Calcium and Heart Disease: Do Supplements Cause Heart Attacks?

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A study came out recently that tied calcium supplementation to heart attack risk.

It came to my attention as a blurb in a magazine that a patient brought in to me.  I found it hard to believe.

Here’s why.  Calcium doesn’t just get into the blood stream.  All that calcium stays in the gut unless there is sufficient vitamin D to draw it through the gut into the blood stream.  The vitamin D activity is regulated by parathyroid hormone.

In the absence of ingested calcium, the body will simply increase calcium by taking it from the bones.  Women trying very hard to slow this absorption of bone (and block osteoporosis) are often unsuccessful despite taking calcium and vitamin D.  So the idea of all that calcium flooding the system and generating increased heart attacks seems a bit of a stretch.

Upon initial examination, the claim of increased risk seems genuine.  WebMD, that bastion of all things medical, ran an article on the most recent study.  In an analysis of a subgroup of women in the WHI larger study by New Zealand researchers, women taking calcium were at increased risk.  The article cites to thirteen other studies that support the link.

But even in the article, the experts don’t seem to agree.  One of them points out that we’re selecting from a subgroup in a larger study to prove a VERY generalized point.

So I went looking at the study, which was published in the prestigious BMJ in April.  It looks pretty damning, except that they exempted any women who were already taking calcium or vitamin D from this reanalysis.  Among women who started taking calcium and vitamin D as part of the study, there was increased stroke and heart attack risk.  Women who were already taking the supplements were excluded because they were somehow protected from the sudden burst of calcium into their systems.

But in the larger study as a whole, the whole cohort of women in the WHI did not have increased risk from taking vitamin D and calcium.  Another group of researchers  had come to that conclusion looking at the same information two years previously.  They found that the women taking calcium and vitamin D had slightly lower death rates.

When I went looking for other information, the same researchers in New Zealand also published another analysis of many different studies in which they concluded that -of course- they were right and calcium/vitamin D supplementation results in increased heart attack risk.   When you look at all those studies, out of 11, 921 people 143 had a problem in the calcium groups compared to 111 in the placebo groups.  While statistically significant, it isn’t outside the range of error.

But surely someone else has studied the sudden death rate of people snarfing calcium and vitamin D willy-nilly?  Yes, they have.  In the UK, they studied 9,000 women who had just started those dangerous vitamins and found that they had no increased risk over two years.  In fact, their risk seemed to go down a bit.

So how do we reconcile these data?  It occurred to me that the controlling hormone in this situation is parathyroid hormone.  Might that not be a factor?  In August, other researchers published their findings that elevated parathyroid hormone is an independent risk factor for heart disease.  The risk from elevated parathyroid hormone far exceeds the suspected risk from calcium supplementation.

So the women in the WHI who were not taking calcium and vitamin D were more likely to have higher parathyroid hormone levels.  Those elevated levels, not the supplementation with calcium and vitamin D, would explain the research discrepancies.

So should you take calcium supplements?  Consult your doctor.  I get mine from leafy green vegetables (until they come out with the negative studies on those).  I’ll stick all the studies below so you can print them out for your overworked PCP.

BMJ. 2011 Apr 19;342:d2040. doi: 10.1136/bmj.d2040.

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.

Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR.

Source

Department of Medicine, University of Auckland, Private Bag
92 019, Auckland 1142, New Zealand.

Abstract

OBJECTIVES:

To investigate the effects of personal calcium supplement
use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D
Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the
recent meta-analysis of calcium supplements and cardiovascular risk.

DESIGN:

Reanalysis of WHI CaD Study limited access dataset and
incorporation in meta-analysis with eight other studies. Data source WHI CaD
Study, a seven year, randomised, placebo controlled trial of calcium and
vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling
postmenopausal women. Main outcome measures Incidence of four cardiovascular
events and their combinations (myocardial infarction, coronary
revascularisation, death from coronary heart disease, and stroke) assessed with
patient-level data and trial-level data.

RESULTS:

In the WHI CaD Study there was an interaction between
personal use of calcium supplements and allocated calcium and vitamin D for
cardiovascular events. In the 16,718 women (46%) who were not taking personal
calcium supplements at randomisation the hazard ratios for cardiovascular
events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for
clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial
infarction or revascularisation), whereas in the women taking personal calcium
supplements cardiovascular risk did not alter with allocation to calcium and
vitamin D. In meta-analyses of three placebo controlled trials, calcium and
vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95%
confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P =
0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to
1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or
calcium and vitamin D, complete trial-level data were available for 28,072
participants from eight trials of calcium supplements and the WHI CaD
participants not taking personal calcium supplements. In total 1384 individuals
had an incident myocardial infarction or stroke. Calcium or calcium and vitamin
D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to
1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15
(1.03 to 1.27), P = 0.009).

CONCLUSIONS:

Calcium supplements with or without vitamin D modestly
increase the risk of cardiovascular events, especially myocardial infarction, a
finding obscured in the WHI CaD Study by the widespread use of personal calcium
supplements. A reassessment of the role of calcium supplements in osteoporosis
management is warranted.

Comment in

BMJ. 2011;342:d3520.

BMJ. 2011;342:d3538.

BMJ. 2011;342:d3543.

BMJ. 2011;342:d2080.

Praxis (Bern 1994). 2011 Jul 27;100(15):933-4.

BMJ. 2011;342:d3530.

BMJ. 2011;342:d3541.

Nat Rev Endocrinol. 2011;7(7):373.

PMID: 21505219

BMJ. 2010 Jul 29;341:c3691. doi: 10.1136/bmj.c3691.

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

Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS,
Gamble GD, Reid IR.

Source

Department of Medicine, Faculty of Medical and Health
Sciences, University of Auckland, Private Bag 92 019, Auckland 1142, New
Zealand.

Abstract

OBJECTIVE:

To investigate whether calcium supplements increase the risk
of cardiovascular events.

DESIGN:

Patient level and trial level meta-analyses.

DATA SOURCES:

Medline, Embase, and Cochrane Central Register of Controlled
Trials (1966-March 2010), reference lists of meta-analyses of calcium
supplements, and two clinical trial registries. Initial searches were carried
out in November 2007, with electronic database searches repeated in March 2010.

STUDY SELECTION:

Eligible studies were randomised, placebo controlled trials
of calcium supplements (>or=500 mg/day), with 100 or more participants of
mean age more than 40 years and study duration more than one year. The lead
authors of eligible trials supplied data. Cardiovascular outcomes were obtained
from self reports, hospital admissions, and death certificates.

RESULTS:

15 trials were eligible for inclusion, five with patient
level data (8151 participants, median follow-up 3.6 years, interquartile range
2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration
4.0 years). In the five studies contributing patient level data, 143 people
allocated to calcium had a myocardial infarction compared with 111 allocated to
placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035).
Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to
1.50, P=0.11), the composite end point of myocardial infarction, stroke, or
sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23,
P=0.18). The meta-analysis of trial level data showed similar results: 296
people had a myocardial infarction (166 allocated to calcium, 130 to placebo),
with an increased incidence of myocardial infarction in those allocated to
calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59,
P=0.038).

CONCLUSIONS:

Calcium supplements (without coadministered vitamin D) are
associated with an increased risk of myocardial infarction. As calcium
supplements are widely used these modest increases in risk of cardiovascular
disease might translate into a large burden of disease in the population. A
reassessment of the role of calcium supplements in the management of osteoporosis
is warranted.

Comment in

BMJ. 2010;341:c4997.

BMJ. 2010;341:c4995.

BMJ. 2010;341:c4993.

Praxis (Bern 1994). 2010 Dec 15;99(25):1577-8.

Evid Based Med. 2010 Dec;15(6):181.

Ann Intern Med. 2010 Nov 16;153(10):JC5-7.

BMJ. 2010;341:c3856.

BMJ. 2010;341:c5003.

PMID: 20671013

Pharmacoepidemiol Drug Saf. 2010 Jan;19(1):59-64.

Calcium supplementation, cardiovascular disease and
mortality in older women.

Shah SM, Carey IM, Harris T, DeWilde S, Cook DG.

Source

Division of Community Health Sciences, St George’s
University of London, London SW17 0RE, UK. sushah@sgul.ac.uk

Abstract

PURPOSE:

To investigate the long-term cumulative effect of calcium
and vitamin D supplementation on cardiovascular outcomes and death in older
women.

METHODS:

We undertook an observational cohort study using UK
electronic primary care records in the Doctor’s Independent Network (DIN-LINK)
database; 9910 women aged 60-89 who started calcium and vitamin D
supplementation between 2000 and 2005, with no heart disease or stroke history
and who survived disease free for 2 years after supplement initiation were
studied. The main outcome was first occurrence of myocardial infarction (MI),
stroke or death more than 2 years after initiation.

RESULTS:

In the period from 2 years after supplement initiation,
women who had received >600 days supplementation in these first 2 years were
no more at risk of MI, stroke or death (hazard ratio 0.82 (0.67-1.01)) compared
to women who received < or = 90 days supplementation in the first 2 years.
Outcomes in the first 2 years were analysed separately and showed similar
baseline risks in our comparison groups.

CONCLUSION:

Two years after initiation, women who have consistently
received supplementation with calcium and vitamin D do not experience more
cardiovascular events or deaths than women who received minimal
supplementation.

PMID: 19757413

J Gerontol A Biol Sci Med Sci. 2009 May;64(5):559-67. Epub
2009 Feb 16.

Calcium plus vitamin D supplementation and mortality in
postmenopausal women: the Women’s Health Initiative calcium-vitamin D
randomized controlled trial.

LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA,
Cummings SR, Gass M, Johnson KC, Ko M, Larson J, Manson JE, Stefanick ML,
Wactawski-Wende J.

Source

WHI Clinical Coordinating Center, Fred Hutchinson Cancer
Research Center, 1100 Fairview Avenue North, M3-A410, PO Box 19024, Seattle, WA
98109-1024, USA. alacroix@whi.org

Abstract

BACKGROUND:

Calcium and vitamin D (CaD) supplementation trials including
the Women’s Health Initiative (WHI) trial of CaD have shown nonsignificant
reductions in total mortality. This report examines intervention effects on
total and cause-specific mortality by age and adherence.

METHODS:

The WHI CaD trial was a randomized, double-blind,
placebo-controlled trial that enrolled 36,282 postmenopausal women aged 51-82
years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of
elemental calcium carbonate and 400 IU of vitamin D(3) daily or placebo with
average follow-up of 7.0 years.

RESULTS:

The hazard ratio (HR) for total mortality was 0.91 (95%
confidence interval [CI], 0.83-1.01) with 744 deaths in women randomized to CaD
versus 807 deaths in the placebo group. HRs were in the direction of reduced
risk but nonsignificant for stroke and cancer mortality, but near unity for
coronary heart disease and other causes of death. HRs for total mortality were
0.89 in the 29,942 women younger than 70 years (95% CI, 0.79-1.01) and 0.95 in
the 6,340 women aged 70 and older (95% CI, 0.80-1.12; p value for age
interaction = .10). No statistically significant interactions were observed for
any baseline characteristics. Treatment effects did not vary significantly by
season.

CONCLUSIONS:

In the WHI CaD trial, supplementation did not have a
statistically significant effect on mortality rates but the findings support
the possibility that these supplements may reduce mortality rates in
postmenopausal women. These data can neither support nor refute recommendations
for higher dose vitamin D supplementation to reduce cancer or total mortality.

PMID: 19221190

Am Heart J. 2011 Aug;162(2):331-339.e2.

Parathyroid hormone, vitamin D, renal dysfunction, and
cardiovascular disease: Dependent or independent risk factors?

Anderson JL, Vanwoerkom RC, Horne BD, Bair TL, May HT, Lappé
DL, Muhlestein JB.

Source

Cardiovascular Department, Intermountain Medical Center,
Murray, UT; Cardiology Division, University of Utah School of Medicine, Salt
Lake City, UT.

Abstract

BACKGROUND:

Vitamin D (Vit D) deficiency has been associated with
prevalent and incident cardiovascular (CV) disease, suggesting a role for
bioregulators of bone and mineral metabolism in CV health. Vitamin D deficiency
leads to secondary hyperparathyroidism, and both primary and secondary
hyperparathyroidism are associated with CV pathology. Parathyroid hormone (PTH)
is an important regulator of calcium homeostasis, and its impact on CV disease
risk is of interest. We tested whether elevated PTH is associated with CV
disease and whether risk associations depend on Vit D status and renal
function.

METHODS:

Patients in the Intermountain Healthcare system with
concurrent PTH and Vit D as 25-hydroxy-vitamin D (25[OH]D) levels were studied
(N = 9,369, age 63 ± 16 years, 36% male). Parathyroid hormone levels were
defined as low (<15 pg/mL), normal (15-75 pg/mL), or elevated (>75
pg/mL). Prevalence and incidence of hypertension, diabetes, hyperlipidemia,
coronary artery disease/myocardial infarction, heart failure, stroke, and
peripheral vascular disease were determined by the International Classification
of Diseases, Ninth Revision codes documented in electronic medical records at
baseline and, for incident events, during an average of 2.0 ± 1.5 years
(maximum 7.5 years) of follow-up.

RESULTS:

Parathyroid hormone elevation at baseline was noted in 26.1%
of the study population. Highly significant differential CV
prevalence/incidence rates for most CV risk factors, disease diagnoses, and
mortality were noted for PTH >75 pg/mL (by 1.25- to 3-fold). Parathyroid
hormone correlated only weakly (r = -0.15) with 25(OH)D and moderately with
glomerular filtration rate (r = -0.36). 25(OH)D, standard risk factors, and
renal dysfunction variably attenuated PTH risk associations, but risk persisted
after full multivariable adjustment.

CONCLUSIONS:

Elevated PTH is associated with a greater prevalence and
incidence of CV risk factors and predicts a greater likelihood of prevalent and
incident disease, including mortality. Risk persists when adjusted for 25(OH)D,
renal function, and standard risk factors. Parathyroid hormone represents an
important new CV risk factor that adds complementary and independent predictive
value for CV disease and mortality.

Copyright © 2011 Mosby, Inc. All rights reserved.

PMID: 21835295

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