Menopause Live (11 July, 2011) from IMS

Bolland and associates have recently reported on a re-analysis of the Women’s Health Initiative (WHI) observational study on calcium and vitamin D supplementation. The WHI study showed no cardiovascular risk associated with such supplementation [1]. They differentiated the treatment arm of the WHI study into women naïve to calcium and vitamin D supplementation and women using supplementation, prior to the start of the study. In those naïve to supplementation, they found an increased risk of cardiovascular events when compared to placebo (the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (p = 0.05 for clinical myocardial infarction or stroke, p = 0.04 for clinical myocardial infarction or revascularization)). No change in cardiovascular risk was evident in patients on supplementation prior to study start.

The results for the calcium-naïve patients were included in meta-analyses of placebo-controlled trials of calcium or calcium + vitamin D supplementation. Complete trial-level data were available for 28, 072 participants from eight trials. In total, 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium + vitamin D increased the risk of myocardial infarction (relative risk (RR) 1.24, 95% confidence interval (CI) 1.07–1.45, p = 0.004) and the composite of myocardial infarction or stroke (RR 1.15, 95% CI 1.03–1.27, p = 0.009). The authors concluded that calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is advocated.

Comment
This publication raises more questions than answers. The group of Mark Bolland and Ian Reid from Auckland, New Zealand recently reported increases in rates of cardiovascular events in women allocated to calcium supplements in the Auckland Calcium Study, a 5-year randomized, placebo-controlled trial in healthy older women, in which cardiovascular events were pre-specified secondary endpoints [2]. Subsequently, they carried out a meta-analysis of cardiovascular events in randomized, placebo-controlled trials of calcium supplements (without vitamin D co-administration) [3]. Calcium supplements significantly increased the risk of myocardial infarction by 31% in five trials involving 8151 participants where patient level data were available, and by 27% in 11 (with vitamin D) trials involving 11 ,921 participants. The authors postulate that calcium supplementation, irrespective of dosage, acutely increases serum calcium concentration and is associated with an increase in carotid artery plaque thickness, aortic calcification and the incidence of myocardial infarction. 

The authors argue that, although the relative increase in risk is small, it is important in view of the widespread usage of calcium supplementation. They furthermore argue that the comparisons of the benefits of calcium on fracture prevention with the risk of cardiovascular events suggest that the risk-to-benefit profile is unfavorable: in their analysis, treating 1000 patients with calcium or calcium + vitamin D for 5 years would cause an additional six myocardial infarctions or strokes (number needed to harm = 178) and prevent only three fractures (number needed to treat = 302). The authors admit that subgroup analyses of multiple endpoints are a statistical challenge.

Where does this leave the clinician? Serum calcium levels are critical for normal cellular function. In conditions of lowered serum calcium, calcium is mobilized from bone. In order to prevent this from happening, the diet needs to contain minimum levels of calcium that is absorbed. Postmenopausal women need a dietary reference intake (DRI) of 1200 mg of elemental calcium and 600 IU vitamin D (800 IU after age 70), according to the latest 2010 guidelines of the Institute of Medicine [4].

The most important message from the Auckland group is that routine calcium and vitamin D supplementation to the entire population of postmenopausal women cannot be supported. This implies that patients should be encouraged rather to maximize dietary calcium intake (by increasing dietary intake of low-fat dairy products) and to restrict supplemental calcium to only cover the shortfall between dietary intake and the DRI. Vitamin D status can be detected by the estimation of serum 25-hydroxyvitamin D. As diet contains limited vitamin D, vitamin D supplementation can be tailored independently of calcium supplementation to attain serum 25-hydroxyvitamin D levels in excess of 20 ng/ml.

Even when following this simple rule, it is uncertain whether all harm will be avoided, as in the WHI re-analyses harm was independent of supplementation dose, and it was postulated that it was a result of the acute rise in serum calcium soon after ingestion, an effect that is not seen with normal dietary calcium intake. It thus follows that all postmenopausal women using calcium supplementation should be screened and treated for conditions predisposing to cardiovascular events, such as hypertension, dislipidemias and diabetes.

The matter is more complicated in proven cases of osteoporosis receiving treatment with bone-active drugs. The anti-fracture efficacy of these drugs was proven in clinical trials in which all patients (including the placebo arm) received calcium + vitamin D supplementation, thus obscuring any cardiovascular harm. In my country, the approval of these drugs for anti-fracture efficacy is linked to the concomitant supplementation with calcium + vitamin D.

Only time and more studies will tell whether the work of the Auckland group is clinically relevant or whether it is the result of vigorous mining of subgroup data. What is clear though is that this work is part of an increasing body of evidence questioning a world where both health-care providers and patients have been led to believe that various forms of routine nutritional supplementation are not only essential, but also safe, for normal aging. In the meantime, I strongly suggest that any calcium supplementation be tailored to cover only the calcium shortfall, after optimizing dietary calcium intake and vitamin D according to the serum level of 25-hydroxyvitamin D. Such supplementation should hardly ever exceed 500 mg of elemental calcium or 800 IU of vitamin D.

Tobie J de Villiers
Panorama MediClinic and Department of Obstetrics & Gynecology, University of Stellenbosch, Cape Town, South Africa

References
1. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. 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 2011 Apr 19;342:d2040.
http://www.ncbi.nlm.nih.gov/pubmed/21505219
2. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008;336:262-6.
http://www.ncbi.nlm.nih.gov/pubmed/18198394
3. 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.
http://www.ncbi.nlm.nih.gov/pubmed/20671013
4. Institute of Medicine of the National Academies. Press release, 11/30/201