Nearly six years ago in this column, I discussed what was then a little-known problem associated with long-term use of bisphosphonates, the valuable drugs that protect against fractures caused by bone loss. The drugs, among them Fosamax, Actonel and Boniva, can slow bone loss, increase bone density and cut fracture rates in half in women with established osteoporosis.
Reports had begun to emerge that some women taking bisphosphonates for many years suffered an unusual fracture of the femur, the long bone of the thigh. There was little or no trauma; in most cases the women were simply standing or walking when the femur snapped in half. In some, breaks occurred in both thighs, and many of the fractures were unusually slow to heal.
Experts think the fractures happened because of the way the drugs work: by slowing the rate of bone remodeling, the normal process by which injured bone heals. As a result, microfractures that occur through normal wear and tear are not repaired. Although bone density may be normal, the bone can become brittle and crack under minor stress.
In the years since, hundreds of cases of atypical femur fractures have been reported among women and some men taking bisphosphonates for five or more years. A number of studies have tried to assess the risk, and last fall the Food and Drug Administration issued a “safety announcement” and required that the drugs’ labels warn physicians and patients to be alert for this potential complication.
Weighing the Research
But many questions remain, including who is most at risk for femur fractures and whether the risks outweigh the important benefits of taking a bisphosphonate for many years. The latest assessment was published Feb. 23 in The Journal of the American Medical Association by a team of physicians and epidemiologists in Toronto.
The team, led by Laura Y. Park-Wyllie, an epidemiologist who is a doctor of pharmacology at St. Michael’s Hospital, gathered treatment and fracture data among all 205,466 women in Ontario aged 68 or older who had been treated with a bisphosphonate. They identified those who had suffered femur fractures occurring below the hip and above the knee — called subtrochanteric or femoral shaft fractures — and compared each case with those of up to five other women the same age who had been free of this injury.
Those who had taken the drugs for five years or longer were more than twice as likely to have had such a fracture as those who took them only briefly. But because X-rays of the bone were not reviewed, it is not certain that the fractures were linked to the drugs. At the same time, long-term use of bisphosphonates prevented many more fractures than it might have caused; the risk of osteoporotic femur fractures, a far more common injury, was reduced by 25 percent, Dr. Park-Wyllie said in an interview.
“Compared to the number of fractures prevented,” she said, “the actual risk of a subtrochanteric femur fracture is small” — 1 case in 1,000 in the sixth year of therapy and 2.2 cases in 1,000 the seventh year.
A report published last year in The New England Journal of Medicine found no increase in atypical femur fractures, but that study did not include enough patients taking bisphosphonates for many years to produce a reliable result. Preliminary data from a much larger study has indicated that the risk of atypical femur fractures increased from 2 cases a year per 100,000 users after two years of bisphosphonate therapy to 78 cases a year per 100,000 after eight years on the drug.
In a report from a 27-member task force of the American Society for Bone and Mineral Research (published online in September in The Journal of Bone and Mineral Research), the experts noted that the way bisphosphonates work can reduce the “toughness” of bones. “It is highly likely that case reports and case series of atypical femur fractures will continue to accumulate,” the task force wrote, noting that another 47 cases had been reported since their analysis was prepared. Many cases are not reported, and in an unknown number of cases physicians may not recognize the fractures as atypical.
The task force called for an international registry of cases, including details that could help define who is most at risk.
First, an Evaluation
What should patients and doctors do?
“Relative to the millions of fractures that occur every year in the United States, the number of atypical femur fractures should not discourage the use of these effective drugs by patients with osteoporosis who are at high risk of fracture,” a leader of the task force, Dr. Elizabeth Shane, said in an interview. (Dr. Shane is a bone specialist at Columbia University Medical Center.)
Initial excitement about bone-protecting drugs led to prescriptions for millions of women who were not necessarily at high fracture risk, and many experts now urge a thorough evaluation before a bisphosphonate is prescribed. In addition to bone density test results, the evaluation should take into account a patient’s smoking and drinking habits, thinness, family history of osteoporosis, previous osteoporotic fractures, drug prescriptions and weight-bearing exercise regimen. An online evaluation tool developed by the World Health Organization is at www.shef.ac.uk/FRAX, though some experts have criticized it as incomplete.
The task force said a decision to treat should be “based on an assessment of benefits and risks,” and added, “patients who are deemed to be at low risk of osteoporotic-related fractures should not be started on bisphosphonates.”
Even those with osteoporosis in the spine but little or no problem in their hips, the experts concluded, should consider alternative remedies.
While no one knows what the optimal length of drug treatment should be, five years on a bisphosphonate seems to confer an adequate benefit; after that, patients should consider taking a “drug holiday.”
Before resuming therapy, the patient’s risk factors for fracture should be reassessed. The task force noted that half of currently known patients with atypical fractures had been on bisphosphonates for seven years.
Furthermore, in 70 percent of cases, patients reported experiencing pain or discomfort in the thigh or groin for weeks or months before the femur fractured. Anyone on a bone drug who develops such a pain should be carefully evaluated, first with an X-ray and, if nothing is seen but the cause is uncertain, by a bone scan or M.R.I.
When a problem like a defect in the shell of the femur is found and the patient has pain, a fracture is highly likely, Dr. Shane said, and the task force recommended inserting a rod in the bone to keep it from breaking.
Furthermore, Dr. Jennifer Schneider of Tucson, an internist who after seven years on Fosamax suffered a nontraumatic femur fracture that took two years to heal, notes that the damage is often bilateral — so when a problem is found in one leg, the other leg should be thoroughly examined. Among patients in an online support and information group she established, some reported suffering a second atypical fracture in the other thigh.
Dr. Schneider invites patients who have had such a fracture to write to her at jennifer@jenniferschneider.com.
