In line with earlier studies of the general population, the findings should encourage a thoughtful approach to calcium, experts say.
Bolstering the idea that calcium supplements are harmful to the heart, a new observational study shows that patients with CVD who take these pills are at added risk of recurrent disease.
The increase in risk was more pronounced in men and when the calcium was not accompanied by vitamin D supplementation, researchers led by Xiaowen Zhang, PhD (University of Hong Kong, China), report in the Journal of the American Heart Association.
“The cardiovascular safety of calcium supplementation in individuals with established CVD remains understudied,” apart from a few earlier reports on aortic stenosis, Zhang and senior author Ching-Lung Cheung, PhD (University of Hong Kong), told TCTMD in an email. “Most previous studies focused on the general elderly population or individuals with osteoporosis, largely overlooking patients with established CVD, who have a substantially higher risk of recurrent events.”
Most surprising among the new findings “was the null association in patients using both calcium and vitamin D, in contrast to the positive association seen with calcium alone. This suggests that calcium-only supplementation may be harmful for patients,” they said. “Notably, many individuals take calcium without vitamin D, despite it being well recognized that vitamin D facilitates calcium absorption.”
For the researchers, the clinical implications of their results are “clear and straightforward.”
“When prescribing calcium, it should be combined with vitamin D unless contraindicated. If patients are unwilling or unable to take vitamin D supplements, clinicians may instead advise adequate sunlight exposure or a calcium-rich diet rather than calcium supplementation alone. We believe this recommendation is pragmatic, easy to follow, and rational,” they advised.
Supplement use is common among elderly patients, with many taking calcium as a means of treating or preventing osteoporosis as they age.
Erin D. Michos, MD (Johns Hopkins University School of Medicine, Baltimore, MD), commenting on the findings for TCTMD, noted that the link between calcium supplementation and CV events “has been seen now over and over again—now, not in every study, but in enough studies [of] broad populations that are really quite concerning.”
Michos drew a distinction, however, between calcium obtained through supplements versus through dietary sources. In her own work analyzing data from the Multi-Ethnic Study of Atherosclerosis (MESA), Michos has demonstrated that adults free of heart disease with high levels of dietary calcium have a lower 10-year risk of atherosclerotic disease, as evidenced by changes in coronary artery calcium (CAC). Those in MESA who took calcium supplements, on the other hand, were more vulnerable to having CAC.
The current report, she agreed, is the first to narrow its perspective to look exclusively at patients with established CVD. It reaffirms earlier studies in the population and serves as a reminder to have a cautious, thoughtful approach to taking supplements, said Michos.
Hong Kong Data
Zhang and colleagues retrospectively analyzed data from electronic health records on 237,782 patients at least 40 years old who were newly diagnosed with CVD in Hong Kong between 2006 and 2015. Among them, 16% were prescribed calcium supplements and the remainder were not.
The researchers conducted propensity-score matching to account for baseline differences when comparing the treatment and control groups (n = 17,720 in each). Before matching, individuals in the calcium group were older and more apt to be women, have lower serum calcium and higher serum creatinine levels, and have histories of chronic kidney disease (CKD), osteoporosis, or major fractures as well as the associated comorbidities and medical therapy.
After matching, the mean age was 77.0 years and 58.2% were women. Around 43% percent had CKD, 31% diabetes, 17% major fractures, and 5% osteoporosis.
The risk of recurrent CVD events (acute MI, stroke, and coronary heart disease) was greater in the treatment versus control groups, as were the individual components. The risk of CVD-related hospitalization or an accident with emergency department attendance also was elevated with calcium supplementation.
Risk With vs Without Calcium Supplements
Events per 1,000 Person-Years
HR (95% CI)
Treatment
Control
Composite
184.9
167.5
1.10 (1.07-1.14)
Acute MI
23.7
21.7
1.10 (1.03-1.18)
Stroke
63.3
60.2
1.06 (1.01-1.10)
Coronary Heart Disease
91.2
84.4
1.09 (1.05-1.13)
CVD Hospitalization or Accident With ED Visit
140.3
119.8
1.16 (1.13-1.20)
Yet the risk of composite adverse CV events was only elevated among patients taking calcium without vitamin D (HR 1.21; 95% 1.17-1.25), not among those taking both supplements (HR 0.97; 95% CI 0.93-1.01). Among those on calcium only, the added risk was seen across all doses and durations but was highest at daily doses of at least 1,000 mg (HR 1.58; 95% 1.47-1.70). Additionally, the impact was more pronounced in men (HR 1.15; 95% CI 1.09-1.20) than in women (1.07; 95% CI 1.03-1.11).
“To be frank, the 21% increased risk of recurrent CVD associated with calcium-only use could be considered modest to moderate by some readers,” Zhang and Cheung acknowledged. “However, given that this excess risk may be preventable simply by adding vitamin D—a modifiable factor that is inexpensive and generally very safe—it is important to emphasize the need to use calcium together with vitamin D in patients with major CVDs.”
A separate analysis of a prospective cohort study, the Hong Kong Osteoporosis Study, confirmed the higher risk with calcium supplements and found it may be augmented in people who obtain them over the counter versus with a prescription, as well as in people who are overweight.
‘More Is Not Necessarily Better’
In their email to TCTMD, the researchers explained that the connection between calcium intake and calcification in the arteries relates to the balance between intestinal absorption versus bodily storage and renal excretion. This balance is often disrupted in older adults, especially those who have CVD.
Unlike dietary calcium, which is generally absorbed gradually, “calcium supplements can cause a sharp, transient increase in circulating calcium levels before returning to baseline,” they said. “It is plausible that these repeated acute rises in blood calcium may, over time, facilitate vascular calcification.”
Moreover, calcium “promotes coagulation,” Michos pointed out. “ And so, when you raise your serum calcium even temporarily, you [become] potentially more hypercoagulable.”
The apparent protective effect of vitamin D may relate to enhanced bone metabolism, Zhang and Cheung suggest.
Another interesting area to pursue in research, they noted to TCTMD, is the possibility that the gut microbiome may be impacted differently by calcium supplements depending on whether they’re accompanied by vitamin D, with implications for CVD. “This is because unabsorbed calcium may pass through the gut and influence the gut microbiota,” they said. “Accordingly, we plan to evaluate differences in gut microbiota between individuals receiving calcium supplementation alone and those receiving calcium supplementation with vitamin D.”
Michos led a 2021 review, published in JACC, on the topic of supplements and their implications for CV health. She said that when counseling patients, the message should be “more is not necessarily better.”
Although it’s important to get an adequate intake of calcium for bone health—the recommendations are that women over 50 and men over 70 should get 1,200 milligrams per day—going above that amount won’t add benefit. Luckily, “calcium is not too hard to get [from] the diet,” Michos specified, adding that leafy green vegetables, white beans, and fish are all good sources. In her own practice, she said, she advises patients to keep a food diary for a few weeks to figure out their calcium intake. If it’s not possible for an individual to eat a diet with sufficient calcium, “then they should take the smallest amount of supplement to reach [the goal].”
These conversations are particularly relevant for patients like in this study who’ve already had a cardiovascular event, said Michos. It’s important to think holistically about prevention, she added, given the myriad of modifiable risk factors, such as lipid or blood pressure levels, that can be addressed.