Bone response to intermittent parathyroid hormone (PTH) is both genetic and sex specific
The response to teriparatide varies significantly by genetic background and sex, which may help explain differing outcomes in human patients. Further research is needed to explore these factors in broader populations.
Where it sits
this study against the rest of the teriparatide (pth 1-34) corpusSummary and findings
This study investigated the genetic and sex-specific determinants of bone response to intermittent teriparatide (PTH 1-34) in male and female mice from eight genetically diverse inbred strains over four weeks. The findings indicate that the response to PTH varies significantly by strain and sex, with notable differences in bone phenotypes. No therapeutic claims are made.
Abstract
<h4>ABSTRACT</h4> 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. <h4>LAY SUMMARY</h4> Teriparatide, a drug used to treat osteoporosis, consists of the active portion of parathyroid hormone (PTH). Information from clinical studies suggests that not all patients will respond to this medication. We used eight strains of inbred mice to study the impact of genetic background and sex on the response to PTH. We learned that response to PTH is driven by both genetics and sex. Some strains responded at the femur, but not the spine and vice versa. These results may explain why a failure to respond at the hip in humans is more common than at the spine.