**Calcium Supplements and Cardiovascular Disease in Older Women**

**Background**

The safety of calcium supplementation is being questioned in response to
a recently published clinical trial that showed trends of higher
cardiovascular event rates in older postmenopausal women who received
high dose calcium supplementation.^1^ Calcium has been shown to have
favorable effects on bone mineral density (BMD) in postmenopausal women;
however, benefits on fracture risk are less clear. Non-compliance with
calcium supplements due to gastrointestinal effects, primarily
constipation, may contribute to the difficulties in determining
effectiveness. Calcium is known to have favorable effects on
high-density lipoprotein (HDL) and the ratio of HDL to low-density
lipoprotein (LDL). In addition, calcium has been shown to have favorable
although transient effects on blood pressure lowering and inconsistent
effects on weight loss. Moreover, observational studies have suggested
that postmenopausal women with high calcium intake have fewer
cardiovascular events than women with low calcium intake. The two most
commonly utilized salts in supplements are calcium carbonate and calcium
citrate. Calcium citrate is more expensive, more soluble, and better
absorbed without regard to meals and in the setting of concomitant acid
suppression therapy.

**Present Study**

A randomized, placebo-controlled trial including 1471 healthy
postmenopausal women was conducted in New Zealand over 5 years to
evaluate the effects of calcium supplementation (1 gram/day of calcium
citrate) on BMD and fractures.^2^ In a preplanned secondary analysis
reported by Bolland and colleagues, vascular events including death,
sudden death, myocardial infarction (MI), stroke, transient ischemic
attack (TIA), and the composite endpoint of MI, stroke, or sudden death
were investigated. Ninety percent of patients had complete follow-up.
Tablet compliance was 85% in those patients still taking study
medication at the end of the 5 years. Mean age of patients was 74 years.

In looking at adjudicated cardiovascular events reported by participants
(or family members), MI was more frequently reported in the calcium
group (24 events in 21 women vs. 10 events in 10 women; relative risk,
RR, 2.12 \[95% confidence interval, CI, 1.01-4.47\]). Non-significant
increases in stroke (RR 1.42 \[95% CI 0.83-2.43\]) and the composite
endpoint (RR 1.47 \[0.97-2.23\]) were observed. When unreported
information from a hospital admissions database was included in the
analysis, the differences in events between groups were less
significant, although similar trends remained. Relative risk of MI and
of reaching the composite endpoint were 1.49 (95% CI 0.86-2.57) and 1.21
(95% CI 0.84-1.74) in the calcium group vs. placebo, respectively.
Additional analysis suggested that the adverse cardiovascular effects
with calcium supplementation became apparent at approximately 24 months,
were sustained, and were higher in those with good compliance. Amounts
of dietary supplementation of calcium and vitamin D were not discussed
in detail. The higher number of baseline smokers in the calcium group,
although not statistically significant, was not explained.

The results of this study do not unequivocally show an adverse
cardiovascular effect of calcium but do reveal a signal that warrants
further study. The trial was small in size to evaluate cardiovascular
endpoints. The population was comprised mainly of elderly Caucasian
women with age appropriate BMD, and findings may not be widely
generalizable to other patient populations (i.e., younger women, women
on additional osteoporosis therapy, women with high fracture risk).
Until further information is known, the potential for adverse
cardiovascular effects as observed in this trial should be a
consideration when deciding on the appropriateness of calcium
supplementation in patients.

**Additional Evidence**

Data from other clinical trials evaluating potential cardiovascular
effects associated with calcium are limited. The Women's Health
Initiative investigators published a secondary analysis of
cardiovascular event risk with calcium plus vitamin D
supplementation.^3^ Overall, their investigation showed no significant
increase or decrease in cardiovascular events among 36,000
postmenopausal women aged 50-79 years of age (mean age 62 years) over a
7 year study period. MI or coronary heart disease death was verified in
499 vs. 475 women in calcium/vitamin D and placebo groups, respectively
(hazard ratio, HR 1.04 \[95% CI 0.92-1.18\]). Meaningful comparisons to
the population in the Bolland analysis are difficult, as the women in
the Women's Health Initiative were younger, taking a different calcium
salt (calcium carbonate) plus vitamin D, and 50% were using estrogen
replacement therapy. In a study evaluating the effects of calcium
carbonate supplementation on bone structure and fracture in 1460 women
with a mean age of 75 years, Prince and colleagues also reported on
safety.^4^ Incident ischemic heart disease was diagnosed in 56 (7.7%)
and 51 (7%) patients in calcium-treated and placebo groups respectively.
Authors stated that there was no difference in risk between groups (HR
1.12; 95% CI 0.77-1.64). Although the absolute numbers were small and no
significant differences in cardiovascular events were detected in these
individual trials, Bolland and colleagues state that the numerical
trends are consistent with their findings. Taken as a whole, further
investigation is warranted.

**Future Study**

Additional study is needed to further explore the potential for
cardiovascular risk with calcium supplementation. It is expected that
data from existing clinical trials will be re-examined and combined to
more clearly demonstrate whether a true risk exists.

**Implications**

Results of the Bolland study were unexpected and in contrast to previous
studies (although mainly observational) that suggested calcium may be
cardioprotective. Whether calcium supplementation confers an independent
cardiovascular risk and if so, in whom, is unclear at this time. Based
on the information from this study and until additional information is
known, it is reasonable to re-evaluate the need for and amount of
calcium supplementation, especially in older women.

-   Current recommended daily adequate intake of calcium according to
    the Institute of Medicine is 1000 mg for individuals less than 50
    years of age and 1200 mg for those 51 years of age and older.^5^

-   Results from the Bolland study raise the possibility that calcium
    supplementation (1 gm/day of calcium citrate) in elderly women may
    be associated with increased risk of cardiovascular events, although
    the data is far from convincing.

-   In light of this new data regarding the impact of calcium citrate
    supplementation on cardiovascular risk, it may be reasonable to
    consider the following:

    -   Re-evaluate total intake of daily calcium in patients, including
        intake from dietary sources, before calculating the amount of
        supplementation needed to achieve target calcium intake.

    -   Consider the potential safety concerns along with benefits on
        bone health on an individual basis. Benefits of calcium
        supplementation in older women with relatively low risk of
        fracture may not outweigh the potential cardiovascular risk.

-   The mean age of the women in the Bolland study was 74 years. In the
    Women's Health Initiative study, the mean age was 62 years. The lack
    of increased cardiovascular event rate in the calcium group of the
    Women's Health Initiative study may indicate that calcium
    supplementation is safer in this younger population. However, the
    potential for confounding factors influencing the results of the
    Women's Health Initiative study (i.e., noncompliance, use of calcium
    carbonate salt) cannot be completely ruled out at the present time.

-   Implications in other populations (i.e., younger women, women on
    additional therapy for osteoporosis, women with high risk or
    previous fracture) are currently unknown.

-   It is unclear whether the addition of vitamin D, dose of calcium, or
    calcium salt influences the cardiovascular safety of calcium
    supplementation at this time.

**References:**

1\. Bolland MJ, Barber AP, Doughty RN, et al. Vascular events in healthy
older women receiving calcium supplementation: randomized controlled
trial. BMJ. 2008;336:262-266.

2\. Reid IR, Mason B, Horne A, et al. Randomized controlled trial of
calcium in healthy older women. Am J Med. 2006; 119:777-785.

3\. Hsia J, Geiss G, Ren H, et al. Calcium/vitamin D supplementation and
cardiovascular events. Circulation. 2007;115:846-854.4. Prince RL,
Devine A, Dhaliwal SS, et al. Effects of calcium supplementation on
clinical fracture and bone structure. Arch Intern Med. 2006;166:869-875.

4\. Prince RL, Devine A, Dhaliwal SS, et al. Effects of calcium
supplementation on clinical fracture and bone structure. Arch Intern
Med. 2006;166:869-875.

5\. Office of Dietary Supplements, National Institutes of Health.
Dietary supplement fact sheet: calcium. Available at:
<http://dietary-supplements.info.nih.gov/factsheets/calcium.asp>.
Accessed March 5, 2008.

**Prepared:** March 2008

**Contact person:** Lisa Longo, PharmD, BCPS

> Clinical Pharmacy Specialist
>
> VA Pharmacy Benefits Management Service