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Atypical Femoral Fractures with Long-Term Bisphosphonate Use

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Atypical Femoral Fractures with Long-Term Bisphosphonate Use

March 22, 2010

The Issue

Recently, reports of atypical femoral fractures in patients taking long-term bisphosphonate therapy have appeared in the lay press, raising concern among patients. Many patients have called their rheumatologists asking whether they should discontinue therapy. On March 10, 2010, the FDA released a communication stating that it was reviewing this potential safety concern (see www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203891.htm).

The Data

Beginning in 2005, a number of case reports were published describing unusual, low-energy, subtrochanteric femoral fractures occurring in patients taking alendronate therapy for 5-10 years, including patients who were not osteoporotic by DXA criteria. Concerns were raised that these atypical fractures may have been due to the effects of long-term bisphosphonate therapy on bone integrity. The proposed mechanism was impairment of normal bone remodeling, with inadequate repair of microfractures and resultant bone fragility. In 2008, Neviaser et al. published a series of 70 of these low-energy fractures, 36% of which occurred in patients taking alendronate for an average of 6.9 years, and concluded that alendronate was a significant risk for this atypical fracture.(1) Later that year, the same group published a case-control study of 41 of these fractures compared to 82 more typical intertrochanteric fractures and again concluded that long-term bisphosphonate use was associated with these atypical fractures.(2) They noted a unique X-ray pattern common to the patients with the subtrochanteric fractures that was highly associated with alendronate use.

In 2009, two large registry-based studies examined this issue. The first paper, referenced in the FDA communication, found that the ratio of subtrochanteric fractures to typical intertrochanteric fractures in a national Danish cohort was equal in both untreated and alendronate-treated patients, including those on long-term therapy.(3) The authors concluded that both types of fractures should be regarded as osteoporotic fractures. The second study found that femoral shaft fractures occurred at a rate of 1/1000 per year in a Swedish population, 46-fold greater than the rate in non-bisphosphonate treated individuals, but concluded that this was an acceptable risk in light of the overall reduction in fracture risk of 15/1000 per year seen in the Fracture Intervention Trial, a controlled study of alendronate therapy.(4, 5) Indeed, the age-adjusted incidence of hip fracture declined steadily in the U.S. from 1995 through 2005, coincident with the introduction of bisphosphonate therapy into the market, though causality has not been demonstrated, while the incidence of subtrochanteric femur fractures has remained unchanged.(6, 7) Both registry studies did suggest that subtrochanteric fractures were more common in patients being treated with glucocorticoids.

Despite published reports of atypical femoral fractures with long-term bisphosphonate use, there is no conclusive evidence at this time directly linking long-term bisphosphonate use to these fractures. No clear mechanism been identified that would explain such a link, without which it is impossible to determine whether any specific agent might be associated with a greater risk than others with the same mechanism of action. The FDA is continuing to actively review this issue. For now, there appears to be insufficient evidence to warrant discontinuing these drugs in osteoporotic patients. However, there appears to be diminished benefit in patients taking bisphosphonates for more than 5 years.(8) For such patients, rheumatologists should discuss the potential risks and benefits of continued therapy with their patients, and then make treatment decisions together.

The Bottom Line

  1. There are case reports of atypical subtrochanteric stress fractures in patients taking bisphosphonates long-term (i.e., greater than 5 years).
  2. At present, there is no conclusive registry data supporting a significantly increased risk for these types of fracture, and no clear mechanism identified to explain such a risk.
  3. Bisphosphonates have proven beneficial in preventing osteoporotic fractures in patients with osteoporosis. It has been suggested that this benefit may be attenuated after very long term therapy (e.g., after 10 years).
  4. At present, there is no data regarding any potential utility of bone density measurements or biomarkers of bone turnover to inform decisions regarding continuation of therapy.
  5. Doctors should discuss these atypical fractures as well as the more common insufficiency fractures with their osteoporosis patients who are on long term bisphosphonate therapy, to help them decide whether to continue therapy after 5-10 years. At present, it would appear to be premature to discontinue therapy because of these concerns.
  6. Consider clinical assessment (e.g., FRAX) to identify patients with low risk of insufficiency fractures and do not initiate or continue bisphosphonate therapy in those individuals.

Hotline Authors and Editors: Arthur Kavanaugh, MD, Eric Ruderman, MD

Disclosures: Nothing to disclose.

The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.

References

  1. Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 2008;22(5):346-50.
  2. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 2009;20(8):1353-62.
  3. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 2009;24(6):1095-102.
  4. Schilcher J, Aspenberg P. Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop 2009;80(4):413-5.
  5. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348(9041):1535-41.
  6. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA 2009;302(14):1573-9.
  7. Nieves JW, Bilezikian JP, Lane JM, Einhorn TA, Wang Y, Steinbuch M, et al. Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int;21(3):399-408.
  8. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296(24):2927-38.

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