In an unusual move that may prompt millions of women to rethink their use of popular bone-building drugs, the Food and Drug Administration published an analysis that suggested caution about long-term use of the drugs, but fell short of issuing specific recommendations.
The F.D.A. review, published in The New England Journal of Medicine online on Wednesday, was prompted by a growing debate over how long women should continue using the drugs, known as bisphosphonates, which are sold as generic versions of brands like Fosamax and Boniva, as well as Novartis’s Reclast.
The concern is that after years of use, the drugs may in rare cases actually lead to weaker bones in certain women, contributing to “rare but serious adverse events,” including unusual femur fractures, esophageal cancer and osteonecrosis of the jaw, a painful and disfiguring crumbling of the jaw bone.
Although the concerns about the long-term safety of bone drugs are not new, the F.D.A. performed its own systematic review of the effectiveness of bisphosphonates after years of use. The agency’s analysis, which found little if any benefit from the drugs after three to five years of use, may prompt doctors around the country to rethink how they prescribe them.
The F.D.A. review analyzes only long-term use and does not address whether a woman should be prescribed a bone drug in the first place to reduce her fracture risk. Because serious complications are so rare, most doctors believe that for women with documented osteoporosis who are at very high risk for spinal fractures, the benefits of the drugs far outweigh the risks. However, some women with moderate bone density and no other risk factors continue to take the drugs for years even though they are unlikely to gain any benefits.
“I think a lot of people are going to come off this drug,” said Dr. Clifford J. Rosen, an endocrinologist and researcher at the Maine Medical Center Research Institute.
Bones are in a constant state of remodeling, but after age 30 or so, a woman’s bones start to dissolve faster than they can be rebuilt, and after menopause she may develop thin, brittle bones that are easily broken. Bisphosphonates slow this process. The drugs are incorporated into newly formed bone and can persist there for years, long after a patient stops taking them.
The F.D.A. report offered little specific guidance about long-term use, saying that the decision to continue or stop treatment should be based on an individual assessment of risks, benefits and preferences discussed between a patient and her doctor. The agency did say that women at low risk for fracture or with a bone density near normal may be good candidates to stop therapy after three to five years, but older patients at higher fracture risk and bone density “in the osteoporotic range” may benefit from continued therapy.
But an accompanying article by Dr. Rosen and others, also published in The New England Journal of Medicine, offers more specifics, concluding that the women most likely to benefit from long-term use of the drugs are those who, after three to five years of treatment, continue to have very low bone density, as measured by something called a “T score” that is lower than minus 2.5. Women with a history of spinal fracture or with an existing fracture also are most likely to benefit from long-term use of the drugs, the researchers concluded.
However, many women who are prescribed bone drugs have been given a diagnosis of osteopenia, moderate to low bone density that is not low enough to be called osteoporosis. These women are unlikely to benefit from long-term use and should probably stop taking the drugs after about three years, the researchers said.
It is not clear how many women would be affected based on those recommendations, but many women tire of the therapy and stop taking it on their own anyway, partly because of inconvenient requirements like remaining upright after taking the drugs and common side effects of heartburn, nausea and flulike symptoms. Even so, the researchers estimate that perhaps 60 percent to 70 percent of current users would be candidates for stopping the drugs after three to five years.
The recommendations are based on findings from two industry-sponsored studies led by the University of California, San Francisco, that focused on long-term use of the drugs. A study of Fosamax, which is sold generically as alendronate, continued for 10 years, and a study of Reclast, an injectable form of the drug zoledronic acid, continued for six years. According to the F.D.A. analysis, both studies showed significant reductions in fracture risks during the first three to four years of use but little or no benefit with longer use.
In the Fosamax trial, 10.6 percent of Fosamax users suffered a fracture during the first three years of use, compared with 21 percent of those in the placebo group, according to the F.D.A. analysis. But there was no benefit seen among women who continued the drug for the next 5 to 10 years. In the Reclast trial, 9.8 percent of women taking the drug suffered a fracture in the first three years of the study, compared with 20 percent of women who were taking a placebo. By four to six years, the benefit had narrowed, with 8.6 percent of Reclast users suffering fractures, compared with 12 percent in the placebo group.
The two studies did not show any increased risk of serious side effects with long-term use of bisphosphonates, but experts say the studies simply were not large enough to detect a relatively rare adverse event. Even so, there have been numerous case reports of the unusual fractures and other side effects, prompting widespread concern about the risks with long-term use. No one knows how common the femur fractures are, but estimates have ranged from 1 in 10,000 users to 10 in 10,000.
Women should be reassured that serious complications are rare, saidDennis M. Black, a professor of epidemiology and biostatistics at U.C.S.F. and the lead author of the article that accompanied the F.D.A. report.
“The reality is there is a lot of uncertainty in this situation,” Dr. Black said. “The F.D.A. report was very general, and we tried to be much more specific and use evidence from the best trial available. Hopefully people who are using this drug will be reassured.”
Dr. Rosen said that even though the F.D.A. report was vague on specific recommendations, he was pleased to see the analysis published.
“It’s a very new thing that they submit a paper to The New England Journal that presents all sides of the argument,” Dr. Rosen said. “I think it’s a good thing, because I’ve been on these advisory committees for years, and we get a big crowd in Washington, but the doctors never see the results.”