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Parathyroid Hormone Remediates Radiation Damage in a Murine Model of Distraction Osteogenesis via Histological Evaluation
Sagar S. Deshpande, BS1, Steven Y. Kang, MD1, Alexis Donneys, MD, MS1, Peter A. Felice, MD2, Rodriguez J. Jose, MD1, Noah S. Nelson, BS1, Samir S. Deshpande, n/a3, Steven R. Buchman, MD1.
1University of Michigan, Ann Arbor, MI, USA, 2Medical University of South Carolina, Charleston, SC, USA, 3Kalamazoo College, Kalamazoo, MI, USA.
Radiation is known to be detrimental to bone and soft tissue repair, resulting in an unacceptably high incidence of devastating wound healing complications. This is effected through a mechanism of both direct cellular and vascular depletion. We sought to utilize an anabolic regimen of parathyroid hormone (PTH), an FDA-approved bone therapeutic, to remediate this deficiency. The purpose of this study was to allow for the successful utility of distraction osteogenesis in an irradiated field utilizing an intermittent regimen of PTH for the purpose of craniofacial reconstruction in head and neck cancer victims.
20 male Lewis rats were randomly split into three groups, DO (n=5), XRT/DO (n=10), and XRT/DO/PTH (n=5). XRT/DO and XRT/DO/PTH underwent 5 day fractionated XRT of the left mandible at 7 Gy per day and were allowed to recover for two weeks. All groups underwent mandibular distractor placement. Groups were distracted at 0.3mm every 12 hrs to a 5.1mm (a critical-sized defect for an irradiated, distracted mandible), and sacrificed on post-operative day (POD) 40. XRT/DO/PTH received 60mg/kg of PTH daily for 3 weeks, starting on POD 4. Coronal sections were obtained and stained using Hematoxylin & Eosin (H&E), Safranin O, and Gomori Trichrome. Statistical analysis was performed with ANOVA and subsequent Tukey or Games-Howell post-hoc tests, dependent on data heterogeneity.
: Gomori Trichrome demonstrated a significantly increased osteocyte number (133.44 ± 10.25 vs 67.86 ± 9.47, p=0.000) and significantly decreased empty lacunae (2.50 ± 1.20 vs 15.64 ± 7.79, p=0.000) in XRT/DO/PTH compared to XRT/DO. There were no significant differences between DO and XRT/DO/PTH. Safranin O demonstrated no cartilage presence. H&E staining demonstrated more woven bone within the regenerate of DO as well as XRT/DO/PTH specimens.
PTH has been previously shown to remediate radiomorphometrics, vascular analysis, and biomechanical strength in an irradiated model of distraction osteogenesis. This study has demonstrated both qualitative and quantitative metrics of radiation-induced remediation of cellularity utilizing parathyroid hormone, demonstrating its potential for use in irradiated fields. PTH therapy was able to remediate the detriments to osteocyte number as well as prevent empty lacunae formation. Furthermore, PTH stimulated new osteoid growth, as established by H&E. Finally, PTH maintains the intramembranous healing mechanism intrinsic to DO, as the Safranin O stain showed no evidence of a cartilaginous intermediate. As such, this abstract has demonstrated that anabolic regimens of PTH are a powerful tool for remediating the damage of radiation and allowing for successful utilization of distraction osteogenesis.
Figure 1. PTH therapy remediates osteocyte count. * indicates significance (p<0.05) with respect to DO. ** indicates significance with respect to XRT/DO/PTH.
Figure 2. PTH therapy remediates empty lacunae count. * indicates significance (p<0.05) with respect to DO. ** indicates significance with respect to XRT/DO/PTH.
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