Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis

BMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c3691 (Published 30 July 2010)
Cite this as: BMJ 2010;341:c3691

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Dear Editor,

The recent meta-analysis of 15 randomized blinded placebo-controlled trials1, published in August 2010 evaluating calcium alone supplement use (at least 500 mg daily) in more than 12,000 patients aged 40 years and over was widely reported in the media2,3,4,5. The pooled results suggested that calcium supplements were associated with a significant increased risk of myocardial infarction (MI) [pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038)]. A trend towards increased risk of stroke and sudden death was also found, but this result was not statistically significant. This meta-analysis excluded studies that involved co- administered calcium and vitamin D supplements1.

The aim of our study is to determine, using a large national pharmacy claims database, the effect of this meta-analysis1 and the associated media coverage on the prescription of calcium and vitamin D in the Irish population pre and post publication.

Methods: We examined the Irish HSE-Primary Care Reimbursement Services (HSE-PCRS) pharmacy claims database which includes prescriptions dispensed under the largest community drug scheme, the GMS (General Medical Services) scheme in Ireland. This scheme provides free health services, including medicines to 1.2 million people in Ireland. It is a means-tested scheme for people aged <70 years, but from July 2001 to December 2008 was free to all those aged 70 years and over. It is estimated that over 97% of this older age group still avail of the GMS scheme6. While the HSE-PCRS population cannot be considered representative of the entire population, as the elderly, the young and the socially disadvantaged are overrepresented, it is estimated to account for approximately 70% of all medicines dispensed in primary care7.

Over the period from August 2009 to April 2011, the prescribing rate of the following three distinct groups of patients, prior to and following the journal publication were examined by segmental regression analysis.

1. Patients receiving calcium alone.
2. Patients receiving combinations of calcium and vitamin D.
3. Patients receiving vitamin D alone.

Analysis was performed using SAS (V9.1SAS Institute Inc) and significance at p<0.05 is assumed.

Combinations of calcium and vitamin D products were by far the most commonly prescribed of the 3 groups studied, with an average of 77,292 prescriptions issued monthly over the study period. Vitamin D alone was the next most commonly prescribed with a monthly average of 12,078 prescriptions. Calcium alone had the lowest frequency of prescribing amongst the 3 groups with an average of 2807 prescriptions issued per month. The frequency of prescribing was adjusted according to the number of eligible patients per month.

Figure 1 presents the changes in prescribing in the three groups over the period August 2009 to April 2011.

Figure 1- Prescribing rates of calcium and vitamin D products over the period of August 2009 to April 2011.

The prescribing rate of calcium alone products fell from 2.02/1000 eligible patients prepublication to a rate of 1.88/1000 eligible patients post-publication (p<0.0001). No significant changes were noted in the prescribing rates for calcium and vitamin D or vitamin D only products.

Discussion: We found a statistically significant decline in the rate of prescribing of calcium alone products in Ireland following the publication of a meta- analysis raising concerns regarding the safety of calcium supplements alone and a significant increased risk of myocardial infarction1. Previous evidence suggests that alarming medical news and warnings to the general public can influence prescribing practice in a positive or negative way. Examples include the dramatic reduction in the use of oral hormone therapy following publication of the oestrogen-progestin arm of the Women's Health Initiative (WHI)8 trial in July 2002 with an estimated 56% decline in oral oestrogen/progestin prescriptions within a year of the publication9. In 2004, Rofecoxib was withdrawn from the market as a result of concerns regarding its cardiovascular safety10. A subsequent study found that there was a shortlived initial increase in the prescription of an alternative COX-2 inhibitor (Celecoxib)11.A pattern of marked decline in all COX-2 inhibitors ensued, presumably as a result of prescriber's fear of a possible class effect. A sharp decline in new users of thiazolidinediones was noted following reports on the cardiovascular safety of rosiglitazone12. The initial response of prescribers to media reports concerning the third-generation oral contraceptive pill13 led to immediate cessation in some users14 and a subsequent rise in abortions15. None of the three initial studies on which the report was based were prospective and randomised and the increased risk of venous thromboembolism may have been attributable to biases and confounding factors in the study designs16.Previous studies using the HSE-PCRS prescribing database have confirmed the influence of media reports on prescribing practice in comparison with advice provided by the regulatory authority17, 18. No official warnings from regulatory authorities including the Medicines and Healthcare products Regulatory Agency (MHRA) or Irish Medicines Board (IMB) were issued on foot of this meta-analysis1. The MHRA noted the limitations of the study, and concluded that no action was necessary based on current evidence, but agreed that further research was needed in this area19. Our results appear to confirm the influence of the media on prescribing practice of calcium alone preparations.

A recently published re-analysis of the Women's Health Initiative data shows women allocated to calcium and vitamin D administration who were not taking personal calcium supplements were also at increased risk of cardiovascular events20.Meta-analyses of trials21,22,23,24 found that calcium supplements used with or without vitamin D modestly increase cardiovascular risk, suggesting their use in osteoporosis management should be reassessed. The impact of this recent article on prescribing of calcium and vitamin D products in Ireland cannot yet be assessed, due to the unavailability of more recent figures. Patients are informed of the risk associated with medications individually by their physicians, pharmacists, patient information leaflet or package insert or as a group by the media. Pharmacovigilance identifies and responds to safety issues regarding marketed medicines. However, communicating drug safety information can be quite complex and is often fraught with vested interests from the regulatory authorities, the pharmaceutical industry, health care professionals and consumer groups. A number of studies have found that the mainstream media are often the first source from which the public, including health professionals, learn about medical advances25,26.

This study had a number of limitations. The fact that the prescribing database is not linked to diagnoses allows one to make a presumptive diagnosis only, on the basis of drugs that patients were prescribed. Similarly, it was not possible to identify the incidence of possible cardiac events in those being prescribed calcium alone. Other differences such as bio-availability of preparations, actual compliance and body mass index could not be explored in our observational study. However, our study population is representative of patients offered calcium supplementation and choice of preparations in real-life practice.

Given the apparent influence of media reporting of health issues on both the prescribing habits of health care professionals and the behaviour of consumers, a systematic and united approach to urgent issues regarding drug safety is required to ensure that prescribers can advise patients appropriately. In addition such information should be disseminated in a clear fashion to avoid undue public concern.

References

1 Bolland MJ, Avenell A, Baron JA, Grey A, McLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341:1-9

2 Wilkinson E. Calcium pills 'increase' risk of heart attack (29th July 2010). http://www.bbc.co.uk/news/health-10805062. Accessed August 9th,2011

3 Women who take calcium supplements 'increase risk of heart attack by up to 30% (30th July 2010). http://www.dailymail.co.uk/health/article- 1298862/Women-calcium-supplements-increase-risk-heart-attack- 30.html.Accessed August 9th, 2011

4 Adams S. Calcium pills 'increase heart attack risk.(30th July 2010).http://www.telegraph.co.uk/health/healthnews/7916657/Calcium-pills- increase-heart-attack-risk.html.Accessed August 9th,2011

5 Calcium increases heart attack risk. http://www.irishtimes.com/newspaper/breaking/2010/0730/breaking13.html.A... August 10th, 2011.

6 Naughton C, Bennett K, Feely J. Prevalence of chronic disease in the elderly based on a national pharmacy claims database. Age Ageing 2006; 35: 633-6.

7 Feely J, Chan R, McManus J, O'Shea B. The influence of hospital based prescribers on prescribing in general practice. Pharmacoeconomics 1999; 16(2): 175-181

8 Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333

9 Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291: 47-53

10 Solomon S, McMurray J, Pfeffer M, Wittes J, Fowler R, Finn P, Anderson W, Zauber A, Hawk E, Bertagnolli M. Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-80

11 Williams D, Singh M, Hind C. The effect of the withdrawal of rofecoxib on prescribing patterns of COX-2 inhibitors in Scotland. Br J Clin Pharmacol. 2006 September 1; 62(3): 366-368

12 Shah, B. R., Juurlink, D. N., Austin, P. C. and Mamdani, M. M. (2008), New use of rosiglitazone decreased following publication of a meta- analysis suggesting harm. Diabetic Medicine, 25: 871-874. doi: 10.1111/j.1464-5491.2008.02462.

13 Jick H, Jick SS; Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and non-fatal venous thromboembolism in women using oral contraceptives with different progestogen components. Lancet 1995; 346:1589-93.

14 Hope S. Twelve per cent of women stopped taking their pill immediately after they heard the CSM' s warning.Lancet 1996 , 347, 576.

15 Iverson O, Nilsen S. Abortions increased by nearly 8% in Norway, BMJ 1996;313:363

16 Bhathena RK. The 1995 Pill scare and its aftermath: lessons learnt. Journal of Obstetrics and Gynaecology (1998) Vol. 18, No. 3, 215-217

17 Williams D, Kelly A, Feely J. Influence of media and regulatory changes on prescribing of cotrimoxazole and trimethroprim in Ireland.Pharmacoepidemiology and Drug Safety.2000;9:313-317

18 Williams D, Kelly A, Carvalho M, Feely J. Effect of the British warning on contraceptive use in the General Medical Service in Ireland. IMJ 1998; 91:201-Accessed 15th August,2011.

19 Calcium supplements: study of possible risks on heart and circulatory system. http://mhra.gov.uk/home/groups/l-cs- el/documents/committeedocument/con096942.pdf.

20 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

21 Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354:669-83.

22 Hsia J, Heiss G, Ren H, Allison M, Dolan NC, Greenland P, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007;115: 846-54.

23 Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low- trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D: RECORD): a randomised placebo-controlled trial. Lancet 2005; 365:1621-8.

24 Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-91

25 Geller G, Tambor ES, Bernhardt BA, Rodgers J, Holtzman NA. Houseofficers' reactions to media coverage about the sequencing of the human genome. Soc Sci Med. 2003;56:2211-2220

26 Larsson A, Oxman AD, Carling C, Herrin J (2003) Medical messages in the media-barriers and solutions to improving medical journalism. Health Expect 6: 323-331.

Competing interests: None declared

Cora McGreevy1, Clinical Lecturer in Geriatric and Stroke Medicine

Kathleen Bennett2, David Williams1

1-Department of Geriatric and Stroke Medicine,RCSI,Beaumont Hospital, Dublin, Ireland2-Department of

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We disagree with the comments made by Professor Tayek. He has overlooked that the lipid data were available only in a subgroup of 223 participants. The difference in LDL between the groups was not statistically significant (P=0.37). Baseline measurements of cholesterol were available for one other study, and again there were no statistically significant differences between the groups.[1] He then compares our meta- analysis of randomized controlled trials with previous meta-analyses of observational studies. We agree that observational studies and meta- analysis of observational studies can produce misleading results; however our analysis was of randomized controlled trials, in which the data were collected prospectively, so the comments are not relevant.

1. Reid IR, Ames R, Mason B, Reid HE, Bacon CJ, Bolland MJ, et al. Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men. Arch Intern Med 2008;168:2276-82.

Competing interests: Competing interests were declared in the manuscript.

Mark J Bolland, Senior Research Fellow

Andrew Grey, Ian R Reid

University of Auckland

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Thanks for pointing out this mistake. Your interpretation is correct- the sentence should have read "190 strokes occurred in people allocated to calcium compared with 156 in people allocated to placebo (RR 1.24, 95%CI 0.99-1.56, P=0.07)". The error arose in the final draft before the manuscript was submitted when the sentence was changed to try and improve the readability of the article, and the change in meaning was unfortunately overlooked. A correction has been issued.

Competing interests: None declared

Mark J Bolland, Senior Research Fellow

University of Auckland

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Dear Sirs,

I reviewed with some interest the meta-analysis, "Effect of calcium supplements on risk of myocardial infarction and cardiovascular events" (BMJ 2010;341:c3691). Within the discussion of recurrent cardiovascular events (Section: Results; subsection: Patient level analysis, fourth paragraph), the text reads, "Stroke occurred in 190 people allocated to calcium compared with 156 allocated to placebo (1.24, 0.99 to 1.56, P=0.07)." This statement appeared to contradict a prior statement that "During follow-up, 167 people allocated to calcium and 143 allocated to placebo had a stroke" (same subsection, second paragraph). Thus, I wonder whether the authors had intended to report that "190 strokes occurred in 167 people allocated to calcium compared with 156 strokes in 143 people allocated to placebo." Your clarification would be much appreciated.

I applaud the authors for their discussion of this significant topic.

Competing interests: None declared

Hillard T. Spencer, Chief Resident

Department of Orthopaedic Surgery, University of California, Los Angeles

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Recent data suggests that additional calcium intake may increase the rate of myocardial infarction (MI) (1). Bolland et al described that a calcium intake > 500 mg/day is associated with an Odds Ratio of 1.31 (CI:1.02-1.67, p=0.035) for increase MI risk. They found that a total of 143 elderly had an MI who were treated with calcium and 111 had an MI who were given placebo at an average age of 75. Calcium intake was associated with a 6% versus 5% (Calcium versus placebo intake) MI rate after approximately 5 years. According to their data, one additional MI would occur per 100 elderly patients treated with calcium if the analysis is an accurate prediction of future events.

This author has one minor allocation problem with the analysis and one major clinical problem with meta-analysis that have a low odds ratio. Bolland's et al meta-analysis consists of 5 clinical trials with patient level data (1). One of these references a recent publication (2), which listed 31 MIs in the calcium treated group and 21 MIs in the placebo treated. Reviewing patient characteristics (Table 1), patients enrolled in the calcium treated arm had a higher LDL cholesterol compared to placebo (4.39 versus 4.26 mmol/l). While this data was not marked as significant in the published table (2), this author compared the mean and SD where the signal was equal to the treatment diff = 4.39 - 4.26 = 0.13; s = weighted average SD = sqrt[ (732*1.16*1.16 + 739*0.98*0.98) / (732 + 739) ] = 1.073. The noise = SE = s * sqrt [ 1/732 + 1/739 ] = 0.056 ; Signal:Noise ratio = t-ratio = 0.13/0.056 = 2.32 ; p=0.02 from t-table.

Therefore, LDL cholesterol was significantly elevated in the calcium treatment group which may, in part, contributed to the increased MI rate reported (1). If these study data are removed from the analysis, then 112 MIs were seen in calcium treated group and 90 MIs in those given placebo, for a corrected odds ratio of 1.24. Was this now significant? Was there more asymmetry with the LDL cholesterol in other four clinical trials used in the meta-analysis?

Historically, the Nurses Health Study (3) provided data that postmenopausal estrogen therapy was associated with a reduced odds ratio for Coronary Heart Disease (CHD); (OR 0.56, CI:0.40-0.80, p<0.05). However, the prospective randomized Women Health Initiative (WHI) clinical trial demonstrated the opposite result (4). CHD was increased by an Odds Ratio of 1.29 (1.02-1.63, p<0.05). While retrospective data analysis suggested a reduced risk by approximately half, in fact the risk of CHD was significantly increased by a relative 29%.

Similar meta-analysis have also lead investigators down the wrong road with regards to vitamin E therapy for the prevention of MI (5,6). Vitamin E intake was associated with a reduced Odds Ratio for CHD risk in women (0.66, CI 0.50-0.87, p<0.05) and for men (0.64, CI: 0.49-0.83, p <0.05) (5,6). While these data were provided by prolific researchers and published in an outstanding journal (like the earlier work on Hormone Replacement Therapy), their data was also misleading. In a very large prospective randomized, blinded placebo control trial, treatment with Vitamin E failed to substantiate any benefit in the prevention of CHD (Odd Ratio 1.02, CI:0.90-1.15; Ref 7).

Retrospective analysis of data is very dangerous and most meta- analysis have yet to be validated by prospective data. While publication space is becoming ample with electronic storage, facts to be place in these sites must be reviewed with the utmost rigor. May be editors should not publish Odds Ratios between 0.5 and 2.0. No prior analysis with such a weak Odds Ratio has ever been validated in a prospective randomized blinded clinical trial to this author's knowledge. Preventing publications of misleading or inaccurate data is paramount to promote hypothesis worth testing.

References

1 Bolland MJ, Avenell A, Baron JA, Grey A, McLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:1-9.

2 Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR. Vascular events in healthy older women receiving calcium supplementation: randomized controlled trial. BMJ 2010;1-8.

3 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. New England Journal of Medicine 1991;325(11):756-761.

4 Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women's health initiative randomized controlled trial. JAMA-EXPRESS 2002;288(3):321-332.

5 Stampfer MJ, Hennekens CH, Manson JE, Golditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. New England Journal of Medicine 1993;328(20)1444-1449.

6 Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart diease in men. New England Journal of Medicine 1993;328(20)1450-1456.

7 The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E Supplementation and Cardiovascular Events in High-Risk Patients. New England Journal of Medicine 2000;342(3)154-159.

Competing interests: None declared

John A. Tayek, Professor of Medicine-In Residence

Harbor-UCLA Medical Center

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In their recent meta-analysis, Bolland and colleagues [1] suggest supplements of calcium without coadministered supplement of vitamin D to increase the risk of myocardial infarction.

In clinical trials investigating cardiovascular outcomes placebos are often used as the control against active drugs. Placebo tablets frequently contain calcium. For example, metformin placebo tablets may each contain about 60 mg calcium (as calcium phosphate) of which typically between 4 and 6 tablets are taken per day. Thus, a daily calcium supplement of about 240-300 mg can be anticipated in those patients allocated placebo metformin. As pointed out by Bolland and colleagues, the aspect of calcium suppplements to potentially promote cardiovascular disease is less investigated and if such effect exists, as yet, to my knowledge, a dose- response has not been established. Thus, although the study by Bolland and colleagues represents studies using more than 500 mg calcium supplements per day, it is probably unknown if less daily supplement could also be harmful with respect to cardiovascular disease.

If the findings from Bolland and colleagues represent a true effect of calcium supplement, it is conceivable that the apparent protective effect of active drugs such as antihypertensive drugs, lipid-lowering drugs etc. on cardiovascular outcomes observed in previous clinical trials could, at least partly, be due to unknown and unanticipated harmful effects of the placebos used in these trials. Thus, by possibly delivering additional calcium to the atherosclerotic process in those patients allocated placebo, the use of placebos containing calcium could obscure the conclusions in clinical trials of cardiovascular disease.

1. Bolland M.J., Avenell A., Baron J.A. et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341:c3691.

Competing interests: None declared

Soeren S. Lund, MD

Self-employed

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Although I advocate the use of some supplements, I do NOT recommend calcium supplements.

A new study shows that high vitamin A levels and low vitamin D levels could be a risk factor for osteoporosis (1).

Calcium supplements do not prevent the risk of fractures, and because there's some evidence that they cause cardiovascular events, it is more prudent to obtain calcium from food sources, and avoid these supplements. Patients can opt for lactose-free milk, yogurt, kale, salmon, and a host of other natural high-calcium foods, and supplement with vitamin D (with some healthy fats so it can be absorbed). Vitamin A supplements should be avoided.

Some evidence shows that vitamin K can prevent fractures, and magnesium is important to assimilate vitamin D and thus to strengthen bones.

Thus, although other research is required to prove or disprove their safety, the evidence shows that calcium supplements are an unnecessary risk, and that other nutrients are required to prevent fractures.

1. Mata-Granados JM, Cuenca-Acevedo R, Luque de Castro MD, et al. Vitamin D deficiency and high serum levels of vitamin A increase the risk of osteoporosis evaluated by Quantitative Ultrasound Measurements (QUS) in postmenopausal Spanish women. Clin Biochem ; 2010 Sep;43(13-14):1064-8.

Competing interests: None declared

Ettore Hector Corsi, biologist

Nutrition Consultant

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3 September 2010

Professor Baron, with Dartmouth College, holds a use patent for calcium supplements as a chemopreventive agent. This was not described in the conflict of interest statement in the manuscript. We apologise for this oversight.

Competing interests: None declared

Mark J Bolland, Senior Research Fellow

John A Baron

University of Auckland

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It may be easily derived from densitometry that adolescents need 450 mg net elementary calcium per day on average to build up their skeleton. Elderly people lose 80 mg/day by natural degradation of their skeleton due to mechanical disuse. This unuseful calcium has to be removed from the system to ensure proper electrolytical function, to say it in simple words. A total of roughly 300 mg calcium ions are present in 3 liters of our serum to serve as one of the electrolytes. This concentration must be kept within very tight limits.

I have never seen a normal adolescent taking calcium supplementation. It is simply a misbelieve that elderly would benefit from 500 to 1500 mg extra calcium to reverse the bone degradation process. There is no conclusive pathway which could explain that.

Therefore, it is not surprising that excess calcium supplementation results in vascular calcification and kidney stones (NEnglJMed 354;7). "Bone Appetite!" .

Competing interests: None declared

Peter Schneider, Deputy Head

University Clinic Wuerzburg, Clinic and Policlinic for Nuclear Medicine

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To the editor,

Further to our earlier response, in which we addressed several important issues relating to our paper, we now respond to other issues raised by correspondents.

Some of the correspondents' criticisms of our paper are factually incorrect: all-cause mortality is reported in the paper; the number of included studies is correct; a quality assessment was carried out; the patient-level meta-analysis was carried out correctly (it included both a one-step technique where both intra-study and between-study effects were modelled and a two-step technique that incorporated studies with trial level data); and the lack of a linear relationship between baseline dietary calcium intake and the risk of MI with calcium supplements does not preclude calcium supplements themselves increasing the risk of MI.

Other correspondents ask for information already presented in the paper: there was no difference in the risk associated with citrate or carbonate preparations, or by gender.

Some correspondents have claimed the study is flawed for other reasons: the role of other nutrients was not considered, study inclusion and exclusion criteria were not highlighted, young men and women were not included in the meta-analysis, baseline cardiovascular risk factors were not gathered or reported in some studies, data on outcomes were gathered using different methods in different studies and are unpublished and impossible to verify, only 5/11 studies supplied patient-level data, cardiovascular outcomes were not the primary endpoint of the studies, a plausible biological reason for the increased cardiovascular risk from calcium was not presented, the increased cardiovascular risk from calcium was due to the age of the participants not the calcium supplements, observational studies of calcium intake were not included in this meta- analysis of randomized trials, the covariance structure in the secondary Poisson regression analyses was not reported, and finally, most of the studies were dated.

None of these issues is compelling. The key points are that our meta- analysis was of randomized placebo-controlled trials and that any differences in the baseline groups for cardiovascular risk factors or ingestion of other nutrients are due to chance. For such differences to explain our findings there would have to have been a failure of randomization in the contributing studies, such that groups allocated to calcium had a higher baseline prevalence of cardiovascular risk factors. This is extremely unlikely and not supported by the baseline data provided in the paper. Therefore, any difference in outcomes in these studies is most likely related to the treatment allocation, rather than the alternative explanations proposed by correspondents. Finally, we disagree with the suggestion that there is no plausible mechanism for the increased cardiovascular risk from calcium supplements. Putative mechanisms are advanced in the paper, and have been described in more detail elsewhere.1 Even if this were not the case, it does not invalidate a consistent pattern of results from a number of large randomised controlled trials- there are many instances in medicine in which our understanding of biology is unable at present to adequately explain observed phenomena.

Most of the numerous comments by Professor Nordin and colleagues are dealt with above or in our previous response. With regard to the remaining concerns: this was a meta-analysis. The draft protocol was circulated to all the authors of the 15 studies eligible for inclusion with a request for comments. Suggested amendments were incorporated into the protocol, which was reviewed and approved by all investigators participating in the patient-level meta-analysis before data collation and analysis commenced. We did not "cherry-pick" studies: only 15 studies met the relatively broad pre-specified inclusion and exclusion criteria, and these criteria were agreed to by all those contributing data. In a recent meta-analysis of calcium supplements on fracture and bone density,2 Tang and colleagues identified only 16 eligible studies of calcium supplements, and all nine of the studies with at least 100 participants were included in our meta- analysis. The present study was analyzed by intention-to-treat. A per- protocol analysis can be considered a form of a sub-group analysis where inclusion in the compliant or non-compliant groups is defined after randomization, and inherently related to it. Such analyses have well-known limitations and a corresponding limited role in the assessment of harms or benefits of treatments.3

Dr Lewis and colleagues make a number of criticisms that have been previously addressed. They also criticise the choice of endpoints, which were pre-specified in the protocol and approved by investigators before any data were gathered. Dr Lewis and colleagues ask why the analysis for MI was restricted to ICD code 410 (acute MI) rather than the broader category of ischaemic heart disease (ICD 411-414). The endpoint we studied was MI, and it would not be sensible to include events with ICD codes 411- 414 in the category of MI when, by definition, acute MI has been excluded. They also criticise the stroke endpoint for being too broad. We included all strokes, regardless of underlying mechanism, because that is standard practice in such analyses, and at the time some of the studies were undertaken, imaging to classify strokes as haemorrhagic or ischaemic was not routinely undertaken. We did not include TIAs because these events are much more difficult to accurately diagnose than stroke. We used sudden death in the composite endpoint for consistency with our previous study, but as pointed out in Table 3 of our paper, this classification was not frequently used. They next question the handling of events where the date of event was not known, incorrectly referring to these events as "unverified" and incorrectly stating the majority were in the calcium groups. There were no appreciable differences in such events between groups (P=0.7), and the approach we took is the most conservative way of handling such events. We have now repeated the analysis excluding these events, but the hazard ratio does not change. We do not believe applying a Bonferroni correction is appropriate, as such an adjustment would not change the hazard ratios and there is lower burden of proof for toxicity of preventive interventions. Finally, Dr Lewis and colleagues supplied data that were included in our trial-level meta-analysis, so their current paper4 does not alter our conclusions. Despite being aware of our results, they did not report data for MI and stroke separately, so unfortunately the findings from their paper cannot be compared with those of our meta- analysis.

We reiterate our conclusion that a reassessment of the role of calcium supplements in osteoporosis management is timely. Meta-analyses of trials of calcium supplements without vitamin D report that the relative risk of any fracture with calcium is 0.90 (95% CI 0.80-1.0, P=0.052, n=9 studies, n=6,517 participants),2 of hip fracture is 1.50 (95% CI 1.1- 2.1, P=0.02, n=3 studies, n=5,574 participants),5 and of myocardial infarction is 1.27 (95%CI 1.01-1.59, P=0.038, n=11 studies, n=11,921 participants).6 These results challenge the beliefs that calcium supplements are safe and effective.

1. Reid IR, Bolland MJ, Grey A. Does Calcium Supplementation Increase Cardiovascular Risk? Clin Endocrinol (Oxf) 2010:Published online 23 Feb.

2. 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;370:657-666.

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. Lewis JR, Calver J, Zhu K, Flicker L, Prince RL. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. J Bone Miner Res 2010.

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

6. 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.

Competing interests: Competing interests were declared in the original manuscript

Mark J Bolland, Senior Research Fellow

Alison Avenell, John A Baron, Andrew Grey, Graeme S MacLennan, Greg D Gamble, Ian R Reid

University of Auckland

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