Reference
Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
Design
Patient level and trial level meta-analysis of previously completed randomized control trials (RCTs) involving calcium supplementation. The researchers’ objective was to investigate the effect of calcium supplementation on the risk of cardiovascular events based on the combined data from previous RCTs. Eligible studies included RCTs using calcium supplements (elemental calcium > 500 mg/day), with more than 100 participants of mean age 40 years and study duration of more than one year. Trials involving co-administration of calcium and vitamin D were excluded from the analysis. One hundred ninety potentially relevant studies were reviewed and 15 trials were considered eligible for meta-analysis, 5 with patient level data and 11 with trial level data.
Participants
The study included 485,044 subjects (144,577 men) aged 35-70 years old from 10 European countries who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort. Mean follow-up was 8.9 years.
End Points
The primary endpoints were time to first myocardial infarction (MI), time to first stroke, and time to first event for the composite end point of MI, stroke, or sudden death. The secondary end point was time to death (all-cause mortality).
Key Finding
While no individual trial reported a statistically significant effect on cardiovascular end points, the pooled analysis of 11 RCTs showed that calcium supplementation without co-administration of vitamin D is associated with a 30% increase in the incidence of MI and smaller, non-significant, increases in the risk of stroke and mortality.
Commentary
There are several limitations to this study that render the conclusions dramatically overstated. Meta-analysis can be a useful tool, but it is important to note that this meta-analysis is based on a collection of past studies that have different designs, end points, doses and study populations. High-quality meta-analyses combine studies that are “combinable” (ie, have similar design, dose, duration, and study population). Meta-analyses that combine heterogeneous studies are not considered as conclusive. In this case none of the original trials analyzed included cardiovascular outcomes as primary end points, and data on cardiovascular end points were not gathered in a standardized manner. The cardiovascular data were retrieved from the authors of the original trials through a collection of unpublished data, hospital admissions, and death certificates. Seven of the 15 trials evaluated had no, or incomplete, data on cardiovascular outcomes, and only 5 of the 15 studies accounted for almost all of the cardiovascular outcomes. The remaining trials suggest no increase in risk, yet the authors represent the results as though all 15 trials suggest increased risk. Overall this review is a re-analysis of secondary findings gathered in a non-standardized manner from a subset of the available published human studies on calcium supplementation. This form of meta-analysis may be appropriate for generating hypotheses and justifying funding for additional studies, but it is far from conclusive.
The authors determined that only 15 studies were ‘eligible for analysis’, which eliminated data from hundreds of relevant studies. In addition, studies that included the co-administration of vitamin D were not included in the analysis. This eliminated important trials, including the Women’s Health Initiative,1 which demonstrated calcium plus vitamin D had no effect on the risk of coronary heart disease or stroke. In addition, malabsorption of calcium occurs with low serum concentrations of vitamin D, and currently experts opine that serum 25-dihydroxyvitamin D (25(OH) D) concentrations should be above 50–75 nmol/L for optimal calcium absorption.2 Most calcium dietary supplements contain vitamin D, and most knowledgeable practitioners would not prescribe calcium in isolation, which renders the results of this analysis irrelevant to real-world scenarios. Further it is premature to make any conclusions about calcium in cardiac risks without also looking at other synergistic nutrients, such as vitamin K2 and magnesium. National survey data shows that a large portion of the US population is deficient in these nutrients and that they are all required in the complex vascular biology that promotes or prevents calcium deposits in the coronary arteries.3
The median age range of the participants used in the meta-analysis was 70–79 years with only 1.2% of participants taking any calcium supplements at baseline. The age of this patient population represents a group with high incidence of chronic kidney disease as evidenced by reduced glomerular filtration rate (GFR), which is associated with increased mortality from cardiovascular disease.4 Overall, the results of this study apply to older adults previously not exposed to supplemental calcium, but not to other populations. The authors point out that the findings of this analysis are consistent with trials of patients with renal failure, in which calcium supplements have been associated with an increase in mortality.5 This raises interesting questions about the impact of calcium supplementation without vitamin D on calcium absorption in older individuals who may have compromised kidney function. However, the results of the analysis do not address questions related to calcium supplementation in younger women (or men), which is an age period that is most important for establishing strong bones. It is important that the results of this study are placed in context with the total body of evidence on calcium supplementation, which demonstrates that adequate calcium intake through a combination of diet and supplementation is vital to building and maintaining healthy bones and reducing the risk of osteoporosis.
Practice Implications
A large body of scientific evidence demonstrates that an adequate calcium intake plays an important role in building and maintaining bone mass. Calcium is a nutrient that is difficult to obtain in adequate amounts from most diets, except for large dairy consumers. National survey data show that about 90% of teenage girls, more than 2/3 of women ages 19–50, and more than 90% of women over 50 fall short of achieving the Adequate Intake (AI) for calcium from diet alone.6 Further, the 2005 Dietary Guidelines for Americans recognize that calcium is a shortfall nutrient for Americans of all ages and both genders.7
The current meta-analysis provides preliminary evidence that calcium supplementation without vitamin D in an older population with no previous calcium supplementation may be associated with a slight increase in cardiovascular events. The authors point out that the magnitude of the increase in risk is small, but this small increase can translate to a large burden on a population basis. We must also consider that the small increase in risk observed may be eliminated when combined with the decrease in mortality associated with vitamin D supplementation.8 No definitive conclusions can be made about the benefits or risks of calcium supplementation without considering variables like kidney function and levels of other relevant nutrients involved in vascular biology, such as vitamin D, vitamin K2, and magnesium. Even if these risks are proven real through additional research, the slight increase in risk has to be weighed against the positive effects of calcium supplementation (with vitamin D, K2, and magnesium) on bone.
Naturopathic and other integrated practitioners should always advocate for patients to obtain all of their essential nutrients from food. However clinical experience and national survey data suggest that we are far from reaching this standard. Clinicians should approach calcium supplementation in context with individual dietary habits. After an assessment of an individual’s approximate dietary calcium intake, the balance of the recommended intake for their age and sex should be met through supplementation. It seems prudent to recommend calcium in combination with other synergistic nutrients for bone health. Clinicians should also verify serum 25-dihydroxyvitamin D concentrations are adequate for efficient calcium absorption. In most cases, concomitant vitamin D supplementation will be required to maintain optimal vitamin D levels. Clinicians desiring to be conservative might reconsider before making recommendations for women over age 70 and those with heart disease. Women at high risk for heart disease and low risk for osteoporosis may present a different benefit-versus-risk evaluation than women who present with the inverted scenario. To date there is no evidence of risk to younger women who take calcium. Individuals with chronic kidney disease as evidenced by reduced GFR may represent a cohort where isolated calcium supplementation is not advisable.
