Dietary Calcium and Blood Pressure

Hypertension, one of the major risk factors for the development of cardiovascular disease, is a highly prevalent condition that affects more than 50 million Americans. The National Heart, Lung, and Blood Institute Task Force on Research in Hypertension [1] identified the primary prevention of hypertension as a high-priority area of research; the Task Force strongly emphasized the need for nutritional research. Among lifestyle and environmental factors that may have important roles in the cause of hypertension, calcium intake has received considerable attention. Early reports relating harder drinking water to lower mortality from cardiovascular causes generated interest in the association between calcium (as well as magnesium) and blood pressure [2-4]. Potential antihypertensive effects of dietary calcium are of great interest because dietary calcium intake can be increased at low cost and with few or no side effects. We have previously summarized [5-7] several observational studies and clinical trials of calcium intake and blood pressure; in two of these reviews [5, 6], we pooled the data from clinical trials. Since the publication of our previous overviews, many additional studies have been published. Updated reviews of both observational and experimental studies are needed to assess current knowledge and to help direct further research. In an updated review of observational studies [8], we pooled the observational data, which we had not done in the earlier review. These mostly cross-sectional studies have mixed results but in aggregate provide evidence of small, statistically significant inverse associations between calcium intake and blood pressure. The results of properly conducted clinical trials provide the strongest evidence for the existence of a causal relation between an independent variable and an outcome measure. Several clinical trials have tested the effect of dietary calcium supplementation on blood pressure [9-34]. Here, we provide an updated review of the experimental human studies of calcium supplementation and blood pressure, including a pooling of clinical trial data. We briefly discuss mechanisms by which dietary calcium might affect blood pressure. Methods We attempted to identify, review, and include all randomized clinical trials assessing the effect of dietary calcium supplementation on blood pressure. We identified trials through a search of previous review articles, a MEDLINE search (January 1982 to December 1993), a manual review of articles in major journals, and a review of abstracts from scientific meetings. We sought to identify all relevant studies that had been published through December 1993. Independent reviewers abstracted data in duplicate from the identified studies. These data included, to the extent provided within each paper, mean systolic and diastolic blood pressure (at baseline and follow-up or the change between baseline and follow-up blood pressures), standard deviation or standard error for blood pressures, t-statistics or P values, calcium dose and formulation, duration of intervention, type of design (crossover or parallel), mean age of participants, percentage of participants who were male, percentage of participants who were white, initial blood pressure status, and whether the study was double-blinded. Measures of compliance were not reported for most studies and thus were not abstracted. For parallel trials, the blood pressures abstracted were the changes from baseline (final value baseline value) for the intervention group minus the change from baseline for the control group. For crossover trials, the abstracted values were the final blood pressures for the intervention group minus those for the control group. When we abstracted studies that provided stratified data and analyses (by blood pressure status, race, sex, or calcium dose or formulation), we maintained the stratification so that we could pool the data by strata. A third author reviewed the duplicate abstraction forms for inconsistencies; discrepancies were reconciled by consensus. We pooled data using weighted averages, with weights equal to the inverse of the variance of the observed effect (Appendix) [35]. Trials were excluded from pooling if the calcium supplementation was part of a multifactorial trial or if the data presentation posed analytic problems (see below). We also did separate analyses for trials in normotensive and hypertensive persons and for parallel and crossover design trials. Not all studies reported the variance measures needed to calculate weights for the pooled analysis. For these studies, we used a weighted average of the reported variances. We used two methods to determine whether other factors, such as age, sex, calcium dose, and trial duration, modified the effects of calcium on blood pressure. First, in the nonparametric approach, we calculated Spearman correlation coefficients, which weight each trial equally. Second, because different trials were based on different numbers of participants, we did separate parametric weighted (by sample size) linear regression analyses of the estimate of the effect on each of the four factors. Results We identified 26 randomized clinical trials that assessed the effect of calcium supplementation on blood pressure. Two of these trials had two active treatment arms: One used two different calcium doses [25] and 1 used two different calcium formulations [17]. One trial stratified data by race [15] and another, by sex [9]. This stratification induces correlation between two pairs of effect estimates, whereas our statistical methods for pooling data require independence; however, the error is negligible (< 0.05 mm Hg). Because 3 trials reported data separately for hypertensive and normotensive persons, we abstracted 33 separate strata from the 26 trials, as shown in Table 1 and Table 2. Table 1. Randomized Trials of Calcium Supplementation in Normotensive Persons* Table 2. Randomized Trials of Calcium Supplementation in Hypertensive Persons* Trials Involving Normotensive Persons Thirteen trials studied normotensive persons; 3 of these also included hypertensive persons. Mean participant age ranged from 21 to 48 years. Six trials included both sexes, 3 studied men only, and 4 studied women only; 4 included black persons. Nine trials were double-blinded, 3 trials were open, and 1 trial (by Vinson and colleagues [17]) was doubleblinded in one of the two methods used for calcium supplementation (gluconate and yeast). Eight trials had parallel designs, with sample sizes ranging from 14 to 471 persons; 5 trials had crossover designs, with sample sizes of 7, 8, 29, 32, and 50 persons, respectively. Duration of intervention and follow-up ranged from 1 week to 4 years (median, 8 weeks). Calcium doses in these studies ranged from 0.5 to 2.0 g. Except for two trials that used diets rich in calcium [18, 19] and both arms of Vinson and colleagues' trial [17], most trials used tablets containing calcium carbonate. Systolic and diastolic blood pressure significantly decreased in 2 of these 13 trials. Seven trials had negative results consisting of either a nonsignificant beneficial effect or direct association between calcium intake and blood pressure; 4 trials had mixed results. Of the studies with mixed results, 3 showed a significant effect for either systolic or diastolic blood pressure, but not for both; in Vinson and colleagues' study [17], only the calcium yeast supplement affected systolic blood pressure. Trials Involving Hypertensive Persons Sixteen trials randomly assigned hypertensive persons, including the three trials that included both normotensive and hypertensive persons. The age range in most trials was broad, with most participants in middle age. All but one trial included both sexes to varying degrees, and Johnson and colleagues [11] studied only women. Five studies included black persons. All trials were double-blinded. Eleven studies used a crossover study design, with sample size ranging from 8 to 48 persons; five studies used a parallel design, with sample size ranging from 27 to 90 persons. Interventions lasted from 5 days to 4 years (median, 8 weeks). The calcium doses ranged from 0.4 to 2.16 g (median, 1.0 g). Thirteen of the studies reported no significant reductions in blood pressure; among these, Johnson and coworkers [11] reported a decrease in systolic blood pressure of 20 mm Hg after 4 years of follow-up (P = 0.06), and Grobbee and Hofman [24] reported a decrease of 2.4 mm Hg in diastolic blood pressure (P = 0.11). Two trials had mixed results: McCarron and Morris [12] reported a decrease of 3.8 mm Hg in systolic blood pressure after 8 weeks (P = 0.02), and Lasaridis and associates [29] found a decrease of 5.4 mm Hg in systolic blood pressure (P = 0.05). In Saito and coworkers' study [32], systolic blood pressure decreased by 10.4 mm Hg and diastolic blood pressure decreased by 2.3 mm Hg, a significant effect (P = 0.01) for mean blood pressure. Pooling of Trials To quantify the effect of calcium supplementation on blood pressure, we pooled data from all trials, including those that studied both normotensive and hypertensive persons. We did not include four of the trials in the final pooling of data. Lyle and colleagues [15] did not provide unadjusted blood pressure data but rather adjusted the data for compliance with the intervention and for baseline variables such as age, skinfold thicknesses, and dietary calcium intake. We excluded the study by Van Beresteijn and associates [19] because it used a multifactorial intervention that included both magnesium and calcium. Bloomfield and coworkers' study [22] was excluded because it did not provide an effect estimate but rather reported that calcium had no effect. We excluded Tanji and colleagues' study [33] because the data could not be pooled: The trial design was crossover, but results were presented as if the study were parallel; in addition, the sample size at the end of