Effects of Zoledronic Acid in Experimental Periapical Lesions in Rats: An Imaging and Histological Analysis

Abstract The aim of this study was to assess the imaging and histological features of experimental periapical lesions, including the adjacent alveolar bone, in rats under zoledronic acid treatment. The study used 40 male Wistar rats distributed into 8 groups of 5 animals each: G1: induction of periapical lesion (PL) and weekly intraperitoneal administration (WIPA) of saline solution (0.9% NaCl) for 4 weeks; G2: PL induction and WIPA of zoledronic acid (0.15 mg/kg/week) for 4 weeks; G3: PL induction and WIPA of saline solution for 8 weeks; G4: PL induction and WIPA of zoledronic acid for 8 weeks; G5:WIPA of saline solution for 4 weeks and subsequent PL induction; G6: WIPA of zoledronic acid for 4 weeks and subsequent PL induction; G7: WIPA of saline solution for 8 weeks and subsequent PL induction; G8: WIPA of zoledronic acid for 8 weeks and subsequent PL induction. The administration of zoledronic acid or saline solution continued after PL induction until the euthanasia. Thus, cone beam computed tomography and histological analysis were performed. Statistical analyzes were performed by ANOVA and Kruskal-Wallis test. Groups treated with zoledronic acid showed significantly smaller size of PL than the groups treated with 0.9% NaCl (p<0.05). PLs were formed by chronic inflammation ranging from mild to moderate, with no difference between groups. In all specimens, no mandibular necrosis was observed. In conclusion, the presence of PLs apparently does not represent an important risk factor for the development of bisphosphonate-related osteonecrosis of the jaws.

Resumo O objetivo deste estudo foi avaliar as características histológicas e de imagem de lesões periapicais experimentais, incluindo o osso alveolar adjacente, em ratos sob tratamento com ácido zoledrônico. O estudo utilizou 40 ratos Wistar, machos, distribuídos em 8 grupos de animais cada: G1: indução de lesão periapical (LP) e administração intraperitoneal semanal (AIS) de solução salina (NaCl 0.9%) por 4 semanas; G2: indução de LP e AIS de ácido zoledrônico (0,15 mg/kg/week) por 4 semanas; G3: indução de LP e AIS de solução salina por 8 semanas; G4: indução de LP e AIS de ácido zoledrônico por 8 semanas; G5- AIS de solução salina por 4 semanas e subsequente indução de LP; G6- AIS de ácido zoledrônico por 4 semanas e subsequente indução de LP; G7: AIS de solução salina por 8 semanas e subsequente indução de LP; G8: AIS de ácido zoledrônico por 8 semanas e subsequente indução de LP. A administração de ácido zoledrônico ou solução salina continuou após indução de LP até a eutanásia. Após isso, tomografia computadorizada de feixe cônico e análise histológica foram realizadas. Análises estatísticas foram realizadas por ANOVA e teste de Kruskal-Wallis. Os grupos tratados com ácido zoledrônico mostraram LPs significativamente menores que os grupos tratados com NaCl 0.9% (p <0.05). LPs eram formadas por inflamação crônica variando de leve a moderada, sem diferença entre os grupos. Em todos os espécimes, necrose mandibular não foi observada. Em conclusão, a presença de LPs aparentemente não representa um fator de risco importante para o desenvolvimento de osteonecrose relacionada ao uso de bisfosfonatos.

O efeito do ácido zoledrônico na microestrutura óssea analisado pela micro-CT em mandíbulas de ratos wistar / Zoledronic acid effect on the bone microarchitecture of the jaw of rats by Micro-CT

Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações...

Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The "t-student" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae...

Clinical study of correlation between C-terminal cross-linking telopeptide of type I collagen and risk assessment, severity of disease, healing after early surgical intervention in patients with bisphophonate-related osteonecrosis of the jaws

INTRODUCTION: The utility of the C-terminal cross-linking telopeptide test (CTX) as a method for staging Bisphosphonate-related osteonecrosis of the jaws (BRONJ) and its healing process was examined. MATERIALS AND METHODS: A total 19 patients who were diagnosed with BRONJ underwent a fasted morning CTX test, were enrolled in this study. The serum CTX values ranged from 50 to 630 pg/mL (mean 60). The risk assessment was rated according to the CTX values of the individual patient (minimal risk, > or =150 pg/mL, moderate, 100 to 150 pg/mL, high, < or =100 pg/mL). The BRONJ scores were then calculated according to the number of BRONJ lesions and their stage. The operation was done as soon as possible, regardless of BORNJ stage. RESULTS: The mean duration of bisphosphonate therapy was 4.1 years. Of the 19 patients, 15, 2 ans 2 received alendronate, risedronate and zoledronate, respecively. Of the 19 patients who underwent a sequestrectomy, saucerization and smoothing, 15 healed after the initial surgery, 1 patient healed after one more surgical procedure, 3 patients did not heal completely but showed improvement in symptoms. Therefore, 17 out of the 19 patients healed completely with complete mucosal coverage and the elimination of pain. The risk assessment using the CTX value and disease severity were not correlated (r=-0.264, P=0.275). In addition, the risk assessment using CTX value and healing after surgery were not correlated (r=-0.147, P=0.547). CONCLUSION: The serum CTX should be considered carefully by clinicians as part of overall management. Early surgical intervention is of benefit in the treatment of stage II BRONJ.