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March 25, 2010 — Subtrochanteric and diaphyseal femur fractures are rare, even with bisphosphonate use for up to 10 years, according to the results of an analysis of 3 trials reported online March 24 in the New England Journal of Medicine.

"Patients who are being treated with bisphosphonates for osteoporosis should not stop taking their medications because of fear about these fractures," Elizabeth Shane, MD, professor of medicine, Division of Endocrinology, Columbia University College of Physicians & Surgeons, New York, NY, and author of an accompanying editorial told Medscape Diabetes & Endocrinology.

"It is of the utmost importance to provide some reassurance to patients and physicians about the relative rarity of these fractures and to point out that bisphosphonates are effective in treating osteoporosis and preventing fractures."

No Clear Evidence Bisphosphonates Linked With Femur Fractures

On March 10, as reported by Medscape Medical News, the US Food and Drug Administration (FDA) issued an alert that it had no evidence to conclude that bisphosphonates increased the risk for subtrochanteric and diaphyseal femur fractures. The agency, therefore, recommended that patients taking bisphosphonates should continue to do so, unless advised otherwise by their treating clinician.

"Compared to typical fractures of the hip that are prevented by bisphosphonates, atypical femoral shaft fractures are rare; they account for 2-4% of all hip fractures," Dr. Shane said. "Those associated with bisphosphonates account for only about one third of that 2-4%."

Another study, as covered by Medscape Diabetes & Endocrinology, found that these rare, low-energy femur fractures associated with long-term bisphosphonate treatment are typically transverse or slightly oblique, diaphyseal, or subtrochanteric, with thickened cortices and a unicortical beak.

Dennis M. Black, PhD, MD, from the University of California, San Francisco, and colleagues note that several recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. However, a population-based study did not support this association, and this relationship has not been studied in randomized trials.

The study authors are members of the Fracture Intervention Trial (FIT) and Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT) Steering Committees.

In the current study, they conducted secondary analyses using data from 3 large, randomized trials of bisphosphonates: FIT, the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and HORIZON-PFT.

For all hip and femur fractures, fracture records and radiographs (when available) were reviewed to identify femur fractures below the lesser trochanter (subtrochanteric fractures) and above the distal metaphyseal flare (diaphyseal fractures). Atypical features were evaluated, and relative hazards for subtrochanteric and diaphyseal fractures were calculated for each study.

Among 14,195 women enrolled in these trials, 284 records were reviewed for hip or femur fractures. There were a total of 12 subtrochanteric or diaphyseal femur fractures in 10 patients, occurring at a combined rate of 2.3 per 10,000 patient-years.

Relative hazard for subtrochanteric or diaphyseal femur fractures vs placebo was 1.03 for alendronate use in the FIT trial (95% confidence interval [CI], 0.06 - 16.46), 1.50 for zoledronic acid use in the HORIZON-PFT trial (95% CI, 0.25 - 9.00), and 1.33 for continued alendronate use in the FLEX trial (95% CI, 0.12 - 14.67). These increases in risk were not statistically significant, but CIs were wide.

Strengths, Weaknesses of Study

When asked about the study strengths and weaknesses, Dr. Shane told Medscape Diabetes & Endocrinology that "all the parent studies (FIT, FLEX, and HORIZON PFT) were large, randomized, placebo controlled, and rigorously conducted. A large number of women were studied (> 14,000), and there were 55,000 [person-] years of observation."

She also pointed out that unlike most case reports and case series, this study provides a denominator, namely the number of women exposed to the drug, as well as information on duration of exposure and compliance.

"The data on 5 versus 10 years of alendronate provide some reassurance that these fractures are rare even in women treated for 10 years, as some studies have linked long-term treatment with these fractures," Dr. Shane said.

Study weaknesses noted by Dr. Shane included inability to determine features of atypia because radiographs of the 12 femoral shaft fractures were not available.

"Most of the women received only 3-4 years of bisphosphonates, and in some lower doses were used (alendronate 5 mg/day) than are usually prescribed," Dr. Shane said. "The fractures of the femur were so rare that the study did not have enough statistical power to determine whether there was a significant association with bisphosphonates."

Fractures Rare but More Research Needed

On the basis on these findings, the study authors concluded that fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. Although no significant increase in risk was associated with bisphosphonate use, the study was underpowered for definitive conclusions.

"It is reasonable to consider drug holidays for patients on long term bisphosphonates (>5 years), but this is a very complicated issue, and decisions must be individualized," Dr. Shane said. "New research suggests that continuing alendronate after 5 years is associated with fewer new vertebral fractures and fewer hip fractures in women with hip T scores <-2.5." (Schwartz et al., Journal of Bone and MIneral Research, 2010).

Regarding additional research, Dr. Shane recommended large studies comparing patients with and without these fractures to determine the risk factors for their occurrence, perhaps using large healthcare organizations such as the Kaiser Permanente system.

"These fractures are very hard to study because they are so rare," Dr. Shane concluded. "We need an international registry of these fractures with uniform reporting on important clinical features — such as age, bone density, accurate drug exposures, concomitant drug use. The experience with atypical subtrochanteric fractures highlights the difficulty in detecting rare side effects of drugs and the importance of post-marketing surveillance studies for widely used drugs."

Merck and Novartis supported this study. Merck employs 2 of the study authors, and Novartis employs another study author. Some of the other study authors have disclosed various financial relationships with Merck, Novartis, Amgen, Roche, Nycomed, Procter & Gamble, the Medical Research Council, AstraZeneca, GlaxoSmithKline, Medtronics, Nastech, Nestle, Fonterra Brands, Ono Pharma, Osteologix, Pfizer, Lilly, Sanofi-Aventis, Tethys, Unilever, Unipath, Inverness Medical, Ortho Clinical Diagnostics, OSI Prosidion, Takeda, the National Osteoporosis Foundation, and/or GlaxoSmithKline Nutrition.

Dr. Shane is co-chair of the task force on atypical subtrochanteric fractures convened by the American Society for Bone and Mineral Research, and she receives research support from Merck, Novartis, and Eli Lilly, but she is not on any pharmaceutical industry speaker's bureaus or advisory boards, nor does she or any member of her family own equity in such companies.

N Engl J Med. Published online March 24, 2010.