Medicine, University of Tennessee, Knoxville, Tennessee

Address reprint requests to: Michael B. Zemel, Ph.D., The University of Tennessee, 1215 W. Cumberland Ave., Room 229, Knoxville, TN 37996. E-mail: mzemel{at}utk.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION HYPERTENSION IN THE U.S. DIETARY CALCIUM AND HYPERTENSION MECHANISMS OF THE... FOOD-BASED INTERVENTIONS: THE... CALCIUM AND WEIGHT CONTROL CONCLUSION REFERENCES

 
Regulation of intracellular calcium plays a key role in hypertension and obesity. Dysregulation of calcium homeostasis appears to be a fundamental factor linking these conditions. Regulation of intracellular calcium in key disease-related target tissues by calcitrophic hormones provides the opportunity to modulate disease risk with dietary calcium. Overall, sub-optimal calcium intakes contribute to the etiology of salt-sensitivity and hypertension. High salt diets exert a calciuretic effect, serving to exacerbate the physiological consequences of sub-optimal calcium diets. Among these are increases in 1,25-dihydroxyvitamin D, which increases vascular smooth muscle intracellular calcium, thereby increasing peripheral vascular resistance and blood pressure. Dietary calcium reduces blood pressure in large part via suppression of 1,25-dihydroxyvitamin D, thereby normalizing intracellular calcium. The practical relevance of this approach has been confirmed in the DASH (Dietary Approaches to Stop Hypertension) trial, which demonstrated that increasing low-fat dairy product and fruit and vegetable consumption exerted profound blood pressure-lowering effects. The magnitude of this effect among hypertensives was comparable to that typically found in pharmacological trials of mild hypertension. 1,25-dihydroxyvitamin D also stimulates calcium influx in human adipocytes, resulting in stimulation of lipogenesis, inhibition of lipolysis and expansion of triglyceride stores. Accordingly, suppression of 1,25-dihydroxyvitamin D by dietary calcium has been identified as a target, which may contribute to the prevention and management of obesity. Indeed, laboratory, clinical and population data all indicate a significant anti-obesity effect of dietary calcium, although large-scale prospective clinical trials have not yet been conducted to definitively demonstrate the scope of this effect. Thus, available evidence indicates that increasing dietary calcium intakes may result in reductions in fat mass as well as in blood pressure.

Key words: blood pressure, calcium, hypertension, obesity

Key teaching points:

• Calcitrophic hormones, including 1,25-dihydroxyvitamin D, regulate intracellular calcium levels in vascular smooth muscles cells and in adipocytes. This presents an opportunity to influence hypertension and metabolic disease risk using dietary calcium to modulate 1,25-dihydroxyvitamin D levels.

• Increasing dietary calcium attenuates salt-sensitivity and lowers blood pressure, especially in hypertensive individuals.

• A food pattern that emphasizes low-fat dairy products (3–4 servings daily) and fruits and vegetables (8 servings) exerts significant antihypertensive effects. These effects are comparable in magnitude to pharmacological management of mild hypertension.

• 1,25-dihydroxyvitamin D stimulation of calcium influx in adipocytes results in increased lipogenesis, inhibition of lipolysis, and expanded triglyceride stores. Conversely, reducing 1,25-dihydroxyvitamin D levels by increasing dietary calcium results in reduction of fat mass and augmentation of weight and fat loss during caloric restriction.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION HYPERTENSION IN THE U.S. DIETARY CALCIUM AND HYPERTENSION MECHANISMS OF THE... FOOD-BASED INTERVENTIONS: THE... CALCIUM AND WEIGHT CONTROL CONCLUSION REFERENCES

 
Regulation of intracellular calcium plays a key role in hypertension, insulin resistance, and obesity. Dysregulation of intracellular calcium may represent a fundamental factor linking these three conditions. The observation that regulation of intracellular calcium in key disease-related target tissues occurs, in part, via calcitrophic hormones, which are under the control of dietary calcium, provides insight into the potential for modulation of cardiovascular and metabolic disease risk by dietary calcium. This review focuses on such modulation of hypertension and obesity.

	HYPERTENSION IN THE U.S.

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Hypertension affects approximately 50,000,000 adults, or 24% of the adult population in the U.S. Further, aging is accompanied by a progressive increase in the incidence and prevalence of hypertension, such that more than half of all Americans over the age of 65 are affected. Moreover, the prevalence of hypertension increases markedly with body mass index (BMI), such that a BMI of 30–34.9 (Obesity Class 1) is associated with a 2.5-fold increase in prevalence and a BMI of 35 or greater (Obesity Classes 2 and 3) is associated with a 4.5-fold increase in hypertension prevalence in adults under the age of 55 [1]. Thus, both the aging of the population and the present obesity epidemic [2] are expected to increase the prevalence of hypertension and its associated morbidity and mortality in the U.S. Finally, African-Americans suffer hypertension with both greater frequency and greater consequence than the population at large [3]. African-Americans experience approximately twice the risk of hypertension experienced by Caucasians, with a greater fraction of African-Americans suffering uncontrolled hypertension compared to the overall U.S. hypertensive population. African Americans with hypertension also have a corresponding increase in the risk of stroke, end-stage renal disease, congestive heart failure, left ventricular hypertrophy and sudden death. Although African-Americans exhibit a greater prevalence of obesity than the overall population [2], excessive risk of hypertension is seen in this population even after controlling for BMI.

	DIETARY CALCIUM AND HYPERTENSION

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The concept that dietary calcium could have a meaningful impact on blood pressure regulation first emerged with the publication of two papers by McCarron et al. [4,5] in the early 1980s. These landmark papers demonstrated that low intake of calcium-containing foods was associated with hypertension and that dietary calcium consumption by U.S. adults was inversely related to the probability of being hypertensive. Subsequently, a number of other epidemiological studies and clinical trials have confirmed this association. Meta-analyses of 42 such clinical trials in non-pregnant study populations [6], as well as in pregnancy-induced hypertension and pre-eclampsia [7,8], demonstrate significant blood pressure reductions resulting from increasing calcium intake by 1,000 to 2,000 mg/day. However, findings from these meta-analyses demonstrate considerable heterogeneity in the blood pressure response to increased calcium. This heterogeneity may be explained by several factors, including a threshold effect, consistent with the 600–700 mg/day calcium threshold originally suggested by the data presented by McCarron et al. [5]. A key factor contributing to the heterogeneity of response is the baseline blood pressure status of the study group. The systolic pressure response to calcium supplementation was -3.86 mm Hg in the hypertensive patients versus -0.15 mm Hg in the normotensive individuals in the six studies that provided separate analyses based on blood pressure status. Thus, the inclusion of normotensives in many of these studies may have diluted the potential effect of the dietary intervention. The heterogeneity in blood pressure response to calcium may also be explained by the intake of other nutrients, interactions among nutrients, and the source of dietary calcium. Indeed, studies that utilized dietary sources of calcium demonstrated approximately twofold greater, and more consistent, effects on blood pressure compared to those that utilized supplements [8].

	MECHANISMS OF THE ANTIHYPERTENSIVE EFFECT OF CALCIUM

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Role of Calcitrophic Hormones
The effects of dietary calcium on blood pressure regulation appear to be paradoxical, as increasing intracellular calcium increases vascular smooth muscle tone, peripheral vascular resistance, and blood pressure, while increasing dietary calcium exerts the opposite effect. The protective effect of calcium on blood pressure can be explained in part by the influence of calcitrophic hormones on intracellular calcium.

1,25-dihydroxyvitamin D stimulates calcium influx in a variety of cells, including vascular smooth muscle cells. This effect is rapid, as it is mediated by the membrane vitamin D receptor rather than via a classical nuclear-receptor-mediated mechanism [9,10]. As a consequence, 1,25-dihydroxyvitamin D exerts a pressor effect, serving to promote contraction and increase peripheral vascular resistance [reviewed in 11]. Accordingly, low calcium diets, which elicit a 1,25-dihydroxyvitamin D response, would be expected to increase blood pressure, whereas high calcium diets, by virtue of suppressing 1,25-dihydroxyvitamin D levels, would be expected to reduce vascular smooth muscle cell intracellular calcium, peripheral vascular resistance and blood pressure (Fig. 1).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Mechanism of dietary calcium modulation of blood pressure. 1,25-(OH)2-D stimulates calcium influx into vascular smooth muscle cells, thereby increasing vascular tone and blood pressure. Dietary calcium reduces the stimulus for Ca2+ influx by suppressing 1,25-(OH)2-D production.

The populations that have most consistently exhibited antihypertensive responses to dietary calcium are those that are salt-sensitive, such as African-Americans and the elderly [11,12]. Exaggerated pressor responses to salt appear to be mediated in large part by calcitrophic hormones, which stimulate the transfer of calcium from the extracellular space to the vascular smooth muscle cell, where it stimulates contraction and increased peripheral vascular resistance, as noted above. In contrast, salt-insensitive individuals are more likely to be dependent upon calcium release from intracellular stores, and, consequently to exhibit little or no response to dietary calcium interventions [11].

What is the mechanism of salt-induced increases in calcitrophic hormones? An antithetical relationship between the renal handling of sodium and calcium has long been recognized, and an increase in the renal filtered load of either cation increases the excretion of the other [13]. Consequently, salt-sensitive individuals exhibit a tight relationship between sodium and calcium excretion, such that increasing dietary salt increases urinary calcium loss, eliciting calcitrophic hormone response, and, eventually increasing intracellular calcium, peripheral vascular resistance and blood pressure [12–19]. Increasing dietary calcium prevents this sequence of events in salt-sensitive individuals [12–19].

This effect of calcium can be demonstrated by examining renal calcium leak in essential hypertension, especially in salt-sensitive individuals. Even when adequate calcium is consumed, salt-sensitive hypertensives exhibit a renal calcium leak with an approximate twofold increase in calcium excretion compared to nonhypertensive or salt-resistant individuals. This primary calcium leak, which may be exacerbated by dietary salt, causes a transient reduction in serum ionized calcium and, consequently, an increase in parathyroid hormone (PTH). Activation of renal 1-alpha-hydroxylase by PTH then results in increased 1,25-dihydroxyvitamin D, which acts on vascular smooth muscle cells to increase peripheral vascular resistance and blood pressure (Fig. 2). However, as indicated above, increasing dietary calcium, thereby preventing the increase in 1,25-dihydroxyvitamin D and blood pressure, can compensate for the response to this leak. We have demonstrated this finding in a number of studies in which dietary calcium intakes were increased for periods of up to one-year in African-American hypertensives [14–20]. These studies exploited the relationship between renal sodium and calcium handling, demonstrating that an increase in either cation resulted in increased excretion of the other. Thus, increased sodium excretion exacerbated the calcium leak noted above, while increasing dietary calcium resulted in increased sodium excretion, even at fixed levels of sodium intake. This resulted in the expected decrease in intravascular volume, calcitrophic hormone levels, intracellular calcium (measured in circulating cells), peripheral vascular resistance and blood pressure [14–20]. This interaction between sodium and calcium in blood pressure control is supported by epidemiological data derived from a Montreal population. Hamet et al. [21] reported that calcium had a significant impact on blood pressure in individuals in the highest tertile of sodium intake, with a 26 mm Hg decrease in systolic pressure associated with moving from the lowest to the highest tertile of calcium intake while at the highest tertile of sodium intake. Moreover, dietary sodium only appeared to exert a hypertensive effect in those individuals in the lowest tertile of calcium intake.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Role of renal calcium leak in essential hypertension. Hypertensives exhibit an increase in urinary calcium losses, which is exacerbated on high salt diets. This results in a transient decrease in serum ionized Ca2+. The parathyroid gland responds to this decrease with the release of parathyroid hormone (PTH), which activates the renal 1--hydroxylase, resulting in increased 1,25-(OH)2-D production. 1,25-(OH)2-D serves as a stimulus to increase vascular smooth muscle intracellular Ca2+.

	FOOD-BASED INTERVENTIONS: THE DASH STUDY

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Many studies have examined the role of individual nutrients such as calcium on blood pressure. However, the practical relevance of dietary calcium modulation of blood pressure needs to be evaluated within the context of foods. As such, recent attention has focused on the role of dietary patterns. The DASH (Dietary Approaches to Stop Hypertension) study was conducted as a clinical trial of the effects of dietary patterns of nutrients as they occur together in food, rather than the effects of individual nutrients, on blood pressure [22]. For eight weeks, participants consumed one of the following diets: a control diet similar to the typical American diet; a "fruits and vegetables" diet; or a "combination" diet high in low-fat dairy foods, fruits, and vegetables, and reduced in total fat. Energy intake was adjusted to ensure a constant body weight and sodium content of the three diets was equal (3000 mg sodium/day). The control diet provided calcium, potassium, and magnesium at about the 25th percentile of the average U.S. diet. The fruits and vegetables diet (8 servings/day) provided potassium and magnesium at the 75th percentile. However, calcium was left at the 25th percentile. The combination diet that included low-fat dairy foods increased calcium to the 75th percentile of the average U.S. diet. The DASH study is unique, not only for its study of dietary food patterns, but also for its careful sampling and overrepresentation of African-Americans (nearly 60%), women, and untreated hypertensives. In addition, the study was sufficiently powered to allow for subsequent retrospective subgroup analyses.

The fruit and vegetable diet reduced systolic pressure and diastolic pressure by 2.8 and 1.1 mm Hg, respectively, with substantially greater decreases of 7.2 mm Hg systolic and 2.8 mm Hg diastolic pressure in the hypertensive subgroup. However, the combination dairy/fruit and vegetable diet was significantly more effective, producing 5.5 and 3.0 mm Hg reductions in systolic and diastolic pressure, respectively, in the total study cohort. However, the hypertensive subgroup exhibited markedly greater reductions of 11.4 mm Hg systolic and 5.5 mm Hg diastolic pressure in response to the combination diet.

These effects were apparent within two weeks and persisted through the remainder of the trial. The effects of this combination diet in the hypertensive subgroup are comparable to those observed in pharmacological trials in mild hypertension [23]. Although this was a study of food patterns rather than single nutrients, DASH results are remarkably concordant with predictions of the effects of dietary sources of calcium from previous epidemiological studies [5,8]. Notably, these hypotensive effects of the DASH diet were accomplished with no change in dietary sodium, and the investigators suggested that achieving a population-wide reduction in blood pressure similar to that found with the DASH diet would reduce coronary heart disease by approximately 15% and stroke by 27%. However, the possibility of even greater risk reduction in susceptible subgroups is likely, as subsequent subgroup analysis of the DASH data demonstrates a greater blood pressure-lowering effect of the combination diet in African-Americans than in whites [24]. Interestingly, another subgroup analysis of DASH data demonstrates that the DASH combination diet reduces cardiovascular risk independently of its effects on blood pressure, by lowering circulating homocysteine levels [25]. Based on this reduction in homocysteine levels, researchers predicted that switching from a typical U.S. diet to the DASH combination diet could reduce the risk of atherosclerotic disease by 7% to 9%.

In a follow-up study, adding a low-sodium intervention to the DASH diet produced additional decrements in blood pressure [26]. However, these additional improvements are modest (<2 mm Hg) and require a level of sodium restriction that patients find unpalatable, resulting in significant compliance problems. In contrast, the DASH diet produced significant reductions in blood pressure at all levels of sodium intake evaluated in the follow-up study, with greater effects observed in individuals on the higher sodium diets. This may be a preferred approach, as diets such as the DASH combination diet are far less restrictive and are therefore less likely to produce compliance problems.

	CALCIUM AND WEIGHT CONTROL

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During the course of conducting a clinical trial of the antihypertensive effect of calcium in obese African-Americans, we noted that increasing dietary calcium from 400 to 1,000 mg/day for one year resulted in a 4.9 kg reduction in body fat. Although the data were inexplicable at the time, they have been recently re-evaluated and placed in a logical theoretical framework based upon our recent work describing the role of intracellular calcium in regulating adipocyte lipid metabolism and lipogenic gene expression [27]. This work, described below, suggests that calcium-rich diets produce significant metabolic effects in addition to those discussed above. Specifically, the combination of direct effects on blood pressure regulation and those on adiposity and weight control may together result in a marked reduction in the risk of hypertension and associated metabolic disease.

Studies of the mechanism of action of agouti, an obesity gene expressed in human adipocytes, demonstrate that agouti protein stimulates calcium influx [28,29] and promotes energy storage in human adipocytes by coordinately stimulating the expression and activity of fatty acid synthase, a key enzyme in de novo lipogenesis, and inhibiting lipolysis in a calcium-dependent fashion [30,31]. This action of agouti was fully mimicked by calcium channel agonists and inhibited by calcium channel antagonists [30,31]. Moreover, treating transgenic mice overexpressing agouti with a calcium channel antagonist (nifedipine) for four weeks resulted in significant decreases in lipogenesis and in adipose tissue mass [32]. Thus, adipocyte calcium modulates energy storage and may be a logical target for interventions to control adiposity (Fig. 3). We considered the possibility that 1,25-dihydroxyvitamin D may stimulate calcium influx in the adipocyte, as it does in other tissues discussed earlier in this manuscript, leading to stimulation of lipogenesis, inhibition of lipolysis, and expansion of adipocyte triglyceride stores. If so, suppressing 1,25-dihydroxyvitamin D levels by increasing dietary calcium may inhibit adiposity and promote weight loss (Fig. 4).

View larger version (17K): [in this window] [in a new window]   Fig. 3. Agouti modulation of adipocyte lipid metabolism. Agouti stimulates adipocyte Ca2+ influx. Increased adipocyte intracellular calcium ([Ca2+]i stimulates fatty acid synthase (FAS) transcription and activity, resulting in increased de novo lipogenesis, and also inhibits lipolysis. Consequently, adipocyte triglyceride stores are expanded.

View larger version (16K): [in this window] [in a new window]   Fig. 4. Role of dietary calcium in modulating adipocyte lipid metabolism. 1,25-(OH)2-D stimulates adipocyte Ca2+ influx. This results in stimulation of fatty acid synthase (FAS) transcription and activity, increased de novo lipogenesis, and decreased lipolysis. Consequently, adipocyte triglyceride stores are expanded. Dietary calcium reduces the stimulus for Ca2+ influx by suppressing 1,25-(OH)2-D production, thereby permitting down-regulation of lipogenesis and up-regulation of lipolysis, resulting in reduced adipocyte triglyceride stores.

This concept was confirmed in transgenic mice expressing agouti in adipose tissue under the control of the aP2 promoter, similar to the human pattern of expression. Mice placed on low calcium (0.4%)/high fat/high sucrose diets for six weeks exhibited marked increases in adipocyte lipogenesis, inhibition of lipolysis and accelerated increases in body weight and adipose tissue mass. However, high calcium (1.2%) diets reduced lipogenesis by 51% and stimulated lipolysis three- to five-fold, resulting in 26% to 39% reductions in body weight and adipose tissue mass [27]. The magnitude of these effects depended upon the source of dietary calcium, with dairy sources of calcium exerting significantly greater effects than calcium carbonate.

The relevance of this finding at the population level was assessed via analysis of data from the National Health and Nutrition Examination Survey (NHANES III). Odds ratios for percent body fat as a function of calcium intake were estimated by logistic regression, with age, race/ethnicity, activity level and caloric intake as covariates. The odds of being in the highest quartile of body fat were reduced from 1.0 for the first quartile of calcium intake to 0.75, 0.40 and 0.16 for the second, third and fourth quartiles of calcium intake, respectively, for women [27]. The regression model for males similarly demonstrated a significant inverse relationship between dietary calcium and body fat, although the same simple dose-response relationship found in women was not evident [27].

These data have significant implications for the prevention or attenuation of diet-induced obesity, but do not directly address the issue of whether high calcium diets will exert any effect on established obesity. Accordingly, a follow-up study was conducted to determine whether increasing dietary calcium will reduce metabolic efficiency and accelerate fat loss secondary to caloric restriction following dietary induction of obesity [33]. Administration of the same low calcium/high fat/high sucrose diet to aP2-agouti transgenic mice for six weeks resulted in a 100% increase in adipocyte intracellular Ca²⁺ and a corresponding twofold increase in total fat pad mass, demonstrating that dysregulation of adipocyte intracellular Ca²⁺ is associated with increased adiposity in aP2-agouti transgenic mice. The animals were then placed on an energy restricted (70% of an ad libitum fed control group) diet for an additional six weeks. Energy restriction on the low calcium diet failed to reduce intracellular Ca²⁺ and only reduced body weight and fat pad mass by 11% and 8%, respectively. In contrast, energy restriction in conjunction with high calcium (1.2%) diets normalized intracellular calcium and resulted in 19% to 29% reductions in body weight and 42% to 69% decreases in fat pad mass, depending upon the calcium source (calcium carbonate versus dairy). Interestingly, the animals on the low calcium diets were unable to increase adipocyte lipolysis or suppress lipogenesis despite being on an energy-restricted regimen. In contrast, the high calcium diets caused marked reductions in fatty acid synthase expression and activity (35% to 81%), two- to threefold increases in lipolysis and increases in core temperature (0.48–0.67°C) and uncoupling protein-2 expression [33] during energy restriction. These data demonstrate that high calcium diets suppress adipocyte intracellular Ca²⁺ by decreasing 1,25-(OH₂)-D, thereby shifting the partitioning of dietary energy from energy storage to energy expenditure.

Recent findings from other laboratories support a beneficial role for calcium in weight control. In a two-year prospective study of 54 normal weight women participating in an exercise intervention, the dietary calcium:energy ratio was a significant negative predictor of changes in both body weight and body fat [34]. Moreover, increased total calcium and dairy calcium intakes predicted fat mass reductions independently of caloric intake for women at lower energy intakes (below the mean of 1876 kilocalories per day) [34]. A similar beneficial effect of dietary calcium on body fat mass accumulation has been demonstrated in growing children [35]. A significant inverse relationship between dietary calcium and body fat was recently reported in a five-year longitudinal study of preschool children (R²=0.51) [35].

Davies et al. have conducted a series of calcium intervention studies designed with primary skeletal endpoints, and have recently re-evaluated these data with a body weight endpoint [36]. The re-analysis involved 780 women who participated in five clinical trials (i.e., four observational and one double-blind, placebo-controlled randomized trial). They noted significant negative associations between calcium intake and body weight for all age groups (3rd, 5th, and 8th decades of life), and an odds ratio for being overweight of 2.25 for young women in the lower half versus the upper half of calcium intake [36]. Data from the randomized controlled trial demonstrated a calcium treatment effect of 0.325 kg weight loss per year over four years with no intentional change in caloric intake. Overall, the relationships derived from this re-analysis indicate that a 1,000 mg/day increase in calcium intake is associated with an 8 kg reduction in body weight [36]. Thus, accumulating data from experimental animal and human studies support a beneficial role for dietary calcium in weight management.

	CONCLUSION

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In the twenty years since McCarron’s first report of an inverse relationship between dietary calcium and blood pressure regulation, sufficient evidence has emerged to support a firm conclusion that dietary calcium plays a key role in blood pressure control, with diets low in calcium serving to increase risk and higher calcium intakes exerting a protective effect. This effect is largely mediated via inhibition of 1,25-dihydroxyvitamin D levels as an increase in this hormone in response to low calcium diets increases vascular smooth muscle intracellular calcium, thereby increasing peripheral vascular resistance. Although there is some heterogeneity of response to dietary calcium, those with elevated blood pressure, and especially those who are salt-sensitive, are likely to respond favorably to calcium interventions, with food sources of calcium exerting greater effects than supplemental sources. This has now been demonstrated by the DASH study, in which a food consumption pattern rich in low-fat dairy products and in fruits and vegetables exerted hypotensive effects comparable to those typically found in pharmacological trials of mild hypertension.

Finally, obesity is a major risk factor for hypertension, and emerging data implicate 1,25-dihydroxyvitamin D as a factor that stimulates adipocyte triglyceride storage and promotes obesity. Laboratory, clinical and population data all indicate a significant antiobesity effect of dietary calcium, although large-scale prospective clinical trials have not yet been conducted to definitively demonstrate the scope of this effect. Nonetheless, available evidence indicates that increasing dietary calcium intakes may result in reductions in fat mass as well as in blood pressure.

Received April 26, 2001.

	REFERENCES

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