Dose-dependent effect of parathyroid hormone on fracture healing and bone formation in mice

Background: Parathyroid hormone (PTH) is the only clinically approved osteoanabolic drug for osteoporosis treatment. However, PTH is not established for the treatment of fracture healing, and doses of PTH diverge significantly between different studies. We hypothesized that the effect of PTH on promoting fracture healing and bone formation is dose dependent. Materials and methods: In vivo, mice were treated with PTH (10, 40, and 200 mg/kg) in a closed femoral fracture model. Fracture healing was analyzed after 4 weeks. The fourth lumbar vertebra was analyzed to assess systemic effects. In addition, osteoblasts from calvaria of mice were treated in vitro with PTH doses of 10(-5)-50 nM, and their differentiation was analyzed after 26 days. Results: In vivo, PTH dose-dependently stimulated bone formation in the fracture callus and the vertebral body. However, PTH treatment did not increase biomechanical stiffness of the fractured femora in a dose-dependent manner. The increased bone formation in the 200 mg/kg group was associated with a depletion of osteoclasts, indicating diminished bone remodeling. Of interest, in vitro, we observed diminished mineralization with the highest doses of PTH in osteoblast cultures. Conclusions: PTH dose-dependently stimulates bone formation in vivo. However, during fracture healing, this did not result in a dose-dependent increase of the mechanical stiffness of the fracture callus. Taken together, our in vivo and in vitro data indicate that the dose-dependent effects of PTH during fracture healing are based on the actions on multiple cell types, thereby influencing not only bone formation but also osteoclastic callus remodeling. (C) 2017 Elsevier Inc. All rights reserved.