IADR Abstract Archives
Inflammation and suppressed angiogenesis in Zoledronic acid-induced Osteonecrosis of the Jaws
Objectives: Over the past few decades, bisphosphonates (BPs) have become the primary class of drugs prescribed for the management of bone pathologies associated with excessive bone resorption such as osteoporosis, Paget’s disease, and primary and secondary bone malignancies. Although BPs are effective treatment agents for these conditions, their use has also been associated with significant side effect such as bisphosphonate related osteonecrosis of the jaws, viz BRONJ. Our study utilized Zoledronic acid (ZA), the most potent drug among the BPs and most common drug implicated in the BRONJ pathogenesis to develop a BRONJ rat model that involved extraction of maxillary molars.
Methods: Sprague-Dawley rats(n=28) were divided into four groups out of which two test groups were injected ZA (intraperitoneally, once weekly) for three weeks, followed by maxillary teeth extraction (first two molars) and a contralateral soft tissue defect without any exposure of bone. ZA was continued for two or four more weeks and the rats sacrificed at either end of two or four weeks healing. Gross examination, micro-CT evaluation and histological assessment were used to confirm the BRONJ lesion. Histomorphometrical analysis was used to quantify total necrosis and inflammatory infiltrate and compared to that of controls. Further, total vascularity was quantified and compared to that of corresponding controls at boh time points to assess the effects of ZA on healing defect.
Results: BRONJ lesion was confirmed in all of the rats administered ZA (100%), on gross examination, micro-CT evaluation and histological assessment following surgical bone exposure and not with soft tissue defect alone. Histologically, significantly higher necrosis (25048± 3489 sq μm vs 4076 ± 3489 sq μm, p〈0.0001) and excessive inflammation (22945 ± 2481 vs 2794 ± 252.3 sq µm, p< 0.0001) were evident in BRONJ lesions. In contrast, total vascularity was significantly suppressed in ZA group (0.1749 ± 0.01324 µm vs 0.2792 ± 0.02233, p=0.0011).
Conclusions: This in vivo study successfully established a BRONJ rat model that confirmed the critical role of ZA-induced local anti-angiogenesis in etiopathogenesis of BRONJ. This model can be a valuable tool to conduct further interventional studies to prevent the localized effect of ZA in the development of BRONJ.
Methods: Sprague-Dawley rats(n=28) were divided into four groups out of which two test groups were injected ZA (intraperitoneally, once weekly) for three weeks, followed by maxillary teeth extraction (first two molars) and a contralateral soft tissue defect without any exposure of bone. ZA was continued for two or four more weeks and the rats sacrificed at either end of two or four weeks healing. Gross examination, micro-CT evaluation and histological assessment were used to confirm the BRONJ lesion. Histomorphometrical analysis was used to quantify total necrosis and inflammatory infiltrate and compared to that of controls. Further, total vascularity was quantified and compared to that of corresponding controls at boh time points to assess the effects of ZA on healing defect.
Results: BRONJ lesion was confirmed in all of the rats administered ZA (100%), on gross examination, micro-CT evaluation and histological assessment following surgical bone exposure and not with soft tissue defect alone. Histologically, significantly higher necrosis (25048± 3489 sq μm vs 4076 ± 3489 sq μm, p〈0.0001) and excessive inflammation (22945 ± 2481 vs 2794 ± 252.3 sq µm, p< 0.0001) were evident in BRONJ lesions. In contrast, total vascularity was significantly suppressed in ZA group (0.1749 ± 0.01324 µm vs 0.2792 ± 0.02233, p=0.0011).
Conclusions: This in vivo study successfully established a BRONJ rat model that confirmed the critical role of ZA-induced local anti-angiogenesis in etiopathogenesis of BRONJ. This model can be a valuable tool to conduct further interventional studies to prevent the localized effect of ZA in the development of BRONJ.