The irradiated human mandible

Mandibular bone is known to be susceptible to irradiation damage, especially when radiation dose exceeds 50 Gy. This can result in compromised wound healing and ultimately osteoradionecrosis (ORN). ORN presents as an area of exposed bone with no tendency of healing. The aim of this thesis was to investigate the effects of radiotherapy on the mandible, in order to elucidate the disruptions of bone physiology that might contribute to the development of ORN, focusing on different aspects of bone: vascularity, trabecular structure, bone turnover and bone marrow. Bone tissue was obtained from irradiated and non-irradiated edentulous patients during dental implant surgery in the anterior mandible. In irradiated patients, mandibular resorption is generally less severe than in non-irradiated patients, because frequently these patients have become edentulous shortly before the start of their cancer treatment. Because edentulism initiates a process of atrophy in the mandible, it was important to define the characteristics of (non-irradiated) mandibular bone in physiological resorption. In Chapter 2 the mandibular bone of non-irradiated individuals was analyzed using histomorphometry and micro-CT. There was no significant difference between men and women for any of the measured parameters, except for the number of osteoclasts, which was higher in women. Only in women, bone volume was negatively associated with turnover. A higher bone mineral density was observed in the trabecular bone of the more severely resorbed edentulous mandibles. In chapter 3, larger volumes of bone from cadaveric edentulous mandibles were investigated. Molar, premolar and anterior segments were analyzed using micro-CT. No significant differences were found between men and women. Cortical bone mineral density (BMD) increased towards the inferior border of the mandible. Overall, cortical BMD was higher in areas with highest strains and lower in areas subject to the most mandibular resorption. Only in the premolar region, impaired bone quality was associated with increased mandibular resorption. In Chapters 4, 5 and 6 the effects of radiotherapy were investigated. In irradiated patients, vascular density and vascular area fraction of the mandibular bone marrow were lower. In bone samples with a local point dose (Dmax) of ≥50 Gy the mean vascular diameter and perimeter was higher than in samples with a Dmax <50 Gy, whereas the percentage of smaller vessels was lower. A longer interval between radiotherapy and biopsy was associated with a larger mean vessel perimeter and lower percentage of smaller vessels. This may indicate either a direct radiation damage to the smallest vessels or an impaired angiogenesis. Radiotherapy dramatically impaired bone turnover in the mandible. However, deterioration of the trabecular structure only affected bone irradiated with a Dmax of <50 Gy. Apoptotic osteocytes and empty lacunae were counted as a measure for osteocyte death. Apoptotic osteocytes were not increased in the irradiated bone but the amount of empty lacunae was significantly higher. The bone marrow adiposity was significantly increased in the irradiated bone but not bone marrow fibrosis. In conclusion, radiation disrupts bone homeostasis at multiple levels. Based on the results of this study and the existing literature, we speculated on the following order of events after irradiation: Osteocyte death occurs early after irradiation. A lack of osteocyte and osteoblast signaling, as well as a deprivation of osteoclast precursors, leads to persistent lack of osteoclastogenesis. Irradiation-induced damage to the mesenchymal stem cells in bone decreases osteoblastogenic potential and increases marrow adipogenesis. Subsequently, a fragile bone matrix void of osteocytes persists, which, in a dose-dependent absence of regenerative and remodeling potential, is vulnerable to infection and necrosis, particularly when a disruption of the overlying soft tissue barrier is introduced. This could as such be a key event in the pathogenesis of ORN.