Senescent Cells Involved in Deterioration of Bone Microstructure by High-Frequency Parathyroid Hormone 1-34 Administration and Bone Loss.

Abstract

Osteoporosis is characterized by reduced bone mass and structural deterioration, leading to increased fracture risk, particularly in older adults. Parathyroid hormone (PTH) is a widely used anabolic therapy for osteoporosis; however, rapid bone loss after treatment discontinuation presents a significant clinical challenge. Cellular senescence has been implicated in age-related bone fragility. However, its role in PTH-induced bone remodeling and post-treatment bone loss remains unclear. This study aimed to investigate the effects of PTH administration frequency on bone microarchitecture and cellular senescence in young and aged mice. High-frequency PTH administration improved trabecular bone volume in both age groups, but caused cortical bone thinning, increased porosity, and elevated osteoclast activity in aged mice. PTH induces senescent osteoblast-lineage-enriched cell accumulation in aged, but not young mice, accompanied by upregulation of senescence-associated markers and activation of the mechanistic Target of Rapamycin Complex 1 pathway. Co-administration of the senolytic agents dasatinib and quercetin during PTH treatment reduced senescent cell burden, improved cortical porosity, and mitigated rapid bone loss after PTH discontinuation in aged mice. These findings indicate that senescent osteoblast-lineage-enriched cells contribute to bone fragility and post-treatment bone loss in aged individuals, suggesting that targeting senescence may enhance the efficacy and sustainability of PTH therapy for osteoporosis.