9 June, 2014:  

Clinical guidelines recommend the routine use of calcium and vitamin D supplementation for the prevention of fractures, especially at old age. Recent publications highlight the strong debate which has erupted in the past 5 years on the safety profile and efficacy of this treatment. I will try to put things in order for those who were not able to follow the situation more closely. In one review, Dr Weaver explains the problem [1]: 'Recently, calcium supplementation has been linked to both increased and decreased cardiovascular disease risk, creating considerable uncertainty. Moreover, recent reports have shed uncertainty over the effectiveness of calcium supplements to reduce risk of fracture.' In another review, Dr Reid took this issue further and summarized his view as follows [2]: '… findings suggest that calcium supplements have little role to play in the modern therapeutics of osteoporosis …". So what actually is going on? Are we heading for another revolution in clinical practice? What ignited the fire?

Comment

The well-known recommendation to promote calcium and vitamin D intake for prevention and treatment of osteoporosis was formulated many years ago, when no other specific therapies (except for hormone replacement for menopausal women) was available. The NAMS 2006 statement refers to calcium and vitamin D in the context of menopause: 'Adequate calcium is considered a key component of any bone-protective therapeutic regimen … the target calcium intake for most postmenopausal women is 1,200 mg/day … with a daily oral intake of [vitamin D] at least 400–600 IU … there is strong support for the importance of ensuring adequate calcium intake in all women, particularly those in peri- or postmenopause' [3]. The 2010 NAMS statement on the management of osteoporosis says: 'Management focuses first on non-pharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake' [4]. Bolland and colleagues were the first to raise the issue of potential cardiovascular adverse events in calcium users [5]. In a relatively small group (1471 healthy women, mean age 74 years, enrolled in a fracture prevention trial with 5-year follow-up), those who were assigned to calcium citrate at 1000 mg/day had more cardiac events than women in the placebo group: the relative risk for myocardial infarction was 2.12. A bitter war of opinions started then with the WHI investigators leading the fight against Bolland's group. They claimed that supplementation effects of calcium + vitamin D were not apparent in regard to the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among users of calcium + vitamin D was only suggestive [6]. In parallel, efficacy issues on the need for routine calcium or vitamin D intake were recently discussed as well. As an example, Theodoratou and colleagues, who summarized 268 reviews and meta-analyses, concluded that 'Earlier evidence from randomized, controlled trials that vitamin D supplementation (with or without calcium) increases bone mineral density and reduces the risk of fractures in older people is not seen in clinical trials that examined vitamin D only supplementation' [7].

It is not possible to get into a thorough analysis of all the arguments that were raised since 2008, when Bolland's study was published, because the format of Menopause Live comments can only provide a glimpse of the scope. However, some societies and organizations have already changed their phrasings into more careful ones when recommending on calcium + vitamin D supplementations. The 2013 updated IMS recommendations on preventive strategies for midlife health say: 'Routine dietary calcium supplementation cannot be justified in terms of efficacy and health economics. Calcium supplementation should be restricted to bridge the shortfall between dietary intake and the Recommended Dietary Allowances (RDA), and to patients being treated for high fracture risk' [8]. I believe that the best way to summarize the benefit–risk balance would be (1) current evidence supports a primary strategy of preferring dietary calcium and vitamin D over supplements with the goal of reaching the RDA; (2) however, the reality is that most western diets do not achieve that intake, so modest supplementation is probably of value and there is no clear evidence that it is harmful.
Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Weaver CM. Calcium supplementation: is protecting against osteoporosis counter to protecting against cardiovascular disease? Curr Osteoporos Rep 2014;12:211-18.
http://www.ncbi.nlm.nih.gov/pubmed/24671370 
2. Reid IR. Should we prescribe calcium supplements for osteoporosis prevention? J Bone Metab 2014;21:21-8.
http://www.ncbi.nlm.nih.gov/pubmed/24707464 
3. The role of calcium in peri- and postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause 2006;13:862-77.
http://www.ncbi.nlm.nih.gov/pubmed/17106282 
4. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:25-54.
http://www.ncbi.nlm.nih.gov/pubmed/20061894 
5. Bolland MJ, Barber PA, Doughty RN, 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
6. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study. Osteoporos Int 2013; 24:567-80.
http://www.ncbi.nlm.nih.gov/pubmed/23208074 
7. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014;348:g2035.
http://www.ncbi.nlm.nih.gov/pubmed/24690624 
8. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316-37.
http://www.ncbi.nlm.nih.gov/pubmed/23672656