title: Role of parathyroid hormone therapy in reversing radiation-induced nonunion and normalization of radiomorphometrics in a murine mandibular model of distraction osteogenesis.
abstract: BACKGROUND
  The use of mandibular distraction osteogenesis (MDO) for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis has been described but, in fact, has seen limited clinical utility. Previous laboratory work has shown that radiation (XRT) causes decreased union formation, decreased cellularity, and decreased mineral density in an animal model of MDO. Our global hypothesis is that radiation-induced bone damage is partly driven by the pathologic depletion of both the number and function of osteogenic cells. Parathyroid hormone (PTH) is a U.S. Food and Drug Administration-approved anabolic hormonal therapy that has demonstrated efficacy for increasing bone mineral density for the treatment of osteoporosis. We postulate that intermittent systemic administration of PTH will serve as an anabolic stimulant to cellular function that will act to reverse radiation-induced damage and enhance bone regeneration in a murine mandibular model of DO.
  
  
  METHODS
  A total of 20 isogenic male Lewis rats were randomly assigned into 3 groups. Group 1 (XRT-DO, n = 7) and group 2 (XRT-DO-PTH, n = 5) received a human bioequivalent dose of 70 Gy fractionated over 5 days. All groups including group 3 (DO, n = 8) underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Four days later, mandibular DO was performed at a rate of 0.3 mm every 12 hours to reach a maximum gap of 5.1 mm. Group 2 was injected PTH (60 μg/kg) subcutaneously daily for 3 weeks following the start of MDO. On postoperative day 41, all left hemimandibles were harvested. Micro-CT at 45-μm voxel size was performed and radiomorphometrics parameters of bone mineralization were generated. Union quality was evaluated on a 4-point qualitative grading scale. Radiomorphometric data were analyzed using 1-way ANOVA, and union quality assessment was analyzed via the Mann-Whitney test. Statistical significance was considered at p ≤ .05.
  
  
  RESULTS
  Groups 1 and 2 appropriately demonstrated clinical signs of radiation-induced stress ranging from alopecia to mucositis. Union quality was significantly higher in PTH-treated XRT-DO animals, compared with XRT-DO group animals (p = .02). Mineralization metrics, including bone volume fraction (BVF) and bone mineral density (BMD), also showed statistically significant improvement. The groups that were treated with PTH showed no statistical differences in union or radiomorphometrics when compared with DO in nonradiated animals.
  
  
  CONCLUSIONS
  We have successfully demonstrated the therapeutic efficacy of PTH to stimulate and enhance bone regeneration in our irradiated murine mandibular model of DO. Our investigation effectively resulted in statistically significant increases in BMD, BVF, and clinical unions in PTH-treated mandibles. PTH demonstrates immense potential to treat clinical pathologies where remediation of bone regeneration is essential.
authors: Departments of Otolaryngology-Head and Neck Surgery and Plastic Surgery, University of Michigan Health System, Ann Arbor, Michigan.
authors: K Kelly
authors: KK
authors: Gallagher
authors: Sagar
authors: S
authors: Deshpande
authors: Catherine N
authors: CN
authors: Tchanque-Fossuo
authors: Alexis
authors: A
authors: Donneys
authors: Deniz
authors: D
authors: Sarhaddi
authors: Noah S
authors: NS
authors: Nelson
authors: Douglas B
authors: DB
authors: Chepeha
authors: Steven R
authors: SR
authors: Buchman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D007279:Injections, Subcutaneous; D008297:Male; D008334:Mandible / Q000473:pathology / Q000601:surgery*; D023421:Models, Animal; D019857:Osteogenesis, Distraction; D010025:Osteoradionecrosis / Q000628:therapy*; D010027:Osteotomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000628:therapy; D011897:Random Allocation; D051381:Rats; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone
keywords: distraction osteogenesis; mandible; mineral density; parathyroid hormone; radiation