To the Editor: The long-term safety of bisphosphonates for thetreatment of osteoporosis has been questioned. Two case serieshave suggested a link between prolonged bisphosphonate therapyand atypical fractures. In one series, a small number of patientssustained low-energy nonvertebral fractures while receivinglong-term alendronate therapy; three were fractures of the femoralshaft.1 Bone biopsies in these patients showed evidence of severelysuppressed bone turnover and fracture healing that was delayedor absent. In the other series, low-energy subtrochanteric fractureswere found in nine women who had been receiving long-term alendronatetherapy.2 Theoretically, bisphosphonates suppress bone turnoverand thus might be associated with accumulated microdamage inbone. To our knowledge, no study has demonstrated microdamageaccumulation in patients treated with bisphosphonates, and datafrom studies in animals remain difficult to interpret becausesupranormal doses of bisphosphonates are used. Nevertheless,the possibility that bisphosphonates alter bone strength withprolonged use appears to exist.
We identified 15 postmenopausal women who had been receivingalendronate for a mean (±SD) of 5.4±2.7 yearsand who presented with atypical low-energy fractures, definedas fractures occurring in a fall from a standing height or less.All patients sustained subtrochanteric or proximal diaphysealfractures. Bisphosphonate use was observed in 37% of all patientspresenting with low-energy subtrochanteric or diaphyseal fractures.Fractures of the subtrochanteric or diaphyseal regions are relativelyrare in postmenopausal women, representing 6% of all osteoporotichip fractures in our patient population (unpublished data).
Ten of the 15 patients were found to share a unique radiographicpattern, defined as a simple transverse or oblique (30°)fracture with beaking of the cortex and diffuse cortical thickeningof the proximal femoral shaft. We call this pattern "simplewith thick cortices" (Figure 1). These patients had an averageduration of alendronate use of 7.3±1.8 years, which wassignificantly longer than the duration of 2.8±1.3 yearsfor the five patients without this pattern (P<0.001). Corticalthickening was present in the contralateral femur in all thepatients with this pattern. Three of the 15 patients had a historyof femoral fractures, all in the contralateral femur, whereasno patients had a history of vertebral fractures. Vitamin Dand parathyroid hormone measurements and bone densitometry werenot performed during fracture care; therefore, we cannot determinethe status of the patients with respect to metabolic bone disease.
Figure 1. Radiographs of Fractures of the Femoral Shaft Showing the "Simple with Thick Cortices" Pattern.
Panel A shows a fracture of the femoral shaft in an 83-year-old woman with a 9-year history of alendronate use. Panel B shows a similar fracture in a 77-year-old woman with a 5-year history of alendronate use.
Our results provide further evidence of a potential link betweenalendronate use and low-energy fractures of the femur. In lightof the limitations of our study, a prospective study is indicated.Although many possible explanations exist, patients with theunique radiographic pattern shown here may represent a subgroupof the population that is more susceptible to the effects ofprolonged suppression of bone turnover. Additional studies areneeded to characterize this subgroup and to establish a clearassociation between atypical fractures of the femur and prolongedbisphosphonate treatment.
Brett A. Lenart, B.S. Dean G. Lorich, M.D. Joseph M. Lane, M.D. Weill Cornell Medical College New York, NY 10021 lanej{at}hss.edu
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 letterwas reported.
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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. 
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