SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.