Evaluation of the peri-implant repair process in rats treated with oncologic dose or osteoporotic dose of zoledronate

Author(s)

Luan Felipe Toro

• Document type: Master's Dissertation
• Press: Botucatu. 2019-03-22.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu
• Defense date: 2019-02-20
• Advisor: Edilson Ervolino; Valdir Gouveia Garcia

Abstract

Bisphosphonates (BPs) are drugs widely used for the treatment of conditions that cause osteolysis, by inhibition of the bone resorption process. High potency BPs, such as zoledronate, are used to control the progression of bone metastasis in osteotropic malignant neoplasms or for the treatment of severe osteoporosis. However, one of its adverse effects is the occurrence of medication-related osteonecrosis of the jaws (MRONJ). Among the main local risk factors for MRONJ are invasive dental procedures, such as surgeries for installation of osseointegratable dental implants. Despite the increased number of clinical reports of MRONJ after installation of dental implants in patients treated with BPs, there are few studies that aim to understand the changes triggering this condition. So, the objective of this study was to analyze the peri-implant repair process in the tibia of rats treated with oncologic dose or osteoporotic dose of zoledronate and to evaluate the existence of correlation between this process and the occurrence of osteonecrotic lesions. Forty female rats (6 months old) were distributed in two experiments: Experiment I: rats received intraperitoneal (IP) injections of 0.45ml of 0.9% sodium chloride (NaCl) solution (group VEI-ONC, n=10) or this same solution added by 100µg/Kg of zoledronate (group ZOL-ONC, n=10), every 4 days for 8 weeks; Experiment II: rats received IP injections of 0.45ml of 0.9% NaCl solution (group VEI-OST, n=10) or this same solution added by 100µg/Kg of zoledronate (group ZOL-OST, n=10), every 28 days for 24 weeks. In both experiments, 16 weeks after the beginning of drug protocol, all animals were submitted to installation of a titanium implant in both right and left tibiae. Euthanasia was performed at day 56 postoperatively. After dissection and a through clinical examination of the peri-implant area, left tibiae were submitted to microtomographic scanning for analysis of the microarchitecture and structuring of peri-implant bone tissue and, later, to ground-section histological processing for histometric analysis of the bone/implant contact (BIC), a parameter for evaluation of the osseointegration of titanium implants. The right tibiae were submitted to conventional histological processing after demineralization, and the histological sections were stained by hematoxilin-eosin for histopathological analysis of the peri-implant tissues and adjacencies, histometric analysis of the percentage of total bone tissue (PTBT) and the percentage of non-vital bone tissue (PNVBT) in the peri-implant area, or intended for immunohistochemical reaction for detection and quantification of bone morphogenetic protein 2/4 (BMP2/4), runt-related transcription factor 2 (RUNX2), osteocalcin (OCN) and tartrate-resistant acid phosphatase (TRAP). Data were statistically analyzed at significance level of 5%. ZOL-ONC presented higher percentage of bone volume and lower total porosity in relation to groups VEI-ONC and ZOL-OST, and higher PTBT in relation to group VEI-ONC. Groups ZOL-ONC and ZOL-OST presented higher PNVBT and smaller number of RUNX2-positive cells and OCN-positive cells than groups VEI-ONC and VEI-OST, respectively, as well as extensive areas of non-vital bone tissue and foci of inflammation. BIC and the number of BMP2/4-positive cells and TRAP-positive cells did not differ amongst groups, however, these last cells exhibited features of inactivity in ZOL-ONC and ZOL-OST. Thus, it is concluded that the treatment with oncologic dose or osteoporotic dose of zoledronate does not negatively affects osseointegration of titanium implants and the amount of peri-implant bone tissue, but it does cause areas of non-vital bone tissue and inflammation foci, suggesting that installation of osseointegratable implants should be viewed with great caution in such conditions, since it may constitute an important local risk factor for the onset of MRONJ. (AU)

• FAPESP's process: 17/16364-2 - Evaluation of the peri-implant repair process in rats treated with oncologic dose or osteoporotic dose of zoledronate
• Grantee: Luan Felipe Toro
• Support Opportunities: Scholarships in Brazil - Master