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The Journal of Clinical Endocrinology & Metabolism 90(7):3824 –3829 Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-2205
Effects of Calcium Supplementation on Body Weight and Blood Pressure in Normal Older Women: A Randomized Controlled Trial Ian R. Reid, Anne Horne, Barbara Mason, Ruth Ames, Usha Bava, and Gregory D. Gamble Department of Medicine, University of Auckland, Auckland 1020, New Zealand Context: Epidemiological data suggest that high calcium intakes are associated with decreased body weight and blood pressure. However, there is little evidence from randomized trials that addresses these important issues. Objective: The objective of this study was to assess the long-term effects of calcium on body weight and blood pressure. Design: This is a substudy of an ongoing, double-blind, randomized, controlled trial of calcium supplementation. End points were assessed at 30 months. Setting: This study was performed at a university medical center. Participants: Normal postmenopausal women (mean age, 74 yr; mean weight, 67 kg; mean blood pressure, 134/70 mm Hg at baseline) participated in this study. Intervention: Study subjects were treated with calcium (1 g/d; n ⫽ 732) and placebo (n ⫽ 739).
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IGH INTAKES OF calcium, either in the diet or as supplements, are now widely recognized as having beneficial effects on bone mass (1, 2) and, possibly, fracture incidence (3). However, other health benefits may result from high calcium intakes, including decreased body weight. Many epidemiological studies have identified inverse relationships between adiposity and calcium intake (4 –13). For example, Lin et al. (11) found that calcium intake in young women (as a ratio to caloric intake) was inversely related to weight and fat gain over a period of 2 yr. In preschool children, Carruth and Skinner (4) found that calcium was inversely related to fat mass, and McCarron (12) found an inverse relationship between calcium intake and body weight in the National Health and Nutrition Examination Survey I. More recently, Zemel et al. (5) reported a similar result from National Health and Nutrition Examination Survey III, in that the relative risk of being in the highest quartile for adiposity was 0.16 for those in the highest quartile for calcium intake (compared with those in the lowest quartile). This hypothesis has recently been given a major boost by the work of Davies et al. (13). They reevaluated five previFirst Published Online April 12, 2005 Abbreviations: BMI, Body mass index; DXA, dual energy x-ray absorptiometry. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Main Outcome Measures: Body weight and blood pressure were the main outcome measures. Results: Weight decreased by 368 ⫾ 132 g (mean ⫾ SE) with calcium treatment and by 369 ⫾ 134 g with placebo (P ⫽ 0.93). Fat and lean masses did not show an effect of calcium. Blood pressure showed transient reductions of 1–2 mm Hg at 6 months in the calcium group, resulting in a significant between-group difference only for systolic pressure (P ⫽ 0.048). At 30 months, the change from baseline in systolic pressure was 0.0 ⫾ 0.9 mm Hg in the calcium group and 2.4 ⫾ 0.9 mm Hg in the placebo group (P ⫽ 0.14). For diastolic pressures, the changes were ⫺0.2 ⫾ 0.4 and 0.8 ⫾ 0.4 mm Hg, respectively (P ⫽ 0.13). In those with baseline calcium intakes less than 600 mg/d, the treatment effect was greater and did persist. Conclusions: Calcium supplementation of 1 g/d does not produce biologically significant effects on body weight, and its hypotensive effect is small and transient in most women. (J Clin Endocrinol Metab 90: 3824 –3829, 2005)
ously published studies in 780 women, aged 20 – 80 yr. Their observational data showed significant negative associations between calcium intake and weight; a 1000-mg difference in calcium intake was associated with an 8-kg difference in body weight. Calcium intake explained 3% of the variance in body weight. In a randomized, controlled trial, they found that calcium supplementation was associated with a negative effect on body weight of 346 g/yr over 4 yr (P ⬍ 0.025). They concluded that calcium intake might play an important role in weight regulation. With the recognition of obesity as one of the principal health problems of affluent countries, the possibility that a safe and inexpensive nutrient such as calcium might play a role in weight control is a pivotal issue that needs to be adequately assessed. Despite the epidemiological and clinical data pointing toward an important role of calcium intake in the regulation of body weight, there is no authoritative clinical study addressing this question (14). We are currently conducting a randomized, controlled trial of calcium supplementation in the prevention of fractures. All subjects have reached 30 months, the first follow-up visit at which body composition is measured. We have used these data to assess the long-term effects of calcium supplementation on body weight. In addition, we have reassessed the effects of this intervention on blood pressure, because there is also an inconsistent body of evidence suggesting that this is a potential benefit of the use of calcium.
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Subjects and Methods This is a substudy of a randomized controlled trial of calcium supplementation in normal postmenopausal women, designed to assess the effects of calcium on fracture incidence.
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subsequent ones. Therefore, the mean of the second and third readings has been used in all analyses. The study was approved by the local ethics committee, and each subject gave written, informed consent.
Subjects
Statistics
The entry criteria for the study required that subjects be more than 5 yr postmenopausal and more than 55 yr of age. Women receiving therapy for osteoporosis or taking calcium supplements were ineligible, as were those with any other major ongoing disease, including serum creatinine greater than 1.8 mg/dl (0.2 mmol/liter), untreated hypo- or hyperthyroidism, liver disease, serum 25-hydroxyvitamin D below 10 g/liter (25 nmol/liter), malignancy, or metabolic bone disease. None of the subjects had been regular users of hormone replacement therapy, anabolic steroids, glucocorticoids, or bisphosphonates in the previous 1 yr. Lumbar spine bone density (Lunar Expert, Lunar Corp., Madison, WI) was not below the age-appropriate normal range (i.e. z-score greater than ⫺2). Women were recruited by advertisement and by mail-outs using electoral rolls; 2421 women responded to these invitations, of whom 641 did not meet the inclusion criteria, and 309 decided not to participate. Some 1471 women meeting the selection criteria for the study were randomized to calcium (n ⫽ 732) or placebo (n ⫽ 739). Their baseline characteristics are shown in Table 1.
Continuous normally distributed variables were analyzed using a mixed models approach to repeated measures (Proc Mixed, version 8.12, SAS Institute, Cary, NC). This approach ensures that all available data can be included in the analysis even when some subjects have missing data. A variety of preplanned models were run: an intention to treat analysis, with and without imputation (maximum likelihood) of missing values, and with and without adjustment for compliance; a per protocol analysis; and an analysis of the change in blood pressure, excluding those taking blood pressure-lowering medication. The intention to treat analysis was prespecified as the primary analysis. Significant main and interaction effects were explored using the method of Tukey to preserve the overall 5% significance level. All tests were two-tailed. A sample size of 600 in each group provides a power of 80% to detect differences (at the 5% significance level) of at least 16% of 1 sd. This equates to 520 g for a change in body weight, 3.4 mm Hg for a change in systolic blood pressure, and 1.5 mm Hg for a change in diastolic blood pressure.
Results
Protocol Treatments were allocated randomly using a minimization algorithm balancing for current thiazide use, age, and the occurrence of fractures resulting from minimal trauma after the age of 40 yr. Subjects received 1 g elemental calcium daily as citrate (Citracal, Mission Pharmacal, San Antonio TX) or an identical placebo. They were asked to take two tablets (each containing 200 mg elemental calcium) before breakfast and three tablets in the evening. Dietary calcium intake was assessed using a validated food frequency questionnaire (15). Compliance was assessed by tablet counts and was calculated from the number of tablets taken as a percentage of the number that should have been taken.
Measurements Body weight was measured at each visit using electronic scales with subjects wearing light indoor clothing without shoes. No assessment of the variation in clothing weight between visits was made. At baseline and 30 months, total body scans using a Lunar Expert instrument (GELunar, software version 1.7, Lunar Corp.) were carried out. This is a fan-beam, dual energy x-ray absorptiometry (DXA) scanner. Blood pressure was measured using a Dinamap automatic monitor (Johnson & Johnson, Tampa, FL) at each visit. Measurements were made after the woman had been sitting for 5 min. Three recordings were made 3 min apart, as programmed automatically by the device. Analysis of the data showed that the first recording was significantly higher than the
TABLE 1. Characteristics of study subjects at baseline Characteristic
Placebo
Calcium
n 739 732 Age (yr) 74.3 (4.3) 74.2 (4.2) Years since menopause 25.0 (6.3) 24.6 (6.4) Weight (kg) 67.1 (11.8) 66.9 (11.5) Height (cm) 159.2 (5.9) 158.9 (5.6) 26.4 (4.2) 26.5 (4.3) BMI (kg/m2) Calcium intake (mg/d) 853 (381) 861 (390) Systolic blood pressure (mm Hg) 133.9 (22.9) 134.9 (22.6) Diastolic blood pressure (mm Hg) 69.6 (10.0) 70.1 (10.7) Serum 25-hydroxyvitamin D 20.8 (7.8) 20.6 (7.6) (g/liter)b Current smokers (%) 2.6 3.4 Data are mean (SD). a Between-groups comparisons. b Multiply by 2.5 to obtain nmol/liter.
Pa
0.83 0.27 0.25 0.80 0.65 0.67 0.38 0.40 0.69 0.34
The treatment groups were comparable in all indices at baseline (Table 1). Body weights ranged from 40 –142 kg. Body mass index (BMI) was distributed as follows: less than 20 kg/m2, 3.7%; 20 –25 kg/m2, 36.6%; 25–30 kg/m2, 41.5%; and greater than 30 kg/m2, 18.2%, with a similar pattern in both groups (P ⫽ 0.27). Median alcohol intake was less than one drink per week (P ⫽ 0.63 between-groups). Body weight measurements were available in 1204 subjects at 30 months (82% of the initial cohort), of whom 992 were still taking study medication. The mean compliance over the study period for the 1204 subjects was 78% in the calcium group and 80% in those receiving placebo (P ⫽ 0.26). The reasons for women not having weight measured at 30 months were as follows: 92 remained part of the study, but were only interviewed by telephone at that visit; for three, weight was not recorded at that visit; two were terminally ill; 17 had died; and 153 had withdrawn from the study, mostly for personal reasons or because of other medical problems. Body weight
At baseline, body weight and BMI were unrelated to dietary calcium intake (r ⫽ ⫺0.01 and r ⫽ ⫺0.04, respectively). If this analysis was repeated by comparing BMI across quintiles of dietary calcium intake or by comparing calcium intake across quintiles of BMI, similarly negative results were found (P ⫽ 0.70 and P ⫽ 0.36, respectively). Changes in body weight for the intention to treat population are shown in Fig. 1. At 30 months, body weight (mean ⫾ se) decreased by 368 ⫾ 132 g in the calcium group and by 369 ⫾ 134 g in those taking placebo. Each of these changes was significant within the respective group, but the changes over time were not different between groups (P ⫽ 0.93 for time-treatment interaction, by ANOVA). The change in BMI over the duration of the study was ⫹0.01 ⫾ 0.05 kg/m2 for the calcium group and ⫹0.02 ⫾ 0.05 kg/m2 for the placebo group. These changes were not significantly different (P ⫽ 0.83). When these analyses were repeated using data
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Reid et al. • Calcium Effects on Weight and Blood Pressure
FIG. 1. Changes in body weight in normal postmenopausal women randomized to receive calcium (1 g/d) or placebo for 30 months. Data are the mean ⫾ SE. There was no significant difference between groups (P ⫽ 0.93).
from subjects still taking study medication and with greater than 80% compliance, the changes in body weight were essentially the same (calcium group, ⫺291 ⫾ 160 g, n ⫽ 411; placebo group, ⫺331 ⫾ 160 g, n ⫽ 429; between-groups comparison, P ⫽ 0.86). The effect of calcium supplementation on weight was also analyzed in relation to the baseline dietary calcium intake. When dietary calcium at baseline was incorporated into the ANOVA as a continuous variable, it was unrelated to the change in weight (P ⫽ 0.93). Similarly, if subjects were categorized as having a baseline calcium intake of more or less that 800 mg/d, there was no significant interaction of intake with the treatment effect (P ⫽ 0.27), and the same was true if 600 mg/d was used as the cut-point (P ⫽ 0.38). However, if the analysis was restricted to those with calcium intakes less than 600 mg/d at baseline, a trend toward greater weight loss in those taking calcium (⫺749 ⫾ 262 g, compared with ⫺261 ⫾ 268 g in the placebo group at 30 months) was apparent, but this between-group difference was not significant (P ⫽ 0.19). In the group with calcium intake greater than 600 mg/d, the opposite trend in weight change was apparent (i.e. the calcium group tended to have a more positive weight change). Measurement of body composition by DXA allowed the effects of calcium supplementation on fat mass and lean mass to be assessed separately (Fig. 2). Fat mass did not change significantly in either group (calcium group, ⫹163 ⫾ 146 g; placebo group, ⫹113 ⫾ 145 g), and there was no difference between groups (P ⫽ 0.81). In contrast, there was a significant loss of lean mass in both groups (calcium, ⫺709 ⫾ 62 g; placebo, ⫺667 ⫾ 61 g), but no significant difference between the treatments (P ⫽ 0.63). Blood pressure
Changes in mean systolic and diastolic pressures over the course of the study are shown in Fig. 3. In the entire cohort, both systolic and diastolic pressures tended to rise throughout the study (P ⬍ 0.001). In the calcium group, there were transient reductions in both pressures at 6 months, resulting in a significant between-group difference for systolic blood pressure (P ⫽ 0.048), but not for diastolic blood pressure (P ⫽ 0.37, time-treatment interaction, by ANOVA). At 30 months, the change from baseline in systolic pressure was 0.0 ⫾ 0.9
FIG. 2. Changes in fat mass and lean mass (determined by DXA) in normal postmenopausal women randomized to receive calcium (1 g/d) or placebo for 30 months. Data are the mean ⫾ SE. There was no significant difference between groups (Pfat ⫽ 0.81; Plean⫽ 0.63).
mm Hg in the calcium group and 2.4 ⫾ 0.9 mm Hg in the placebo group (P ⫽ 0.14). For diastolic pressures, the changes were ⫺0.2 ⫾ 0.4 and 0.8 ⫾ 0.4 mm Hg, respectively (P ⫽ 0.13). These analyses were repeated in the 1303 subjects who did not take diuretics or blood pressure-lowering medication during the study. Similar trends were seen; the changes over time remained significant, but those between groups did not reach statistical significance (Pdiastolic ⫽ 0.76; Psystolic ⫽ 0.22). Dietary calcium at baseline was unrelated to the changes in blood pressure (Pdiastolic ⫽ 0.39; Psystolic ⫽ 0.13). However, analyzing separately those with baseline calcium intakes of more or less than 600 mg suggested that the changes in blood pressure were larger and more sustained in subjects with low dietary calcium intakes (Fig. 4). In this group at 30 months, the systolic pressure was 4.9 ⫾ 2.6 mm Hg lower in the calcium group (P ⫽ 0.06), and the diastolic pressure was 2.2 ⫾ 1.1 mm Hg lower (P ⫽ 0.05) than that in the placebo group. Discussion
The present data indicate that calcium supplementation in postmenopausal women with dietary calcium intakes on the order of 800 mg/d causes no significant change in body weight. This study is very much larger than any other randomized, controlled trial that has addressed this question, and it has adequate power to detect a biologically significant effect on weight. We did not formally assess the variation in clothing weight between visits, but this minor contribution to measurement variability is accounted for in the power
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FIG. 3. Changes in systolic (SBP, upper panel) and diastolic (DBP, lower panel) blood pressures in normal postmenopausal women randomized to receive calcium (1 g/d) or placebo for 30 months. Data are the mean ⫾ SE. For systolic blood pressure, there was a significant decrease at 6 months with calcium supplementation and a significant treatment effect overall (P ⫽ 0.048), but there was no treatment effect on diastolic blood pressure (P ⫽ 0.37).
calculation. Despite the positive findings from the report by Davies et al. (13), discussed above, other randomized, controlled trials assessing the effects of calcium intake on weight loss in humans have produced inconsistent results. Zemel et al. (16) studied 41 obese women receiving energy-deficit diets, randomly assigned to a low calcium intake, a calciumsupplemented diet, or a dairy-supplemented diet. Weight losses (mean ⫾ se) over 24 wk in the 32 study completers were 6.60 ⫾ 2.58, 8.58 ⫾ 1.60, and 11.07 ⫾ 1.63 kg, respectively, the low and high calcium groups were not different on post hoc testing. Jensen et al. (17) found that a 1000-mg calcium supplement made no difference to weight changes over a 3-month period in a randomized controlled trial of 62 obese women given low energy diets. In a randomized, controlled trial of calcium supplementation (2, 18), we found that weight gain was 300 g less in the calcium-supplemented group, although this was not statistically significant (our unpublished observations). Shapses et al. (19) also reanalyzed three calcium intervention studies comprising 100 women and found no effect of calcium supplementation on weight loss over 25 wk. Fujita et al. (20) reanalyzed a randomized, controlled trial and reported no effect of calcium supplementation on body weight. However, there was a blunting of the increase in fat mass in those taking an algal calcium preparation, but not in those taking calcium carbonate. All of these studies are small and are underpowered to detect small effects on weight that may still be of biological
FIG. 4. Changes in diastolic blood pressure (DBP) in women randomized to receive calcium (1 g/d) or placebo, according to their baseline dietary calcium intake. Data are the mean ⫾ SE. There was no treatment effect in those subjects with high baseline intakes, but there was a treatment effect in those with intakes below 600 mg/d (P ⫽ 0.05; n ⫽ 301).
significance. However, taken together with the present study, they suggest that calcium supplementation holds little promise as a strategy for weight control. In some ways this negative result is not surprising, because calcium supplements have been used for many decades, and a large number of clinical trials of their effects on the skeleton have already been carried out. If they were to have a substantial effect on body weight, it is likely that it would have been noted some time ago. In addition to the clinical and epidemiological data already reviewed, there are data from animal studies that suggest an effect of calcium on weight. Stern et al. (21, 22) reported lower weight gain in rats on a high-calcium diet, and Metz et al. (23, 24) reported similar findings. Papakonstantinou et al. (25) reported that rats fed a high calcium diet that was also supplemented with milk protein had 29% less carcass fat. This was contradicted by similar studies in lean and obese mice and rats reported by Zhang and Tordoff (26). They found no effect of calcium consumption on energy intake,
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body weight, or carcass fat content, except in a single study in which they postulated that the high calcium content of the diet had made it unpalatable, decreasing food intake. This explanation might apply to other animal studies also. Zemel et al. (5, 27) have reported studies in mice overexpressing the agouti gene. They found that dietary calcium supplementation produced a dose-related diminution in weight gain and fat mass. In these studies, high calcium intakes were found to be associated with reduced adipocyte fatty acid synthase activity and increases in lipolysis (28). Zemel (29) hypothesized that a high calcium intake suppresses PTH and 1,25dihydroxyvitamin D, which leads to reductions in the intracellular concentration of calcium in adipocytes. These changes would be expected to decrease lipogenesis and increase lipolysis. High calcium intakes could also cause weight loss, because they bind to fatty acids and bile acids in the gut, leading to fat malabsorption (30 –33). Although all of these mechanisms may be operative in humans, the results of the present study suggest that they are not sufficiently powerful to predominate over the many other factors that impact on appetite, digestion, and energy expenditure. A second, potentially important health benefit from a high calcium intake is a reduction in blood pressure. A relationship between calcium intake and blood pressure has been reported from observational studies in a variety of populations (34 –39), typically showing a decrease in both systolic and diastolic blood pressures of about 0.4 mm Hg for each increase of 100 mg in daily calcium intake (39). Numerous randomized controlled trials of calcium supplementation have been performed, meta-analyses of which show a significant reduction of systolic pressures by about 1 mm Hg without any significant change in diastolic pressures (40 – 42). The present study is by far the largest to address this important question, and its duration is one of the longest; a recent meta-analysis included 42 studies (42) with a median duration of 8 wk and a median of 53 subjects. Thus, the present study of 3000 person-years substantially exceeds the sum of the total clinical trial experience to date in this area. Few previous studies have included significant numbers of postmenopausal women, the group that most uses calcium. The present results are very similar to those of the metaanalyses, showing a small effect on systolic blood pressure, but no change in diastolic blood pressure. The greater duration of the present study gives important new information relating to the time course of the antihypertensive effect of calcium supplementation, which is greatest at 6 months, but minimal thereafter. This is completely consistent with the published data; all studies that have found a beneficial effect of calcium on blood pressure have been less than 6 months in duration. This suggests that the hypotensive effect of calcium is real, but transient. The post hoc analyses in those with a baseline calcium intake less than 600 mg/d, however, do suggest that in these individuals the effects are larger and more persistent. The Griffith’s meta-analysis (42) suggested that dietary calcium might have a greater impact than supplements on blood pressure, but this trend was not statistically significant. With these caveats, we conclude that the therapeutic value of calcium in managing hypertension is likely to be small and insufficient to justify its routine use in hypertensive subjects receiving average calcium intakes.
Reid et al. • Calcium Effects on Weight and Blood Pressure
The effects of calcium supplementation on blood pressure are probably contributed to by the natriuretic effect of calcium (43) and by its effects on PTH and 1,25-dihydroxyvitamin D (44, 45); both of these hormones have pressor effects in vascular smooth muscle cells (46). Calcium supplementation may also increase concentrations of the vasodilator, calcitonin gene-related hormone (47), and have effects on the renin-angiotensin system (48). On the basis of the present study, it is unlikely that changes in calcium intake will produce clinically relevant effects on body weight in postmenopausal women. Whether the same is true in children, young adults, and men will require additional investigation, but there seems to be little reason to hypothesize that these effects would be substantially different in those other groups. This finding should not be seen as a reason to diminish enthusiasm for recommending calcium supplementation. Its well-established beneficial effects on bone and the possibility that it may also improve circulating lipid profiles are both compelling reasons for endorsing its use in postmenopausal women. Acknowledgments We are grateful to Mission Pharmacal (San Antonio, TX) for the supply of calcium citrate tablets and placebo. Received November 10, 2004. Accepted April 6, 2005. Address all correspondence and requests for reprints to: Dr. Ian Reid, Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. E-mail:
[email protected]. This work was supported by the Health Research Council of New Zealand.
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