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AMIFOSTINE PROPHYLAXIS CONFERS LONG-TERM BIOMECHANICAL PROTECTION TO IRRADIATED BONE
Presenter: Presenter: Peter A Felice, MD
Co-Authors: Ahsan S; Donneys A; Deshpande SS; Nelson NS; Perosky JE; Kozloff KM; Buchman SR
University of Michigan School of Medicine

Background: Despite its therapeutic role in head and neck cancer, radiation therapy (XRT) leads to long-term consequences such as pathologic fracture and osteoradionecrosis due to the degradation of bony Biomechanical Properties (BPs). Interestingly, after an 8-week period following XRT, our laboratory noted a paradoxical increase in bony BPs while prophylactic Amifostine (AMF) administration prior to XRT returned BPs to levels of non-irradiated controls. Two important questions arose from these findings: 1) Would the acute increase in BPs of irradiated bone persist in a long-term model, and 2) Would AMF preserve the BPs of irradiated bone at normal levels in a long-term model. We hypothesize the increase in BPs caused by XRT is a transient phenomenon that will degrade with time, and that AMF-induced radioprotection will continue in a long-term model.

Methods: Male Sprague Dawley rats are randomized into three groups: Group 1-Control (n=10); Group 2-XRT (n=10); and Group 3-AMF/XRT (n=9). Groups 2 and 3 receive 35Gy human-equivalent XRT in 5 fractions to the left hemi-mandible. Group 3 receive 100mg/kg subcutaneous AMF 45 minutes prior to XRT. Hemi-mandibles are harvested after 18-weeks for Biomechanical Testing (BMT) analysis of BPs and compared to our short-term, 8-week BPs.

Results: 8-week XRT specimens show a significant increase above AMF/XRT and Controls for Yield Load, Ultimate Load, and Failure Load; 18-week XRT specimens show no increase or difference in BPs. In addition, consistent with 8-week results, no difference in BPs is seen between 18-week AMF/XRT and Controls, confirming AMF protects irradiated bone in a long-term model (See Figures).

Conclusions: AMF prophylaxis prior to XRT successfully preserves BPs at levels of normal, native bone in a long-term model. Furthermore, the short-term paradoxical augmentation of BPs in irradiated bone is a transient effect that degrades with time. These findings elucidate the temporal pathophysiology of the effects of XRT on bone and affirm the potential utilization of AMF to protect bone from long-term, XRT-induced damages.


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