Further Doubt on Heart-Healthiness of Calcium Supplements

The cardiovascular safety of calcium supplementation was not supported for individuals with established cardiovascular disease (CVD) in a population-based cohort study from Hong Kong.

Among those prescribed calcium supplementation, there was an increased risk of recurrent adverse CVD events relative to controls (184.9 vs 167.5 events per 1,000 person-years, HR 1.10, 95% CI 1.07-1.14) in a propensity score-matched analysis.

Notably, the excess risk was observed for calcium supplementation by itself (HR 1.21, 95% CI 1.17-1.25) and not with combination calcium-vitamin D (HR 0.97, 95% CI 0.93-1.01), according to Ching-Lung Cheung, PhD, of University of Hong Kong, and colleagues reporting in the Journal of the American Heart Association.

“Given the increased risk of CVD recurrence, caution should be exercised in prescribing or using calcium supplements in patients with CVD. Our observational results, consistent with meta-analyses, suggest that a combination of calcium and vitamin D supplementation is less concerning,” study authors wrote.

“Importantly, most randomized controlled trials evaluating calcium supplements were not specifically designed or adequately powered to evaluate cardiovascular outcomes, particularly in individuals with established CVD,” they noted.

Calcium supplements are commonly used to treat or prevent calcium deficiency, which can lead to osteoporosis. Meanwhile, the relationships between calcium intake and cancer, CVD, weight management, dementia, and other conditions have been more controversial.

“The connection between calcium supplementation and the recurrence of CVD events seems plausible, as circulating calcium plays an important role in vascular and cardiovascular health. Studies have demonstrated that circulating calcium levels directly contribute to the development of coronary artery calcification and aortic calcification, both of which are strongly related to recurrent CVD,” according to Cheung and colleagues.

It is also plausible that the combination of calcium with vitamin D mitigates the adverse effects of calcium.

“In animal models, vitamin D has been shown to regulate cholesterol efflux and macrophage polarization and inflammatory process via vitamin D receptor in vessel walls,” study authors wrote. They added that correcting the vitamin D deficiency prevalent in Asian populations could improve CVD outcomes even for users of calcium.

“Furthermore, calcium supplements require vitamin D to be absorbed into bones; whether the different degree of absorption results in heterogeneous mineral metabolism in coronary arteries warrants future investigation,” they suggested.

For their study, Cheung and colleagues relied on electronic hospital records for information on individuals ages ≥40 years newly diagnosed with CVD in 2006-2015 in Hong Kong.

People prescribed oral calcium supplements (e.g., calcium carbonate, calcium lactate, calcium gluconate) and calcium supplements with vitamin D (either calcitriol or vitamin D2/D3 prescribed concurrently) made up the treatment group (n=38,586). Patients who had never been prescribed calcium supplements were the controls (n=192,460).

From propensity score matching, investigators were left with a matched cohort of 17,720 patients in each study arm. This cohort had an average age of 77 years and were 58.2% women. The prevalence of diabetes was 30.6%, and osteoporosis was around 5%. Antiplatelet use came close to 80%, and just over half the patients were on lipid-lowering agents.

The study had a total follow-up time of 102,969.6 person-years.

Individual recurrent CVD endpoints supported a disadvantage for calcium users:

• Acute myocardial infarction: HR 1.10 (95% CI 1.03-1.18)
• Stroke: HR 1.06 (95% CI 1.01-1.10)
• Coronary heart disease: HR 1.09 (95% CI 1.05-1.13)

In particular, men prescribed calcium had a pronounced association with recurrent CVD events (HR 1.15, 95% CI 1.09-1.20) compared with women (HR 1.07, 95% CI 1.03-1.11).

Besides recurrent CVD events, there was also a greater likelihood of CVD-related hospitalization or accident and emergency department attendance in the calcium supplementation group (HR 1.16, 95% CI 1.13-1.20).

However, the observational study left room for unobserved residual confounding, the researchers cautioned.

“Additionally, the estimated risk may be biased toward the null by exposure misclassification from the potential OTC [over-the-counter] calcium supplement use. OTC use is more likely to occur in the controls than in the treatment group, thus leading to an underestimation,” the authors noted.

They also acknowledged that vitamin D deficiency is prevalent among East Asians, who also tend to have lower average dietary calcium intake.