Tumor Radiotherapy-Induced Sympathetic Hyperactivation Orchestrates Rapid Systemic Bone Loss

Radiation therapy (RT) is widely used in cancer treatment but is associated with an increased risk of fractures, with underlying mechanisms remaining unclear. Here, we investigated RT-induced bone loss in an esophageal carcinoma mouse model and examined the role of the sympathetic nervous system (SNS). A total of 90 male C57BL/6J mice were employed in this study. Mice were subcutaneously inoculated with esophageal carcinoma cells and treated with localized RT (20 Gy in four fractions) with or without chemical sympathectomy. RT markedly increased norepinephrine levels and tyrosine hydroxylase expression in bone, accompanied by upregulation of β1-adrenergic receptor and β2-adrenergic receptor. In addition, RT induced increases in inflammatory markers in the vertebrae, and all these changes were attenuated by 6-OHDA. Micro-CT analysis revealed significant trabecular bone loss in the vertebrae, femur, and tibia following RT, as indicated by reduced BV/TV, whereas sympathectomy substantially mitigated bone loss. Histological and molecular analyses showed that RT increased osteoclast activity and osteocyte apoptosis while suppressing osteoblast function; these changes were largely reversed by 6-OHDA. In addition, RT reduced tumor volume, and sympathetic ablation further enhanced this antitumor effect. In summary, our results suggest that localized radiotherapy may induce systemic bone loss by triggering excessive activation of the SNS. Its potential mechanism may be related to increased osteocyte apoptosis, enhanced osteoclastogenesis, and impaired osteoblast activity. Therefore, targeting the SNS may represent a potentially effective strategy for preventing radiation-associated bone loss.