Abstract

We updated our previous systematic review of the effect of supplemental calcium on blood pressure. We extended our previous searches on MEDLINE and EMBASE to May 1997 and examined citations from relevant articles. We contacted the authors of eligible trials to ensure the accuracy and completeness of data, and to identify unpublished trials. We included any study in which investigators randomized hypertensive or normotensive people to calcium supplementation or alternative therapy and measured blood pressure for at least 2 weeks. In addition to 32 trials included in the prior metaanalysis, 10 new trials contributed to this metaanalysis. Two pairs of independent reviewers abstracted data and assessed the validity of the study data according to six quality criteria. We calculated the differences in blood pressure change between the calcium supplementation and control groups and pooled the estimates with each trial weighted with the inverse of the variance using a random effects model. The predictors of blood pressure reduction that we examined included method of supplementation, baseline blood pressure, and the methodologic quality of the studies.

The pooled analysis shows a reduction in systolic blood pressure of 1.44 mm Hg (95% confidence interval 2.20 to 0.68; P< .001) and in diastolic blood pressure of 0.84 mm Hg (95% confidence interval 1.44 to 0.24; P< .001). We found statistically significant heterogeneity of results across trials (P .02), which persisted when we looked at the nondietary trials alone, but not when we restricted our analysis to dietary trials. Although there was a trend toward larger effects with dietary interventions, none of the possible mediators of blood pressure reduction explained differences in treatment effect.

We conclude that calcium supplementation leads to a small reduction in systolic and diastolic blood pressure. The effect of supplemental calcium in the diet is at least as great as nondietary supplementation. Am J Hypertens 1999;12:84 –92 © 1999 American Journal of Hypertension, Ltd.

The effect of dietary modifications on blood pressure control has generated great controversy. Animal data and the results of some observational studies support the hypothesis that calcium supplementation can reduce blood pressure1,2; however, the results have been both inconsistent and subject to bias. We,3 as well as others,4,5,6,7 have previously conducted metaanalyses of randomized control trials (RCT) of calcium supplementation. The most recent metaanalyses showed a small but statisti-cally significant reduction in systolic blood pressure and a nonsignificant trend toward reduction in diastolic blood pressure.3,4

We noted a number of limitations of these metaanalyses. There were large and statistically significant differences (heterogeneity) between the results of the studies, and the data available at the time were inadequate to address many of the hypotheses that might explain these variations. The most important issue we were not previously able to address had to do with the method of calcium supplementation. Because of nutrient interactions, it is plausible that dietary calcium, which occurs in combination with other nutrients, may confer different effects on blood pressure than calcium provided as a supplement.

Since the publication of our metaanalysis, additional studies have been conducted that now allow us to achieve a more precise estimate of the treatment effect, and examine the hypothesis regarding dietary versus nondietary calcium supplementation. Also during this time there has been increased recognition of the need for cumulative metaanalysis, in which rigorous systematic overviews are updated as new studies become available, to ensure that clinicians know the best current estimates of treatment effects.8 Based on the additional studies and our interest in addressing previous limitations and increasing the precision of our estimates of calcium's effect on blood pressure, we conducted an updated metaanalysis to include all recently published trials.

Methods

Inclusion criteria

We included any randomized controlled trials studying the effect of calcium supplementation on blood pressure in nonpregnant normotensive or hypertensive patients. Studies were excluded if they met any of the following criteria: blood pressure was measured in <80% of the patients randomized; trials with <2 weeks of intervention; the intervention group ingested a total of <1000 mg of calcium each day; duplicate reports on the same patients; or study results not available in a form to allow statistical pooling.

Search strategy

We used the Cochrane Collaboration strategy9 to search for relevant articles and the MESH terms “calcium” or “calcium compounds” and “blood pressure” or “hypertension” to search the MEDLINE database from January 1993 to May 1997. We combined these results with key word searches of “randomized controlled trials” and “metaanalysis” as well as a text word search of the word “randomized.” We restricted the search to RCT or metaanalyses in human participants. We used the terms “calcium carbonate,” “calcium citrate,” “calcium gluconate,” or “calcium and diet” and “blood pressure” or “hypertension” to search the EMBASE (Excerpta Medica, New York, NY) database, using the same restrictions already stated.

Two members of the investigative team independently reviewed the abstracts of each article identified through the search process. We retrieved all articles judged as potentially relevant by either reviewer. A translator with both a medical and epidemiology background reviewed non-English language articles. We reviewed citations from all retrieved articles to identify other potentially relevant studies. In addition, we contacted key researchers in the field to identify additional unpublished data sources. Finally, we contacted the authors of all the articles excluded from the previous metaanalysis due to insufficient data for abstraction.

Methodologic quality assessment

Two members of the investigative team independently reviewed each article to assess its methodologic quality. We based a methodologic quality score on the major sources of potential bias and error in assessing the role of calcium supplementation on blood pressure.10 Empiric evidence of bias guided our criteria for the validity of the studies,11 which included the following: concealment of random allocation; blinding of participants, caregivers, and blood pressure measurers; number of blood pressure measurements; use of random-zero sphygmomanometer; formal training of blood pressure measurers; and specification of measurement techniques.

Data collection

Two of us (LG, RJC) abstracted all data independently and resolved any disagreements by consensus. We contacted the primary authors to request additional information if the reported study results did not allow the computation of summary statistics or the published information precluded a comprehensive assessment of validity.

Analysis

For combining effects across studies, we relied on the approaches to combining data from continuous outcome variables that Fleiss has described.12 For combining across studies, we used a random effects model that accounts for differences in treatment effect between studies. When authors did not provide the test statistics, but reported P values, we computed the corresponding test statistic from tables for the normal distribution. When the authors did not specify the nature of the test, we assumed a one-sided approach to be conservative. For cross-over trials, when it was necessary, we estimated the standard deviations based on the standard deviations reported for a particular treatment condition.

We explored potential sources of heterogeneity of study results that we identified prior to completing the analysis. These included age and sex of subjects, normotensive versus hypertensive participants, baseline calcium, dietary versus nondietary calcium supplementation, and the methodological quality of the studies. If none of these factors appeared to explain the variability, we concluded the source of heterogeneity was unknown.

Results

We identified 67 randomized trials of calcium supplementation in nonpregnant study populations. Of the 67, 42 proved to be eligible for the overview,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54 of which ten were not included in our prior metaanalysis. We excluded one study that we previously had included55 because the treated group ingested <1000 mg of calcium daily. A study published by Belizan et al,45 excluded from our previous metaanalysis due to insufficient data for abstraction, now has been included as additional data were provided by the authors. A study by Hakala and Karvetti46 previously excluded due to confounding with weight loss intervention, is included in this metaanalysis. In all, we excluded 25 studies for the following reasons: one study was not truly randomized56; eight studies had a treatment duration of ≤2 weeks57,58,59,60,61,62,63,64; 12 papers included participants already included in other reports65,66,67,68,69,70,71,72,73,74,75,76; two trials reported insufficient results for us to use their data in the aggregate analysis77,78; and in two studies the treatment group ingested <1000 mg of calcium.55,79

In ten17,18,19,24,32,34,39,49,50,53 of the 42 (23.8%) eligible trials, the authors presented the data in such a way as to allow a direct computation of the summary statistics. In 23 (74.2%) of the remaining 31 studies, the authors provided us with additional data that allowed for the pooling of results. In addition to the Belizan et al45 and Hakala and Karvetti46 trials, eight studies not included in the prior metaanalysis were included in the current study.47,48,49,50,51,52,53,54

Two studies14,15 tested different dosages of calcium allowing for several comparisons of treatment effects with an identical control group. We selected only one treatment arm with the highest level of elemental calcium to compare with the control arm. Multiple formulations of calcium were used in two studies.13,16 In these cases, we selected the calcium carbonate formulation.

Table 1 displays the characteristics of each trial including number of participants, methodologic quality score, calcium formulation, elemental calcium, and treatment duration. In total, 4560 participants were included in this overview, 2068 randomized to calcium supplementation, 2059 receiving no calcium or placebo, and 433 involved in cross-over trials in which they received both calcium and placebo. The majority of the trials reported an intervention lasting for 4 to 14 weeks. Eight trials29,31,34,35,39,46,50,51 had an intervention period of 6 months or longer. In nine14,20,21,28,35,40,46,53,54 of the 42 trials, calcium was administered as a dietary supplement.

TABLE 1

INTERVENTION CHARACTERISTICS AND STUDY QUALITY SCORES IN RANDOMIZED CONTROLLED TRIALS EXAMINING THE RELATIONSHIP OF CALCIUM SUPPLEMENTATION OR CALCIUM RICH DIET AND SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN NORMOTENSIVE AND HYPERTENSIVE SUBJECTS

First Author, Year of Publication, Study Design Number of Participants (Intervention/Control) Quality Score of Studies* (Score Range 0–6) Calcium Formulation Elemental Calcium (mg/day) Treatment Duration (weeks) 
Nondietary interventions      
Belizan,45 1983 30/27 Calcium gluconate 1000 22 
Sunderrajan,46 1984cx 17/17 Calcium carbonate 1000 
Johnson31 1985 59/56 Calcium carbonate 1500 208 
McCarron,26 1985cx 80/80 Calcium carbonate 1000 
Grobbee,24 1986 46/44 Calcium citrate 1000 12 
Nowson,15 1986 31/33 Calcium carbonate 1600 
Resnick,41 1986cx,ci 8/8 Calcium carbonate 2000 
Strazzullo,25 1986cx,ci 17/17 Calcium gluconate 1000 15 
Van Berestyn,42 1986 29/29 Calcium carbonate 1500 
Cappuccio,23 1987cx 18/18 Calcium gluconate 1600 
Lyle,30 1987 37/38 Calcium carbonate 1500 12 
Meese,16 1987cx 19/17 Calcium carbonate 800 
Siani,38 1987cx 8/8 Calcium gluconate 1000 
Thomsen,29 1987 14/14 Calcium gluconate 2000 52 
Vinson,13 1987 4/5 Calcium carbonate 500 
Zoccali,37 1987cx,ci 11/11 Calcium gluconate 1000 
Siani,22 1988cx 14/14 Calcium gluconate 1000 
Zoccali,43 1988cx 21/21 Calcium gluconate 1000 
Orwoll,39 1990ci 34/28 Calcium carbonate 1000 156 
Tanji,19 1991cx 28/28 Calcium carbonate 1200 12 
Cutler,34 1992 237/234 Calcium carbonate 1000 26 
Lyle,27 1992 21/21 Calcium carbonate 1500 
Galloe,18 1993cx 20/20 Calcium gluconate 2000 12 
Jespersen,33 1993cx 7/7 Calcium carbonate 1000 
Pan,17 1993cx 14/15 Calcium citrate and placebo Vitamin D 800 11 
Weinberger,32 1993cx 46/46 Calcium carbonate 1500 
Petersen,51 1994ci 10/10 Calcium gluconate 2000 26 
Zhou,44 1994 30/27 Calcium carbonate 1000 14 
Gillman,49 1995 51/50 Calcium citrate malate 600 12 
Sacks,50 1995ci 34/31 Calcium carbonate 1000 26 
Lijnen,48 1996ci 16/16 Calcium gluconate 2000 16 
Davis,47 1997 17/17 Calcium gluconate 1500 
Sanchez,52 1997 10/10 Calcium gluconate 1500 
Dietary interventions      
Margetts,21 1986cx,ci 39/39 Other dietary manipulation 1076 
Rouse,40 1986 18/18 Other dietary manipulation 1177 
Bierenbaum,35 1988cx 50/50 Milk/dairy product suppl 1150 26 
Morris,14 1988 142/139 Other dietary manipulation 1500 12 
Hakala,46 1989 31/37 Other dietary manipulation 1163 52 
Van Beresteijn,28 1990 28/25 Milk/dairy product suppl 1180 
Kynast-Gales,20 1992cx 7/7 Milk/dairy product suppl 1515 
McCarron,54 1997 274/274 Milk/dairy product suppl 1886 10 
Appel,63 1997 151/154 Milk/dairy product suppl 1265 
First Author, Year of Publication, Study Design Number of Participants (Intervention/Control) Quality Score of Studies* (Score Range 0–6) Calcium Formulation Elemental Calcium (mg/day) Treatment Duration (weeks) 
Nondietary interventions      
Belizan,45 1983 30/27 Calcium gluconate 1000 22 
Sunderrajan,46 1984cx 17/17 Calcium carbonate 1000 
Johnson31 1985 59/56 Calcium carbonate 1500 208 
McCarron,26 1985cx 80/80 Calcium carbonate 1000 
Grobbee,24 1986 46/44 Calcium citrate 1000 12 
Nowson,15 1986 31/33 Calcium carbonate 1600 
Resnick,41 1986cx,ci 8/8 Calcium carbonate 2000 
Strazzullo,25 1986cx,ci 17/17 Calcium gluconate 1000 15 
Van Berestyn,42 1986 29/29 Calcium carbonate 1500 
Cappuccio,23 1987cx 18/18 Calcium gluconate 1600 
Lyle,30 1987 37/38 Calcium carbonate 1500 12 
Meese,16 1987cx 19/17 Calcium carbonate 800 
Siani,38 1987cx 8/8 Calcium gluconate 1000 
Thomsen,29 1987 14/14 Calcium gluconate 2000 52 
Vinson,13 1987 4/5 Calcium carbonate 500 
Zoccali,37 1987cx,ci 11/11 Calcium gluconate 1000 
Siani,22 1988cx 14/14 Calcium gluconate 1000 
Zoccali,43 1988cx 21/21 Calcium gluconate 1000 
Orwoll,39 1990ci 34/28 Calcium carbonate 1000 156 
Tanji,19 1991cx 28/28 Calcium carbonate 1200 12 
Cutler,34 1992 237/234 Calcium carbonate 1000 26 
Lyle,27 1992 21/21 Calcium carbonate 1500 
Galloe,18 1993cx 20/20 Calcium gluconate 2000 12 
Jespersen,33 1993cx 7/7 Calcium carbonate 1000 
Pan,17 1993cx 14/15 Calcium citrate and placebo Vitamin D 800 11 
Weinberger,32 1993cx 46/46 Calcium carbonate 1500 
Petersen,51 1994ci 10/10 Calcium gluconate 2000 26 
Zhou,44 1994 30/27 Calcium carbonate 1000 14 
Gillman,49 1995 51/50 Calcium citrate malate 600 12 
Sacks,50 1995ci 34/31 Calcium carbonate 1000 26 
Lijnen,48 1996ci 16/16 Calcium gluconate 2000 16 
Davis,47 1997 17/17 Calcium gluconate 1500 
Sanchez,52 1997 10/10 Calcium gluconate 1500 
Dietary interventions      
Margetts,21 1986cx,ci 39/39 Other dietary manipulation 1076 
Rouse,40 1986 18/18 Other dietary manipulation 1177 
Bierenbaum,35 1988cx 50/50 Milk/dairy product suppl 1150 26 
Morris,14 1988 142/139 Other dietary manipulation 1500 12 
Hakala,46 1989 31/37 Other dietary manipulation 1163 52 
Van Beresteijn,28 1990 28/25 Milk/dairy product suppl 1180 
Kynast-Gales,20 1992cx 7/7 Milk/dairy product suppl 1515 
McCarron,54 1997 274/274 Milk/dairy product suppl 1886 10 
Appel,63 1997 151/154 Milk/dairy product suppl 1265 

cx, cross-over study; ci, cointervention.

*

A quality score of 6 corresponds to the highest quality level

Table 2 presents the individual study results from the nondietary and dietary trials. Table 3 presents the summary results. The pooled analysis of all studies showed a reduction in systolic blood pressure of −1.44 mm Hg (95% CI, −2.20 to −0.68; P < .001) and a reduction in diastolic blood pressure of −0.84 mm Hg (95% CI, −1.44 to −0.24; P < .001).

TABLE 2

SUMMARY OF VIRAL-SPECIFIC CHANGE IN SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN RCT STUDYING THE EFFECT OF NONDIETARY CALCIUM SUPPLEMENTATION ON BLOOD PRESSURE

   Systolic Blood Pressure Diastolic Blood Pressure 
First Author, Year of Publication Position of Blood Pressure Measurement Mean BP at Study End Mean Baseline mm Hg Mean Difference mmHg (SD) Mean Baseline mm Hg Mean Difference mm Hg (SD) 
Nondietary interventions       
Belizan,45 1983       
Women Lateral 102 −2.40 (1.03) 68 −4.50 (1.46) 
Men Lateral 113 −0.80 (1.05) 71 −6.00 (1.94) 
Sunderrajan,36 1984       
Normotensive Sitting NA 1.89 (2.78) NA 1.89 (2.50) 
Hypertensive Sitting NA −1.63 (5.93) NA −4.13 (2.50) 
Johnson,31 1985       
Normotensive Sitting 120 0.00 (3.01) 74 0.00 (1.67) 
Hypertensive Sitting 141 −13.0 (6.52) 86 0.00 (2.79) 
McCarron,26 1985       
Normotensive Standing 113 1.30 (2.00) 75 1.00 (2.62) 
Hypertensive Standing 144 −5.60 (2.10) 92 −2.30 (1.40) 
Grobbee,24 1986 Sitting 143 −0.40 (2.27) 83 −2.40 (1.90) 
Nowson,15 1986       
Normotensive Sitting  0.00 (2.97)  0.30 (2.33) 
Hypertensive Sitting 157 1.60 (3.83) 92 1.30 (2.90) 
Resnick,41 1986       
Salt-sensitive Sitting NA NA NA −8.0 (6.0) 
Salt-insensitive Sitting NA NA NA 7.0 (6.0) 
Strazzullo,25 1986 Standing 145 −8.60 (4.98) 98 −1.70 (2.56) 
Van Beresteyn,42 1986 Supine 115 −1.36 (1.88) 65 0.79 (1.66) 
Cappuccio,23 1987 Standing 156 2.00 (4.17) 112 0.40 (2.64) 
Lyle,30 1987       
White Sitting 115 −2.44 (2.00) 75 −1.89 (2.31) 
Black Sitting 114 −3.63 (3.85) 71 4.02 (5.67) 
Meese,16 1987 Sitting 143 −5.00 (4.21) 95 −2.00 (2.83) 
Siani,38 1987 Supine 154 5.10 (8.01) 96 1.30 (4.10) 
Thomsen,29 1987 Supine 124 −0.50 (6.10) 76 −1.30 (3.78) 
Vinson,17 1987 Supine 114 7.90 (4.93) 74 2.40 (2.05) 
Zoccali,37 1987 Sitting 141 6.45 (3.35) 88 4.64 (2.21) 
Siani,22 1988 Supine 139 2.20 (4.94) 91 0.70 (3.68) 
Zoccali,43 1988 Sitting 142 −2.80 (2.97) 88 −2.80 (2.47) 
Orwoll,39 1990 Sitting 131 2.60 (3.54) 84 3.08 (2.63) 
Tanji,19 1991 Sitting 146 3.00 (4.20) 95 2.00 (2.40) 
Cutler,34 1992 Sitting 126 −0.46 (0.67) 84 0.20 (0.46) 
Lyle,27 1992 Sitting 133 −5.90 (1.99) 87 −7.20 (1.71) 
Galloe,18 1993 Sitting 168 2.20 (4.49) 97 3.30 (2.75) 
Jespersen,33 1993 Supine 148 −0.57 (7.20) 93 −0.86 (3.88) 
Pan,17 1993 Sitting 136 −7.09 (7.89) 72 −0.87 (3.29) 
Weinberger,32 1993       
Normotensive Sitting 116 1.00 (3.00) 72 −1.00 (2.64) 
Hypertensive Sitting 131 −2.00 (5.68) 87 −1.00 (2.92) 
Petersen,51 1994 Sitting 145 4.50 (13.2) 81 −8.20 (5.10) 
Zhou,44 1994 Sitting 158 −14.6 (4.48) 103 −7.11 (2.43) 
Gillman,49 1995 Sitting 102 −2.20 (11.0) 58 −0.80 (7.16) 
Sacks,50 1995 Sitting NA 3.70 (2.45) NA 3.60 (2.32) 
Lijnen,48 1996 Supine 114 −5.70 (2.18) 73 −3.50 (1.79) 
Davis,47 1997 Mean 24 h ambulatory 125 −1.72 (1.20) 91 −0.49 (0.35) 
Sanchez,52 1997 Sitting 166 1.60 (1.60) 99 0.40 (1.21) 
Dietary interventions       
Margetts,21 1986 Sitting NA −3.50 (1.75) NA −1.20 (1.00) 
Rouse,40 1986 Sitting NA 1.90 (2.30) NA 2.30 (1.40) 
Bierenbaum,35 1988 Sitting 119 −2.00 (2.19) 79 −1.00 (1.33) 
Morris,14 1988       
Normotensive Standing 113 −1.00 (1.04) 77 −0.90 (0.80) 
Hypertensive Standing 145 −3.60 (1.50) 94 −1.20 (0.86) 
Hakala,46 1989 Sitting 129 3.80 (11.9) 84 3.20 (4.53) 
Van Beresteijn,28 1990 Supine 114 −2.82 (1.83) 63 0.43 (1.89) 
Kynast-Gales,20 1992 Supine 136 −8.29 (8.12) 83 −0.14 (6.15) 
McCarron,54 1997 Sitting 134 −1.80 (0.78) 85 −1.20 (0.46) 
Appel53 1997 Sitting 131 −2.70 (0.83) 84 −1.90 (0.60) 
   Systolic Blood Pressure Diastolic Blood Pressure 
First Author, Year of Publication Position of Blood Pressure Measurement Mean BP at Study End Mean Baseline mm Hg Mean Difference mmHg (SD) Mean Baseline mm Hg Mean Difference mm Hg (SD) 
Nondietary interventions       
Belizan,45 1983       
Women Lateral 102 −2.40 (1.03) 68 −4.50 (1.46) 
Men Lateral 113 −0.80 (1.05) 71 −6.00 (1.94) 
Sunderrajan,36 1984       
Normotensive Sitting NA 1.89 (2.78) NA 1.89 (2.50) 
Hypertensive Sitting NA −1.63 (5.93) NA −4.13 (2.50) 
Johnson,31 1985       
Normotensive Sitting 120 0.00 (3.01) 74 0.00 (1.67) 
Hypertensive Sitting 141 −13.0 (6.52) 86 0.00 (2.79) 
McCarron,26 1985       
Normotensive Standing 113 1.30 (2.00) 75 1.00 (2.62) 
Hypertensive Standing 144 −5.60 (2.10) 92 −2.30 (1.40) 
Grobbee,24 1986 Sitting 143 −0.40 (2.27) 83 −2.40 (1.90) 
Nowson,15 1986       
Normotensive Sitting  0.00 (2.97)  0.30 (2.33) 
Hypertensive Sitting 157 1.60 (3.83) 92 1.30 (2.90) 
Resnick,41 1986       
Salt-sensitive Sitting NA NA NA −8.0 (6.0) 
Salt-insensitive Sitting NA NA NA 7.0 (6.0) 
Strazzullo,25 1986 Standing 145 −8.60 (4.98) 98 −1.70 (2.56) 
Van Beresteyn,42 1986 Supine 115 −1.36 (1.88) 65 0.79 (1.66) 
Cappuccio,23 1987 Standing 156 2.00 (4.17) 112 0.40 (2.64) 
Lyle,30 1987       
White Sitting 115 −2.44 (2.00) 75 −1.89 (2.31) 
Black Sitting 114 −3.63 (3.85) 71 4.02 (5.67) 
Meese,16 1987 Sitting 143 −5.00 (4.21) 95 −2.00 (2.83) 
Siani,38 1987 Supine 154 5.10 (8.01) 96 1.30 (4.10) 
Thomsen,29 1987 Supine 124 −0.50 (6.10) 76 −1.30 (3.78) 
Vinson,17 1987 Supine 114 7.90 (4.93) 74 2.40 (2.05) 
Zoccali,37 1987 Sitting 141 6.45 (3.35) 88 4.64 (2.21) 
Siani,22 1988 Supine 139 2.20 (4.94) 91 0.70 (3.68) 
Zoccali,43 1988 Sitting 142 −2.80 (2.97) 88 −2.80 (2.47) 
Orwoll,39 1990 Sitting 131 2.60 (3.54) 84 3.08 (2.63) 
Tanji,19 1991 Sitting 146 3.00 (4.20) 95 2.00 (2.40) 
Cutler,34 1992 Sitting 126 −0.46 (0.67) 84 0.20 (0.46) 
Lyle,27 1992 Sitting 133 −5.90 (1.99) 87 −7.20 (1.71) 
Galloe,18 1993 Sitting 168 2.20 (4.49) 97 3.30 (2.75) 
Jespersen,33 1993 Supine 148 −0.57 (7.20) 93 −0.86 (3.88) 
Pan,17 1993 Sitting 136 −7.09 (7.89) 72 −0.87 (3.29) 
Weinberger,32 1993       
Normotensive Sitting 116 1.00 (3.00) 72 −1.00 (2.64) 
Hypertensive Sitting 131 −2.00 (5.68) 87 −1.00 (2.92) 
Petersen,51 1994 Sitting 145 4.50 (13.2) 81 −8.20 (5.10) 
Zhou,44 1994 Sitting 158 −14.6 (4.48) 103 −7.11 (2.43) 
Gillman,49 1995 Sitting 102 −2.20 (11.0) 58 −0.80 (7.16) 
Sacks,50 1995 Sitting NA 3.70 (2.45) NA 3.60 (2.32) 
Lijnen,48 1996 Supine 114 −5.70 (2.18) 73 −3.50 (1.79) 
Davis,47 1997 Mean 24 h ambulatory 125 −1.72 (1.20) 91 −0.49 (0.35) 
Sanchez,52 1997 Sitting 166 1.60 (1.60) 99 0.40 (1.21) 
Dietary interventions       
Margetts,21 1986 Sitting NA −3.50 (1.75) NA −1.20 (1.00) 
Rouse,40 1986 Sitting NA 1.90 (2.30) NA 2.30 (1.40) 
Bierenbaum,35 1988 Sitting 119 −2.00 (2.19) 79 −1.00 (1.33) 
Morris,14 1988       
Normotensive Standing 113 −1.00 (1.04) 77 −0.90 (0.80) 
Hypertensive Standing 145 −3.60 (1.50) 94 −1.20 (0.86) 
Hakala,46 1989 Sitting 129 3.80 (11.9) 84 3.20 (4.53) 
Van Beresteijn,28 1990 Supine 114 −2.82 (1.83) 63 0.43 (1.89) 
Kynast-Gales,20 1992 Supine 136 −8.29 (8.12) 83 −0.14 (6.15) 
McCarron,54 1997 Sitting 134 −1.80 (0.78) 85 −1.20 (0.46) 
Appel53 1997 Sitting 131 −2.70 (0.83) 84 −1.90 (0.60) 
TABLE 3

SUMMARY ESTIMATES USING RANDOM EFFECTS MODEL OF SYSTOLIC AND DIASTOLIC BLOOD PRESSURE IN 42 RANDOMIZED CONTROLLED TRIALS AND SPECIFIED SUBGROUPS COMPARING CALCIUM SUPPLEMENTATION WITH PLACEBO

Blood Pressure Type Mean Change of Blood Pressure in mm Hg (95% Confidence Interval) Test of Homogeneity Test Comparing Subgroup Estimates 
All studies (n = 42)    
Systolic blood pressure −1.44 (−2.20, −0.68) χ2 = 69.52, P = .02 NA 
Diastolic blood pressure −0.84 (−1.44, −0.24) χ2 = 86.64, P = .001 NA 
Dietary (n = 9) and Nondietary (n = 33) interventions   
Systolic blood pressure    
Dietary −2.10 (−2.93, −1.26) χ2 = 7.43, P = .59 P = .14 
Nondietary −1.09 (−2.12, −0.06) χ2 = 58.54, P = .02  
Diastolic blood pressure    
Dietary −1.09 (−1.67, −0.52) χ2 = 9.39, P = .40 P = .67 
Nondietary −0.87 (−1.71, −0.03) χ2 = 74.84, P < .001  
Blood Pressure Type Mean Change of Blood Pressure in mm Hg (95% Confidence Interval) Test of Homogeneity Test Comparing Subgroup Estimates 
All studies (n = 42)    
Systolic blood pressure −1.44 (−2.20, −0.68) χ2 = 69.52, P = .02 NA 
Diastolic blood pressure −0.84 (−1.44, −0.24) χ2 = 86.64, P = .001 NA 
Dietary (n = 9) and Nondietary (n = 33) interventions   
Systolic blood pressure    
Dietary −2.10 (−2.93, −1.26) χ2 = 7.43, P = .59 P = .14 
Nondietary −1.09 (−2.12, −0.06) χ2 = 58.54, P = .02  
Diastolic blood pressure    
Dietary −1.09 (−1.67, −0.52) χ2 = 9.39, P = .40 P = .67 
Nondietary −0.87 (−1.71, −0.03) χ2 = 74.84, P < .001  

For both estimates of treatment effect we found evidence of heterogeneity (systolic: χ2 = 69.5, df = 49 P = .02, diastolic: χ2 = 86.6, df = 51, P = .001). There were varying amounts of data to test the six a priori hypotheses. For example, we could compute a methodologic quality score for all studies, but we could abstract information on mean baseline calcium intake in only 15 of 42. Of all the a priori hypotheses regarding sources of heterogeneity, only the comparisons of trials that reported subgroups with hypertensive versus normotensive patients yielded statistically significant differences in estimates of treatment effect. There was no new data in this regard from our previous metaanalysis, and, as we reported in that article, when we compared mean baseline systolic and diastolic blood pressure in hypertensive study populations as defined by the authors of these six trials, we found a large overlap of these mean values with the ones from the other trials. Furthermore, when we used the information on average baseline systolic and diastolic blood pressure, we found no relationship with treatment effect, using both crude weighted and unweighted regressions. Thus, we conclude that a real difference in the effect of calcium in people with different baseline blood pressures is unlikely.

In comparing the summary treatment effect estimates for dietary (n = 9) and nondietary (n = 33) trials, there was little evidence for a difference in systolic (P = .14) or diastolic (P = .67) blood pressure (Table 3). The estimate of systolic blood pressure reduction in the dietary trials was −2.10 mm Hg (95% CI: −2.93 to −1.26) compared to −1.09 mm Hg (95% CI: −2.12 to −0.06) in the nondietary trials. The reduction of diastolic blood pressure was −1.09 mm Hg (95% CI: −1.67 to −0.52) for the dietary trials and −0.87 mm Hg (95% CI: −1.71 to −0.03) for the nondietary trials. There was no compelling evidence for heterogeneity in the dietary trials (systolic: P = .59, diastolic: P = .40), but there remained statistically significant heterogeneity in the nondietary trials (χ2 = 58.5, df = 39, P = .02, diastolic: χ2 = 74.8, df = 41, P < .001).

Of the nine dietary trials, three21,40,46 compared a lactovegetarian or lacto-ovo-vegetarian with an omnivorous diet; four14,20,35,53 compared diets with high versus low dairy products; one trial28 compared a diet with dairy products to one with mineral-poor dairy products; and one trial54 compared methods of dieting, both attempting to increase low fat dairy products. Excluding the vegetarian trials from the analysis and just focusing on dairy supplementation, the estimate of blood pressure reduction was −2.16 mm Hg (95% CI: −3.04 to −1.29) for systolic and −1.28 mm Hg (95% CI: −1.86 to −0.69) for diastolic blood pressure. These estimates were not different from those from the nondietary supplementation trials (Psystolic = .12, Pdiastolic = .44).

Discussion

This updated metaanalysis of the effect of calcium on blood pressure in nonpregnant adults used explicit inclusion and exclusion criteria, a comprehensive literature search with inclusion of unpublished studies, assessment of the validity of eligible studies, and a rigorous data analysis. We contacted the investigators of all the original studies, and 74% responded.

Several new insights were revealed in this metaanalysis as compared with our original publication,3 and the previous metaanalyses.4,5,6,7 Originally, we found a small statistically significant effect of calcium on lowering systolic blood pressure independent of baseline blood pressure, and a smaller trend toward reduction in diastolic blood pressure that did not reach statistical significance. In the present metaanalysis, the point estimate of the effect on systolic, and particularly on diastolic, blood pressure was slightly larger. Furthermore, the increased number of trials increased the precision of our estimates, and we were able to exclude chance as an explanation for the decrease in diastolic blood pressure with calcium supplementation.

Another important finding has to do with our a priori hypothesis that dietary and nondietary interventions may differ in their effect on blood pressure reduction. We were unable to address this issue in our first metaanalysis because of an inadequate number of trials of dietary interventions. The current analysis showed that, although the effect on systolic and diastolic blood pressure was nearly twice as large with dietary trials, the difference was not statistically significant (P = .14 systolic, P = .67 diastolic). Trials with low-fat dairy supplementation provided a larger estimate of reduction than other dietary trials, but the difference between these trials and the nondietary supplementation trials still failed to reach conventional levels of statistical significance.

In addition to the trend toward a greater blood pressure reduction in the dietary trials, we also found greater consistency in their results in comparison to the nondietary trials. This is reflected in the statistically significant heterogeneity for the whole group of studies, and for the restricted sample of the nondietary trials, heterogeneity that we don’t find when we look only at the dietary trials. Thus, inferences about the effect of dietary supplementation may be somewhat stronger than inferences about nondietary calcium sources.

The modest response in systolic and diastolic blood pressure reduction we found does not justify the use of calcium supplementation as a sole treatment for patients with mild hypertension. Calcium supplementation at the population level is a complex issue, requiring consideration of multiple possible benefits (including increases in bone density) and multiple harms (including kidney stone formation). Our results contribute information to this debate in that a reduction of the mean systolic blood pressure by 1.4 mm Hg and diastolic blood pressure by 0.8 mm Hg in the population level could appreciably reduce cardiovascular morbidity and mortality. These findings provide further support for achieving minimal levels of calcium intake, particularly in vulnerable populations.

We thank Dr. Dereck Hunt and Dr. Rose Hatala for their help in conducting the overview and Dr. David McCarron for his helpful comments on our manuscript. We would also like to acknowledge the contributions of Deborah Maddock for administrative assistance and Lisa Buckingham for database management. As well, we are indebted to all of the authors who provided us with additional information regarding their studies.

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Author notes

*
This study was funded by a grant from the Dairy Council. Dr. R.