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To investigate de effect of PAb gel on the bone tissue of rats submitted to Bisphosphonate-related osteonecrosis of the jaws (BRONJ). Initially, 54 animals were submitted to BRONJ model by Zoledronic Acid (ZA) (0.1 mg/kg 3x/wk for 9 wk, ip), followed by the 1st upper left molar extraction at the 8th wk. After tooth removal, the animals were divided into 3 groups, ZA that received placebo gel or PAb gel that received 1% PAb gel, inside the dental alveolus. The control Group (CONTROL) received 0.1 mg/kg of 0.9% saline and then placebo gel. Three weeks after tooth extraction, the animals were euthanized, and maxillae were colleted for macroscopic, radiographic, histological and Raman spectomery assays. Additionally, GSK3b, beta-catenin, and Runx2 mRNA expressions were determined. Blood samples were collected for the analysis of Bone-specific alkaline phosphatase (BALP) levels. PAb gel improved mucosal healing, increased the number of viable osteocytes, while it reduced the number of empty lacunae, as well as the amount of bone sequestration. Furthermore, PAb gel positively influenced the number and functionality of osteoblasts by stimulating Wnt signaling, thereby inducing bone remodeling. Additionally, PAb gel contributed to improved bone quality, as evidenced by an increase in bone mineral content, a decrease in bone solubility, and an enhancement in the quality of collagen, particularly type I collagen. PAb gel mitigated bone necrosis by stimulating of bone remodeling through Wnt signaling and concurrently improved bone quality. PAb gel emerges as a promising pharmacological tool for aiding in BRONJ therapy or potentially preventing the development of BRONJ.

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OBJECTIVE: This study aimed to evaluate the efficacy of ozone therapy in the preoperative (prevention) and/or postoperative (treatment) of MRONJ. MATERIAL AND METHODS: Forty male Wistar rats were caudally treated with zoledronic acid (ZOL) and to ozone therapy before extraction (prevention, POG), after extraction (treatment, TOG), or both (prevention and treatment, TPOG), and treated with saline (SAL). The animals received intramuscular fluorochrome (calcein and alizarin), and 28 days postoperatively, they were euthanized, and the tissues were subjected to microtomographic computed tomography (microCT), LASER confocal, and histomorphometric analyses. RESULTS: Micro-CT showed a higher bone volume fraction average in all groups than that in the ZOL group (P < 0.001), the ZOL group showed high porosity (P = 0.03), and trabecular separation was greater in the TOG group than in the POG group (P < 0.05). The mineral apposition rate of the POG group was high (20.46 ± 6.31) (P < 0.001), followed by the TOG group (20.32 ± 7.4). The TOG group presented the highest mean newly formed bone area (68.322 ± 25.296) compared with the ZOL group (P < 0.05), followed by the SAL group (66.039 ± 28.379) and ZOL groups (60.856 ± 28.425). CONCLUSIONS: Ozone therapy modulated alveolar bone repair in animals treated with ZOL, mainly after surgery trauma, leading to bone formation as healing tissue. CLINICAL RELEVANCE: Osteonecrosis has been a challenge in dentistry, and owing to the lack of a consensus regarding therapy, studies presenting new therapies are important, and ozone has been one of the therapies explored empirically.

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PURPOSE: To assess the prophylaxis effect of pentoxifylline and tocopherol (PENTO) on the frequency and severity of medication-related osteonecrosis of the jaw (MRONJ) diagnosed at three months in patients with cancer submitted to tooth extractions during the treatment with bone-modifying agents. METHODS: This case series was conducted at the outpatient dental clinic of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) between April 2021 and April 2022. Patients ≥ 18 years old were included; those with maxillary metastasis or who performed head or neck radiotherapy were excluded. The PENTO protocol was prescribed two weeks before and two weeks after the tooth extraction, and patients were reassessed one week, one month, and three months after the extraction. The main outcome was the development of MRONJ. RESULTS: Of the 114 screened patients, 17 were included; they were aged between 43 and 73 years and were mostly female (88.2%). Thirty-two tooth extractions were performed (22 in the maxilla and 10 in the mandible). Breast cancer was the most predominant neoplasm (70.6%), being metastatic in 35.3% of patients. Also, all patients used intravenous bisphosphonates. Stage 1 MRONJ was diagnosed in three patients (17.6%), representing three (9.4%) of all tooth extractions. The repair of MRONJ was achieved 30 days after the PENTO protocol. CONCLUSION: The prophylaxis use of PENTO reduced the severity of injuries, was well-tolerated, and showed patient compliance.

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Introducción: dada la alta prescripción de bifosfonatos, presentamos sus efectos adversos en la esfera odontológica, siendo una complicación poco frecuente, pero de difícil tratamiento. Sin necesidad de suspender el tratamiento, dado el importante beneficio en cuanto a la prevención de fractura por fragilidad. Estas fracturas causan una alta morbimortalidad en contraposición al bajo riesgo que conlleva la Osteonecrosis mandibular asociada a bifosfonatos. Objetivo: orientar al personal de salud que maneja estos fármacos y quien asiste dichas complicaciones a poseer conocimientos para la prevención de osteonecrosis. Identificar y diferenciar los pacientes con mayor riesgo, de acuerdo con la dosis de bifosfonatos y la frecuencia del tratamiento. Materiales y Método: se realizó una revisión bibliográfica en las siguientes fuentes: Scielo, Google académico, Medline/Pubmed, Biblioteca Virtual en Salud (Brasil), desde el año 2005 a la fecha, idiomas español, portugués e inglés. Los descriptores utilizados son bifosfonatos, mandíbula, maxilar, odontología, osteonecrosis, osteonecrosis de los maxilares asociada a bifosfonatos. Resultados: las últimas pautas de tratamiento fueron modificadas en 2014, por consenso de la Asociación Americana de cirugía Oral y Maxilofacial. La patogénesis de la osteonecrosis maxilar asociada a bifosfonatos no está completamente definida, aunque las publicaciones tratan de explicarla. El riesgo de desarrollarla por terapia oral es menor que por su administración vía intravenosa. Discusión: el médico que prescribe el antirresortivo debe conocer el estado de salud dental de su paciente y, en lo posible, remitirlo a examen con el odontólogo antes de iniciar la terapia con bifosfonatos.

Introduction: Given the high prescription of bisphosphonates, we present their adverse effects in the dental sphere, being an infrequent complication, but difficult to treat. There is no need to suspend treatment, given the important benefit in terms of prevention of fragility fractures. These fractures cause high morbimortality as opposed to the low risk associated with bisphosphonate-associated osteonecrosis of the jaw. Objective: To orient the health personnel who handle these drugs and who assist these complications to have knowledge for the prevention of osteonecrosis. To identify and differentiate patients at higher risk, according to the dose of bisphosphonates and frequency of treatment. Materials and Method: A literature review was performed in the following sources: Scielo, Google academic, Medline/Pubmed, Virtual Health Library (Brazil), from 2005 to date, Spanish, Portuguese and English languages. The descriptors used were bisphosphonates, mandible, maxilla, dentistry, osteonecrosis, osteonecrosis of the jaws associated with bisphosphonates. Results: The latest treatment guidelines were modified in 2014, by consensus of the American Association of Oral and Maxillofacial Surgery. The pathogenesis of bisphosphonate-associated maxillary osteonecrosis is not completely defined, although publications try to explain it. The risk of developing it by oral therapy is lower than by intravenous administration. Discussion: The physician who prescribes the antiresorptive drug should know the dental health status of his patient and, if possible, refer him for examination by a dentist before initiating bisphosphonate therapy.

Introdução: dada a alta prescrição de bisfosfonatos, apresentamos seus efeitos adversos na esfera odontológica, uma complicação rara, mas de difícil tratamento. Sem a necessidade de suspender o tratamento, dado o importante benefício em termos de prevenção de fraturas por fragilidade. Essas fraturas causam alta morbidade e mortalidade, em contraste com o baixo risco associado à osteonecrose da mandíbula associada aos bisfosfonatos. Objetivo: orientar a equipe de saúde que manipula esses medicamentos e que atende a essas complicações para que tenham conhecimento sobre a prevenção da osteonecrose. Identificar e diferenciar os pacientes de maior risco, de acordo com a dose de bisfosfonatos e a frequência do tratamento. Materiais e Método: foi realizada uma revisão da literatura nas seguintes fontes: Scielo, Google acadêmico, Medline/Pubmed, Biblioteca Virtual em Saúde (Brasil), de 2005 até a presente data, idiomas espanhol, português e inglês. Os descritores utilizados foram: bisfosfonatos, mandíbula, maxila, odontologia, osteonecrose, osteonecrose dos maxilares associada a bisfosfonatos. Resultados: as diretrizes de tratamento mais recentes foram modificadas em 2014, por consenso da Associação Americana de Cirurgia Oral e Maxilofacial. A patogênese da osteonecrose da mandíbula associada a bisfosfonatos não está totalmente definida, embora a literatura tente explicá-la. O risco de desenvolvê-la com a terapia oral é menor do que com a administração intravenosa. Discussão: o médico que prescreve o medicamento deve estar ciente do estado de saúde bucal do paciente e, se possível, encaminhar o paciente para ser examinado por um dentista antes de iniciar a terapia com bisfosfonatos.

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PURPOSE: To assess radiographic presentation of anatomical structures, bony changes and soft tissue calcifications on panoramic radiographs of oncologic patients under high dose antiresorptive drug therapy (ART) before exposure to dental extraction. METHODS: Panoramic radiographs of 57 patients under ART, taken previously to tooth extraction, and 57 control patients were evaluated by two oral radiologists regarding bone pattern, anatomical structures visibility, estimation of cortical width, mandibular cortical index (MCI), and presence of soft tissue calcifications. Parameters were compared between ART and age- and gender-matched healthy control groups. Bone patterns were further assessed by regions with or without tooth extractions and according to uneventful healing or MRONJ development. All comparisons were made using chi-square test with significance level set at 5%. RESULTS: Mandible and posterior maxilla presented more sclerotic bone patterns in patients under ART, regardless of tooth extraction and MRONJ development status (p < 0.05). Heterogeneous bone pattern was identified in two regions that both were subsequently affected by MRONJ. Anatomical structure visibility and presence of soft tissue calcifications was not different among groups (p > 0.05). ART patients showed significantly more C0 (thickening) and C1 MCI (p < 0.05). CONCLUSION: Sclerotic bone pattern and thicker mandibular cortices may represent a consequence of ART rather than MRONJ specific findings. Prospective studies on larger patient samples radiographically followed-up during the ART treatment are advised, with specific attention to heterogenous trabecular bone pattern as a possible MRONJ predictor.

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The aim of this study was to evaluate the awareness of patients using bisphosphonates (BP) regarding their risks and benefits. Sixty-five patients using BP were included. Each participant completed a self-administered questionnaire consisting of 13 questions, including sociodemographic and general information on BP. Data were analyzed using descriptive statistics, and a binomial test was used to assess patient knowledge about BP, considering a 5% significance level. Fifty-nine (90.2%) patients were unaware or had never heard of BP drugs and only 3 (4.6%) knew their indications. Only 6 patients (9.2%) said they knew about the oral complications caused by BP. Sixty-three patients (96.9%) said they were not referred to the dentist before starting BP treatment. Patients using BP do not have satisfactory knowledge regarding the risks and benefits of BP. Physicians and dentists must be prepared to inform and counsel BP users about their adverse effects and possible risk factors. Our results emphasize the importance of public policies, whether individual or collective, to be taken to increase knowledge about BP to avoid medication-related osteonecrosis of the jaw.

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Surgical trauma in those under a prolonged use of bisphosphonates, can lead to mediation-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the preventive therapies for MRONJ. Following four cycles of zoledronic acid administration, Wistar rats had their molar extracted, and were organized into nine treatment groups: negative control group (NCG), treated with saline solution and blood-clot in the alveolus; positive control group (PCG), with blood-clot in the alveolus; BG, ß-tricalcium phosphate-based biomaterial; DG, 10% doxycycline gel; aG, antimicrobial photodynamic therapy; and DBG, aBG, aDG, and aDBG, using combination therapy. After 28 days, the lowest bone volume (BV/TV) was reported in PCG (42.17% ± 2.65), and the highest in aDBG (69.85% ± 6.25) (p < 0.05). The higher values of daily mineral apposition rate were recorded in aDBG (2.64 ± 0.48) and DBG (2.30 ± 0.37) (p < 0.001). Moreover, aDBG presented with the highest neoformed bone area (82.44% ± 2.69) (p < 0.05). Non-vital bone was reported only in the PCG (37.94 ± 18.70%). Owing to the key role of the biomaterial, the combination approach (aDBG) was the most effective in preventing MRONJ following tooth extraction.

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BACKGROUND: This study investigated the effect of antimicrobial photodynamic therapy (PDT), using methylene blue (MBO) and photobiomodulation therapy (PT), on the alveolar bone of rats submitted to bisphosphonate-induced osteonecrosis of the maxillaries (OMB) model using zoledronic acid (ZA). METHODS: Sixty rats divided into six groups were used: SALINE, PDT, ZA, ZA+PDT, ZA+PT, and ZA+MBO. Three weekly administrations (Days 0, 7, and 14) of ZA 0.20 mg/kg or saline solution were performed. After one month (Day 42), the exodontia of the left lower first molars were performed. An additional dose of ZA was administered at Day 49. PDT was performed on days 42, 45, 49, and 54. One month after exodontia (Day 70), the animals were euthanized to obtain samples for imaging and microscopic analysis. ANOVA/Bonferroni tests were used for statistical analysis. RESULTS: The ZA+PDT group showed a significantly lower percentage of apoptotic osteocytes than the ZA group (p < 0.001). The ZA+MBO, ZA+PT, and PDT groups significantly reduced the number of mononuclear cells compared to the ZA group (p < 0.001). The ZA+PT and ZA+PDT groups showed a significant reduction in the number of CD 68+ (p < 0.001) and CD3+ (p = 0.002) cells compared to the ZA group. The number of cells expressing INF-y had a significant reduction in the groups co-treated with PT and PDT compared to the ZA group (p < 0.001). CONCLUSIONS: We conclude that PDT and PT attenuated the severity of OMB and the inflammatory process due to a reduction of macrophages, T lymphocytes, and cytokines that stimulate the activity of these cells.

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Considering the lack of studies determining the real TPTD efficacy in individuals who develop MRONJ, our objective was to combine the available data on MRONJ cases treated with TPTD. The findings demonstrated that TPTD in combination with another therapy, especially antibiotic therapy, can be considered an effective protocol for MRONJ. PURPOSE: To integrate the data published on the effect of teriparatide (TPTD) therapy on cases of medication-related osteonecrosis of the jaws (MRONJ) into a comprehensive analysis of clinical features. METHODS: An electronic search was undertaken in six databases. Descriptive analyses of clinicodemographic data of MRONJ were carried out. Poisson regression was also run to evaluate predictors of total resolution of MRONJ treated with TPTD. RESULTS: Twenty-six publications comprising 111 cases were included. Most reported cases affected female individuals (82.0%) with a mean age of 76.54 years. Osteoporosis (76.5%) represented the main reason for using antiresorptive drugs, with bisphosphonates (98.1%) as the most frequently reported. Comorbidities were commonly present. The most related trigger factor of MRONJ was dental extraction (61.7%). Mandible (75.8%) was the most commonly affected site, with a mean evolution time of 5 months. MRONJ stage 2 (61.3%) was the most prevalent. Regarding TPTD treatment, in 45.1% cases, TPTD was used alone, with the total resolution being observed in 59.5% of the individuals. Associated therapy (54.9%) included surgery, antibiotic therapy, and laser therapy. Mean follow-up was 8.7 months. Poisson regression demonstrated that individuals with MRONJ stage 1 were 1.21 times more likely to present total resolution of osteonecrosis than individuals with MRONJ stage 3 (CI = 1.02-1.43; p < 0.023). Individuals who had undergone treatment with TPTD in association with another therapeutic modality were 1.21 times more likely to present total resolution of osteonecrosis than those who had undergone treatment with TPTD alone (CI = 1.40-1.39; p < 0.010). CONCLUSION: TPTD in combination with another therapy, especially antibiotic therapy, should be considered an effective therapeutic modality for MRONJ.

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OBJECTIVE: Bisphosphonates and denosumab are both antiresorptive medications, each with their own mechanism of action; yet both may result in the same adverse effect: medication-related osteonecrosis of the jaw (ONJ). The present systematic review aims to answer the following question: "Are bisphosphonate-related ONJ and denosumab-related ONJ any different, regarding clinical and imaging aspects?" METHODS: This review followed the Joanna Briggs Review's Manual, and the searches were performed on PubMed, Cochrane, Scopus, Web of Science, and Lilacs databases and on the grey literature (ProQuest, Open Grey, and Google Scholar). RESULTS: The searches resulted in 7535 articles that were critically assessed. Based on the selection criteria, seven studies were included in the review: five cross-sectional studies and two randomized clinical trials. A total of 7755 patients composed the final population. An increase in bone sequestra, cortical bone lysis, and bone density was observed in bisphosphonate-related ONJ, while larger bone sequestra, more frequent periosteal reactions, and mandibular canal enhancement were noted in denosumab-related ONJ. CONCLUSION: This systematic review demonstrated that the imaging characteristics of bisphosphonate-related and denosumab-related ONJ are not similar. Although clinically similar conditions, they were found to be radiographically distinct. More studies are necessary to further elucidate these differences.

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Objective: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication of chronic bisphosphonate (BP) use. The hormone relaxin is able to induce the multistep differentiation process of human osteoclastogenesis, exhibits antifibrotic and anti-inflammatory actions, and promotes vasodilatation, wound healing, and angiogenesis. The present study aimed to evaluate the effects of relaxin in the prevention and management of BRONJ. Material and Methods: Thirty-six male Sprague Dawley rats were randomly divided into four groups. Rats in group 1 (n = 10) received relaxin and BP simultaneously for 12 weeks. Rats in group 2 (n = 10) received injections of BP for 12 weeks, followed by relaxin for another 12 weeks. Rats in group 3 (n = 10) received only BP injections, and those in group 4 (control, n = 6) received only saline. Necrosis and inflammation in the rats' mandibles were evaluated as indicators of BRONJ. Results: Necrosis and inflammation were not detected in group 1 (BP + relaxin). In group 3 (BP only), incidence rates of necrosis and inflammation were 90% and 60%, respectively. Conclusions: Our findings suggest that relaxin may be potently effective in preventing BRONJ and have some benefit in the treatment of existing BRONJ (AU)

Objetivo: A osteonecrose da mandíbula relacionada ao bisfosfonato (BRONJ) é uma desafiadora complicação do uso crônico de bisfosfonato (BP). O hormônio relaxina é capaz de induzir o processo múltiplo de diferenciação da osteoclastogênese humana, exibe ações anti-fibróticas e anti-inflamatórias e promove vasodilatação, cicatrização de feridas e angiogênese. O presente estudo teve como objetivo avaliar os efeitos da relaxina na prevenção e tratamento do BRONJ. Material e Métodos: Trinta e seis ratos Sprague Dawley machos foram divididos aleatoriamente em quatro grupos. Os ratos do grupo 1 (n = 10) receberam relaxina e BP simultaneamente por 12 semanas. Os ratos do grupo 2 (n = 10) receberam injeções de BP por 12 semanas, seguidos de relaxina por mais 12 semanas. Os ratos do grupo 3 (n = 10) receberam apenas injeções de BP e os do grupo 4 (controle, n = 6) receberam apenas solução salina. Necrose e inflamação nas mandíbulas dos ratos foram avaliadas como indicadores de BRONJ. Resultados: Necrose e inflamação não foram detectadas no grupo 1 (BP + relaxina). No grupo 3 (somente BP), as taxas de incidência de necrose e inflamação foram de 90% e 60%, respectivamente. Conclusões: Nossos resultados sugerem que a relaxina pode ser potentemente eficaz na prevenção do BRONJ e ter algum benefício no tratamento do BRONJ existente.(AU)

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Treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.

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El objetivo de este trabajo es revisar los conocimientos actuales sobre el manejo clínico-odontológico de pacientes que consumen medicamentos antirresortivos y medicamentos antiangiogénicos o quimioterapéuticos, en relación con la prevención y/o el tratamiento de la osteonecrosis de los maxilares asociada a medicamentos. Se evaluaron similitudes y diferencias entre los bifosfonatos, denosumab y medicamentos antiangiogénicos, así como el manejo clínico de pacientes, vacaciones de medicamentos y el manejo de osteonecrosis de los maxilares ya instalada. Se encontraron similitudes en la presentación clínica, la prevención, el uso de antibioticoterapia antes de procedimientos invasivos y el tratamiento de la osteonecrosis ya instalada. Entre las diferencias, podemos mencionar que el tratamiento quirúrgico respondería mejor en pacientes medicados con denosumab o antiangiogénicos, y su suspensión sería más efectiva si se iniciara un proceso de osteonecrosis, al igual que su tasa de resolución. En cuanto a las vacaciones de medicamentos, no hay datos concluyentes para guiar esta decisión, al igual que no existe un protocolo clínico de atención en pacientes que consumen denosumab o antiangiogénicos (AU)

The aim of this study is to review the currents knowledge about the clinical and dental management of patients who consume antiresorptive and antiangiogenic agents or chemotherapeutic drugs, in relation to the prevention and/or treatment of osteonecrosis of the jaws related to medication. Similarities and differences between bisphosphonates, denosumab and antiangiogenic medications were evaluatted, as well as the clinical management of patients, drugs holidays and management of osteonecrosis of the jaws already setted. Similarities were found in the clinical presentation, prevention, use of antibiotic therapy before invasive procedures and the treatment of osteonecrosis already installed. Regarding the differences, we can mention that the surgical treatment would be better in patients medicated with denosumab or antiangiogenics and its suspension would be more effective if an osteonecrosis process is initiated, as well as its resolution rate. There are no conclusive data about drug holidays to guide this decision, and no clinical protocol of care in patients who consume denosumab or antiangiogenic agents (AU)

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Abstract Treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.

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Os bisfosfonatos (BF) são amplamente utilizados no tratamento de doenças osteolíticas como metástases ósseas e osteoporose. A osteonecrose dos maxilares associada ao uso de BF (OMAB) é caracterizada pela presença de osso exposto ou que pode ser sondado através de uma fístula que persiste por mais de oito semanas em pacientes com história de terapia de BF e sem história de radioterapia na região de cabeça e pescoço e/ou sem doença metastática nos maxilares. A incidência de OMAB aumenta com a potência, duração do tratamento e dose de BF recebida. Até o presente momento, a fisiopatologia da OMAB não está clara, dificultando a prevenção e o tratamento. O objetivo deste estudo foi avaliar o efeito da administração de altas doses Ácido Zoledrônico (AZ) por período prolongado no osso esponjoso da mandíbula e da metáfise proximal do fêmur de ratos Wistar. Para relacionar as descobertas à fisiopatologia da OMAB, o regime de administração de BF de um modelo animal relevante desta lesão foi reproduzido. Seis animais receberam AZ (0,6 mg / kg) e seis receberam solução salina no mesmo volume (Controles). Os compostos foram administrados por via intraperitoneal em cinco doses a cada 28 dias. A eutanásia dos animais ocorreu após 150 dias de início da terapia. As hemimandíbulas e fêmures direitos foram escaneados usando Micro-tomografia computadorizada (Micro-CT) de alta resolução (14 m). Para a primeira análise realizada neste estudo, os dados morfométricos do osso esponjoso foram calculados na região do segundo e primeiro molar na mandíbula e na metáfise do fêmur usando CTAnalyzer (Bruker, Bélgica). Para a segunda análise, cinco amostras de hemimandíbulas de cada grupo foram cortadas em lâminas histológicas (5 m) e coradas com Hematoxilina e Eosina. Para comparar os parâmetros morfométricos na Micro-CT e histologia, as imagens de Micro-CT foram espacialmente alinhadas à histologia. Os dados morfométricos do osso alveolar foram calculados usando o software CTAnalyzer (Bruker, Bélgica) na região entre as raízes mesial e distal do primeiro molar. A densidade da área vascular (área vascular/área total; VA/TA) e os dados histomorfométricos ósseos foram estimados usando Axiovision na mesma região (entre as raízes mesial e distal do primeiro molar). Foi adotada significância estatística de 5% ( = 0,05). Os animais tratados com AZ apresentaram aumento significativo na porcentagem de volume ósseo (p <0,05) com trabéculas mais espessas, osso mais compacto com menor separação trabecular na mandíbula e no fêmur. Na mandíbula, o aumento da densidade óssea e diminuição da separação trabecular foram fortemente correlacionados com a diminuição da área vascular observada no grupo AZ (p <0,05). Em conclusão, o tratamento de longa duração com altas doses de AZ foi significativamente associado ao aumento na densidade óssea e à diminuição dos espaços medulares, canais nutritivos e vasculatura do osso alveolar. A análise com Micro-CT revelou alterações semelhantes na estrutura óssea tanto na mandíbula quanto no fêmur do grupo AZ.(AU)

Bisphosphonates (BFs) are widely used in the treatment of osteolytic diseases such as bone metastases and osteoporosis. The osteonecrosis of the jaws related to BF (ONB) is characterized by the presence of exposed bone or bone that can be probed through a fistula that persists for more than eight weeks in patients with a history of BF therapy and without history of head and neck radiotherapy and / or without metastatic disease in the jaws. The incidence of ONB increases with potency, duration of treatment and dose of BF received. Thus far, the pathophysiology of ONB is unclear, hampering prevention and treatment. The aim of this study was to objectively assess the effect of long-term high-dose Zoledronic Acid (ZA) on cancellous bone in the jaw and femur of Wistar rats. In order to link our findings to the physiopathology of ONB, the therapeutic regiment of a relevant ONB animal model was reproduced. Twelve Wistar rats were randomly divided in two groups: six received Zoledronic acid (ZA; 0.6 mg / kg) and six (Controls) received saline solution in the same volume. The compounds were administrated intraperitoneally in five doses each 28 days. The rats were killed after 150 days of the therapy onset. Mandibles and femurs were scanned using a high-resolution (14m) micro-computerized tomography (Micro-CT). For the first analysis carried in this study, cancellous bone morphometric data were calculates in the region of the second and first molar in the mandible and in the proximal femur using CTAnalyzer (Bruker, Belgium). For the second analysis five samples were cut into histological slices (5m) and stained with Hematoxylin and Eosin. In order to compare the same morphological structures in Micro-CT and histology, the Micro-CT images were aligned to histology. Alveolar bone morphometric data (Micro-CT) was calculated using CTAnalyzer (Bruker, Belgium) in the region between the mesial and distal roots of the first molar. Blood vessels density and bone histomorphometric data were calculated using Axiovision (Carl Zeiss, Germany) in the same region used for Micro-CT evaluation. Statistical significance of 5% (=0.05) was adopted. ZA treated rats presented significant increase in the percentage of bone volume (p<0.05) with thicker trabeculae and more compact bone with smaller marrow spaces in the mandible and femur. In the mandible, the increase in bone density and decrease of marrow spaces size was strongly correlated with the decrease in the vascular area noticed in the ZA group (p<0.05). In conclusion, long-term high-dose ZA treatment was significant associated with the increase of bone density and the diminution of medullary spaces and nutritive canals size as well as decrease in vascularity of the alveolar bone. Micro-CT investigation showed similar changes in bone structure in the mandible and femur in the ZA group.(AU)

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Abstract This paper describes two cases in which the use of leucocyte-rich and platelet-rich fibrin (LPRF) combined with bone resection did not result in complete tissue response in the treatment of medication-related osteonecrosis of the jaw (MRONJ). It has been recently described in patients receiving subcutaneous administration of RANK-inhibitors, such as Denosumab, and anti-angiogenic drugs, such as Bevacizumab, as observed in our cases. Due to promising results in recent studies, more patients will receive these medications in order to avoid skeletal complications due to metastatic bone disease and, therefore, this scenario has a potential to become a comparable challenge to the bisphosphonate- induced jaw necrosis in the area of Oral and Maxillofacial Surgery. No convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANK-inhibitor therapy. Based on the findings in the literature and in both cases described herein can be concluded that the use of LPRF should be considered in the treatment of patients with DRONJ.

Resumo Este artigo descreve dois casos onde a ressecção óssea associada à fibrina rica em plaquetas e leucócitos (LPRF) não resultou em resposta completa no tratamento da osteonecrose dos maxilares relacionados à medicações (MRONJ). Como observado nos casos aqui relatados, MRONJ foi recentemente descrito na literatura em pacientes que recebem a administração subcutânea de inibidores-RANK, como Denosumab ou drogas anti-angiogenicas, como Bevacizumab. Estudos recentes com resultados promissores indicam que mais pacientes serão tratados com estas terapias para evitar complicações esqueléticas devido às metástases ósseas. Portanto, este cenário pode tornar-se um desafio clínico comparável às osteonecroses dos maxilares relacionados aos bisfosfonatos na área de Cirurgia Bucomaxilofacial. Até o momento, nenhuma técnica cirúrgica foi descrita com eficiência para superar as lesões da mucosa com exposição óssea e que não cicatrizam devido a terapia com inibidores de RANK. Com base na literatura e nos achados dos casos reportados, podemos concluir que o uso do LPRF pode ser considerado no tratamento de pacientes com osteonecrose dos maxilares relacionados ao Denosumab.

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This paper describes two cases in which the use of leucocyte-rich and platelet-rich fibrin (LPRF) combined with bone resection did not result in complete tissue response in the treatment of medication-related osteonecrosis of the jaw (MRONJ). It has been recently described in patients receiving subcutaneous administration of RANK-inhibitors, such as Denosumab, and anti-angiogenic drugs, such as Bevacizumab, as observed in our cases. Due to promising results in recent studies, more patients will receive these medications in order to avoid skeletal complications due to metastatic bone disease and, therefore, this scenario has a potential to become a comparable challenge to the bisphosphonate- induced jaw necrosis in the area of Oral and Maxillofacial Surgery. No convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANK-inhibitor therapy. Based on the findings in the literature and in both cases described herein can be concluded that the use of LPRF should be considered in the treatment of patients with DRONJ.

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PURPOSE: To investigate whether termination of bisphosphonates (BPs) affects resolution of bone exposure and symptomatic disease in patients with established medication-related osteonecrosis of the jaw (MRONJ). PATIENTS AND METHODS: The studied population included 84 patients with established MRONJ who discontinued BP therapy before treatment (n = 21), at treatment initiation (n = 38), or later (or never) in the treatment course (n = 25). These 3 groups were compared using Kaplan-Meier curves and log-rank tests for differences in the respective times to resolution of 1) bone exposure for any treatment modality, 2) bone exposure not requiring radical surgery, and 3) disease symptoms. RESULTS: Patients who continued BPs after the start of treatment exhibited significantly delayed resolution of symptoms (median 12 months; 95% confidence interval 8 to 15) compared with those who discontinued BPs before (3 months; 2 to 5) and at (6 months; 3 to 7) presentation (P < .005). CONCLUSIONS: Independent of treatment modality and MRONJ stage at presentation, discontinuing BP before or at treatment initiation is associated with faster resolution of MRONJ symptoms compared with continuing the drug throughout jaw treatment. Patients should be counseled that continuing their BP medication after an established MRONJ diagnosis (compared to stopping the BP at diagnosis) may delay resolution of maxillofacial symptoms by approximately 6 months.

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