[50]. I-BET151 clinical trial Concern about bisphosphonate use

in relation to atypical subtrochanteric fractures arose from case reports that described patients with subtrochanteric fractures who had been exposed to bisphosphonates, particularly long-term treatment with alendronate (Fosamax®/Fosavance®, alendronate sodium, Merck Sharp & Dohme Limited). The association between long-term bisphosphonate use and unusual diaphyseal fractures was first described by Odvina et al. in 2005 [31] who reported nine patients with osteoporosis or osteopenia who had been treated with alendronate for 3–8 years and sustained atraumatic fractures in the course of their normal daily activities. Three patients had fractures of the femoral shaft and two had fractures of the proximal femur. Of these five patients, fracture healing was radiographically assessed in four. All four patients had delayed or absent fracture healing ranging from 4 months to 2 years while on alendronate treatment. This and subsequent case reports are summarized in Table 1. The mean and median

age of patients was 65 years (range 35–85). All cases involved treatment with alendronate, except for five patients who took SB202190 cell line risedronate (Actonel®, risedronate sodium, Procter and Gamble Pharmaceuticals) and three who took pamidronate (Aredia®, pamidronate disodium, Novartis Pharmaceuticals Limited). One patient had been taking ibandronate (Bonviva®/Boniva®, ibandronic acid, Roche) for 1 year AZD3965 in vitro following long-term alendronate use, and one had been taking risedronate for 5 years following 7 years of pamidronate use. There were no published case reports of subtrochanteric fractures following the use of once-yearly zoledronic acid 5 mg (Aclasta®/Reclast®, zoledronic acid anhydrous, Novartis Pharmaceuticals Limited), although cases following treatment with the monthly 4-mg dose have been reported [36, 38]. The mean and median duration of bisphosphonate for use was 7.3 and 7.5 years, respectively (range 1–16), and the majority of

patients had unilateral fractures (29 out of 43; 67.4%). Table 1 Case reports of incidents of subtrochanteric fracture following bisphosphonate use (all cases in women unless otherwise indicated) Reference Total patients (patients ST/FS/PF fracture) Age (years) Location Radiographic features Bilateral? Prodromal symptoms (duration) Osteoporosis diagnosis? Prior bisphosphonate Duration of use (years) Concomitant therapy Healing (months of follow-up) Odvina et al. [31] 9 (5) 52 Femoral shaft   No   No (osteopenia) ALN 8 Ca, D No (9) 68a Femoral shaft Yes Yes ALN 8 Ca, D No (8) 67 Femoral shaft Yes No (osteopenia) ALN 5 Oestrogen, Ca, D Yes (5) 49 Proximal femur No Yes (GIO) ALN 3 Pred, Ca, D No (8) 64 Proximal femur No Yes (GIO) ALN 4 Pred, Ca, D Yes (3) Husada et al.