Influência da baixa dose de bifosfonato de alta potência associado à droga imunossupressora no reparo ósseo alveolar em camundongos c57bl/6j
Carregando...
Data
2022-08-18
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os efeitos sistêmicos causados pelos bifosfonato nitrogenados (BFn) ainda permanecem pouco conhecidos, especialmente no que diz respeito à sua relação com o sistema imunológico dos pacientes que fazem uso dessa droga de modo prolongado. Na maioria das vezes, a indicação do uso contínuo dos BFns ocorre como terapia adjuvante ao tratamento de neoplasias malignas associados às drogas imunossupressoras, o que aumenta consideravelmente o risco para o desenvolvimento das osteonecroses dos maxilares relacionado ao uso de BPns (OMIMs). O objetivo do presente trabalho foi investigar as concentrações plasmáticas de marcadores ósseos, bem como a microarquitetura óssea dos alvéolos dentários pós-exodontia de camundongos tratados com BFn de alta potência com ou sem associação de droga imunossupressora. Foram utilizados 60 camundongos machos da linhagem C57BL6/J, com idades entre 8 a 10 semanas, pesando cerca de 28 gramas, divididos em quatro grupos de acordo com o tratamento: C – controle, 0,05ml de soro fisiológico 0,9% via intraperitoneal (IP), DEXA – 5mg/Kg de dexametasona (IP), ZOL – 50 µg/kg de ácido zoledrônico, e DEXA+ZOL – 5mg/Kg de dexametasona + 50 µg/kg de ácido zoledrônico 1 vez ao dia por cada semana . Após quatro semanas de tratamento, todos os animais foram submetidos à exodontia do incisivo superior direito, continuando até o período de eutanásia de 30 dias pós-exodontia, quando coletou-se o sangue para as análises de cálcio, fosfato, TRAP e FAL, bem como as maxilas com os alvéolos para análises microtomográfica (microCT). Os dados quantitativos foram submetidos ao teste One Way ANOVA seguido de Tukey, considerando-se p≤0,05. Os resultados demonstraram que o grupo DEXA exibiu níveis plasmáticos de cálcio e TRAP significativamente mais elevados em comparação com os grupos ZOL e DEXA+ZOL, e significativamente mais elevados de fosfato que o grupo ZOL (p≤0,05). Não foram detectadas diferenças nos níveis da FAL. A análise pelo microCT revelou menor porporção óssea (BV/TV), % e espessura de trabéculas (Tb.Th, mm) no grupo DEXA em comparação com os demais. Não foram observadas diferenças significantes referentes a número (Tb.N) e separação de trabéculas (Tb.Sp). Histologicamente o grupo DEXA+ZOL apresentaram alvéolos preenchidos por tecido ósseo maduro em meio a medula óssea
The systemic effects caused by nitrogenous bisphosphonates (BFn) are still poorly understood, especially with regard to their relationship with the immune system of patients who use this drug for a long time. Most of the time, the indication of continuous use of BPns occurs as an adjuvant therapy to the treatment of malignant neoplasms associated with immunosuppressive drugs, which considerably increases the risk for the development of osteonecrosis of the jaws related to the use of BPns (OMIMs). The aim of the present study was to investigate the plasma concentrations of bone markers, as well as the bone microarchitecture of post-extraction dental alveoli in mice treated with high-potency BFn with or without immunosuppressive drug association. Sixty male mice of the C57BL6/J strain, aged between 8 and 10 weeks, weighing about 28 grams, were divided into four groups according to treatment: C – control, 0.05ml of 0.9% saline via intraperitoneal (IP), DEXA – 5mg/kg dexamethasone (IP), ZOL – 50 μg/kg zoledronic acid, and DEXA+ZOL – 5mg/kg dexamethasone + 50 μg/kg zoledronic acid once a day for each week. After four weeks of treatment, all animals underwent extraction of the upper right incisor, continuing until the euthanasia period of 30 days post-extraction, when blood was collected for the analysis of calcium, phosphorus, TRAP and FAL, as well as as the jaws with the alveoli for microtomographic analysis (microCT). Quantitative data were submitted to the One Way ANOVA test followed by Tukey, considering p≤0.05. The results demonstrated that the DEXA group exhibited significantly higher plasma levels of calcium and TRAP compared to the ZOL and DEXA+ZOL groups, and significantly higher phosphate than the ZOL group (p≤0.05). No differences were detected in FAL levels. MicroCT analysis revealed lower bone proportion (BV/TV), % and thickness of trabeculae (Tb.Th, mm) in the DEXA group compared to the others. No significant differences were observed regarding the number (Tb.N) and separation of trabeculae (Tb.Sp). Histologically, the DEXA+ZOL group presented alveoli filled with mature bone tissue in the midst of bone marrow predominantly constituted by connective tissue, while the ZOL alveoli were filled with bone trabeculae = with numerous empty spaces of osteocytes. Based on these data, it is concluded that, although the administration of ZOL interferes with systemic markers of bone turnover, its administration did not affect the morphological parameters of alveolar bone repair, even in association with dexamethasone. On the other hand, the isolated use of dexamethasone induced systemic and local changes in bone tissue, causing a delay in post-exodontia repair when used alone.
The systemic effects caused by nitrogenous bisphosphonates (BFn) are still poorly understood, especially with regard to their relationship with the immune system of patients who use this drug for a long time. Most of the time, the indication of continuous use of BPns occurs as an adjuvant therapy to the treatment of malignant neoplasms associated with immunosuppressive drugs, which considerably increases the risk for the development of osteonecrosis of the jaws related to the use of BPns (OMIMs). The aim of the present study was to investigate the plasma concentrations of bone markers, as well as the bone microarchitecture of post-extraction dental alveoli in mice treated with high-potency BFn with or without immunosuppressive drug association. Sixty male mice of the C57BL6/J strain, aged between 8 and 10 weeks, weighing about 28 grams, were divided into four groups according to treatment: C – control, 0.05ml of 0.9% saline via intraperitoneal (IP), DEXA – 5mg/kg dexamethasone (IP), ZOL – 50 μg/kg zoledronic acid, and DEXA+ZOL – 5mg/kg dexamethasone + 50 μg/kg zoledronic acid once a day for each week. After four weeks of treatment, all animals underwent extraction of the upper right incisor, continuing until the euthanasia period of 30 days post-extraction, when blood was collected for the analysis of calcium, phosphorus, TRAP and FAL, as well as as the jaws with the alveoli for microtomographic analysis (microCT). Quantitative data were submitted to the One Way ANOVA test followed by Tukey, considering p≤0.05. The results demonstrated that the DEXA group exhibited significantly higher plasma levels of calcium and TRAP compared to the ZOL and DEXA+ZOL groups, and significantly higher phosphate than the ZOL group (p≤0.05). No differences were detected in FAL levels. MicroCT analysis revealed lower bone proportion (BV/TV), % and thickness of trabeculae (Tb.Th, mm) in the DEXA group compared to the others. No significant differences were observed regarding the number (Tb.N) and separation of trabeculae (Tb.Sp). Histologically, the DEXA+ZOL group presented alveoli filled with mature bone tissue in the midst of bone marrow predominantly constituted by connective tissue, while the ZOL alveoli were filled with bone trabeculae = with numerous empty spaces of osteocytes. Based on these data, it is concluded that, although the administration of ZOL interferes with systemic markers of bone turnover, its administration did not affect the morphological parameters of alveolar bone repair, even in association with dexamethasone. On the other hand, the isolated use of dexamethasone induced systemic and local changes in bone tissue, causing a delay in post-exodontia repair when used alone.
Descrição
Palavras-chave
Ácido zoledrônico, Dexametasona, Osteonecrose, Regeneração óssea, Zoledronic acid