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 3 weeks after the initiation of drug treatment. Moreover, antivascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) was administered once every 2 days just after tooth extraction for 2 weeks. Soft and hard tissue wound healing was evaluated 2 and 4 weeks post-extraction using histomorphometry, microcomputed tomography and immunohistochemistry. ZA monotherapy did not induce impaired oral wound healing and ONJ-like lesions 2 and 4 weeks post-extraction, respectively. Tooth extraction socket healing worsened with severe anti-angiogenesis by CY monotherapy and CY/ZA combination therapy 2 weeks 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 4 weeks 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.

Medication‐related osteonecrosis of the jaw‐like lesions in rodents: A comprehensive systematic review and meta‐analysis

“…Saline or phosphate‐buffered saline was used as a control, except for one study . Zoledronic acid (ZA) and osteoprotegerin (OPG)‐Fc monotherapy were used to create BRONJ‐ and DRONJ‐like lesions in five studies, respectively, whereas ZA was administered in combination with chemotherapeutic agents and/or dexamethasone (DEX) to develop BRONJ‐like lesions in four studies . Alendronate monotherapy was also used to create BRONJ‐like lesions in one study .…”

“…Anti‐sclerostin monoclonal antibody‐related ONJ was not investigated in this review. Maxillary and mandibular first molars were extracted in eight and two studies, respectively. Mandibular second molars were extracted in one study .…”

“…Many studies reported that ZA monotherapy induced impaired wound healing of tooth extraction sockets with uncovered mucosa and exposed bone at 2, 4 or 12 weeks after tooth extraction, although the dosages of ZA administered differed among the studies . Akita et al and Kuroshima & Yamashita reported that ZA and chemotherapeutic combination therapy significantly increased wound open area with exposed bone at 4 weeks after tooth extraction . One study reported that OPG‐Fc, a RANKL inhibitor, significantly induced exposed bone with a mucosal defect (Table ) …”

“…MicroCT scanning or position emission tomography (PET) was used to evaluate tooth extraction socket healing. Akita et al and Kuroshima & Yamashita showed that ZA monotherapy significantly increased bone mass and bone mineral density (BMD) in the tooth extraction sockets with necrotic bone, whereas ZA/chemotherapeutic combination therapy significantly reduced bone mass and BMD of tooth extraction sockets in BRONJ‐like lesions . Bi et al reported that triple administration of ZA, Dex and chemotherapeutic drugs significantly increased BMD of necrotic bone in the tooth extraction sockets.…”

“…Soundia et al reported that increases in the numbers of detached osteoclasts were observed in ZA‐treated mice with extraction of diseased vs. healthy teeth. On the other hand, Akita et al and Kuroshima & Yamashita showed that ZA and chemotherapeutic combination therapy significantly decreased the number of osteoclasts on bone surfaces of tooth extraction sockets when compared with controls . Bi et al demonstrated that ZA monotherapy significantly decreased the number of osteoclasts and osteoblasts within the tooth extraction sockets.…”