21. The Effect of Parathyroid Hormone on Non-vascularized Bone Graft Reconstruction in the Irradiated Murine Mandible

Purpose: Radiation is critical component of the current treatment algorithm for head and neck malignancies. Despite advances in radiation technology, bone within the treatment field is subject to significant adverse effects that often leads to devastating complications such as pathologic fractures and osteoradionecrosis. Reconstruction of segmental mandibular defects arising from such complication remains a vexing problem as time tested techniques, such as non-vascularized bone grafting, have been rendered unusable due to high failure rates. Parathyroid hormone (PTH) is a naturally occurring hormone, that is already clinically utilized as an FDA approved treatment for osteoporosis and offers potential as a therapeutic intervention to improve bone healing in the setting of radiation. In this study, we aim to investigate the ability of PTH to augment non-vascularized bone grafting for mandibular reconstruction of radiation in a murine model. Methods: Forty-two male isogenic Lewis rats were divided into 3 groups: control bone graft without radiation, control irradiated bone graft (XBG), and irradiated bone graft with parathyroid hormone treatment (XBG + PTH). Additional Lewis rates were utilized as graft donors. The XBG and XBG +PTH groups received radiation therapy with a fractionated dose of 35Gy. All rats underwent reconstruction of a 5mm defect of the left hemi-mandible with a 5mm non-vascularized bone graft from the iliac crest, secured with custom Resorb-X plates. The XBG+ PTH group was administered recombinant 60 µg/kg PTH (1-34) daily for 21 days beginning of post-operative day one. After a 60-day recovery period, left hemi-mandibles were harvested and evaluated for bony union and overall bone quality (P < 0.05). Results: Animals exposed to radiation (XBG group) had significantly reduced bony union rates compared with control non-radiated animals (42% vs 80%, p = 0.042) as well as significant reductions in all metrics of bone quality. Administration of parathyroid hormone improved bony union rates compared to radiation without treatment (62% versus 42%). Parathyroid hormone additionally helped reverse radiation induced bone damage as demonstrated by restoration of bone mineral density (XBG 383mg/mL, XBG + PTH 525 mg/ml, control 608 mg/mL), tissue mineral density (XBG 647 mg/mL, XBG + PTH 833mg/mL, control 728 mg/mL), and bone volume fraction (XBG 0.45, XBG + PTH 0.53, control 0.74) to near that of controls. Although not statistically significant a similar trend was observed across all biomechanical metrics; stiffness (XBG 41 N/mm, XBG + PTH 217 N/mm, control 283 N/mm), ultimate load (XBG 15 N, XBG + PTH 47 N, control 58 N), failure load (XBG 15N, XBG + PTH 24N, control 57 N). Conclusion: Administration of intermittent parathyroid hormone potentiates the negative sequalae of radiation leading to improved healing, union rates and bone quality of non-vascularized bone grafting in an irradiated murine mandible model.