Optimal administration frequency and dose of teriparatide for acceleration of biomechanical healing of long-bone fracture in a mouse model

Despite preclinical studies demonstrating the effectiveness of teriparatide for skeletal repair in small animals, inconclusive data from clinical trials have raised questions regarding the optimal teriparatide dosing regimen for bone repair. To address this, we assessed the effect of teriparatide frequency and dose on long-bone healing using a mouse femur osteotomy/fracture model. Eight-week-old male ICR mice were subjected to open femur osteotomies, then randomized into following five groups (n=8 per group): vehicle; low dose/high frequency: 3g/kg/dose, 3 times/day; low dose/low frequency: 9g/kg/dose, 1 time/day; high dose/high frequency: 9g/kg/dose, 3 times/day; high dose/low frequency: 27g/kg/dose, 1 time/day. Skeletal repair was assessed by microcomputed tomography, mechanical testing, and histology 4weeks after surgery. High-dose and/or high-frequency teriparatide treatment increased callus bone volume but failed to have a significant impact on the biomechanical recovery of fractured femurs, possibly because of impaired cortical shell formation in fracture calluses. Meanwhile, low-dose/low-frequency teriparatide therapy enhanced callus bone formation without interfering with cortical shell formation despite a lesser increase in callus bone volume, leading to significant two and fourfold increases in ultimate load and stiffness, respectively. Our findings demonstrate that administering teriparatide at higher doses and/or higher frequencies raises fracture callus volume but does not always accelerate the biomechanical recovery of fractured bone, which points to the importance of finding the optimal teriparatide dosing regimen for accelerating skeletal repair.