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November 2010

Effect of calcium supplements on risk of myocardial infarctionand cardiovascular events: meta-analysis.

OBJECTIVE: To investigate whether calcium supplements increase the risk of cardiovascular events. DESIGN: Patient level and trial level meta-analyses. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. STUDY SELECTION: Eligible studies were randomised, placebo controlled trials of calcium supplements (>or=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates. RESULTS: 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). CONCLUSIONS: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

BMJ. 2010 Jul 29;341:c3691

Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women.

BACKGROUND AND PURPOSE: High intakes of calcium, potassium, and magnesium have been hypothesized to reduce risks of cardiovascular disease, but only a few prospective studies have examined intakes of these cations in relation to risk of stroke. METHODS: In 1980, 85 764 women in the Nurses’ Health Study cohort, aged 34 to 59 years and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires from which we calculated intakes of calcium, potassium, and magnesium. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes (129 subarachnoid hemorrhages, 74 intraparenchymal hemorrhages, 386 ischemic strokes, and 101 strokes of undetermined type) had been documented. RESULTS: Intakes of calcium, potassium, and magnesium were each inversely associated with age- and smoking-adjusted relative risks of ischemic stroke, excluding embolic infarction of nonatherogenic origin (n=347). Adjustment for other cardiovascular risk factors, including history of hypertension, attenuated these associations, particularly for magnesium intake. In a multivariate analysis, women in the highest quintile of calcium intake had an adjusted relative risk of ischemic stroke of 0.69 (95% CI, 0.50 to 0.95; P for trend=0.03) compared with those in the lowest quintile; for potassium intake the corresponding relative risk was 0.72 (95% CI, 0.51 to 1.01; P for trend=0.10). Further simultaneous adjustment for calcium and potassium intake suggested an independent association for calcium intake. The association of risk with calcium intake did not appear to be log linear; the increase in risk was limited to the lowest quintile of intake, and intakes > approximately 600 mg/d did not appear to reduce risk of stroke further. The inverse association with calcium intake was stronger for dairy than for nondairy calcium intake. Intakes of calcium, potassium, and magnesium were not related to risk of other stroke subtypes. CONCLUSIONS: Low calcium intake, and perhaps low potassium intake, may contribute to increased risk of ischemic stroke in middle-aged American women. It remains possible that women in the lowest quintile of calcium intake had unknown characteristics that made them susceptible to ischemic stroke.

Stroke. 1999 Sep;30(9):1772-9

Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women.

To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986. Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.

Am J Epidemiol. 1999 Jan 15;149(2):151-61

The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials.

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 < or = .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 Jan;12(1 Pt 1):84-92

Effects of calcium supplementation on serum lipid concentrations in normal older women: a randomized controlled trial.

PURPOSE: To determine the effect of supplementation with calcium citrate on circulating lipid concentrations in normal older women. SUBJECTS AND METHODS: As part of a study of the effects of calcium supplementation on fractures, we randomly assigned 223 postmenopausal women (mean [+/- SD] age, 72 +/- 4 years), who were not receiving therapy for hyperlipidemia or osteoporosis, to receive calcium (1 g/d, n = 111) or placebo (n = 112) for 1 year. Fasting serum lipid concentrations, including high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, were obtained at baseline, and at 2, 6, and 12 months. RESULTS: After 12 months, HDL cholesterol levels and the HDL cholesterol to LDL cholesterol ratio had increased more in the calcium group than in the placebo group (mean between-group differences in change from baseline: for HDL cholesterol, 0.09 mmol/L (95% confidence interval [CI]: 0.02 to 0.17; P = 0.01); for HDL/LDL cholesterol ratio, 0.05 (95% CI: 0.02 to 0.08; P = 0.001). This was largely due to a 7% increase in HDL cholesterol levels in the calcium group, with a nonsignificant 6% decline in LDL cholesterol levels. There was no significant treatment effect on triglyceride level (P = 0.48). CONCLUSION: Calcium citrate supplementation causes beneficial changes in circulating lipids in postmenopausal women. This suggests that a reappraisal of the indications for calcium supplementation is necessary, and that its cost effectiveness may have been underestimated.

Am J Med. 2002 Apr 1;112(5):343-7

Effects of calcium supplementation on body weight and blood pressure in normal older women: a randomized controlled trial.

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). 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. 2005 Jul;90(7):3824-9