Healthy adults who have high levels of calcium intake are not at an increased risk of cardiovascular disease, according to a systematic review and meta-analysis.

The researchers defined the recommended upper intake levels as 2,000 to 2,500 mg of calcium per day. The review included four randomized trials and 27 observational studies that had data on calcium intake and cardiovascular outcomes.

Lead researcher Mei Chung, MPH, PhD, of Tufts University in Boston, and colleagues published their results online Oct. 24 in the Annals of Internal Medicine.

“Our systematic review, which synthesizes data from trials and cohort studies, has implications for a new evidence-based approach to establish dietary reference intake values that include chronic disease and long-term outcomes, for which direct evidence from randomized trials often is lacking,” they wrote. “In the absence of direct evidence from trials, synthesis of large population-based cohort studies may improve the strength of evidence and provide complementary data for clinical or policy decision making.”

The researchers searched MEDLINE, the Cochrane Central Register of Controlled Trials, Scopus and other publications from 1966 through July 2016. They included English-language studies in which no more than 20 percent of participants had known cardiovascular disease.

This systematic review was an update to one published in 2009 that examined the effects of calcium and vitamin D on 17 health outcomes.

Pfizer Consumer Healthcare supported the research through an unrestricted educational grant to the National Osteoporosis Foundation (NOF). The researchers said they did not know about Pfizer’s funding until they submitted the final manuscript to the NOF.

The final analysis involved four randomized, controlled trials, one nested case-control study and 26 cohort studies.

“On the basis of our assessments of internal validity, precision of risk estimates, and consistency of results from randomized trials and prospective cohort studies, we conclude that calcium intake (from either food or supplement sources) at levels within the recommended tolerable upper intake range (2000 to 2500 mg/d) are not associated with [cardiovascular disease] risks in generally healthy adults,” the researchers wrote. “Although a few trials and cohort studies reported increased risks with higher calcium intake, risk estimates in most of those studies were small (±10% relative risk) and not considered clinically important, even if they were statistically significant.”

The researchers said the systematic review and meta-analysis had a few limitations, including that cardiovascular disease outcomes were secondary endpoints in all trials and that they only included English-language publications. They also said cardiovascular disease risks at very high calcium intake levels were uncertain In addition, they did not have good estimates of calcium intake levels from foods and supplements due to adherence issues.

“We believe a trial with sufficient statistical power to detect small differences in adverse cardiovascular outcomes is unlikely to be done,” the researchers wrote. “We recommend future prospective population-based cohort studies that assess total, dietary, and supplemental calcium intake by using validated dietary assessment methodology; ascertain chronic disease outcomes by using standardized outcome measures; and use prospectively developed study protocols, power calculations, and analysis plans.”