The combined effects of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in ovariectomized mice.

Abstract

The purpose of this study was to investigate the combined effects of teriparatide (TPTD) and anti-murine receptor activator of nuclear factor-κB ligand monoclonal antibody (anti-RANKL Ab) on both cancellous and cortical bone healing in ovariectomized mice. Thirteen-week-old mice were divided into the sham-operated group (n=11) or the ovariectomized group (n=44). At 1 month post-operation, all mice underwent bone defect surgery on the left femoral metaphysis (cancellous bone healing model) and right femoral mid-diaphysis (cortical bone healing model). After creating the bone defects, all ovariectomized mice were assigned to one of four groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40μg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, measuring the volumetric bone mineral density and the cortical bone thickness of the tibia as a representative of whole body bone with the use of micro-computed tomography, and histological analysis. Regeneration of cancellous bone volume in the COMB group was the highest among the four groups, and combined treatment accelerated the formation of medullary callus during the early phase of bone regeneration. On the other hand, there were no significant differences in the regeneration of cortical bone volume during the early phase of bone regeneration among the four groups. Furthermore, lamellar bone was not well identified in the all four groups. Volumetric bone mineral density in the tibia in the COMB group was significantly higher compared with that in the CNT and TPTD groups and tended to be higher compared with that in the Ab group. The mean values of cortical bone thickness in the TPTD and COMB groups were significantly higher than that in the CNT group. In a mouse model of postmenopausal osteoporosis, combination therapy of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone more effectively than either agent alone during the early phase of bone regeneration.