The manufacturers of ibandronate have assessed their clinical trials database to determine the incidence of subtrochanteric and diaphyseal femoral fractures in women taking MI-503 ibandronate for post-menopausal osteoporosis. Atypical fractures were defined as ‘mostly non-spine fractures including hip or femur fractures in the subtrochanteric region or shaft and occurring without trauma or in association with low-energy trauma’. For femur fractures, subtrochanteric fracture location was considered as atypical for osteoporosis-related fractures,

defined as a region below the lesser trochanter and a junction between the proximal and middle third of the femoral shaft. In the pivotal trials (MF 4380, BONE, MOBILE and Staurosporine mw DIVA) [4, 71–73], there were nine fracture cases corresponding to these defined locations and characteristics (subtrochanteric, femoral shaft, stress or multiple fractures): six occurred in placebo-treated patients (n = 1,924) and three in ibandronate-treated patients (n = 6,830). In addition, there was one identified case of a femoral shaft fracture in an ibandronate-treated patient in the extension and major phase IIIb trials (MOBILE LTE, DIVA LTE, MOTION and PREVENTION; n = 2,451) [74–77]. Some fractures were reported without identifying the precise location. However,

all of these fractures were associated with trauma and thus did not meet the definition for atypical fractures. An additional 5-year analysis of the marketed regimens of ibandronate (150 mg once monthly and 3 mg IV quarterly) was also carried out from the active comparator-controlled trials and their extensions (MOBILE, DIVA, MOTION, MOBILE LTE and DIVA LTE) Urocanase [71, 72, 74, 75, 77]. No atypical subtrochanteric/diaphyseal femoral fractures were found for either of the marketed regimens (150 mg, n = 1,279; 3 mg, n = 469). Pharmacovigilance data Since fractures are the clinical

outcome of osteoporosis and no treatments are fully effective, fractures are expected in treated patients. It is likely, however, that the number of reports through pharmacovigilance will be small. The number of postmarketing reports of atypical stress fractures in association with alendronate to circa July 2008 was 115 (of which 84 were femur fractures) and included a large number of the cases reported in the literature [78]. Bilezikian et al. have reported that in more than 10 years of risedronate post-approval surveillance to September 2008 (18 million patient-years of exposure), the reporting rate for subtrochanteric fractures was <0.1 per 100,000 patient treatment years of exposure [70]. Postmarketing data from the manufacturers of zoledronic acid have revealed a similarly low rate of subtrochanteric fractures with zoledronic acid 5 mg.