Romosozumab (Romo), a humanized sclerostin antibody, is a bone-forming agent 
under development for treatment of osteoporosis. To examine the effects of Romo 
on bone quality, mature cynomolgus monkeys (cynos) were treated 4 months post- 
ovariectomy (OVX) with vehicle, 3 mg/kg, or 30 mg/kg Romo for 12 months, or with 
30 mg/kg Romo for 6 months followed by vehicle for 6 months (30/0). Serum bone 
formation markers were increased by Romo during the first 6 months, 
corresponding to increased cancellous, endocortical, and periosteal bone 
formation in rib and iliac biopsies at months 3 and 6. Dual-energy X-ray 
absorptiometry (DXA) bone mineral density (BMD) was increased by 14% to 26% at 
the lumbar spine and proximal femur at month 12, corresponding to significant 
increases in bone strength at 3 and 30 mg/kg in lumbar vertebral bodies and 
cancellous cores, and at 30 mg/kg in the femur diaphysis and neck. Bone mass 
remained positively correlated with strength at these sites, with no changes in 
calculated material properties at cortical sites. These bone-quality measures 
were also maintained in the 30/0 group, despite a gradual loss of accrued bone 
mass. Normal bone mineralization was confirmed by histomorphometry and ash 
analyses. At the radial diaphysis, a transient, reversible 2% reduction in 
cortical BMD was observed with Romo at month 6, despite relative improvements in 
bone mineral content (BMC). High-resolution pQCT confirmed this decline in 
cortical BMD at the radial diaphysis and metaphysis in a second set of OVX cynos 
administered 3 mg/kg Romo for 6 months. Radial diaphyseal strength was 
maintained and metaphyseal strength improved with Romo as estimated by finite 
element modeling. Decreased radial cortical BMD was a consequence of increased 
intracortical remodeling, with no increase in cortical porosity. Romo resulted 
in marked improvements in bone mass, architecture, and bone strength, while 
maintaining bone quality in OVX cynos, supporting its bone efficacy and safety 
profile. © 2016 American Society for Bone and Mineral Research.