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COMBINED ACTION OF AMIFOSTINE WITH DEFEROXAMINE RESTORES METRICS OF CALLUS MINERALIZATION IN A MODEL OF PATHOLOGIC FRACTURE HEALING AFTER RADIOTHERAPY
Presenter: Christian Figueredo, Medical Student
Co-Authors: Henry M; Figuredo C; Ahsan S; Deshpande SS; Felice PA; Nelson NS; Buchman SR
University of Michigan

Purpose: Radiotherapy continues to be associated with the debilitating outcomes of pathologic fractures and non-unions. A pharmacologic means to prevent these poor outcomes would be highly desirable. We have previously demonstrated the partial utility of Amifostine (AMF), a radio-protectant, in preserving metrics of callus mineralization in a model of fracture healing after radiotherapy. In this study we sought to enhance the cytoprotective properties of AMF with the synergistic addition of Deferoxamine (DFO), an angiogenic therapy, in order to produce a callus of superior mineralization at the fracture site.

Methods: 35 male Sprague-Dawley rats were randomly assigned to 3 groups: Fracture, radiated fracture, and radiated fracture with combined AMF and DFO therapies. Radiation groups received a fractionated human equivalent dose of radiotherapy and were allowed 2 weeks to recover prior to mandibular osteotomy and external fixation. The therapy group received AMF prophylaxis before radiation and DFO injections following osteotomy. After a 40-day recovery period, mandibles were dissected en-bloc, and callus mineralization was assessed via Micro-CT. The combination group was compared to a previously established AMF group to assess the efficacy of combined therapy. ANOVA was utilized for statistical analysis with significance assessed at p < 0.05.

Results: Combined therapy significantly restored Bone Volume Fraction (BVF, p=0.001) and Bone Mineral Density (BMD, p=0.001) to control levels, representing a beneficial restoration of callus structure and mineralization, respectively. Further, combined therapy evidenced superior BVF (p=0.001) and BMD (p=0.008) compared to AMF protection alone. These results therefore demonstrate both statistical and clinically significant improvement.

Conclusion: Our data demonstrates near total restoration of callus mineralization and structure with the use of combination AMF+DFO therapy from radiation levels. These findings highlight the importance of cytoprotection and restoration of vascularity as a potential synergistic strategy for the prevention of radiation-induced bone injury.


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