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Incidence of Hip and Subtrochanteric/Femoral Shaft Fractures in Postmenopausal Women With Osteoporosis in the Phase 3 Long-Term Odanacatib Fracture Trial |
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| Authors: | Socrates Papapoulos Henry Bone Felicia Cosman David W Dempster Michael R McClung Toshitaka Nakamura José Fernando Molina Restrepo Mary L Bouxsein Dosinda Cohn Anne de Papp Rachid Massaad Arthur Santora |
| Affiliation: | 1. Leiden University Medical Center, Leiden, The Netherlands;2. Michigan Bone & Mineral Clinic, Detroit, MI, USA Contribution: Conceptualization, Investigation, Methodology, Writing - review & editing;3. Columbia University, New York, NY, USA;4. Oregon Osteoporosis Center, Portland, OR, USA;5. University of Occupational and Environmental Health, Fukuoka, Japan Contribution: Formal analysis, Writing - review & editing;6. Reumalab, Medellín, Colombia Contribution: Formal analysis, Writing - review & editing;7. Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, and Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, USA;8. Merck & Co., Inc., Kenilworth, NJ, USA Contribution: Conceptualization, Methodology, Writing - review & editing;9. Merck & Co., Inc., Kenilworth, NJ, USA Contribution: Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing;10. MSD Europe Inc., Brussels, Belgium Contribution: Formal analysis, Writing - review & editing;11. Merck & Co., Inc., Kenilworth, NJ, USA |
| Abstract: | We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged ≥65 years with a bone mineral density (BMD) T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a radiographic vertebral fracture and T-scores ≤−1.5 at the TH or FN were randomized (1:1) to receive ODN 50 mg/week or placebo. All patients received vitamin D3 (5600 IU/week) and calcium (total 1200 mg/d); the analysis included 16,071 women. Rates of all adjudicated low-energy femoral fractures were 0.38 versus 0.58/100 patient-years for ODN and placebo, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI] 0.51–0.82; nominal p < .001), and for low-energy hip fractures were 0.29 versus 0.56/100 patient-years, respectively (HR = 0.52; 95% CI 0.40–0.67; p < .001). The cumulative incidence of combined hip and ST/FS or hip fractures alone in the ODN group was consistently lower than in the placebo group (1.93% versus 3.11% for combined fractures and 1.53% versus 3.03% for hip fractures at 5 years, respectively). However, low-energy ST/FS fractures were more frequent in ODN-treated women than in placebo-treated women (24 versus 6, respectively). Among these, 12 fractures were adjudicated as AFF in 10 patients treated with ODN (0.03/100 patient-years) compared with none in the 6 placebo-treated women (estimated difference 0.03; 95% CI 0.02–0.06). These results provide insight into possible pathogeneses of AFF, suggesting that the current criteria for diagnosing these fractures may need to be reconsidered. © 2021 American Society for Bone and Mineral Research (ASBMR).. |
| Keywords: | BIOCHEMICAL MARKERS OF BONE TURNOVER CLINICAL TRIALS OSTEOPOROSIS THERAPEUTICS |