from Heartwire — a professional news service of WebMD

January 24, 2008 — A new study has shown that calcium supplementation might increase vascular events in elderly women [1]. The findings are somewhat unexpected, because previous trials have shown that calcium improves blood cholesterol levels, senior author Dr Ian R Reid (University of Auckland, New Zealand) told heartwire .

Dr Mark J Bolland (University of Auckland, New Zealand) and colleagues published the findings online in BMJ January 15, 2008.

"This is quite controversial, given that the worldwide calcium-supplement market is worth $3 billion a year," says Reid. "The trial was primarily looking at what calcium supplements do to bone density, but we had a secondary hypothesis right from the outset that calcium might actually prevent heart attack. What we found, to our surprise, was that we didn't see a decrease but an increase, and the findings appear to be quite robust." Reid added, however, that there have been some clues from three other recent studies, including one from Women's Health Initiative (WHI) in the US [2]: "these three did not find significant increases in the number of heart attacks [with calcium], but they have found upward trends."

Dr Erin D Michos (Johns Hopkins University, Baltimore, MD), who was not involved with this new study but cowrote an editorial accompanying the publication of the WHI study on vitamin-D/calcium supplements last year [3], told heartwire : "This is a thought-provoking study, although not definitive, but further work should be done."

Others warned that it is premature to make any treatment decisions on the basis of this new study. British Heart Foundation spokesperson Judy O'Sullivan said more rigorous research was needed before any firm conclusions could be drawn. "Anyone who has been advised by their doctor to take calcium supplements to protect their bones should not stop doing so in light of this study alone without medical advice," she said.

Findings equivocal

The New Zealand team randomized 1471 postmenopausal women (average age 74 years) to either calcium supplementation (1 g/day calcium citrate) or placebo. As well as bone density, they looked at adverse cardiovascular events over five years: death, sudden death, myocardial infarction (MI), angina, other chest pain, stroke, transient ischemic attack, and a composite end point of MI, stroke, or sudden death.

Reid says the study collected data on MIs and strokes "in a much more careful way" than any other previous studies have done. "We got cardiologists and other people involved and audited all those things and went back to patients' hospital records and so on."

MI was more commonly reported in the calcium group than in the placebo group (45 events in 31 women vs 19 events in 14 women, p=0.01), and the composite end point was also reached more often in the calcium group (101 events in 69 women vs 54 events in 42 women, p=0.008). Even after adjudication, MI remained more common in the calcium group, as did the composite end point.

Verified vascular events self-reported by healthy postmenopausal women assigned to calcium supplementation or to placebo, or reported by family members

But when unreported events were added from the national database of hospital admissions in New Zealand, the relative risk of MI was 1.49 in those taking calcium compared with placebo recipients (p=0.16) and that of the composite end point 1.21 in those taking calcium compared with those on placebo (p=0.32).

"Thus, the present study does not unequivocally show an adverse cardiovascular event of calcium but suggests that this matter needs to be considered carefully before calcium supplementation can be broadly advocated," the researchers note.

Michos told heartwire the results are somewhat difficult to interpret, because there appear to be some imbalances between the calcium and placebo arms at baseline, "which may have influenced the higher outcomes seen in the calcium arm."

Also, the New Zealand team did not report serum vitamin-D levels, except to say they excluded those with very severe vitamin-D deficiency, she notes. "While I still believe vitamin D is important and beneficial for cardiovascular health, supplementation with calcium alone (without vitamin D) may not be beneficial for CV [cardiovascular] health."

Age may play a role

Reid says that "there is a possibility that this was a chance finding, but what makes us believe that this is not the explanation is that there have been three other recent studies — one from the UK, one from the US, and one from Australia — that have found upward trends in the numbers of heart attacks with calcium, so we are showing the same sorts of trends."

"Taken together, these four studies raise major concerns about the cardiovascular safety of calcium supplementation, particularly with respect to MI in older postmenopausal women," say the researchers in their paper.

Reid says it is important to consider age. The women in the New Zealand study were quite old, those in the Australian study were similarly elderly, but those in the US — the WHI study — were more than 10 years younger, as were the ones studied in the UK.

"Most of the trials have been done in women in their 50s and 60s, and the signal hasn't come through as strongly in those younger women, so it's probably okay [to use calcium] in those younger women."

High calcium uptake might accelerate calcification of arteries?

The findings from his study may also be stronger, Reid said, because they used quite a high dose, 1 g per day, and a more soluble calcium preparation than others have done, which probably resulted in better compliance. "And our study is a bit longer than some of the others, so that may also explain why we've got a more powerful effect.

"The other thing that makes us think that this is not a chance finding is that it is now pretty well established that patients on dialysis using calcium supplementation are at increased risk of heart attack and death.

"What we think is happening is that the higher calcium intake — and particularly the bolus of calcium that supplementation provides — is somehow accelerating the laying down of calcium in the artery walls of the heart," he notes.

"The way I interpret this is that if you have preexisting heart disease — which probably most of our participants did, although they probably weren't aware of it — then the extra calcium appears to be bad. But if, on the other hand, you are 54 and you have nice clean arteries to your heart, then probably calcium is not going to cause you any major problems. That's my take on it. But I don't know if it can be proven."

He added that the advice they have been providing to women in New Zealand in the past few months, since they became aware of these findings, "is that if you are in the older age group and are known to have heart disease, it's probably not sensible for you to take a calcium supplement. In younger people, calcium supplements look reasonable, but it may be sensible to aim for a smaller dose, say 500 mg/day."

He noted that the study also showed — "in a more clear-cut way than any other" — that calcium substantially slows bone loss, "so going down to 500 mg/day is not going to achieve the same bone benefit, although it is probably a safer balance."

But for patients who really have major problems with osteoporosis, "it's much more sensible to focus on using specific osteoporosis drugs," he said. "If you've got osteoporosis, take other things, don't just rely on extra calcium."

What's next?

Reid says his team has a number of plans to look at this issue going forward. "We are going to try to access the radiographs from women in the study and see if we can quantify calcification in them." They also have another study that has just finished, this time in a few hundred men, in which they are looking at coronary artery calcium. "In the men's study, they are younger, and there is an adverse trend, but it's much smaller," he noted.

And he hopes to coordinate a meta-analysis of the UK, US, and Australian studies and his own "to see if we can use all the available evidence to determine whether there really is something solid here."

Reid has received research support from and acted as a consultant for Fonterra and Mission Pharmacal.

Sources

1. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomized controlled trial. BMJ 2008; DOI:10.1136/bmj.39440.525752.BE. Available at: http://www.bmj.com.
2. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplements and cardiovascular events. Circulation. 2007;115:846-854.
3. Michos ED, Blumenthal RS. Vitamin D supplementation and cardiovascular disease risk. Circulation. 2007;115:827-828.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org , a Web site for cardiovascular healthcare professionals.

Clinical Context

Study Highlights

• In this randomized placebo-controlled trial in an academic medical center in an urban setting in New Zealand, 1471 postmenopausal women (mean age, 74 years) were enrolled. 732 were randomized to 1 g of elemental calcium supplementation and 739 to placebo daily.
• This study was a secondary analysis of a randomized controlled trial of calcium supplementation in healthy postmenopausal women, primarily designed to assess the effects of calcium on bone density and fracture incidence for 5 years.
• Women were included if they had been postmenopausal for more than 5 years, were 55 years or older, and had a life expectancy of more than 5 years.
• Baseline characteristics were similar between the groups.
• The women were followed up every 6 months for 5 years.
• Main outcome measures were adverse cardiovascular events in 5 years: death; sudden death; MI; angina; other chest pain; stroke; transient ischemic attack; and a composite endpoint of MI, stroke, or sudden death.
• Results demonstrated that MI was more commonly reported in the calcium vs the placebo group (45 events in 31 women vs 19 events in14 women; P = .01).
• The composite endpoint of MI, stroke, or sudden death was also more common in the calcium group (101 events in 69 women vs 54 events in 42 women; P = .008).
• After adjudication, MI remained more common in the calcium group (24 events in 21 women vs 10 events in 10 women; relative risk, 2.12; 95% confidence interval [CI], 1.01 - 4.47;
  P = .047).
• For the composite endpoint 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk, 1.47; 95% CI, 0.97 - 2.23;
  P = .076).
• When unreported events were added from the national database of hospital admissions in New Zealand, the relative risk for MI was 1.49 (95% CI, 0.86 - 2.57), and that of the composite endpoint was 1.21 (95% CI, 0.84 - 1.74).
• This process resulted in some attenuation of the calcium effect; however, the rate ratios for MI and for the composite endpoint had borderline significance.
• The respective rate ratios were 1.67 (95% CI, 0.98 - 2.87) and 1.43 (95% CI, 1.01 - 2.04); event rates were 16.3 per 1000 person-years for placebo and 23.3 per 1000 person-years for calcium.
• Limitations to this study included the small size and the lack of generalizability to other ages and racial groups.

Pearls for Practice

• Current evidence has demonstrated that increased calcium intake may lead to improved ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol as well as playing a role in blood pressure reduction and weight loss.
• Calcium supplementation in healthy postmenopausal women may be associated with upward trends in cardiovascular event rates.

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