Alendronate/Dexamethasone Combination Therapy Worsens Soft And Hard Tissue Wound Healing Around Implants In Rat Maxillae

Dental implant treatment in patients prescribed medications is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) around the implants. However, there is no scientific information on how bisphosphonate and/or steroid therapies affect wound healing around implants after implant placement. The aim of this study was to histopathologically and immunopathologically investigate the effects of bisphosphonate and/ or steroid therapy on the early stages of soft and hard tissue wound healing around implants in rat maxillae. Eight-week-old female Wistar rats were used. Alendronate (ALN) monotherapy, dexamethasone (DEX) monotherapy, and ALN/DEX combination therapy were started 4 weeks after tooth extraction of right maxillary first molars. Saline was used as a control (n = 14/group). Implant placement was carried out after grossly and manually confirming no open wounds at 16 weeks post-extraction. Euthanasia was performed at 18 weeks postextraction. Microcomputed tomography, histological stains and immunostaining to detect blood vessels and macrophages were performed to quantitatively analyze wound healing around implants. ALN/DEX combination therapy significantly increased necrotic bone with more empty lacunae and polymorphonuclear cell infiltration with open wounds when compared with all other therapy groups. Necrotic bone was broadly distributed from the crestal bone to the lower area near the apex of the implants in the ALN/DEX group. Interestingly, both ALN/DEX combination therapy and DEX monotherapy significantly increased the number of CD68+NG2- macrophages, whereas only ALN/DEX combination therapy, not DEX monotherapy, significantly shifted the M1/M2 ratio to M1 by significant increases in M1 macrophages and unchanged M2 macrophages in the connective tissue around implants. Within the limitations of this study, these findings may contribute to understanding the early stages of the histopathology and immunopathology of BRONJ-like lesions around dental implants. Continuous accumulation of M1 macrophages without alteration of M2 macrophages may be associated with developing BRONJ around implants.