High-dose romosozumab promoted bone regeneration of critical-size ulnar defect filled with demineralized bone matrix in nonhuman primates

Abstract

Background

Large bone defects are challenging to manage clinically and usually require treatment with bone graft or bone graft substitute. This study evaluated the effect of romosozumab, a sclerostin antibody, in combination with demineralized bone matrix (DBM) on bone regeneration in a critical-size ulnar defect model in nonhuman primates.

Methods

In cynomolgus monkeys (N = 22, male, 10–12 years old), a full-cortex bone defect (0.5 cm long) was created in the left ulnar shaft and filled with DBM. Animals were randomized to receive vehicle (n = 10) or romosozumab (n = 12; 30 mg/kg) subcutaneously, every 2 weeks for 28 weeks. Radiographs of the left ulna were taken every 2 weeks for 28 weeks to monitor bone regeneration response. Ulnae were excised and analyzed by ex-vivo x-ray and micro-computed tomography (micro-CT) to evaluate bone repair, and lumbar vertebrae were excised for bone histomorphometric analysis to evaluate the systemic anabolic response.

Results

In-vivo and ex-vivo x-ray images of surgical ulnae demonstrated that the critical-size ulnar defect fully bridged in 3 romosozumab-treated monkeys at week 28 but not in any vehicle-treated monkey. Micro-CT analysis demonstrated that average new bone volume and new bone area within the defect region were 118 % and 105 % greater, respectively, with romosozumab versus vehicle. Trabecular bone volume per tissue volume and trabecular thickness of lumbar vertebral body were 72 % and 92 % greater, and eroded surface was significantly lower with romosozumab versus vehicle.

Conclusion

High-dose romosozumab in combination with DBM improved bone regeneration in a critical-size ulnar defect model and increased bone mass in non-surgical bone in nonhuman primates.

The translational potential of this article

Clinical management of large bone defect is complex and challenging. More effective management is needed. This paper reports the first nonhuman primate study that evaluated high-dose romosozumab in combination with demineralized bone matrix in a critical-size defect model and provides perspective for the future research evaluating the combination of romosozumab and bone graft or bone graft substitutes in various relevant clinical conditions.