Objective: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) around dental implants, which is rare but severe adverse effect of bisphosphonates, has been increased in clinical situations. However, histopathology and immunopathology of BRONJ around implants are unclear due to the lack of animal models of BRONJ around implants. The aim of this study was to create the animal model of BRONJ-like lesions around implants (Implant-BRONJ) and to investigate histopathology and immunopathology of Implant-BRONJ.
Materials and Methods: Eight-week-old female, wistar rats were used. Grade IV titanium implants with 2.0 mm in diameter and 3.5 mm in length were used. Tooth extraction of right maxillary first molars were performed. Drug administration was carried out at 4 weeks after tooth extraction. Alendronate (ALN) monotherapy, dexamethasone (DEX) monotherapy, ALN/DEX combination therapy, and saline injection (VC) were performed. Implants were placed in the healed extraction sites at 16 weeks post-extraction. All rats were euthanized at 2 weeks after implant placement. Gross healing, structural analysis, histopathological and immunopathological analyses of soft and hard tissue around implants were quantitatively evaluated.
Results: Impaired wounds with exposed bone around implants were observed in all ALN/DEX-treated rats. ALN/DEX significantly increased necrotic bone and empty lacunae, and decreased living bone and osteocyte density when compared with VC. Moreover, ALN/DEX significantly decreased collagen production with the infiltration of polymorphonuclear cells when compared with VC. Thus, compromised soft and osseous healing around implants were defined as Implant-BRONJ-like lesions. ALN/DEX significantly increased macrophages in the connective tissue around implants with suppressed angiogenesis when compared with VC. Interestingly, the ratio of M1/M2 ratio in ALN/DEX was significantly larger than that in VC.
Conclusions: An available animal model of implant-BRONJ-like lesions were created in this study. Suppressed angiogenesis and accumulation of M1 macrophages in the connective tissue around implants may contribute to development of Implant-BRONJ.