Skeletal complications associated with radiation therapy following treatment of pelvic cancers (e.g., cervical, colorectal, and prostate) are well-documented. Problems include reduced bone density, osteoradionecrosis, and increased fracture risk. For example, analysis of recent data demonstrates that postmenopausal women receiving pelvic radiation therapy exhibit a significant increase in hip fractures (relative risks of 1.66, 1.65, and 3.16, respectively, for cervical, rectal, and anal cancers). Increasing rates of cancer survivorship intensify the importance of mitigating long-term side effects of radiation therapy, including fracture risk. To date, pharmacological interventions to prevent bone loss caused by radiation therapy have not been employed. In fact, no animal model currently exists to identify causal mechanisms and to properly develop such therapies. We have identified significant trabecular bone loss in mice four months after administration of low-dose (2 Gy), whole-body ?-irradiation and propose to build upon these data to develop a robust rodent model. We hypothesize that radiation-induced bone loss is relatively rapid and is caused by an increase in osteoclastic bone resorption; therefore, it may be prevented by applying current osteoporosis therapies. This osteoclast activation is mediated by increased local levels of RANKL caused by reactive oxygen intermediates and proinflammatory cytokines generated by irradiated tissue. We propose to examine both the time course of this functional bone loss (using a single-limb radiation exposure model in rats) and the effect of systemic vs. local factors to investigate molecular mechanisms and the efficacy of bisphosphonate and anti-RANKL therapies in future studies. Our long-term objective in developing this animal model is to prevent the increased hip-fracture risk associated with radiation therapy for pelvic cancers. ? ? ?
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