Femur Fractures Rare With Bisphosphonate Use

Laurie Barclay, MD

March 25, 2010

March 25, 2010 (UPDATED March 30, 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.

Dennis Black, PhD, lead author of the current study, told Medscape Diabetes & Endocrinology, "We showed that in women with osteoporosis similar to those in these studies, the benefits of bisphosphonates in terms of fracture reduction outweigh any plausible risk."

"The clinical implications are that for people at high risk of fracture, particularly those with bone density in the osteoporotic range or with an existing spine fracture, any potential risks are outweighed by the benefits of fracture reduction."

Dr. Black is the professor of epidemiology and biostatistics at the University of California–San Francisco (UCSF). He and his colleagues 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 Dr. Shane's editorial, she noted that compared with typical fractures of the hip that are prevented by bisphosphonates, atypical femoral shaft fractures are rare, accounting for 2% to 4% of all hip fractures. Furthermore, those associated with bisphosphonates account for only approximately one third of that 2% to 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.

The current study investigators indicate 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.

Current Study Findings

In the current study, Black and colleagues 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 hazards for subtrochanteric or diaphyseal femur fractures vs placebo were 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.

"Women who have osteoporosis should not hesitate to use bisphosphonates since the benefits clearly outweigh any risks," Dr. Black said. "While not a direct implication of our study, since many of these case reports suggest that atypical fractures may be preceded by thigh pain or stress fractures, women on bisphosphonate therapy who have persistent thigh pain should see their doctor."

Independent Comment Regarding Clinical Implications of Study

Medscape Diabetes & Endocrinology asked Murray J. Favus, MD, professor of medicine and director of the bone program at the University of Chicago, Pritzker School of Medicine, in Chicago, Illinois, for independent comment regarding the clinical implications of this study.

"Bisphosphonates reduce the common hip fractures and can be used long term with proper monitoring and assessment of efficacy and safety, and because of the rarity of subtrochanteric fractures in osteoporotic patients, the long-term bisphosphonate therapy can be used with greater reward than risk," Dr. Favus said.

"Unexplained leg and groin pain may be prodromal symptoms of an impending rare subtrochanteric fracture and therefore must be evaluated, and concomitant use of medications that may have adverse effects on bone and other risk factors for fracture must be monitored."

Strengths, Weaknesses of Study

"The main strength [of this study] is the large cohort of postmenopausal women evaluated thoroughly in randomized clinical trials testing two antiresorptive agents," Clifford Rosen, MD, Maine Medical Center Research Institute, Scarborough, Maine, told Medscape Diabetes & Endocrinology when asked for independent comment. "These data provide insight into the prevalence of this event. The limitation of this study is that few younger postmenopausal women are included in these trials; hence, a proportion of those with subtrochanteric fractures might have been missed."

When also 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.

"These studies were of the highest quality with respect to design," Dr. Favus said. "Another strength of the study is that it was composed of those at highest risk — women with postmenopausal osteoporosis, many of whom had already sustained at least 1 osteoporotic fracture. The major weakness of the study is that even though the 3 studies were each sufficiently powered to determine the efficacy of bisphosphonates in reducing hip fractures, in the aggregate, the study reported was underpowered to determine the risk of the rare subtrochanteric femur fracture in subjects taking bisphosphonates because of the rarity of the specific fracture type."

Additional study weaknesses noted by Drs. Shane and Black included inability to determine features of atypia because x-rays of the 12 femoral shaft fractures were not available, only radiographic or surgical reports.

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.

"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.

She further stated, "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. 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 < [less than] –2.5" (Schwartz et al., Journal of Bone and Mineral Research, 2010).

More Research Needed

"Studies need to be conducted to determine whether any risk factors raise the risk of the subtrochanteric fractures," Dr. Favus said. "Larger, well-designed randomized studies need to be analyzed for a causal relationship between bisphosphonates and subtrochanteric fractures, and the underlying pathophysiology of these fractures, including the state of bone microarchitecture and bone turnover, should be studied further."

Dr. Shane recommended using large healthcare organizations such as the Kaiser Permanente system to compare patients with and without these fractures to determine the risk factors for their occurrence.

"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."

Dr. Black agreed that it would be important to identify if there are any subgroups of patients in whom these drugs are likely to lead to decreased thigh bone strength.

"Potential factors that might interact with bisphosphonates include concurrent use of glucocorticosteroids with bisphosphonates or the use of multiple antiresorptive medications such as bisphosphonates and HRT [hormone replacement therapy]," Dr. Black said. "These potential interactions require further study as well as other risk factors such as subclinical bone disease."

Because the pathogenesis of this disorder is not known, and there are no suitable animal models to test, Dr. Rosen recommended evaluating much larger cohorts through examination of very large databases.

"The bottom line message is that subtrochanteric fractures are very rare events — however, there are some characteristics that are important to recognize, such as femur pain and cortical thickening on x-ray," Dr. Rosen concluded.

Merck and Novartis supported this study. Merck employs 2 of the study authors, and Novartis employs another study author. Dr. Black is the principal investigator on research contracts from Novartis, Roche, Merck, and Amgen to UCSF to run these and other studies. 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, Medtronic, 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.

Drs. Favus and Rosen have disclosed no relevant financial relationships. 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.

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