Do calcium plus vitamin D supplements increase cardiovascular risk?BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2080 (Published 19 April 2011) Cite this as: BMJ 2011;342:d2080
All rapid responses
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.
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-
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
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.
Competing interests: No competing interests
If I am seeking an impartial review of a subject , I would not
commission an editorial written by two experts who acknowledge that they
have received money from manufacturers of some of the products in
Their conclusion of the risks are an opinion rather than fact , and ,
however strong the validity of the case and their impartiality, it is
weakened (in this readers view ) by the declared connections.
Did the BMJ know no other experts in the world on the subject without
declared financial ties? Hopefully there are still some other doctors who
don't receive consultancy fees , lecture fees or serve on advisory boards
for pharmaceutical companies.
Competing interests: I may die of cardiovascular disease.
Dear Sir, The WHI study may not apply to fracture neck of femur
patients. In the WHI study just 18 - 20% of patients were older than 70
years. The median age for fracture neck of femur patients is 82.
Calcium and vitamin D are extensively prescribed to fracture neck of
femur patients; similar to angiotensin converting enzyme inhibitors for
heart failure patients. This paper raises more clinical questions than
First; will clinicians give Calcium and vitamin D supplements for
fracture neck of femur patients with normal Calcium levels?
These are high-risk patients who will benefit from interventions; i.e
Calcium, vitamin D and antiresorptive measures. Yet they are older
patients and most of them have cardiovascular risk factors. The
cardiovascular safety of Calcium has been questioned. However there is
evidence to support that treatment for osteoporotic fracture reduces
mortality in frail older people (1). Also previous studies showed that the
use of calcium and vitamin D on top of bisphosphonates for osteoporosis is
reassuring regarding cardiovascular safety (2).
Second; will clinicians reduce the dose of supplemental Calcium (and
vitamin D); to gain the potential bone benefit and reduce the
cardiovascular risk, a reasonable compromise?
To summarize; Fracture neck of femur patients represents a special
group with potential need for Calcium and vitamin D and high risk for
ishaemic heart disease. More studies are needed to address these issues
and evaluate the benefit/ risk ratio in this frail group of patients.
(1) Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis
treatment on mortality: a meta-analysis. J Clin Endocrinol Metab
(2) Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase
cardiovascular risk? BMJ 2011; 342.
Competing interests: No competing interests