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Prophylactic Amifostine Preserves the Biomechanical Properties of Irradiated Bone in the Murine Mandible
Peter A. Felice, M.D., Salman Ahsan, B.S., Joseph E. Perosky, M.S., Sagar S. Deshpande, B.S., Noah S. Nelson, B.S., Alexis Donneys, M.D., M.S., Kenneth M. Kozloff, Ph.D., Steven R. Buchman, M.D., M.S..
University of Michigan Medical School, Ann Arbor, MI, USA.
Despite its therapeutic aims in the treatment of head and neck cancer, radiation therapy can lead to devastating consequences such as pathologic fracture. We have previously demonstrated that Amifostine prophylaxis mitigates the pernicious effects of radiation on bone in the settings of distraction osteogenesis and fracture repair; expanding on these studies, we established a translational model to analyze the biomechanical properties of native, uninjured, and unoperated mandibles exposed to both radiation and Amifostine administration. We hypothesize that radiation will significantly alter the biomechanical properties of otherwise uninjured bone. We further hypothesize that prophylactic Amifostine will preserve biomechanical properties to levels of normal bone and protect the mandible from the morbidities associated with radiation administration.
Sprague Dawley rats were randomized into three groups; Control, radiation exposure (XRT), and Amifostine pre-treatment with radiation exposure (AMF-XRT) specimens. Irradiated animals received a fractionated dosing schedule of 7Gy/day over five days for 35Gy total human-equivalent radiation dosage to the left hemi-mandible, while Amifostine pre-treated animals received 100mg/kg subcutaneous injection 45 minutes prior to radiation. Hemi-mandibles were harvested at 8 and 18 weeks and a region of interest machined for Yield Load, Ultimate Load, and Stiffness biomechanical testing metrics, as well as for micro-computed tomographic analysis.
The 8-week XRT specimens displayed significant elevations above Controls for all biomechanical testing metrics while 8-week AMF-XRT specimens were maintained at levels comparable to Controls. The 18-week XRT specimens displayed biomechanical properties that were degraded in comparison to Controls, while 18-week AMF-XRT specimens continued to display levels comparable to Controls. The 18-week XRT specimens demonstrated a significant decrease in Yield Load and a trending decrease in Ultimate Load when compared to AMF-XRT specimens. The most noteworthy finding for Tissue Mineral Density micro-computed tomography analysis was a significant decrease in mineralization from 8- to 18-week XRT specimens, while no such change existed for Control and AMF-XRT specimens (See Figures).
Our findings demonstrate a paradoxical and transient elevation in the initial biomechanical properties of irradiated specimens that was not sustained through the later time point of our study. Amifostine pre-treatment, however, provided uninterrupted preservation of the native biomechanical properties of bone at both time points. Micro-computed tomography analysis for irradiated specimens also yielded an elevation in Tissue Mineral Density at 8 weeks, a finding reversed in Amifostine pre-treated specimens at 18 weeks. These outcomes support the contention that Amifostine is capable of providing continuous and consistent protection to bone against the untoward effects of radiation therapy. Clinical trials may now be warranted to determine whether utilizing prophylactic Amifostine is efficacious in preventing collateral damage to bone in treatment protocols for patients requiring radiation therapy.
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