We disagree with several views expressed by Abrahamsen and Sahota about our previous 2010 meta-analysis.(1) Our primary analyses counted people not events. We do not think that a significant increase in risk of myocardial infarction should be discounted because the P value for the increase in risk of the composite of myocardial infarction, stroke or sudden death (P=0.057) does not reach the notional threshold for statistical significance. The evidence for the editorialists' view that the increased cardiovascular risk with calcium supplements was related to dietary calcium intake is weak. When the cohort was grouped by quintiles of dietary calcium intake, 4 of the 5 groups (including the group with the lowest intake) had hazard ratios of 1.2-2.3 for myocardial infarction with calcium supplements, and no dose-response relationship existed between dietary calcium intake and risk of myocardial infarction.

In our current analyses,(2) the editorialists suggest there is a survival benefit in the subgroup of women taking personal calcium supplements at randomization. The attribution of benefit to one subgroup when the formal test of interaction is not significant and there is no benefit in the entire cohort is strongly discouraged.(3-6) Therefore, the interpretation that there is no evidence of a difference in mortality risk with calcium and vitamin D in the subgroups defined by personal calcium use is more appropriate.

We also disagree with the editorialists that randomized controlled trials of bisphosphonates can be used to assess the safety of calcium and vitamin D, because calcium and vitamin D were given to participants in both arms of such studies. Further, results from observational studies should be disregarded, particularly when there is a large database of randomized controlled trials, because of the potential for confounding and the inability to separate causality from association.

Lastly, the editorialists call for more studies. However, analyses of ongoing or other completed studies will be subject to the same limitations that affect our work: the individual studies will be underpowered, not designed to study cardiovascular events, have variable event adjudication, and likely include composite endpoints. An adequately powered, randomised controlled trial would need to be very large and have a long duration of follow-up.(7) How many people would volunteer to take part in a study when the primary hypothesis is one of harm, and the benefits of participating (fracture prevention) are marginal?(8,9) Furthermore, who would fund such a trial and would it receive ethical committee approval?

Assessment of adverse events in clinical trials is difficult, especially when they are unexpected.(10) Trials usually have limited statistical power to detect adverse events, multiple statistical tests are performed, data gathering and event adjudication may not be standardised, and composite endpoints and meta-analysis may be used. If results are dismissed simply for these reasons, harms from agents in clinical trials would be very difficult to detect, and primary trials would need to be much larger and longer than at present, to allow reliable assessment of clinically relevant adverse events.

References

1. Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.

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:d2040.

3. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-8.

4. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000;355:1064- 9.

5. Lagakos SW. The challenge of subgroup analyses--reporting without distorting. N Engl J Med 2006;354:1667-9.

6. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine--reporting of subgroup analyses in clinical trials. N Engl J Med 2007;357:2189-94.

7. Reid IR, Bolland MJ, Grey A. Does calcium supplementation increase cardiovascular risk? Clin Endocrinol (Oxf) 2010;73:689-95.

8. Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta- analysis. Lancet 2007;370:657-66.

9. Reid IR, Bolland MJ, Grey A. Effect of calcium supplementation on hip fractures. Osteoporos Int 2008;19:1119-23.

10. Bolland MJ, Grey A, Gamble GD, Reid IR. Investigating harms in clinical trials - no easy task. Int J Clin Pract 2010;64:1719-22.