Calcium and vitamin D supplements increased the risk of kidney stones but did not prevent broken bones or colorectal cancer in middle-aged and elderly women, according to an extensive study.
The supplements’ only positive effect in the study population — 36,282 normal, healthy women aged 50 to 79 — was a one percent increase in bone density at the hip.
The $18 million study was part of the Women’s Health Initiative, a large federal project that last week reported findings that low fat diets do not protect against breast or colorectal cancer or heart disease. A few years ago, the initiative’s study on hormone treatment after menopause showed it had more health risks than benefits.
In every case, the Women’s Health Initiative was testing hypotheses that arose from studies that observed populations and correlated certain health practices with medical outcomes. But such observational studies, statisticians agree, provide less firm evidence than a clinical trial, like those of the Women’s Health Initiative, which randomly assigned women to a preventive strategy, like hormones or diet or supplements, or not, and looked for definite results — a fractured bone, a case of cancer, a heart attack.
The results from new study on calcium and vitamin D, like the others, confound popular beliefs and raise questions about public health messages that had been addressed to the entire population.
In this case, the participants were randomly assigned to take 1000 milligrams of calcium and 400 international units of vitamin D a day or to take placebos, and were followed for seven years. Researchers looked for effects on bone density, fractures, and colorectal cancer. The lack of an effect on colorectal cancer over the seven-year period was so clear that it has aroused little debate. But the effect on bones is another story.
Osteoporosis specialists said the study, to be published on Thursday in The New England Journal of Medicine, is likely to put a dent in what has become a widespread medical practice of recommending that all women take calcium and vitamin D supplements starting at menopause, if not sooner, as a sort of insurance policy against osteoporosis.
But beyond that there is no agreement on what, if anything, healthy women should do.
The study’s investigators emphasized encouraging hints and biological plausibility in the data. When they looked only at the women who took 80 percent of their pills, the supplements reduced hip fractures by 29 percent. The annual rate of hip fractures in adherent women taking the supplements was 10 per 10,000, compared with 14 per 10,000 in adherent women taking placebos.
In a separate subgroup analysis of all women in the study over 60 years old, they saw a 21 percent reduction in hip fractures in the group taking the supplements. The rate was 19 per 10,000 in women over 60 taking the supplements, compared with 24 per 10,000 in women over 60 taking placebos.
But, of course, the message to women was that everyone over age 50 or so should be taking the supplements and so the public health question would be, What happens if women actually try to do that in the real world? The study’s answer is: more kidney stones and no fewer fractures.
Some doctors say what they want to know is how to advise a woman who insists that she, unlike other women, will actually take the pills year in and year out. And there, the analysis of compliers provides useful information, said Dr. Rebecca Jackson of Ohio State University, the lead author of the paper published today.
But such subgroup analyses are questioned by many statisticians, who point out that there always will be subgroups in a large study showing one effect or another, simply by chance. Some subgroups, as happened in this study, will show a positive effect and others, as also happened in this study, will show a negative effect, but the hypothesis being tested was for the group as a whole. Searching the data after the study is done in order to find subgroups that support a hypothesis can be misleading, statisticians say.
Dr. Jacques Rossouw, a project officer for the study, explained the limitations. “These are secondary analyses and are exploratory to some extent” he said.
Nonetheless, said Dr. Elizabeth G. Nabel, the study’s director, the study does indicate the value of adequate calcium and vitamin D.
“Based on all the results, women — particularly those over 60 — should consider taking calcium and vitamin D for bone health” she said . Others were not so sure. Dr. Ethel Siris, president of the National Osteoporosis Foundation, said the new study has made her question the advice given by many doctors that all women take calcium supplements regardless of what is in their diet. “We didn’t think it hurt, which is why doctors routinely gave it” she explained.
The new study, she says, shows it can hurt to take the supplements: among the women taking them there were an 5 additional cases of kidney stones per 10,000 women a . So, Dr. Siris said, her suggestion is that doctors only urge the supplements upon women who are not getting enough calcium — 1200 to 1500 milligrams a day — from their diets. “Enough is enough,” Dr. Siris said. “Too much of a good thing isn’t a good thing.”
Dr. Clifford J. Rosen, director of the Maine Center for Osteoporosis Research and Education in Bangor, Maine, said he would now reserve the supplements for those women over 70 — the age group with the greatest risk of hip fractures — who are not getting enough calcium and vitamin D. “This is a public health intervention,” Dr. Rosen said. “We’ve been recommending it for everyone but it probably doesn’t work in the majority of people or the effect is small. And there is an increase in kidney stones. It is not a benign intervention.”
Others went further, asking whether healthy women should be taking the supplements at all. Cynthia Pearson, executive director of the National Women’s Health Network, an advocacy group, knew what her organization would say: “Because this isn’t very effective doesn’t mean you have to go look for something else,” she said. “If you consider yourself reasonably similar to those women, which is what most of us aspire to be, don’t worry. Life is good.”
“It’s disappointing” said Susan Ellenberg, a statistician and former official at the Food and Drug Administration who is now at the University of Pennsylvania’s Center for Clinical Epidemiology and Biostatistics. “You would like there to be a simple inexpensive way to prevent hip fractures in older women.”
But, Dr. Ellenberg said, “I think it’s pretty clear that if there’s any effect at all it’s extremely modest. Even when you do those questionable subgroup analyses, there’s just a barely significant effect, and that’s in a very, very large group.”
The study was begun to ask about a popular belief so fervently held that it has become almost a tenet of public health: Since adequate calcium and vitamin D are needed for healthy bones, and since women’s bones normally start to thin after menopause, women should take the supplements to help protect themselves from the devastating bone fractures that can occur with osteoporosis.
And there might be another benefit too: studies that observed people who happened to be taking calcium supplements had indicated that the supplements might reduce colorectal cancer risk. The study was medical science’s one chance to ask in such a rigorous way whether those beliefs about calcium and vitamin D were true. Such large studies, investigators said, tend not to be repeated. Its investigators also realized, of course, that they would be applying the cold light of science to popular messages that have fueled a booming calcium supplement industry, with annual sales, reports Dr. Joel S. Finkelstein, an osteoporosis researcher at the Massachusetts General Hospital in Boston, of $993 million on 2004. Calcium supplements, he wrote in an editorial to be published Thursday in The New England Journal of Medicine, are “the biggest seller of the multibillion-dollar dietary-supplement industry.” Those messages may have falsely reassured many women that the supplements are going to protect them, Dr. Finkelstein said. “Women come to see me all the time saying, ‘How can I possibly have osteoporosis? I exercise and I take calcium and vitamin D,’ ” he said. “The ads for calcium have given many women the impression that they are protected against osteoporosis,” he added. “The message of the study is that calcium and vitamin D by themselves are not enough,” Dr. Finkelstein said. As a therapy to protect against osteoporosis, he said, supplements are “pretty weak.”
Women who actually do have the condition should consider taking one of the seven F.D.A.-approved prescription drugs on the market that have been shown in rigorous clinical trials to prevent fractures, he advised. Six of the drugs inhibit bone breakdown and one spurs the growth of new bone. Now, some osteoporosis specialists are saying the study was flawed, that it should have focused on older women, or it should have used higher doses of vitamin D, or it should have excluded women who were already getting plenty of calcium in their diets.
Dr. Siris said she understands that reaction. When she saw the results of the study, her first instinct was to pick it apart. But, she said, she was put off by the attacks on the Women’s Health Initiative study that showed there were real health risks from hormone treatments for menopause. In the case of the hormone study, she said, she thought the study’s results were right. “Now I find myself thinking there was something wrong with the design of this study because I don’t like the results.” Dr. Siris decided to resist the temptation to shoot the messenger.