Calcium is good for us, right? Milk products are great sources of calcium, and we’re told to emphasize milk products in our diets. Don’t (or can’t) eat enough dairy? Calcium supplements are very popular, especially among women seeking to minimize their risk of osteoporosis. Osteoporosis prevention and treatment guidelines recommend calcium and vitamin D as an important measure in preserving bone density and reducing the risk of fractures. For those who don’t like dairy products, even products like orange juice and Vitamin Water are fortified with calcium. The general perception seemed to be that calcium consumption was a good thing – the more, the better. Until recently.

In a pattern similar to that I described with folic acid, there’s new safety signals from trials with calcium supplements that are raising concerns. Two studies published in the past two years suggest that calcium supplements are associated with an significantly increased risk of heart attacks. Could the risks of calcium supplements outweigh any benefits they offer?

Why Calcium? Osteoporosis

Osteoporosis is a progressive bone condition of reduced bone mass and deterioration of bone tissue, and a correlating increase in fracture risk. 80% of those diagnosed are women. Hips and spines are the most common fracture locations, but they can appear in any bone, and osteoporosis makes fractures more likely. In postmenopausal women over the age of 50, the lifetime risk of a vertebral fracture is about one in three, and one in five for a hip fracture. Because they are so common, hip and vertebral fractures cause considerable aggregate and individual morbidity and mortality. So prevention and treatment are major health issues.

The initial strategy to preventing and managing osteoporosis is ensuring adequate calcium and vitamin D dietary intake, as both influence bone density. Calcium intake influences overall calcium balance: adequate vitamin D and calcium ensure calcium balance is positive. This occurs at about 1000mg per day in premenopausal women, and 1500mg per day in postmenopausal women not taking estrogen. The North American Menopause Society’s (NAMS) 2006 osteoporosis guidelines recommends [PDF] adequate calcium and vitamin D for all postmenopausal women, regardless of osteoporosis risk factors. The guidelines note that requirements increase with age owing to reduced absorption, and recommending adequate intake (preferably via diet) as the preferred sources. The 2010 Canadian guidelines [PDF] are similar, recommending 1200mg of calcium (diet and supplements) and vitamin D for all individuals over the age of 50. The Institute of Medicine recently updated its calcium and vitamin D guidelines (pdf) as well. It concluded with the caution that the consumption of levels beyond those recommended have not been shown to offer additional health benefits, and may in fact be linked to other health problems.

The effectiveness of calcium and vitamin D for the prevention and treatment of osteoporosis has been studied in both observational and prospective clinical trials. Wile there are data to demonstrate that calcium and vitamin D can prevent bone loss, the data on fracture prevention are much less convincing, with some trials showing no effect. Beyond density effects, calcium is also associated with generally positive effects on muscle strength, balance, and the risk of falls. So for most men and women with (or at risk of) osteoporosis, calcium and vitamin D are standard treatments. Given dietary intake in those at greater risk of osteoporosis may be below recommended levels, supplements are often used to meet recommended amounts.

The Safety Signals

Prior studies of calcium supplements have pointed to a possible relationship between calcium supplementation and cardiovascular events. Bolland et al specifically examined the relationship of calcium with the risk of heart attacks and cardiovascular events in a 2010 BMJ meta-analysis. It included all RCTs of calcium supplements (?500 mg/day), with a study size of 100 or more participants, an average age over 40, and a duration of more than one year. Trials that included vitamin D as an intervention were excluded. 15 trials were identified: some with patient-level data, and some with trial level data. Analyses of both sets of data identified a significant increase in heart attacks in those randomized to calcium supplements. The trial-level analysis show a hazard ratio (pdf) of 1.27 with a 95% confidence interval of 1.01 to 1.59 (p=0.038). The patient level analysis revealed a similar hazard ratio for myocardial infarction of 1.31 (95% confidence interval 1.02 to 1.67, p=0.035). Overall, the analysis suggests that calcium supplements increase the relative risk of myocardial infarction by about 30%. Reassuringly, there were no statistically significant increases in the risk of stroke, death, or the composite endpoint of MI+stroke+death in either analysis. Based on the patient-level data, the authors estimated that treating 69 people with calcium for five years will cause one additional heart attack. The authors suggested that in light of calcium’s unimpressive efficacy against fractures, that calcium’s role in osteoporosis prevention and treatment should be reevaluated.

Time to stop the calcium? As noted above, the data to support the use of calcium supplements alone to prevent fractures are, on balance, unimpressive. And there are possible models for how calcium could be causing these harms: vascular calcification is a potential (though not proven) consequence that might be more likely in the elderly patients. However, given calcification can take years, and harms appear shortly after dosing starts, it could be a due to effects on carotid plaque thickness, leading to aortic calcificiation, and subsequent cardiovascular events. (Reid describes potential mechanisms for these harms in a2010 paper in Clinical Endocrinology.)

What happened after this paper was released? There were criticisms of the endpoints, and the fact the composite endpoint was not significant. Concerns were also raised that the trials included were not designed with cardiovascular endpoints – a valid criticism. And many pointed to the fact the studies excluded vitamin D, contrary to treatment guidelines and common use. Now the same group has done a new analysis, incorporating vitamin D. Bolland and associates followed up their calcium-only therapy with a study of calcium + vitamin D. They used the Women’s Health Initiative (WHI) dataset to answer the vitamin D question, added in some other studies, and redid their meta-analysis.

The WHI was a massive 15-year trial of over 161,000 women that sought to answer a number of questions about women’s health. The most well known components were the hormone therapy trials which changed our understanding of the risks and benefits of hormone treatments. The calcium and vitamin D study was a component of the WHI which randomized 36,282 postmenopausal women aged 50-79 into two groups. One group received 1,000 mg of calcium carbonate and 400 UI of vitamin D once daily, the other, placebos. Interesting in the design was that 54% of women were already taking calcium, and 47% were already taking vitamin D, and they were allowed to continue with their therapy, even after randomization. This meant that actual calcium and vitamin D doses women consumed varied from zero to substantially more than the intervention dose. The clinical question the study sought to answer was to understand the effects on fracture risk and the prevention of colorectal cancer — and the results were disappointing: no effects on colorectal cancer, and insignificant effects on fractures (though in a subgroup analysis of compliant patients, significant reductions in hip fractures were noted.)

Bolland sought to analyze the WHI data for cardiovascular effects, and then add these data into the previous meta-analysis. In the over 16,000 women not taking their own calcium and vitamin D, there was a significant increase (hazard ratio 1.22) in myocardial infarction noted in the group randomized to calcium and vitamin D (p=0.04, 95% CI 1.00 to 1.50). Similarly, significant effects were also noted in other composite endpoints. In contrast, women taking their own calcium and vitamin D didn’t show any changes in their cardiovascular risk when randomized to calcium and vitamin D. In addition, no relationship was found between calcium dose and risk of cardiovascular events.

The authors then pooled their own WHI analysis with two other studies of calcium and vitamin D where trial-level data for cardiovascular events were available: In total, over 20,000 participants could be studied. In this pooled analysis, calcium and vitamin D were associated with a significant increases in myocardial infarction (relative risk 1.21), stroke (RR 1.20) and a composite endpoint of both (RR 1.16).

Finally the authors combined the trial level data from their calcium-only meta-analysis with their trial level calcium plus vitamin D data:, resulting in a pool of over 28,000 patients across nine trials. In this analysis, there was risk increase of 1.24 (95% confidence interval 1.07-1.45, P=0.004) for myocardial infarction and 1.15 for the combined endpoint (1.03-1.27, P=0.009).

Difficult to interpret? Yep. The lack of effect of “personal” use of calcium on endpoints, and the lack of dose response, means this isn’t case closed for the clinical question. But the persistent and significant correlation between randomization to calcium, with or without vitamin D, and myocardial infarction, does concern me. There are a number of additional criticisms outlined in the editorial that accompanied the Bolland WHI analysis, and the keen reader is referred there for more.

Evaluation

Is it possible that calcium supplements can be causing harms that could outweigh their benefits? Yes, but the evidence isn’t clear enough to give an definitive answer. These data need to be factored into individual evaluations of diet as well as risk factors for cardiovascular disease and osteoporosis. I’d like to see these findings validated by other groups, as both meta-analyses came from the same group of researchers. The meta-analysis can be a very useful tool, but it’s not without its own limitations, as is often pointed out by the contributors to this blog. Interestingly, a 2010 meta-analysis, from a different group of authors, and using a different methodology, has come to a different evaluation of calcium. So the question remains an open one. More data may help refine our estimates of number needed to treat, and number needed to harm, to inform treatment decisions. And it should help guide advice for younger, premenopausal women, as well as men. So until more data emerges, my tentative recommendations to consumers are as follows:

• Calcium supplementation has been associated with increased risks of cardiovascular events like heart attacks. Until there is more evidence to confirm or refute this association, it’s prudent to be cautious when taking calcium supplements.
• No harms have been shown from calcium consumption via dietary sources. Efforts should be made to first meet dietary requirements through food products, before considering supplements.
• Routine supplementation, in the absence of a dietary deficiency, is not necessary or advisable.
• Calcium supplements may still be advisable for those with low dietary intakes, or those at risk of or being treated for osteoporosis. The risk-benefit assessment for calcium supplements needs to consider risk factors for both osteoporosis and for cardiovascular disease.
• Vitamin D supplements are advisable for most people, and are recommended for the prevention and treatment of osteoporosis. The suggested doses of calcium and vitamin D may vary based on diet, medical conditions, and other considerations. Sources for target doses could include the IOM or recent osteoporosis guidelines (Canada) (USA).

Conclusion

The emerging safety data on calcium may yet become another cautionary tale about the unexpected and undesirable outcomes of targeted supplements. Until more evidence emerges, the safety of calcium supplements will continue to be questioned and debated. But that’s science-based practice: Data can be conflicting, messy, and difficult to interpret. There is always the possibility of unintended consequences when we make therapeutic decisions, and only by rigorously evaluating what we’re doing can we continue to improve the way we prevent and treat disease.

References
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, & Reid IR (2010). Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ (Clinical research ed.), 341 PMID: 20671013

Bolland, M., Grey, A., Avenell, A., Gamble, G., & Reid, I. (2011). Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis BMJ, 342 (apr19 1) DOI: 10.1136/bmj.d2040