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Optimization of Pathologic Fracture Healing after Radiotherapy Utilizing Amifostine in Combination with Deferoxamine
Hannah C. Ratliff, BS Candidate, Alexis Donneys, MD, MS, Yekaterina Polyatskaya, MD, Noah S. Nelson, BS, Cheyenne A. Vasseli, BS, Sagar S. Deshpande, BS, Jose J. Rodriguez, MD, Joshua S. Spiegel, BS, Erin E. Page, BS, Tulsi Patel, BS, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Pathologic fractures and associated non-unions of the mandible arising in previously irradiated bone are complex management dilemmas for reconstructive surgeons. We have previously demonstrated a partial remediation of biomechanical strength and bony union formation with Deferoxamine (DFO), an angiogenic factor, in a murine model of fracture healing following radiotherapy. The purpose of this study was to investigate the prophylactic ability of Amifostine (AMF) in combination with DFO to improve bony union formation by protecting osteocytes exposed to radiation. We hypothesize that combined therapy will increase osteocyte numbers and improve osteocyte function, yielding enhanced bony union formation beyond singular therapies.
Sprague-Dawley rats (n=12/group) were divided into 5 groups as follows: Fracture (Fx), radiated fracture (XFx), radiated fracture plus DFO (XFxDFO), radiated fracture plus amifostine (XFxAMF) and radiated fracture plus combined therapy (Combined). Radiated groups received a human equivalent dose of radiotherapy 2 weeks prior to mandibular osteotomy and external fixation. The combined group received AMF prophylaxis prior to radiation and injections of DFO after surgery. Following a 40-day healing period, mandibles were dissected, assessed for bony union and mechanically tested. All groups were subsequently compared to a previously established non-radiated, non-fractured control group (Control, n=12). ANOVA was used for comparisons between groups and p<0.05 was considered statistically significant.
While all treatment groups significantly improved on the osteocyte number over radiated fracture levels (XFx vs. Fx, XFxDFO, XFxAMF and Combined = 30+11 vs. 70+11, 67+7, 79+13 and 79+5; p=0.000, respectively) only those treated with amifostine reached levels that were not different than controls (Control vs. XFxAMF and Combined = 81+6 vs. 79+13; p=0.997 and 79+5; p=1.0, respectively). This profound effect may imply protective effects against injury associated not only with radiation, but also with the trauma inflicted by the fracture. Despite the effects on osteocyte number, the number of bony unions in radiated groups remained the highest for the combined therapy implying that the overall function of the osteocytes was improved by the addition of DFO to the combined therapy (Bony union by group: Fx=100%, XFx=25%, XFxAMF=57%, XFxDFO=67%, and Combined=80%; see Figure 1).
Our data supports the contention that combination therapy acts in a complementary fashion to conserve osteocyte numbers during fracture healing after radiotherapy. Although singular AMF therapy also maintained these numbers, the combination group presented increased bony unions, implying enhanced function of these osteocytes with the addition of DFO to the treatment paradigm. Based on these findings, we support the continued investigation of this treatment strategy in its potential translation for the management of pathologic fractures and associated non-unions after radiotherapy.
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