Background:
Denosumab is degraded within 6 months. Denosumab-related osteonecrosis of the jaw (DRONJ) worsens oral-heath related quality of life. However, the exact mechanisms and treatment strategy of DRONJ remains unclear. Migration of macrophages, angiogenesis and lymphangiogenesis play important roles in wound repair. The aim of this study was to compare immunopathology in DRONJ-like lesions with that in healed DRONJ-like lesions by cessation of anti-RANKL neutralizing antibody (mAb) in mice.
Methods:
C57BL/6J mice were used. Combination administration of cyclophosphamide (CY) and mAb were performed. Both maxillary first molars were extracted at 3 weeks after drug therapy. At 3 weeks post-extraction with the diagnosis of ONJ-like lesions, mice treated with CY/mAb combination therapy were randomly divided into 2 groups, mAb continuation group and mAb discontinuation group (mAb-C and mAb-D, respectively). Mice were euthanized at 5- and 7-weeks post-extraction. Osseous and soft tissue healing were evaluated using intra-oral photographs, micro computed tomography, histological staining and immunostaining to visualize macrophages and blood and lymphatic vessels.
Results:
Bone exposure in mAb-C at 5- and 7-weeks post-extraction were remained, whereas the wounds in mAb-D at both time points were diminished. Discontinuation of mAb for 2 weeks significantly increased collagen production and living bone with the increase in osteocyte density while significantly decreased necrotic bone with reduced empty lacunae and polymorphonuclear cells in the tooth extraction sockets. The distribution of macrophages in the connective tissues of tooth extraction sockets in mAb-D was significantly promoted when compared with that in mAb-D. Angiogenesis and lymphangiogenesis in the tooth extraction sockets were almost similar between mAb-C and mAb-D at 2 weeks after the cessation of mAb.
Conclusion:
Our findings suggest that accumulation of macrophages in tooth extraction sockets may contribute to the amelioration of CY/mAb induced-ONJ-like lesions rather than angiogenesis and lymphangiogenesis.