Twelve months of denosumab and/or alendronate is associated with improved bone fatigue life, microarchitecture, and density in ovariectomized cynomolgus monkeys.

Prolonged use of antiresorptives like the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with s.c. vehicle (VEH), s.c. DMAb (25 mg/kg/month), or i.v. ALN (50 μg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). 240 cortical beam samples were cyclically tested in 4-point bending at 80, 100, 120, or 140 MPa peak stress. High resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p=0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± IQR fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, and DMAb groups survived 9850 ± 13648 (+395% vs. VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals vs. VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. This article is protected by copyright. All rights reserved.