Calcium supplements associated with increased risk of cardiovascular death in men but not women
- Correspondence to: Dr Mark J Bolland, Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1042, New Zealand;
Implications for practice and research
Calcium supplements increase cardiovascular risk.
The role of calcium supplements in the management of osteoporosis should be reconsidered.
In 2008, a randomised controlled trial (RCT) suggested that calcium supplements might increase the risk of cardiovascular events.1 Subsequent meta-analyses of RCTs examining calcium monotherapy and calcium and vitamin D confirmed these findings. In a pooled analysis of 13 RCTs of calcium with or without vitamin D (n=29 277) including 1391 patients with myocardial infarction (MI) or stroke,2 calcium increased the risk of MI by 25% and stroke by 15–20%. Xiao and colleagues explored this issue in the observational National Institutes of Health-American Association of Retired Persons Diet and Health Study.
A total of 388 229 men and women aged 50–71 years were followed for an average of 12 years. Dietary intake of calcium was assessed at baseline using a self-administered food frequency questionnaire based on intake in the previous year. Frequency and dosage of calcium supplements was recorded. Relationships between dietary and supplemental calcium intake and the risk of mortality from total cardiovascular disease (CVD), heart disease and cerebrovascular disease (ascertained using the National Death Index) during follow-up were assessed using multivariate models.
Calcium supplements were used by 51% of men and 70% of women. In men, there were dose-related increases in the risk of death from total CVD, heart disease and cerebrovascular disease with calcium supplements. In men taking ≥1000 mg/day, the increase in risk was approximately 20% for each endpoint. In women, there was no relationship between calcium supplement use and cardiovascular mortality. There was also no consistent relationship between baseline dietary calcium intake and cardiovascular mortality in either men or women.
RCTs and observational studies often generate discrepant results; notable examples include hormone replacement therapy and cardiovascular events, and antioxidants and cardiovascular events or cancer. Limitations of observational studies include: causality cannot be inferred because of their design; there are often major differences between individuals who use treatments and those who do not; statistical models may not accurately account for baseline differences in these confounding variables, nor for healthy user bias (ie, people who choose to take supplements are healthier than those who do not). Randomisation of study participants overcomes these limitations. Thus, observational studies generate hypotheses and RCTs test them. When there is a large existing dataset of RCTs, observational studies are probably of limited value.
In this study, the results for calcium supplements align with the results from the previous RCTs. There was an increase in cardiovascular mortality in men taking calcium supplements that was strikingly similar to the increased cardiovascular risk observed in the RCTs. No relationship between supplement use and cardiovascular mortality was seen in women. This may be because the study was underpowered, with about 50% fewer deaths in women. Only a small proportion of people who have an MI or stroke die in the short to medium term. Thus, a 20% increase in risk of these events will lead to only a small increase in cardiovascular mortality. Even with its large size, the study by Xiao and colleagues did not have sufficient power to detect such differences in women.
Dietary calcium intake was not associated with cardiovascular mortality; this finding is consistent with previous observational studies. One reason for this could be an increased risk from calcium supplements is related to increases in serum calcium that persist for several hours after ingestion of a calcium supplement, but do not occur after ingestion of a calcium-rich meal. Another possibility is that few individuals obtain an intake of calcium from their diet similar to the total calcium intake of individuals taking calcium supplements.
Dietary calcium intake has not been associated with risk of fracture in observational studies. RCTs demonstrate that calcium supplements have marginal benefits on preventing fractures (10–12% reduction in risk of fracture), that are outweighed by the increased cardiovascular risk. Based on the meta-analyses of calcium with or without vitamin D, treating 1000 patients with calcium for 5 years would cause an additional 6 MIs or strokes, but prevent only 3 fractures.2 Therefore, the widespread use of calcium supplements for bone health should be reconsidered.3