Bone response to intermittent parathyroid hormone (PTH) is both genetic and sex specific.

Teriparatide (PTH 1-34) is an anabolic agent used to treat osteoporosis, yet clinical response varies widely among patients. To investigate genetic and sex-specific determinants of skeletal response, we administered intermittent PTH to male and female mice from eight genetically diverse inbred strains. Mice were treated for four weeks, and bone phenotypes were assessed via DXA, microCT, and mechanical testing. Response to PTH was highly strain- and sex-dependent, with some strains responding at the femur but not the spine, and vice versa. Heritability estimates for PTH-induced changes in bone mineral density (BMD), cortical area, breaking strength, and trabecular bone volume fraction (BV/TV) ranged from moderate to high, with BV/TV showing the strongest genetic influence. Cortical bone response mechanisms differed by sex: males exhibited periosteal expansion, while females showed endosteal remodeling. These findings mirror clinical observations where hip non-response is more prevalent than spine non-response and suggest that genetic background and sex significantly influence therapeutic outcomes. Our data support the use of genetically diverse mouse models to elucidate the genetic architecture of PTH response and highlight the potential for personalized approaches in osteoporosis treatment. Future genome-wide association studies in outbred mice may identify specific loci mediating skeletal responsiveness to PTH, advancing precision medicine strategies for bone anabolic therapies.