Effect of zoledronate during the alveolar healing process in rats: study involving the major risk factors for developing osteonecrosis of the jaws and assessment of antimicrobial photodynamic therapy (aPDT) as preventive therapy

• Grant number: 13/26779-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2014
• End date: July 31, 2016
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Edilson Ervolino
• Grantee: Edilson Ervolino
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Associated researchers: Alaíde Gonçalves ; Cláudio Aparecido Casatti ; João Paulo Mardegan Issa ; Juliano Milanezi de Almeida ; Letícia Helena Theodoro ; Maria José Hitomi Nagata ; Rita Cássia Menegati Dornelles ; Valdir Gouveia Garcia

Abstract

Bisphosphonates (BPs) are a class of drugs used in the treatment of some bone diseases or osteotropic malignancies. BPs exert potent inhibitory effect on bone resorption. Among the adverse effects is the occurrence of bisphosphonate-related osteonecrosis of the jaws (BRONJ). The pathogenesis of the disease is poorly understood, which hinders its prevention and treatment. Among the risk factors for the onset of BRONJ are: chronic use of nitrogen-containing-BPs, especially zoledronate, intravenous route of administration, female gender, older age and oral surgeries, especially exodontia. Among the few therapeutic approaches is preventive antibiotic therapy, which shows failure and adverse effects. Antimicrobial photodynamic therapy (aPDT) has antimicrobial properties and potent biostimulatory effects, placing it as a potential therapeutic strategy for preventive BRONJ. The purpose of this study is to evaluate aPDT effect on alveolar socket and overlying mucosa of rats that show the main risk factors for the development of ONJ. One hundred and twenty rats (female; 20-month-old) will be divided into eight experimental groups: SAL, ZOL, SAL/FS, ZOL/FS, SAL/LLL, ZOL/LLL, SAL/aPDT and ZOL/aPDT. The duration of the treatment plan will be of seven weeks. Rats will receive intraperitonial injections of 0.45 ml solution of 0.9% sodium chloride (SAL, SAL/FS, SAL/LLL, SAL/aPDT groups) or 0.45 ml of same solution added with 100 mg/kg of zoledronate (ZOL, ZOL/FS, ZOL/LLL, ZOL/aPDT groups) with an interval of two days between the applications. After three weeks of treatment, all rats will be submitted to extraction of right mandibular first molar. In groups SAL/FS and ZOL/FS, wound will be covered with 1ml of methylene blue (photosensitizer) and maintained for 60s. In groups SAL/LLL and ZOL/LLL, rats will be submit to irradiation sessions of low-level laser therapy (LLL) at 0, 2 and 4 days after exodontia. In groups SAL/aPDT and ZOL/aPDT, rats will undergo sessions of aPDT at 0, 2 and 4 days after exodontia. After 28 postoperative days, all rats will be euthanized. Subsequently, the hemi-mandibles will undergo histological processing and staining by hematoxylin-eosin, picro-sirius red, Gram or will be submitted to immunohistochemistry. At the extraction site and mucosa overlying will be carried out: histopathological analysis, histomicrobiological analysis for the detection of bacteria, histochemical analysis of collagen maturation level, histometric analysis of new bone tissue and immunohistochemical analysis directed to assess the following biomarkers: proliferating cell nuclear antigen (PCNA), BCL-2 associated X protein (BAX), cleaved caspase-3, platelet/endothelial cell adhesion molecule-1 (PECAM-1), vascular endothelial growth factor (VEGF), runt-related transcription factor-2 (RUNX-2), osteocalcin (OCN), tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear factor- k B (RANKL), osteoprotegerin (OPG), bone morphogenetic protein 2/4 (BMP 2/4) and esclerostin. Results will be analyzed under light microscopy and will be submitted to quantication and statistical analysis at 5% significance level. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ERVOLINO, EDILSON; STATKIEVICZ, CRISTIAN; TORO, LUAN FELIPE; DE MELLO-NETO, JOAO MARTINS; CAVAZANA, THAMIRES PRISCILA; MARDEGAN ISSA, JOAO PAULO; MENEGATI DORNELLES, RITA CASSIA; DE ALMEIDA, JULIANO MILANEZI; HITOMI NAGATA, MARIA JOSE; OKAMOTO, ROBERTA; et al. Antimicrobial photodynamic therapy improves the alveolar repair process and prevents the occurrence of osteonecrosis of the jaws after tooth extraction in senile rats treated with zoledronate. BONE, v. 120, p. 101-113, MAR 2019. (13/25367-4, 12/03067-6, 13/26779-4, 14/02199-1, 15/22395-2)

GADIOLI SANTOS, LUIS FERNANDO; FERNANDES-BREITENBACH, FERNANDA; SANTOS SILVA, RAFAEL AUGUSTO; SANTOS, DAMARIS RAISSA; PERES-UENO, MELISE JACON; ERVOLINO, EDILSON; CHAVES-NETO, ANTONIO HERNANDES; MENEGATI DORNELLES, RITA CASSIA. The action of oxytocin on the bone of senescent female rats. Life Sciences, v. 297, p. 11-pg., 2022-05-15. (12/14464-6, 13/26779-4)

FERNANDES, FERNANDA; STRINGHETTA-GARCIA, CAMILA TAMI; PERES-UENO, MELISE JACON; FERNANDES, FABIANA; DE NICOLA, ANGELA CRISTINA; CASTOLDI, ROBSON CHACON; OZAKI, GUILHERME; QUIRINO LOUZADA, MARIO JEFFERSON; CHAVES-NETO, ANTONIO HERNANDES; ERVOLINO, EDILSON; et al. Oxytocin and bone quality in the femoral neck of rats in periestropause. SCIENTIFIC REPORTS, v. 10, n. 1, MAY 13 2020. (10/09393-7, 13/14262-7, 13/26779-4, 12/14464-6)

TESSARIN, GESTTER W. L.; MICHALEC, OLA M.; TORRES-DA-SILVA, KELLY R.; DA SILVA, V, ANDRE; CRUZ-RIZZOLO, ROELF J.; GONCALVES, ALAIDE; GASPARINI, DANIELE C.; HORTA-JUNIOR, JOSE A. C.; ERVOLINO, EDILSON; BITTENCOURT, JACKSON C.; et al. A Putative Role of Teneurin-2 and Its Related Proteins in Astrocytes. FRONTIERS IN NEUROSCIENCE, v. 13, JUN 27 2019. (09/54141-9, 13/26779-4, 10/52068-0, 12/08833-9, 08/02771-6)

STATKIEVICZ, CRISTIAN; TORO, LUAN FELIPE; DE MELLO-NETO, JOAO MARTINS; DE SA, DANIELA PEREIRA; CASATTI, CLAUDIO APARECIDO; MARDEGAN ISSA, JOAO PAULO; ANGELO CINTRA, LUCIANO TAVARES; DE ALMEIDA, JULIANO MILANEZI; HITOMI NAGATA, MARIA JOSE; GARCIA, VALDIR GOUVEIA; et al. Photomodulation multiple sessions as a promising preventive therapy for medication-related osteonecrosis of the jaws after tooth extraction in rats. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 184, p. 7-17, JUL 2018. (13/26779-4, 12/03067-6, 14/02199-1, 14/14118-6)

TORO, LUAN FELIPE; DE MELLO-NETO, JOAO MARTINS; VENTURA DOS SANTOS, FERNANDA FURUSE; FERREIRA, LETICIA CHAVES; STATKIEVICZ, CRISTIAN; ANGELO CINTRA, LUCIANO TAVARES; MARDEGAN ISSA, JOAO PAULO; MENEGATI DORNELLES, RITA CASSIA; DE ALMEIDA, JULIANO MILANEZI; HITOMI NAGATA, MARIA JOSE; et al. Application of Autologous Platelet-Rich Plasma on Tooth Extraction Site Prevents Occurence of Medication-Related Osteonecrosis of the Jaws in Rats. SCIENTIFIC REPORTS, v. 9, JAN 10 2019. (13/26779-4, 14/02199-1, 14/14542-2)