Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c3691 (Published 29 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: No competing interests
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.
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: No competing interests
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: No competing interests
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: No competing interests
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: No competing interests
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: No competing interests
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: No competing interests
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: No competing interests
Re: Possible explanation for increased risk of myocardial infarction and calcium supplementation
I believe the mechanism of calcium causing the risk of myocardial infarction is partially due to the lack of vitamin K2 supplementation along with Calcium.
Bone Matrix Protein (BMP) is present in the arterial wall. When BMP is exposed to calcium it forms bone. Thus calcification of the artery is formed. Vitamin K2 regulates matrix GLA proteins. These proteins regulate the calcium distribution throughout the body. Without K2, dysregulation occurs and calcium deposits in sections of the body where it does not belong i.e.. arterial walls and kidneys, muscle. Dr. Leon Schurgers a biochemist from the Netherlands has studied this effect. People with higher levels of K2 have a 47% reduction in coronary disease. They also have about 50% less aortic calcification.
It may recommended that we consider looking at supplementing with all the necessary vitamins and minerals necessary for bone health, rather than partially which can disturb the balance of bone metabolism. Dr. Schurgers has found 185 mcg to be adequate to decarboxylate the GLA proteins.
Competing interests: No competing interests