10 June 2019: 

Summary

In 2010 Bolland et al. published a small meta-analysis suggesting increased cardiovascular events among women randomized to calcium.[1] As the initial controversy escalated, driven by fears spread through the popular press, the New Zealand group obtained data from the WHI and published an analysis that they interpreted to show that, in women who were not taking calcium and vitamin D supplements when they were randomized, there were modest increases in cardiovascular events in those assigned to calcium and vitamin D compared to those randomized to placebo.[2] The WHI investigators published a paper attempting to replicate those findings using the same dataset; those analyses -- using exposure at the time of WHI enrollment -- demonstrated no such hazards.[3,4] Now this group comes with a strategy similar to their initial run at calcium, combining a large number of mostly small studies into a meta-analysis. [5] They included 81 studies evaluating a range of vitamin D doses that addressed at least one of 3 outcomes: fractures, falls or bone mineral density (n of studies = 41, 37 and 41, respectively). Over two-thirds were of less than one year’s duration. The relative risk for total fracture was 1.0; 95% CI 0.93-1.07, for hip fracture 1.11; 0.97-1.26 and for falls 0.97; 0.93-1.02. Overall, the authors state “In meta-analysis of 81 randomised controlled trials, vitamin D supplementation did not affect incident fractures or falls, and did not have consistent clinically relevant effects on bone mineral density.“ They write that their results show “that there is reliable evidence that vitamin D supplementation does not have meaningful clinical benefits.”

Commentary

On the surface, the current paper seems credible as it used methods consistent with Cochrane Handbook procedures and it included a large number of studies. However, the largest studies and those of reasonably long duration were excluded because the authors did not consider studies of the most common intervention – calcium plus vitamin D – unless groups differed only by vitamin D. They justify this exclusion because the independent effect of vitamin D could not be distinguished. This would be reasonable for the strictly scientific endeavor of assessing vitamin D in isolation, but it is a disservice to clinical practice since it ignores the real world context as well as the metabolic reality that calcium and vitamin D are both required for bone anabolism. From the broader scientific perspective this is flawed methodology because the authors relied on studies that individually have very limited power due to generally small numbers of participants, and that have limited ability to address fracture rates because of short follow-up. Correct application of epidemiologic methods to a poor sample of data cannot address the failings of the underlying data. Such is the case in this publication as 68% of the studies were of less than a year’s duration. This is far too short to detect an effect on major fractures or a change in bone density. Of 81 trials identified, only 42 or just over half, had fracture as an endpoint and only 20, just under one quarter, had hip fracture as an endpoint. Among the 36 studies of fracture included in the main analyses, 23 (64%) had total sample sizes of under 500 total participants with sample sizes as small as 47. The total number of participants across the 36 studies was 44,790.[5] The WHI trial of Calcium plus Vitamin D (Ca/D) had 81% of that number with 36,282 participants who were followed for an average of 7 years. In a population of women not selected for osteopenia or osteoporosis, the WHI trial of Ca/D demonstrated a reduced Hazard Ratio of 0.71 (95 percent confidence interval, 0.52 to 0.97) in women adherent to the intervention.[6] The adherent analysis was important because the chewable tablets distributed in the early years of the study were too hard for many of the participants to chew, resulting in reduced adherence primarily for that reason. Also in the WHI trial there was also a modest increase in kidney stones (HR 1.17; 95% CI 1.02–1.34) presumably due to the calcium component. Yet it was excluded from this paper. Again the worldwide press took up their theme with articles suggesting that vitamin D supplementation for bone health should be abandoned. In 2013 it was estimated that osteoporosis was the cause of more than 8.9 million fractures annually worldwide, a staggering rate of approximately 1,000 per hour. Fracture rates are higher in developed countries, so that currently roughly one-third of all osteoporotic fractures occur in Europe. But the Western Pacific region including Australia, China, Japan, New Zealand and the Republic of Korea is not far behind accounting for nearly 30% of fractures worldwide.[7] The morbidity and mortality consequences of osteoporotic fractures are substantial, about 25% of people with a hip fracture occurring at age >50 die within a year[8] and hip fracture accounts for the same percent of mortality as breast cancer.[7] The conclusion of this paper is flawed because the authors excluded the data best suited to address the question, including the WHI Trial of Ca/D. While Ca/D caused a modest increase in kidney stones, it resulted in a substantial reduction in hip fracture among adherent women. Kidney stones are rarely fatal while hip fractures are associated with approximately 25% risk of one year mortality. Abandoning the simple low-cost intervention of modest doses of calcium and vitamin D is likely to accelerate the growing global burden of fractures.

Robert D. Langer, MD, MPH
Clinical Professor of Family Medicine, University of Nevada, Reno School of Medicine
Principal Scientist and Medical Director, Jackson Hole Center for Preventive Medicine

References

1. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341
   https://www.ncbi.nlm.nih.gov/pubmed/20671013
2. 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;342
   https://www.ncbi.nlm.nih.gov/pubmed/21505219
3. 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;24:567–580
   https://www.ncbi.nlm.nih.gov/pubmed/23208074
4. Pines A, Langer RD. The cardiovascular safety aspects of calcium supplementations: where does the truth lie? A personal perspective, Climacteric, 2015;18:1, 6-10
   https://www.ncbi.nlm.nih.gov/pubmed/25318377
5. Boland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol, 2018; 6: 847–58
   https://www.ncbi.nlm.nih.gov/pubmed/30293909
6. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus Vitamin D Supplementation and the Risk of Fractures. NEngJMed, 2006;354:669-83
   https://www.ncbi.nlm.nih.gov/pubmed/16481635
7. Hernlund E, Svedbom A, IvergaÌŠrd M, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Arch Osteoporos, 2013; 8:136
   https://www.ncbi.nlm.nih.gov/pubmed/24113837
8. NOF Fast Facts
   https://cdn.nof.org/wp-content/uploads/2015/12/Osteoporosis-Fast-Facts.pdf