Calcium — marvel or menace? The evidence may not be what you suspect

One of the most egregious examples of inaccurate medical reporting and grossly exaggerating a study’s findings, and needlessly frightening millions of women around the world, was seen this week. Does something as simple as taking a calcium supplement really double an older woman’s risk for a heart attack, as was reported in the news? That is very unlikely what you would conclude from reading the actual study. But the evidence might not be what you think, either.

This is another example of why it’s essential for us to understand how a clinical trial is being reported and to go to the original source, because few journalists or even medical spokespeople will. It is also an example of why the source of the news is no assurance of its reliability, as similar versions of the story were written by medical correspondents for Science Daily, Telegraph to Forbes.

Going right to the study behind this week’s news, it was published on the website of the British Medical Journal. This was not the original randomized, controlled clinical trial as had been registered, however, but a secondary look for findings that the original trial was not designed to examine.

The original study was the Auckland Calcium Fracture Study — a randomized controlled clinical trial begun in 1998 of 1,471 postmenopausal women (aged 74 years ± 4 years) in Auckland, New Zealand. It was designed to see if 1 gram of daily calcium citrate supplements prevented fractures in these women. The primary endpoint was the time to the women’s first fracture, with secondary endpoints the incidences of various fractures (vertebral, hip, forearm, and osteoporotic) and the difference between fall frequencies seen among the women in the treatment versus control groups over five years. This is how the trial had been registered with the Australian Clinical Trials Registry (ACTRN 012605000242628). The lead author was Dr. Ian Reed with the University of Auckland Bone Research Group.

The original trial results were released in the Proceedings of the 6th International Symposium on Nutritional Aspects of Osteoporosis in May 2006 in Lausanne, Switzerland. It reported null results. The bone densities among the women on calcium were reportedly only 1.8% (spine) to 1.2% (total body) greater than found in the control group, but the effects on fractures were “inconclusive” and “poor long-term compliance limits its effectiveness.”

[The women on the calcium also experienced increased problems with constipation, saw no effect on body weight, and only transient changes in blood pressures.] Background on bone density, osteoporosis, lifestyle and risk factors, and the conclusions of the U.S. Preventive Services Task Force were covered here. Additional calcium supplement research as a fracture preventive from Auckland and the latest study follows below.**

In this week’s paper, Dr. Reid and colleagues noted that some population studies had found correlations between calcium supplementation and lower rates of cardiovascular disease. It is not known, however, if calcium intake could be a marker for confounding factors such as higher socioeconomic status or healthcare:

Although no randomised controlled trials have been designed primarily to assess the effect of calcium supplementation on vascular event rates or deaths, secondary analyses of the Women’s Health Initiative Study have recently shown no consistent effects in a population of average age 62. Interpretation of the data from this study is hampered by its failure to show consistent effects of calcium on bone density and fractures, poor adherence to study drugs, and a high rate of use of other vasoactive drugs, particularly oestrogen.

Let’s take a close look at the secondary analysis of their Auckland Calcium Fracture Study Dr. Reid and colleagues published this week. First, we clearly see what they meant by poor compliance in the original trial. Of the 1,471 women who began the trial, 336 women in the calcium group (732) and 296 in placebo group (739) dropped out before the 5-year point. So, only 57% of the original cohort completed the study. But among those, compliance was only 85%, meaning the total number of women who actually took calcium or placebo for the study period was only 713 — less than half of the women.

Yet, they only reported on the full cohort of 1,471 women, even though most hadn’t taken the calcium, making any conclusions about calcium spurious.

Even so, there was a difference of only five deaths (all-causes) between the entire calcium and placebo groups. According to their own figures, this is a relative risk difference of only 1.18 (95% CL 0.73-1.92) — not significant.

We could end the discussion right there, as there is clearly no tenable fear with calcium supplements here to pursue, but you might be puzzled as to the source of the headlines...

Since this study was not designed to actually clinically evaluate cardiovascular events, such as heart attacks and strokes, they compiled incidences that were self-reported or reported by family members. They then did a second analysis that included additional events that had not been reported, but that they had identified through the national registry of hospital admissions and had confirmed in the medical records. When the researchers adjudicated the self-reported incidences with confirmed cardiac events “a statistically significant increase in the number of women with any of the end points in the calcium group was no longer found.”

Again, we could end the discussion right there, as there is clearly no tenable cardiovascular endpoint associated with calcium supplements here to pursue, but you might still be puzzled as to the source of the headlines...

By using just the vascular events self reported by the participants or a family member, and not including those they confirmed in the medical records, and when reporting on the entire 1,471 original cohort, not just the women who actually completed the trial, they found relative risks for strokes of 1.44 and heart attacks of 2.24 among the placebo group compared to the women who’d been in the calcium arm of the original study. Untenable correlations, but there’s your headline of a 'doubled risk for heart attacks.'

But even these sketchy selective findings are being contested. The calcium intervention and placebo groups were not similar in their overall cardiovascular disease risk. The calcium group had slighter higher percentages of women who had had previous or were being treated for hypertension, ischemic heart disease and strokes, and more current or former smokers. Doctors writing in BMJ questioned the imbalance between the two groups and the researchers’ failure to control for confounding factors in their computer modeling and regression analysis trying to link calcium to heart attacks. Dr. Luca Puccetti, M.D., president of the Promed Galileo Medical Society in Pisa, for example, also noted they had failed to control for the use of NSAIDs/analgesics and previous hormonal replacement therapy. “These two potent confounders [alone] may completely reverse the results,” he wrote. They also didn’t control for current smoking, vitamin and nutritional intakes or exercise during the study.

Discussing only the relative risks found among the self-reported heart attacks, however, is a nonissue, as Dr. Puccetti noted. When the authors considered all of the confirmed cardiovascular events (and not just those that were self-reported), remember they had found no statistically significant correlation to calcium intake.

To sum up, this study was unable to find higher risks for heart attacks associated with women who took calcium. In their concluding discussion, the researchers again noted that a much larger randomized controlled trial of the effect of calcium carbonate and vitamin D supplementation has recently been published by the Women’s Health Initiative investigators. While the women in that study were younger (mean age 62), they noted: “This study of 36,000 women, followed for seven years, showed no overall effect of the supplementation on cardiovascular event rates.” A subanalysis parsing the data of just the older women in that study, and another smaller trial of women with a mean age of 75, also found no tenable relative risks for cardiovascular events. Women can feel reassured by this evidence.

Despite all of this, incredibly, Dr. Reid and colleagues concluded: “Taken together these four studies raise major concerns about the cardiovascular safety of calcium supplementation, particularly with respect to myocardial infarction in older postmenopausal women... The present data do not permit definitive conclusions to be reached in this regard but do flag cardiac health as an area of concern in relation to calcium use and mandate that this is assessed carefully in future studies of calcium supplementation.”

You couldn’t make this stuff up. This study provided no evidence that calcium supplementation helps prevent fractures in older women, or that it hurts them by causing heart attacks. The only things it reminds us, is the importance of not letting sensational headlines frighten us; of looking at the actual study findings and not the spins; and not basing any health decision on a single study or news report.

© 2008 Sandy Szwarc

** The evidence on calcium in preventing bone fractures in older adults

Dr. Reid and colleagues have studied calcium supplementation use in postmenopausal women for years, reporting some improvement in bone density, but mixed or modest effects on fractures. In 1995, for example, reporting only on just over half (78) of the original 135 women in another 3-year study, they calculated a 0.25% benefit to bone density per year with 1,000 grams of daily calcium, but the study was not large enough to evaluate if calcium supplementation reduced fractures. As opposed to young people and developing bones, it’s popular to believe that increasing bone density through various dietary measures among older adults will mean fewer broken bones, but the evidence is sparse.

The 2002 Australian Fracture Prevention Summit summary of evidence for preventing osteoporosis, which included the Auckland research, concluded it is still unknown whether calcium or vitamin D supplementation might reduce osteoporotic fractures in the population. For most adults, three servings of dairy products would provide most with the recommended amounts to prevent deficiencies. It did recommend supplementation for nursing home residents, however, because of widespread nutritional deficiencies among elderly in Australia. Concerning calcium supplements, it concluded:

Controlled trials of calcium as a monotherapy [taken alone] have found small but consistent effects of calcium on [bone mineral density], averaging 1%–2% over two to three years and showing accumulation over time. Several studies have reported a significant beneficial effect of calcium monotherapy on fracture incidence. However, these findings should be interpreted with caution, as the studies were small and not powered to assess the effects of calcium supplementation on fractures. They may represent selective reporting of fracture results...the effect of this bias towards the reporting of positive results will only be addressed when adequately powered studies with fracture rate as the primary endpoint are undertaken.

The latest study examining the published data on calcium intake and hip fractures among older men and women was just published in last month’s American Journal of Clinical Nutrition. Researchers, led by Dr. Heike A Bischoff-Ferrari of the Department of Rheumatology and Institute of Physical Medicine in Zurich, Switzerland, examined seven prospective cohort studies of 170,991 women and found no association between calcium intake and hip fractures. In five cohort studies of 68,606 men, they found an insignificant 8% lower relative risk between calcium and hip fractures.

The researchers also identified seven randomized controlled clinical trials that had been conducted on calcium supplementation (800-1,200 mg/day) and hip fractures on more than 6,700 people, mostly postmenopausal women, followed for 1.5 to 10.8 years. The pooled results of the randomized controlled trials “yielded a neutral effect of calcium supplementation as compared with placebo for any nonvertebral fracture..." [Figure: relative risks for fractures in the trials.]

They added that the trials might even suggest a 64% greater relative risk of hip fracture associated with calcium supplementation. In proposing an explanation for these untenable findings, they made the distinction between supplementation and correcting nutritional deficiencies, saying: “It is possible that, among the frail subjects at risk of hip fracture, other deficiencies, such as vitamin D deficiency and phosphate deficiency due to low protein intake, should be corrected along with ensuring adequate calcium intake.” Each increase of 500 mg/day of calcium decreases phosphorus absorption by 166 mg, so calcium supplementation could shift an elderly person with relatively low phosphorus intake into phosphate deficiency and increase their fracture risk. It is important to note, however, that they acknowledged that poor statistical power in the pooled studies they analyzed could also explain these relative risks of hip fractures might be due to chance.

The bottom line, they emphasized, randomized controlled clinical trials to date show no reduction in hip fractures with preventive calcium supplementation.