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Mechanisms of Radiation-Induced Bone Loss and Effects on Prostate Cancer Bone Metastases

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Annual summary rept. 1 Jun 2012-31 May 2013

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Patients with prostate cancer frequently receive radiation therapy. Although radiation therapy is effective for the treatment of primary tumors, bystander bone absorbs approximately half of the radiation dose and thus may cause adverse radiation-induced effects at skeletal sites. Indeed, within five years of radiation treatment at the pelvic region cervical, rectal or anal cancer, the risk of hip fracture increases by up to 20 in cancer patients relative to the general population. During the reported project period, a dose-response and time-course study using in situ bone calvarial assays demonstrated that radiation exposure 6-10Gy causes osteocyte apoptosis one week following exposure. Osteoblast apoptosis was not observed during the time course 1-10 days at any dose 2-10Gy. Next, using a single-limb therapeutic radiation model, I examined the direct and indirect effects of radiation on bone in vivo. Our data demonstrate that a relatively low dose of site-directed radiation 2Gy caused direct and systemic bone loss in C57Bl6 mice relative to previously untested sham-irradiated controls and that osteoclastogenesis and marrow adiposity were drastically increased one week following radiation exposure at site of direct irradiation. Assayed sera from irradiated mice revealed no change in classic inflammatory pro-resorptive cytokines IL-1 , IL-6, IL-17, TNF- however, we did observe a significant decline in anti-inflammatory cytokines IL-3, IL-4, IL-10 and RANTESCCL2 relative to sham-irradiated controls. Using dynamic histomorphometry, mineralized surface area of bone at sites of irradiation was reduced, with no change in the number of osteoblasts, indicating that osteoblast function may be impaired by irradiation. We therefore conclude that bone loss resulting from radiation exposure in vivo can be attributed to an increase in osteoclastic bone resorption and reduced mineralization of bone surfaces.

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  • Medicine and Medical Research

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