Osteoclast Inhibitors for Bone Fracture Healing in Mice with High-Turnover Osteoporosis

Abstract

The effectiveness of osteoclast inhibitors for high-turnover osteoporosis-related bone fracture is slightly unclear. This study aimed to examine the effectiveness of continuous administration of reveromycin A (RMA) and bisphosphonate (BP) in an osteoprotegerin knockout (OPG KO) model. The study included 8-week-old male OPG KO mice. The OPG KO mice received continuous saline (OPG SA group, n = 4), BP (OPG BP group, n = 4), or RMA (OPG RMA group, n = 4). The study also included wild-type mice as controls (administered saline; Wild SA group, n = 4). We found that serum alkaline phosphatase activation (parameter for full-body bone formation) was significantly higher in the OPG SA group than in the Wild SA, OPG BP, and OPG RMA groups and was significantly lower in the OPG BP group than in the OPG RMA group (all p < 0.001). Additionally, the blood tartrate-resistant acid phosphatase concentration (parameter for osteoclast activation) was significantly higher in the OPG SA group than in the Wild SA, OPG BP, and OPG RMA groups and was significantly lower in the OPG BP group than in the OPG RMA group (all p < 0.001). Significant increases in the bone healing score and significant decreases in the callus area were observed from 10 to 21 days after the procedure in the OPG SA and OPG RMA groups (all p < 0.001). Moreover, at 21 days, the score was significantly lower (p < 0.01) and the callus area was significantly larger (p < 0.001) in the OPG BP group than in the OPG SA and OPG RMA groups. In the OPG RMA group, the fractured bone segment was indistinguishable from the rest of the bone at 21 days. Our results suggest that RMA is an effective and safe alternative to BP for the treatment of high-turnover osteoporosis.