Effect of anti-angiogenesis induced by chemotherapeutic monotherapy, chemotherapeutic/bisphosphonate combination therapy and anti-VEGFA mAb therapy on tooth extraction socket healing in mice

Abstract

Osteonecrosis of the jaw (ONJ), which is a rare but severe adverse effect, mainly occurs in oncology patients receiving chemotherapeutic agents and bisphosphonates. However, the combined impact of chemotherapy and bisphosphonates on wound healing after tooth extraction remains unknown. The aim of this study was to determine the precise etiology of ONJ induced by chemotherapy and bisphosphonate combination therapy. Mice received zoledronate (ZA) monotherapy, cyclophosphamide (CY) monotherapy or CY/ZA combination therapy. The maxillary first molars were extracted 3weeks after the initiation of drug treatment. Moreover, antivascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) was administered once every 2days just after tooth extraction for 2weeks. Soft and hard tissue wound healing was evaluated 2 and 4weeks post-extraction using histomorphometry, microcomputed tomography and immunohistochemistry. ZA monotherapy did not induce impaired oral wound healing and ONJ-like lesions 2 and 4weeks post-extraction, respectively. Tooth extraction socket healing worsened with severe anti-angiogenesis by CY monotherapy and CY/ZA combination therapy 2weeks post-extraction. However, CY monotherapy rarely induced ONJ-like lesions with severe angiogenesis suppression, whereas CY/ZA combination therapy frequently induced ONJ-like lesions with severe angiogenesis inhibition 4weeks post-extraction. Interestingly, anti-VEGFA mAb therapy delayed osseous wound healing with normal soft tissue wound healing of tooth extraction sockets, although this therapy significantly suppressed blood vessel formation. Our findings suggest that anti-angiogenesis alone is not the main cause of ONJ-like lesions induced by CY/ZA combination therapy. The combination of suppressed osteoclasts and anti-angiogenesis, in addition to other risk factors such as chemotherapy, may contribute to the development of ONJ.