Amifostine Treatment Mitigates the Damaging Effects of Radiation on Distraction Osteogenesis in the Murine Mandible
Laura A. Monson, MD, Aaron S. Farberg, BS, Lin Jing, MD, Catherine N. Tchanque-Fossuo, MD, Alexis Donneys, MD, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
PURPOSE: Prior work in our lab has shown that distraction osteogenesis (DO) following radiation (XRT) on the murine mandible results in incomplete bony bridging and fibrous union. Amifostine (AMF), a radioprotectant, has been previously shown to prevent limb-length discrepancy in immature animals subjected to XRT. The objective of this study was to compare the results of DO in animals given human equivalent doses of XRT both with and without AMF therapy. Our hypothesis is that AMF can mitigate the deleterious effect of radiation on bone healing during DO.
METHODS: 2 groups of male Sprague-Dawley rats underwent 5 day fractionated XRT of the left mandible at 7 Gy per day. Group 1 received no medication during XRT; Group 2 received AMF at 100mg/kg prior to each XRT treatment. Animals were allowed to recover for two weeks, then underwent mandibular distractor placement and were distracted at 0.3mm every 12 hours to a total distance of 5.1mm. The regenerate was allowed to consolidate for 56 days after radiation was completed after which tissue was harvested and underwent analysis both grossly and with micro-CT. A VOI was selected to include the DO regenerate and was determined by the mean intensity projection scan.
RESULTS: Animals receiving AMF appeared to have less severe sequelae of XRT such as signs of stress, mucositis, and alopecia. At harvest, animals who did not receive AMF demonstrated gaps in the regenerate, incomplete bridging, and fibrous unions. In contrast, animals who received AMF demonstrated complete bony bridging of the distraction gap. Using micro-CT analysis, bone mineral density (BMD), bone volume fraction (BVF), tissue mineral density (TMD), and histogram analysis were determined for each group and compared with controls. Animals treated with AMF demonstrated statistically significant higher BMD (525.8801mg/cc v 398.7368; p<0.005), TMD (0.6800 v 0.6179; p<0.05) and BVF (0.6596 v 0.4718; p<0.001).
CONCLUSION: The results of our study demonstrate that DO alone following human equivalent XRT results in incomplete bony bridging and fibrous unions. However, when AMF is given concurrently with XRT, subsequent DO is able to produce a solid regenerate which can be measured with standard micro-CT parameters. This study establishes AMF’s ability to augment bone regeneration in a pathologic model where healing is not routinely observed.