Avaliação da eficácia e segurança do debridamento mecânico no tratamento da peri-implantite experimental em ratas tratadas com zoledronato
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Data
2023-01-19
Autores
Toro, Luan Felipe
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Universidade Estadual Paulista (Unesp)
Resumo
A osteonecrose dos maxilares associada à terapia medicamentosa (ONMM) é um efeito adverso desencadeado pelo uso de drogas com ação antirreabsortiva sobre o tecido ósseo, como é o caso dos bisfosfonatos (BFs). Nos últimos anos tem aumentado o número de casos de ONMM relacionada aos implantes odontológicos (ONMM-IO), durante ou após o uso destes fármacos. Estudos correlacionam tal terapia medicamentosa e a peri-implantite (PI) com o desencadeamento da ONMM-IO. Assim, um tratamento efetivo e seguro para a PI ao longo de uma terapia com BFs pode significar a manutenção do implante e evitar a ocorrência da ONMM-IO. O debridamento mecânico (DM) é o tratamento padrão e a primeira opção de escolha para a maioria dos casos de PI, porém, sua efetividade e segurança em pacientes sob terapia com drogas antirreabsortivas ainda não foram esclarecidas. Diante disso, o objetivo primário do presente estudo foi avaliar a efetividade e a segurança do emprego do DM no tratamento da peri-implantite experimental (PiE) em ratas com implantes osseointegrados e posteriormente tratadas com zoledronato. Ratas Wistar senescentes foram inicialmente submetidas à exodontia do incisivo superior direito e à instalação imediata de um implante de titânio no local. Após 8 semanas, nas ratas em que os implantes se encontravam osseointegrados (N=24), foi realizada a exposição da plataforma do implante e a instalação de um cicatrizador. Os animais foram divididos nos grupos: C (Controle), ZOL, ZOL-PiE e ZOL-PiE-DM. Na 9ª semana, foi iniciado o tratamento medicamentoso, o qual consistiu na administração de 0,45ml de solução de cloreto de sódio 0,9% (grupo C) ou 0,45ml da mesma solução acrescida de 100μg/Kg de zoledronato (grupos ZOL, ZOL-PiE e ZOL-PiE-DM), a cada 4 dias, durante 10 semanas. Decorridas 5 semanas do início do tratamento medicamentoso, foi instalada uma ligadura de algodão ao redor dos implantes para indução da PiE nos grupos ZOL-PiE e ZOL-PiE-DM, a qual foi mantida em posição por 5 semanas (grupo ZOL-PiE) ou por 2 semanas (grupo ZOL-PiE-DM), quando foi removida e executado o tratamento local pelo DM. A eutanásia foi efetuada na 19ª semana. As maxilas contendo os implantes foram dissecadas, submetidas ao processamento laboratorial, e as secções histológicas foram coradas pela hematoxilina-eosina para análise histopatológica, análise histométrica da porcentagem de tecido ósseo total (PTO-T) e da porcentagem de tecido ósseo não vital (PTO-NV) na região peri-implantar, ou destinadas à reação imunoistoquímica para detecção e quantificação do fator de necrose tumoral alfa (TNFα), da interleucina 1 beta (IL-1β), do fator de crescimento do endotélio vascular (VEGF), da osteocalcina (OCN), e da fosfatase ácida resistente ao tartarato (TRAP). Os dados foram analisados estatisticamente com nível de significância de 5%. No grupo C, os tecidos situados ao redor do implante exibiram aspectos de normalidade. No tecido conjuntivo peri-implantar em ZOL, ZOL-PiE e ZOL-PiE-DM foi observada a presença de infiltrado inflamatório de grau leve, intenso e moderado, respectivamente. Da mesma forma, a imunomarcação para TNFα e IL-1β acompanhou os achados histopatológicos. ZOL e ZOL-PiE-DM apresentaram menor imunomarcação para VEGF em relação ao grupo C. Houve menor quantidade de células TRAP-positivas, bem como menor imunomarcação para OCN nos grupos tratados com zoledronato em relação ao grupo C, sendo que ZOL-PiE-DM apresentou ainda menor imunomarcação para OCN em relação ao ZOL. A PTO-T não diferiu entre os grupos, porém, ZOL, ZOL-PiE e ZOL-PiE-DM apresentaram maior PTO-NV em relação ao grupo C, sendo que ZOL-PiE-DM apresentou ainda maior PTO-NV em relação ao ZOL e ao ZOL-PiE. Conclui-se que o DM, empregado de forma convencional e como monoterapia, não se mostrou uma proposta efetiva e, tampouco, segura para o tratamento da PiE em ratas tratadas com dose oncológica de zoledronato, podendo se constituir em um fator de risco agravante e/ou desencadeador da ONMM-IO.
Medication-related osteonecrosis of the jaws (MRONJ) is an adverse drug reaction triggered by the use of antiresorptive agents, such as bisphosphonates (BPs). There has been an increase in dental implant-related MRONJ (MRONJ-DI) cases reported before and after the use of these drugs. Previous studies have shown that there is a correlation between peri-implantitis (PI) in patients undergoing treatment with BPs and the onset of MRONJ-DI. Thus, safe and effective treatment of PI in patients undergoing BPs therapy is needed. Mechanical debridement (MD) is the gold standard approach for the treatment of PI. However, its effectiveness and safety have not been confirmed in patients undergoing antiresorptive drug therapy. Therefore, this study aimed to evaluate the effectiveness and safety of MD for the treatment of experimental peri-implantitis (EPi) in rats undergoing zoledronate therapy. Senescent female Wistar rats were initially submitted to the extraction of the upper right incisor and immediate titanium implant placement. Eight weeks after the implant placement, healing abutments were installed in the osseointegrated implants (N=24) and the animals were divided into four groups as follows: C (Control), ZOL, ZOL-PiE and ZOL-PiE-DM. For ten weeks, rats were submitted to systemic treatment with 0.45ml of sodium chloride solution (0.9%) (group C) or 0.45ml of this same solution plus 100μm/Kg of zoledronate (groups ZOL, ZOL-PiE and ZOL-PiE-DM), every four days. Five weeks after the beginning of the systemic treatment, a cotton ligature was installed around the dental implants to induce EPi in groups ZOL-PiE and ZOL-PiE-DM. The ligature was maintained for five weeks (group ZOL-PiE) or two weeks (group ZOL-PiE-DM), when it was removed and DM was performed. Euthanasia was performed at nineteenth week. The upper jaws were dissected and submitted to laboratory processing. The histological sections were submitted to hematoxylin-eosin staining for histopathological analysis and 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 tumor necrosis factor alfa (TNFα), interleukin 1 beta (IL-1β), vascular endothelial growth factor (VEGF), osteocalcin (ONC) and tartrate-resistant acid phosphatase (TRAP). Data were analyzed considering p<0.05 as statistically significant. In group C, peri-implant tissues had a normal pattern of cellularity and structure. In groups ZOL, ZOL-PiE and ZOL-PiE-DM there was a mild, intense and moderate inflammatory infiltrate in the connective tissues, respectively. Similarly, immunolabeling for TNFα and IL-1β followed histopathological findings. ZOL and ZOL-PiE-DM showed lower immunolabeling for VEGF compared to group C. The number of TRAP-positive cells and the immunolabeling for OCN were lower in the groups treated with zoledronate compared to group C. ZOL-PiE-DM had even lower immunolabeling for OCN compared to ZOL. There was no difference in PTBT between groups, however, in ZOL, ZOL-PiE and ZOL-PiE-DM there was higher PNVBT compared to group C. ZOL-PiE-DM had even higher PNVBT compared to ZOL and ZOL-PiE. Hence, MD used conventionally as monotherapy is not a safe and effective therapy for EPi treatment in rats treated with oncologic dose of zoledronate, which may constitute a risk and/or trigger for the onset of MRONJ-DI.
Medication-related osteonecrosis of the jaws (MRONJ) is an adverse drug reaction triggered by the use of antiresorptive agents, such as bisphosphonates (BPs). There has been an increase in dental implant-related MRONJ (MRONJ-DI) cases reported before and after the use of these drugs. Previous studies have shown that there is a correlation between peri-implantitis (PI) in patients undergoing treatment with BPs and the onset of MRONJ-DI. Thus, safe and effective treatment of PI in patients undergoing BPs therapy is needed. Mechanical debridement (MD) is the gold standard approach for the treatment of PI. However, its effectiveness and safety have not been confirmed in patients undergoing antiresorptive drug therapy. Therefore, this study aimed to evaluate the effectiveness and safety of MD for the treatment of experimental peri-implantitis (EPi) in rats undergoing zoledronate therapy. Senescent female Wistar rats were initially submitted to the extraction of the upper right incisor and immediate titanium implant placement. Eight weeks after the implant placement, healing abutments were installed in the osseointegrated implants (N=24) and the animals were divided into four groups as follows: C (Control), ZOL, ZOL-PiE and ZOL-PiE-DM. For ten weeks, rats were submitted to systemic treatment with 0.45ml of sodium chloride solution (0.9%) (group C) or 0.45ml of this same solution plus 100μm/Kg of zoledronate (groups ZOL, ZOL-PiE and ZOL-PiE-DM), every four days. Five weeks after the beginning of the systemic treatment, a cotton ligature was installed around the dental implants to induce EPi in groups ZOL-PiE and ZOL-PiE-DM. The ligature was maintained for five weeks (group ZOL-PiE) or two weeks (group ZOL-PiE-DM), when it was removed and DM was performed. Euthanasia was performed at nineteenth week. The upper jaws were dissected and submitted to laboratory processing. The histological sections were submitted to hematoxylin-eosin staining for histopathological analysis and 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 tumor necrosis factor alfa (TNFα), interleukin 1 beta (IL-1β), vascular endothelial growth factor (VEGF), osteocalcin (ONC) and tartrate-resistant acid phosphatase (TRAP). Data were analyzed considering p<0.05 as statistically significant. In group C, peri-implant tissues had a normal pattern of cellularity and structure. In groups ZOL, ZOL-PiE and ZOL-PiE-DM there was a mild, intense and moderate inflammatory infiltrate in the connective tissues, respectively. Similarly, immunolabeling for TNFα and IL-1β followed histopathological findings. ZOL and ZOL-PiE-DM showed lower immunolabeling for VEGF compared to group C. The number of TRAP-positive cells and the immunolabeling for OCN were lower in the groups treated with zoledronate compared to group C. ZOL-PiE-DM had even lower immunolabeling for OCN compared to ZOL. There was no difference in PTBT between groups, however, in ZOL, ZOL-PiE and ZOL-PiE-DM there was higher PNVBT compared to group C. ZOL-PiE-DM had even higher PNVBT compared to ZOL and ZOL-PiE. Hence, MD used conventionally as monotherapy is not a safe and effective therapy for EPi treatment in rats treated with oncologic dose of zoledronate, which may constitute a risk and/or trigger for the onset of MRONJ-DI.
Descrição
Palavras-chave
Ácido zoledrônico, Desbridamento, Implantes dentários, Osteonecrose, Peri-implantite, Debridement, Dental implants, Osteonecrosis, Peri-implantitis, Zoledronic acid