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

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 areal bone mineral density (aBMD), cortical bone area at the femoral mid-diaphysis, femur 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 non-response to PTH can be anatomic site specific. Further, our study suggests that genetic background and sex significantly influence bone response to PTH. Our data support the future use of genetically diverse mouse models to elucidate the genetic architecture of skeletal response to PTH.