Romosozumab Improves Bone Mass and Strength While Maintaining Bone Quality in Ovariectomized Cynomolgus Monkeys

Abstract

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.

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab

“…With romosozumab, that benefit may result from the rapid and substantial bone mass accrual, achieving more robust bone mass and improved bone structure prior to transitioning to the follow‐on antiresorptive therapy. In support of this, as has been shown in preclinical studies, romosozumab administration for 12 months in ovariectomized cynomolgus monkeys increased cortical and trabecular bone mass and thickness, and improved bone strength . Improvements in cortical thickness and increases in estimated bone strength of both cortical and trabecular bone at the spine and hip using CT and finite element analysis have also been observed in patients with postmenopausal osteoporosis receiving romosozumab …”

Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass

“…In a quantitative computed tomography (QCT) analysis of a subset of these participants, the effect of romosozumab was assessed on vBMD and bone mineral content (BMC) at the lumbar spine and total hip, and romosozumab was found to significantly increase integral vBMD and BMC at both sites from baseline and compared with both placebo and teriparatide groups . These findings were consistent with preclinical studies that showed increased bone mass after sclerostin inhibition, which also was associated with increased bone strength . Because finite element analysis (FEA) can provide a noninvasive assessment of strength changes after treatment, we sought to evaluate how the changes in vBMD and BMC observed in this study influenced FEA‐estimated strength at the spine and hip.…”

Retention of osteocytic micromorphology by sclerostin antibody in a concurrent ovariectomy and functional disuse model

“…Regardless of the conditions that animals were subjected to (HLS alone, OVX alone, or HLS + OVX), histomorphometry analyses indicate that 5 weeks of Scl‐Ab administration resulted in a rapid and remarkable increase in cortical bone width, which is thought to be associated with robust bone formation at both the periosteum and endosteum. Similar results have been reported in studies of the effect of romosozumab (Scl‐Ab) on bone mass and strength in OVX animals . Our study, however, is the first to report that Scl‐Ab is capable of preserving cortical bone strength and structure by significantly improving bone formation indices in both the periosteum and endosteum.…”