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Atypical Fractures of the Femoral
Diaphysis in Postmenopausal Women Taking Alendronate
  NEJM March 2008
To the Editor: The long-term safety of bisphosphonates for the treatment of osteoporosis has been questioned. Two case series have suggested a link between prolonged bisphosphonate therapy and atypical fractures. In one series, a small number of patients sustained low-energy nonvertebral fractures while receiving long-term alendronate therapy; three were fractures of the femoral shaft.1 Bone biopsies in these patients showed evidence of severely suppressed bone turnover and fracture healing that was delayed or absent. In the other series, low-energy subtrochanteric fractures were found in nine women who had been receiving long-term alendronate therapy.2 Theoretically, bisphosphonates suppress bone turnover and thus might be associated with accumulated microdamage in bone. To our knowledge, no study has demonstrated microdamage accumulation in patients treated with bisphosphonates, and data from studies in animals remain difficult to interpret because supranormal doses of bisphosphonates are used. Nevertheless, the possibility that bisphosphonates alter bone strength with prolonged use appears to exist.
We identified 15 postmenopausal women who had been receiving alendronate for a mean (±SD) of 5.4±2.7 years and who presented with atypical low-energy fractures, defined as fractures occurring in a fall from a standing height or less. All patients sustained subtrochanteric or proximal diaphyseal fractures. Bisphosphonate use was observed in 37% of all patients presenting with low-energy subtrochanteric or diaphyseal fractures. Fractures of the subtrochanteric or diaphyseal regions are relatively rare in postmenopausal women, representing 6% of all osteoporotic hip fractures in our patient population (unpublished data).
Ten of the 15 patients were found to share a unique radiographic pattern, defined as a simple transverse or oblique (≤30°) fracture with beaking of the cortex and diffuse cortical thickening of the proximal femoral shaft. We call this pattern "simple with thick cortices" (Figure 1). These patients had an average duration of alendronate use of 7.3±1.8 years, which was significantly longer than the duration of 2.8±1.3 years for the five patients without this pattern (P<0.001). Cortical thickening was present in the contralateral femur in all the patients with this pattern. Three of the 15 patients had a history of femoral fractures, all in the contralateral femur, whereas no patients had a history of vertebral fractures. Vitamin D and parathyroid hormone measurements and bone densitometry were not performed during fracture care; therefore, we cannot determine the status of the patients with respect to metabolic bone disease.
Our results provide further evidence of a potential link between alendronate use and low-energy fractures of the femur. In light of the limitations of our study, a prospective study is indicated. Although many possible explanations exist, patients with the unique radiographic pattern shown here may represent a subgroup of the population that is more susceptible to the effects of prolonged suppression of bone turnover. Additional studies are needed to characterize this subgroup and to establish a clear association between atypical fractures of the femur and prolonged bisphosphonate treatment.
Brett A. Lenart, B.S.
Dean G. Lorich, M.D.
Joseph M. Lane, M.D.
Weill Cornell Medical College
New York, NY 10021
Supported by the Cohn Foundation.
Dr. Lane reports receiving speaking fees from Aventis, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Procter & Gamble, and Roche. No other potential conflict of interest relevant to this letter was reported.
1. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301. [Free Full Text]
2. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007;89:349-353. [CrossRef][Medline]
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