A Novel Pharmaceutical Therapy Preserves Bone Cellularity in an Irradiated Model of Distraction Osteogenesis
Kevin M. Urlaub, BS, Jeremy V. Lynn, BS, Edward G. Carey, BS, Noah S. Nelson, MPH, Yekaterina Polyatskaya, MD, Alexis Donneys, MD, MS, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
PURPOSE: The use of distraction osteogenesis (DO) in craniofacial reconstruction is precluded by the deleterious effects of radiotherapy on bone and soft tissue, limiting reconstructive options for head and neck cancer (HNC) patients. Our research has previously demonstrated the individual efficacy of both radioprotective amifostine (AMF) and angiogenic deferoxamine (DFO) in improving healing metrics in irradiated models of mandibular DO. Through histologic evaluation, this study investigates the synergistic effects of AMF and DFO as a novel combination therapy in order to expand the utility of DO as a reconstructive technique for HNC patients following radiotherapy (XRT).
METHODS: 30 male Sprague Dawley rats were divided into five groups: DO, XDO, AMF, DFO, and Combined Therapy (CT). With the exception of the DO group, all rats were administered a fractionated, human-equivalent radiation dose of 35Gy, comparable to 70Gy administered to HNC patients clinically. All groups underwent mandibular osteotomy and placement of an external fixator device. Beginning on post-operative day 4, the left hemi-mandible was distracted over the course of 8 days to a critical-sized defect of 5.1mm. All rats were sacrificed on post-operative day 40, and mandibles were dissected and embedded in paraffin. Coronal sections were obtained from the region of interest, defined as the 5.1mm of newly formed bone. Sections were stained using Gomori's Trichrome and analyzed for osteocyte count, osteoid volume, and bone volume. Statistical analysis was performed using ANOVA, with p values less than 0.05 considered significant.
RESULTS: The XDO group demonstrated significant decreases in both osteocyte number and bone volume (p=0.000) and a significantly increased osteoid volume (p=0.017) when compared to DO controls. The AMF, DFO, and CT groups demonstrated a significant increase in osteocyte number in comparison to the XDO group (p=0.006, p=0.000, and p=0.000, respectively), and were not statistically different from DO. Additionally, the CT group had significantly greater bone volume than the AMF, DFO, or Control group (p=0.001; p=0.000, p=0.002), as well as significantly lower osteoid volume (p=0.001; p=0.004, p=0.022).
CONCLUSION: Our combination therapy significantly improved bone cellularity in the context of radiation. While our research has previously demonstrated the efficacy of both AMF and DFO alone, the increased bone volume in comparison to individual therapy and control groups in this study provides preliminary evidence that a complementary effect may be achieved through their use in conjunction. While further investigation surrounding the differing mechanisms through which AMF and DFO promote bone healing and regeneration is necessary, these results corroborate previous work by our laboratory and highlight the potential for pharmaceutical therapies to facilitate the use of DO as a reconstructive technique in HNC patients.
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