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A osteonecrose dos maxilares induzida por medicamentos (MRONJ) caracteriza-se por exposição óssea ou osso que pode ser sondado através de fístula intra ou extraoral, em região maxilofacial, e que não cicatriza dentro de oito semanas. A MRONJ é uma condição rara e debilitante que pode causar dor, disfagia e odor desagradável na cavidade oral, afetando pacientes com histórico ou sob uso contínuo de terapia antirreabsortiva, isolada ou associada a imunomoduladores ou drogas antiangiogênicas, mas sem histórico de radioterapia nos maxilares. O objetivo desta revisão narrativa de literatura é compilar os principais aspectos sobre a etiopatogenia da MRONJ e as opções terapêuticas disponíveis. A etiologia da MRONJ é multifatorial, complexa, e não está totalmente compreendida, não havendo um tratamento definitivo, mas diversas modalidades terapêuticas que visam o controle da dor e da progressão da osteonecrose. Conclui-se com essa revisão que o entendimento da etiopatogenia da MRONJ pelo cirurgião-dentista lhe permite adotar medidas preventivas, bem como o conhecimento das modalidades terapêuticas disponíveis lhe possibilita oferecer o manejo adequado para seu paciente, conforme o estágio da doença.

Medication-related osteonecrosis of the jaw (MRONJ) is characterized by exposed bone or bone that can be probed through an intra or extraoral fistula, in the maxillofacial region, which does not heal within eight weeks. MRONJ is a rare and debilitating condition that can cause pain, dysphagia and unpleasant odor in the oral cavity, affecting patients with a history or continuous use of antiresorptive therapy, alone or associated with immunomodulators or antiangiogenic drugs, but without a history of radiotherapy to the jaws. The aim of this narrative literature review is to compile the main aspects about the etiopathogenesis of MRONJ and the available therapeutic options. The etiology of MRONJ is multifactorial, complex, and is not fully understood, with no definitive treatment, but several therapeutic modalities that aim to control pain and the progression of osteonecrosis. It is concluded from this review that the understanding of the etiopathogenesis of MRONJ by the dental surgeon allows him to adopt preventive measures, as well as the knowledge of the therapeutic modalities available allows him to offer the appropriate management for his patient, depending on the stage of the disease.

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Purpose: Multiple myeloma (MM) is a rare cancer that is typically managed with bisphosphonates to slow bone resorption and prevent skeletal complications. This study aimed to identify imaging patterns in MM patients receiving bisphosphonate therapy. Materials and Methods: This systematic review included studies investigating maxillomandibular bone alterations based on imaging examinations in MM patients treated with bisphosphonates. The selected studies were qualitatively assessed using the Critical Appraisal Tools from SUMARI. Results: Six studies, involving 669 MM patients, were included, with 447 receiving bisphosphonate treatment. The majority were treated with pamidronate, zoledronate, or a combination of both. Seventy patients developed medication-related osteonecrosis of the jaw (MRONJ), predominantly in the mandible, characterized by the presence of bony sequestrum, bone sclerosis, increased periodontal ligament space, osteolytic lesions, and osteomyelitis as observed in imaging analyses. For non-MRONJ lesions, the mandible also exhibited the highest frequency of asymptomatic bone alterations. These ranged from "punched-out" osteolytic lesions or "soap bubble" lesions to solitary bone lesions, areas of bone sclerosis, abnormalities of the hard palate, osteoporosis, non-healed alveoli, and cortical bone rupture. Conclusion: MM patients treated with bisphosphonates display radiographic patterns of maxillomandibular bone lesions. These patterns aid in diagnosis and facilitate early and targeted treatment, thereby contributing to improved morbidity outcomes for these patients.

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PURPOSE: The aim of the present study was to determine the methodological quality of systematic reviews that evaluated the effectiveness of pentoxifylline and tocopherol (PENTO) in the treatment of osteoradionecrosis of the jaw (ORNJ) and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Searches were performed in Databases including PubMed, Scopus, LILACS, DARE, Cochrane Library, and SIGLE through OpenGrey until March 2024, were evaluated by two independent reviewers to answer the following question: Is the use of PENTO protocol effective in the treatment of ORNJ or for the treatment of MRONJ? RESULTS: A total of 256 articles were initially identified; however, following the use of appropriate inclusion and exclusion criteria, five systematic reviews were identified for detailed analysis. The final study sample comprised 588 patients: 397 patients with ORN and 197 patients with MRONJ who were treated with PENTO. The total recovery of individuals who used the PENTO protocol was 62,2 % for ORN and 100 % for MRONJ, with a follow-up period of 1 month to 10 years. The methodological quality of the studies was assessed using the AMSTAR 2 tool, in which four were of low quality and 1 moderate quality. CONCLUSION: The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone exposure. However, the low quality of the relevant reports highlights the need for primary and secondary studies with better methodological rigor to reduce bias and provide reassurance for this treatment option.

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Background: Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but significant adverse event primarily associated with the intake of antiresorptive and antiangiogenic medications. Although antiresorptive and antiangiogenic the-rapies improve life expectancy, particularly in cancer patients, MRONJ may hamper the patient's quality of life due to pain, discomfort, anxiety, depression, speech impairment, difficulty in swallowing and eating, frequent medical and dental evaluations and treatments, and the possibility of treatment discontinuation. Leukocyte­ and Platelet-rich Fibrin (L-PRF) is an autologous platelet aggregate that promotes wound healing by stimulating re-epithelialization, angiogenesis, and extracellular matrix production. Aim: The present systematic review aimed to compare the results in the published literature on whether L-PRF is an effective and predictable adjuvant to surgical debridement of necrotic bone for improving the healing efficacy in patients with MRONJ. Materials and Methods: The PubMed, Scopus, Cochrane, Science Direct, LILACS, and Web of Science databases were searched using the predetermined MeSH terms and eligibility criteria, and the search yielded a total of five articles. Two studies were retrospective, and three studies were case series. Results: Seventeen participants received a combination of surgical debridement, L-PRF membrane, and antibiotics. Complete wound healing was observed in 70% of the participants, and most of them healed without any complications. Conclusions: L-PRF as an adjuvant to surgical debridement of necrosed bone appears to have a positive association with the healing outcome in patients with MRONJ.

Introducción: La osteonecrosis mandibular relacionada con medicamentos (ONMRM) es un evento adverso raro pero significativo asociado principalmente con la ingesta de medicamentos antirresortivos y antiangiogénicos. Aunque las terapias antirresortivas y antiangiogénicas mejoran la esperanza de vida, particularmente en pacientes con cáncer, la ONMRM puede obstaculizar la calidad de vida del paciente debido a dolor, incomodidad, ansiedad, depresión, discapacidad del habla, dificultad para tragar y comer, evaluaciones y tratamientos médicos y dentales frecuentes, y la posibilidad de interrupción del tratamiento. La fibrina rica en plaquetas y leucocitos (L-PRF) es un agregado de plaquetas autólogo que promueve la curación de heridas al estimular la reepitelización, la angiogénesis y la producción de la matriz extracelular. Objetivo: La presente revisión sistemática tuvo como objetivo comparar los resultados en la literatura publicada sobre si L-PRF es un adyuvante efectivo y predecible al desbridamiento quirúrgico del hueso necrótico para mejorar la eficacia curativa en pacientes con ONMRM. Materiales y Métodos: Las bases de datos de PubMed, Scopus, Cochrane, ScienceDirect, LILACS y Web of Science se registraron utilizando los términos DeCS/MeSH predeterminados y los criterios de elegibilidad, y la búsqueda arrojó un total de cinco artículos. Dos estudios fueron retrospectivos, y tres estudios fueron series de casos. Resultado: Diecisiete participantes recibieron una combinación de desbridamiento quirúrgico, membrana L-PRF y antibióticos. Se observó curación completa de heridas en el 70% de los participantes, y la mayoría de ellos se curaron sin ninguna complicación. Conclusión: L-PRF como adyuvante para el desbridamiento quirúrgico del hueso necrótico parece tener una asociación positiva con el resultado de curación en pacientes con ONMRM.

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OBJECTIVE: To identify radiographic findings suggestive of drug-induced osteonecrosis and evaluate radiomorphometric patterns indicative of changes in bone mineral density in individuals transplanted for liver disorders using bisphosphonates. STUDY DESIGN: The study group included panoramic x-rays of liver transplant patients who are being monitored and who present a clinical status of osteoporosis and use bisphosphonates. The control group was made up of liver transplant patients who did not have osteoporosis. On panoramic radiographs, mental index (MI) and mandibular cortical index (MCI) and the presence of radiographic anomalies suggestive of osteonecrosis were evaluated. RESULTS: There were significant statistical results when comparing the groups in relation to the decrease in bone mineral density (BMD) with MCI-C3 (p = 0.036), however, there were none in relation to MI (p = 0.14). There were no valid statistical results when relating MCI (p = 0.94) and MI (p = 0.66) with reduced BMD and use of bisphosphonates. CONCLUSION: Liver transplant individuals using bisphosphonates present greater radiographic signs of bone sclerosis suggestive of a greater propensity to develop osteonecrosis of the jaw and an increased risk of presenting changes suggestive of reduced bone mineral density on panoramic radiographs when compared to liver transplant individuals not using bisphosphonates.

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Abstract Objective For treatment of medication-related osteonecrosis of the jaw, one proposed approach is the use of a topical agent to block entry of these medications in oral soft tissues. We tested the ability of phosphonoformic acid (PFA), an inhibitor of bisphosphonate entry through certain sodium-dependent phosphate contransporters (SLC20A1, 20A2, 34A1-3) as well as Dynasore, a macropinocytosis inhibitor, for their abilities to prevent zoledronate-induced (ZOL) death in human gingival fibroblasts (HGFs). Methodology MTT assay dose-response curves were performed to determine non-cytotoxic levels of both PFA and Dynasore. In the presence of 50 μM ZOL, optimized PFA and Dynasore doses were tested for their ability to restore HGF viability. To determine SLC expression in HGFs, total HGF RNA was subjected to quantitative real-time RT-PCR. Confocal fluorescence microscopy was employed to see if Dynasore inhibited macropinocytotic HGF entry of AF647-ZOL. Endosomal acidification in the presence of Dynasore was measured by live cell imaging utilizing LysoSensor Green DND-189. As a further test of Dynasore's ability to interfere with ZOL-containing endosomal maturation, perinuclear localization of mature endosomes containing AF647-ZOL or TRITC-dextran as a control were assessed via confocal fluorescence microscopy with CellProfiler™ software analysis of the resulting photomicrographs. Results 0.5 mM PFA did not rescue HGFs from ZOL-induced viability loss at 72 hours while 10 and 30 μM geranylgeraniol did partially rescue. HGFs did not express the SLC transporters as compared to the expression in positive control tissues. 10 μM Dynasore completely prevented ZOL-induced viability loss. In the presence of Dynasore, AF647-ZOL and FITC-dextran co-localized in endosomes. Endosomal acidification was inhibited by Dynasore and perinuclear localization of both TRITC-dextran- and AF647-ZOL-containing endosomes was inhibited by 30 μM Dynasore. Conclusion Dynasore prevents ZOL-induced viability loss in HGFs by partially interfering with macropinocytosis and by inhibiting the endosomal maturation pathway thought to be needed for ZOL delivery to the cytoplasm.

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INTRODUCTION: Bisphosphonate (BF) therapy is strongly related to the occurrence of medication-related osteonecrosis of the jaw (ONJ). However, no previous study has evaluated if there are sex-related differences on the ONJ establishment together with bone biomechanical alterations, and if they could have a synergy with the ZA treatment. MATERIALS AND METHODS: This study aimed to analyze the physicochemical properties of mineralized tissues in a zoledronate (ZA)-related osteonecrosis mouse model, by a 2 × 2-factorial design, considering sex (female/male) and treatment (ZA/Saline) factors (n = 8/group). After three ZA (1.0 mg/kg) or saline administrations (days 0, 7, 14), the lower left second molar was extracted (day 42). Further ZA administration (day 49) and euthanasia (day 70) were conducted. After confirmation of ZA-induced jaw necrosis (histologic and microtomographic analysis), spectroscopic and mechanical parameters were assessed. RESULTS: ZA-treated groups presented lower bone density due to impaired healing of tooth extraction socket. Sex-related alterations were also observed, with lower bone density in females. Regarding biomechanical parameters, sex and treatment exerted independent influences. ZA, although decreasing flexural modulus and yield stress, increases stiffness mainly due to a higher bone volume. Females show less resistance to higher loads compared to males (considering dimension-independent parameters). Additionally, ZA increases crystallinity in bone and dental structure (p < 0.05). In summary, although strongly related to osteonecrosis occurrence, ZA modifies bone and dental mineral matrix, improving bone mechanical properties. CONCLUSION: Despite sex-dependent differences in bone biomechanics and density, osteonecrosis was established with no sex influence. No synergistic association between sex and treatment factors was observed in this study.

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O cenário odontológico tem apresentado diversos casos de infecção odontogênica, inclusive com óbitos. Em linha com esses fatos, observa-se o aumento na prescrição de antirreabsortivos ósseos em Serviços de Saúde particulares e do SUS (Sistema Único de Saúde). Os bisfosfonatos injetáveis têm ação comprovadamente benéfica para o controle de metástases ósseas. Contudo, aponta-se a osteonecrose avascular no complexo bucomaxilofacial como um efeito adverso importante. Este tipo de alteração também foi reportado mediante o uso de antiangiogênicos e imunomoduladores. Esta revisão de literatura teve por objetivo delinear um protocolo que respalde a atuação dos Cirurgiões Dentistas Clínicos Gerais nas Unidades de Atenção Primária à Saúde do Município de Campinas-SP, diante da utilização frequente de antirreabsortivos ósseos e uma demanda reprimida por cuidados em Saúde Bucal que se apresenta com a retomada integral das atividades após o pico da pandemia de COVID-19. Com base no conhecimento científico sobre a osteonecrose associada a medicamentos, sugere-se que as equipes das Unidades de Atenção Primária à Saúde atuem de modo preventivo, proporcionando cuidado em Saúde Bucal preferencialmente antes do início do tratamento com antirreabsortivos. No entanto, para pacientes que já estão sob esta terapia e necessitam de intervenções odontológicas invasivas, recomenda-se uma abordagem multidisciplinar, entre Cirurgiões Dentistas da Atenção Primária e da Atenção Secundária, visando ao tratamento de possíveis complicações das intervenções invasivas de urgência. Ademais, pacientes sob uso de antirreabsortivos ósseos requerem monitoramento a longo prazo, para se evitar a necessidade de procedimentos odontológicos invasivos ou mesmo diagnosticar precocemente casos de osteonecrose.

The dental scenario has shown many cases of odontogenic infection, including some that ended with death. Along with these facts, there has been an increasing prescription of antiresorptive drugs, both in private and Unified Health System (SUS) Health Services. Injectable bisphosphonates have well-established beneficial action for controlling osseous metastasis. Nevertheless, avascular osteonecrosis of the bucomaxillofacial complex has been pointed out as an important side effect. Such a condition has also been reported under treatment with antiangiogenic drugs and immunological checkpoints inhibitors. This literature review aimed at offering a protocol to support the clinical practice of general dental practitioners in Primary Health Care Units from Campinas-SP Municipality, in face of frequent use of antiresorptive drugs and a repressed demand for oral health care, which takes place with thorough return of activities after COVID-19 pandemic peak. On the basis of scientific knowledge about medication-related osteonecrosis, it may be suggested that staffs in Primary Health Care Units adopt preventive measures, providing oral health care preferably before the beginning of antiresorptive therapy. However, for patients who are already under antiresorptive therapy and need invasive oral interventions, it is recommended a multidisciplinary approach, comprising Dentists from Primary and Secondary Health Care Units, trying to intercept possible complications of urgent invasive oral interventions. Besides, patients under use of antiresorptive medications require long-term follow-up, to avoid the need for invasive oral procedures or to make early diagnosis of osteonecrosis.

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Purpose: The aim of this study was to evaluate changes in the trabecular bone through texture analysis and compare the texture analysis characteristics of different areas in patients with medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods: Cone-beam computed tomographic images of 16 patients diagnosed with MRONJ were used. In sagittal images, 3 regions were chosen: active osteonecrosis (AO); intermediate tissue (IT), which presented a zone of apparently healthy tissue adjacent to the AO area; and healthy bone tissue (HT) (control area). Texture analysis was performed evaluating 7 parameters: secondary angular momentum, contrast, correlation, sum of squares, inverse moment of difference, sum of entropies, and entropy. Data were analyzed using the Kruskal-Wallis test with a significance level of 5%. Results: Comparing the areas of AO, IT, and HT, significant differences (P<0.05) were observed. The IT and AO area images showed higher values for parameters such as contrast, entropy, and secondary angular momentum than the HT area, indicating greater disorder in these tissues. Conclusion: Through texture analysis, changes in the bone pattern could be observed in areas of osteonecrosis. The texture analysis demonstrated that areas visually identified and classified as IT still had necrotic tissue, thereby increasing the accuracy of delimiting the real extension of MRONJ.

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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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INTRODUCTION: Medication-related osteonecrosis of the jaws (MRONJ) is a complication that develops in patients who use or have used antiresorptive or antiangiogenic medications for the treatment of bone metabolic disease and bone metastases. Clinically, MRONJ is characterized by the appearance of an inflammation in soft tissues and exposure of necrotic bone tissue in mandible or maxilla, for a period of 8 weeks, in patients with no history of head and neck radiotherapy that were being or are being treated with antiresorptive and/or antiangiogenic agents. The fibrin-rich platelets and leukocytes (L-PRF) membrane has been used as an alternative for MRONJ prevention. The aim of this study was to evaluate the use of L-PRF in prevention and treatment of bone necrosis. MATERIAL AND METHODS: The patients included had MRONJ diagnosis confirmed after clinical and radiographic examination and patients whose only therapeutic option was dental extraction. RESULTS: Twenty patients were included in the study and were divided in three groups. Two patients were removed from the study due to previous history of pentoxifylline and tocopherol use. The result of surgical treatment was successful in 57% in group 1 (control/MRONJ prevention), 100% in group 2 (MRONJ prevention), and 80% in group 3 (MRONJ treatment). CONCLUSION: L-PRF is an autologous biomaterial that allows the release of growth factors for a prolonged time, resulting in a better healing, reducing the risk contamination, edema, and postoperative pain, being a great ally in the prevention and treatment of MRONJ because it returns to these patients, mainly quality of life, reducing pain, and recurrent infections commonly seen in the processes of bone necrosis of the jaws.

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Aim: This study aimed to systematically review existing literature regarding the association between dental procedures­such as tooth extractions and periodontal therapy­and occurrence of medication-related osteonecrosis of the jaw (MRONJ) in individuals using bone-modifying drugs. Methods: Search strategies were performed in PubMed, Scopus, Web of Science and Cochrane Library for a timeframe ending in December 2021. Study selection, data extraction and risk of bias were analyzed independently by two researchers. Three meta-analyses were performed, estimating the crude risk ratio (RR), the adjusted odds ratio (OR) and the adjusted hazard ratio (HR) for the association between tooth extraction and MRONJ. Results: Of the 1,654 studies initially retrieved, 17 were ultimately included. The majority of patients with MRONJ in these studies were female, with a mean age of 64 years. Zoledronic acid was the most commonly used drug among patients with MRONJ, and cancer was the most frequent underlying health condition. Regarding the performed meta-analyses, crude and adjusted analyses demonstrated that tooth extraction increased the risk for MRONJ by 4.28 (95% confidence interval [95%CI]: 1.73­10.58), the OR for MRONJ by 26.94 (95%CI: 4.17­174.17), and the HR for MRONJ by 9.96 (95%CI: 4.04­24.55). Conclusion: It was concluded that performing dental procedures, especially tooth extraction, in patients using bone-modifying drugs increased the risk of MRONJ occurrence and, therefore, should be avoided. Further studies, using adjusted data, are warranted

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Objective: To evaluate the effects of inorganic bovine bone graft (Lumina Bone, Criteria, Brazil) and beta-tricalcium phosphate (ß-TCP) graft (ChronOS, Synthes, Brazil) in rats with the risk of developing post-extraction medication-related osteonecrosis of the jaw (MRONJ). Methods: Eighteen male Wistar rats weighing 350 to 450 g were induced to develop MRONJ using zoledronic acid for 5 weeks. In the sixth week, the right maxillary first molar was extracted. The animals in Group I (G1) did not receive bone grafts after tooth extraction, while Group II (G2) animals received inorganic bovine bone grafts, and Group III (G3) animals received beta-tricalcium phosphate (ß-TCP) grafts. Clinical evaluation and histomorphometric and immunohistochemical analyses were performed. ANOVA and Tukey's statistical tests were used and a level of significance was considered to be 5%. Results: In the clinical evaluation, animals from G2 and G3 did not present clinical manifestations of osteonecrosis, unlike the control group (G1) animals, which presented necrotic bone tissue exposure in all samples. In the histomorphometric evaluation, animals in G3 showed greater formation of bone tissue (66%) and less formation of bone lacuna (18%) than animals in G1 (58%/32%) and in G2 (59%/27%) (P < 0.05). Moderate (++) immunostaining was observed in G2 and G3 for RANKL, TRAP, and OC, while G1 showed moderate (++) labeling for OC and mild (+) immunostaining for TRAP and RANKL. Conclusions: Greater formation of bone tissue and fewer bone lacunae were found in animals treated with ß-TCP. In clinical evaluation, bone graft groups presented with the clinical manifestation of MRONJ and showed higher intensity of immunostaining for TRAP and RANKL. Despite the limitations of experimental animal studies, the results of this work may assist in the development of future clinical research for the prevention of MRONJ.

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OBJECTIVES: The aim of this study is to investigate the long-term effects on jaw and femur bone induced by oncologic doses of zoledronic acid in a young rat model. MATERIAL AND METHODS: Six 12-week-old male Wistar rats received zoledronic acid (0.6 mg/kg) and six control rats received saline solution in the same volume. Compounds were administered intraperitoneally in five doses every 28 days. Euthanasia was performed 150 days after therapy onset. After animal sacrifice, their mandibles and femurs were scanned ex vivo using a high-resolution (14 µm) micro-computed tomography. Morphometric bone parameters were calculated using CT-Analyzer (Bruker, Belgium) between the first and second mandibular molars and in the distal femur metaphysis and epiphysis. RESULTS: The treatment group as compared to the controls showed a significantly (p < .05) increased bone quantity (↑BV/TV, ↓Po[Tot], ↑Tb.Th), bone density (↑TMD, ↑BMD), and osteosclerosis of the trabecular bone (↓Tb.Sp, ↓Conn.Dn, ↓Tb.Pf, ↓SMI) in all anatomical sites. Bone remodeling suppression due to zoledronic acid treatment was more pronounced (p < .05) in the femoral metaphysis relative to the mandible and epiphysis. The exploratory linear discriminant analysis showed that for the mandible, it was mainly the bone quantity-related morphometric indices (BV/TV and Tb.Th), while for the femoral epiphysis and metaphysis, it was bone structure-related (Tb.Pf and Tb.N), which are of primary importance to study the treatment effect. CONCLUSION: High doses of bisphosphonates can differently affect the bone quantity, density, and structure in long bones and jawbones. In the metaphysis, bone changes were primarily concentrated in the region of the growth plate. Future studies may consider the use of bone morphometric indices to evaluate the effect of bisphosphonates.

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Abstract 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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Abstract This study aimed to evaluate the potential of strontium ranelate (SR) in medication-related jaw osteonecrosis (MRONJ) after tooth extraction in ovariectomized rats. Thirty ovariectomized rats were divided into three groups (n = 10): bisphophonate (BP) group (zoledronic acid; 0.4 mg/kg/week), SR group (625 mg/kg/day), and control group (saline solution). The lower first molars were extracted after 60 days of drug therapy. Drug administration was continued for another 30 days after tooth extraction. The mandibles were subjected to clinical, histological, radiographic, and microtomographic evaluations. Only the BP group showed clinical changes, characterized by the presence of 70% (n = 7) and 20% (n = 2) of ulcers and extraoral fistulas. Radiographic evaluation demonstrated bone sequestration only in the BP group (n = 7, 70%). Microtomographic analysis revealed increased bone porosity after ovariectomy, particularly in the the control group (p < 0.05). The BP group showed a higher bone surface density, bone volume, and trabecular number than SR and control groups, but with less trabecular separation (p < 0.05). All the animals in the BP group demonstrated histological osteonecrosis. There was no evidence of osteonecrosis in the control and SR groups, which was characterized by the absence of empty osteocyte gaps and associated with the gradual healing of the extraction area. Also, an increased number of blood vessels and a reduced number of osteoclasts were observed in the SR group (p < 0.05). Therefore, SR treatment increased angiogenesis and osteoclastogenesis in the healing socket and was not associated with MRONJ development after tooth extraction in ovariectomized rats.

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Abstract Antiresorptive drugs operate in the bone metabolism modulation and are widely used in the treatment of bone metastases and bone losses related to hormonal deficiency. Although this therapy shows satisfactory results, there are adverse effects associated with its use, such as osteonecrosis of the jaws. Medication-related osteonecrosis of the jaws (MRONJ) is, therefore, a serious and challenging condition with important implications in dentistry. The aim was to conduct a narrative literature review on anti-resorptive drugs and their latest repercussions on the maxillary bones. The review was carried out through a bibliographic search using Decs/Mesh descriptors of interest, in Portuguese and English, in the PubMed, Virtual Health Library (VHL) and Scielo databases. After applying the inclusion and exclusion criteria, a total of 33 studies were selected for analysis. It can be noticed that therapy with anti-resorptive agents is complex, especially in dental practice, since MRONJ is a complication that is difficult to manage. Regarding the therapeutic options, these are divided into conservative, surgical or adjuvant therapy, however, there are no protocols in the literature, and there is no consistency regarding the indication of the suspension of the drug administration - "Drug Holiday". Thus, it is important that the multidisciplinary team seeks strategies that minimize complications and promote control over the use of these drugs. In addition, there is a need for investigations that contribute with guidelines for the management and control of adverse effects resulting from therapy with antiresorptive drugs. (AU)

Resumo As drogas antirreabsortivas atuam na modulação do metabolismo ósseo e são indicadas para o tratamento de metástases ósseas e perdas ósseas relacionadas à deficiência hormonal. Ainda que esta terapia apresente resultados satisfatórios, observam-se efeitos adversos associados ao seu uso, como a osteonecrose dos maxilares. A osteonecrose dos maxilares associada ao uso de medicamentos (OMAM) é, portanto, uma condição séria e desafiadora com implicações importantes na Odontologia. O objetivo foi realizar uma revisão narrativa de literatura sobre as drogas antirreabsortivas e suas respectivas repercussões nos ossos maxilares. A revisão foi realizada através de busca bibliográfica utilizando descritores Decs/Mesh de interesse, em português e inglês, nas bases de dados PubMed, Biblioteca Virtual de Saúde (BVS) e Scielo. Após aplicação dos critérios de inclusão e exclusão, um total de 33 trabalhos foram selecionados para análise. Pode-se constatar que a terapia com agentes antirreabsortivos é complexa, sobretudo na prática odontológica, visto que a OMAM é uma complicação de difícil manejo. Em relação às condutas terapêuticas para esta condição, divide-se em terapia conservadora, cirúrgica ou adjuvante, todavia, não existem protocolos validados na literatura, bem como não há consistência quanto à indicação do intervalo de suspensão da administração da droga - "Drug Holiday". Desse modo, é importante que a equipe multidisciplinar busque estratégias que minimizem as complicações e promovam o controle no uso dessas drogas. Além disso, nota-se a necessidade de realizar investigações que contribuam com diretrizes para o manejo e controle dos efeitos adversos decorrentes da terapia com medicamentos antirreabsortivos. (AU)

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INTRODUCTION: We present here a literature review focusing on the repercussions of osteoporosis on the oral and maxillofacial complex. Osteoporosis is a silent metabolic disorder characterized by reduced bone mineral density (BMD), which can lead to bone fractures, particularly affecting elderly women. The prevalence of this disease has increased significantly worldwide, and since it accelerates bone resorption also in the jaw bones, some attention has been paid to possible oral and maxillofacial manifestations. MATERIALS AND METHODS: The databases PubMed and Google Scholar were searched for reports of oral and maxillofacial changes related to osteoporosis. RESULTS: Several parameters evaluating bone changes in panoramic radiography have been proposed to estimate osteoporosis-related BMD loss, but they tend to warn about the possibility of osteoporosis, rather than being diagnostic criteria. Meanwhile, it seems that osteoporosis-related BMD loss could delay alveolar bone healing and potentiate bone loss in periodontal disease. CONCLUSION: Even though orofacial bones are not compromised by osteoporosis as much as the axial/appendicular skeleton, a regular dental follow-up of osteoporotic patients is advised, especially in the case of periodontal disease and maxillofacial surgery. Further controlled longitudinal studies considering the site-specificity of osteogenesis would be helpful regarding this issue.

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OBJECTIVE: The aim of this study was to evaluate morphological and immunohistochemical features of tooth extraction sites in rats subjected to different antiresorptive drugs. MATERIALS AND METHODS: Wistar rats were allocated into 4 groups according to the treatment: (1) alendronate, (2) raloxifene, (3) strontium ranelate, and (4) control. The animals underwent tooth extraction (60th day of treatment) and afterwards were euthanized (90th day of treatment). Tooth extraction sites were analyzed by means of scanning electron microscopy (SEM), hematoxylin-eosin staining (H&E), and immunohistochemical staining (RANKL and OPG). RESULTS: On H&E analysis, the alendronate group showed greater amounts of non-vital bone, biofilm, inflammatory infiltrate and root fragment, and smaller amount of vital bone. The strontium ranelate group showed great amount of non-vital bone. This group also had lower levels of OPG, while the alendronate group showed lower OPG and RANKL than the other groups. On SEM analysis, the alendronate group showed a considerable number of microcracks on the alveolar bone surface and few Howship lacunae and lack of bone cells as well. The raloxifene, strontium ranelate, and control groups showed a large number of bone cells and Howship lacunae on the bone surface and few microcracks. CONCLUSION: Alendronate therapy is associated with macro- and microscopic features of medication-related osteonecrosis of the jaw at tooth extraction sites, whereas raloxifene therapy is not, and strontium ranelate therapy is associated with non-vital bone. CLINICAL RELEVANCE: Osteonecrosis of the jaws is a serious side effect of alendronate therapy, where tooth extraction is a major risk factor. Considering the significant number of patients undergoing antiresorptive therapies worldwide, the present study investigated whether raloxifene and strontium ranelate interfere with bone repair after tooth extraction in a similar way to bisphosphonates.

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Introduction: The inhibition of osteoclastic activity, associated with different treatment modalities in patients with head and neck cancer, make bones unable to respond to repair processes related to physiological traumas or infection and may result in bone necrosis. The present study aims to report a clinical case of osteoradionecrosis in mandible, and how its sequels were controlled by ozonotherapy. Case report: A 73-year-old female patient with infiltrative ductal breast carcinoma with mandibular metastasis was submitted to chemo and radiotherapy at head and neck region associated with bisphosphonate. Three years later, she was diagnosed with hemimandibular osteoradionecrosis that exhibited communication with oral cavity and with a chronic, suppurative and persistent associated infection. It was applied adjuvant therapy with ozone through the cutaneous fistula and the exposed and necrotic bone. Additionally, non-vital bone debridement was proceeded in two surgical steps. The patient is after a 1-year follow-up non-symptomatic. Conclusion: It is supposed that ozonotherapy, due to its antibacterial and immunoregulatory mechanism of action, was an important therapeutic agent for improving the patient's quality of life.

Introdução: A inibição da atividade osteoclástica, associada a diversas modalidades de tratamento utilizadas em pacientes com câncer de cabeça e pescoço, torna o osso incapaz de responder aos processos de reparo relacionados a traumas fisiológicos ou à infecção, e pode resultar em necrose óssea. O presente estudo tem como objetivo relatar um caso clínico de osteonecrose em mandíbula como consequência do uso de bisfosfonato associado à quimioterapia e à radioterapia para tratamento de câncer de mama com metástase para mandíbula, tendo suas sequelas controladas por meio do uso da ozonioterapia. Relato do caso: Paciente do sexo feminino, 73 anos, com história de carcinoma ductal infiltrante de mama com metástase óssea em mandíbula, a qual foi submetida ao tratamento de quimioterapia e radioterapia em região de cabeça e pescoço; três anos depois, foi diagnosticada com osteonecrose da hemimandíbula direita com exposição completa para a cavidade bucal e infecção crônica, supurativa e persistente. Foi realizada terapia adjuvante com aplicação de ozônio nas fístulas cutâneas e no remanescente ósseo exposto e necrosado, além do desbridamento dos sequestros ósseos em duas etapas cirúrgicas. Paciente encontra-se em acompanhamento há 1 ano, sem sintomatologia associada. Conclusão: Observou-se que a ozonioterapia, em razão da sua ação antibacteriana e cicatrizante, foi um importante agente terapêutico para a melhora da qualidade de vida da paciente.

Introducción: La inhibición de la actividad osteoclástica, asociada con las diversas modalidades de tratamiento utilizadas por los pacientes con cáncer de cabeza y cuello, hace que el hueso no pueda responder a los procesos de reparación relacionados con traumas o infecciones fisiológicas y puede provocar necrosis ósea. El presente estudio tiene como objetivo informar un caso clínico de osteonecrosis mandibular como consecuencia del uso de bisfosfonato asociado con quimioterapia y radioterapia para tartar el cáncer de mama con mandíbula metastásica, controlando sus secuelas mediante el uso de la terapia con ozono. Relato del caso: Paciente de 73 años con antecedentes de carcinoma ductal mamario infiltrante con metástasis en la mandíbula ósea fue sometida a quimioterapia y radioterapia en la región de la cabeza y el cuello. Tres años después, le diagnostica con osteonecrosis hemimandibular derecha con exposición completa a la cavidad oral e infección crónica, supurativa y persistente. La terapia adyuvante se realizó con la aplicación de ozono en las fístulas cutáneas y en el remanente óseo expuesto y necrótico, además del desbridamiento de los secuestros óseos en dos etapas quirúrgicas. El paciente ha estado bajo seguimiento durante 1 años in síntomas asociados. Conclusión: Debido a su acción antibacteriana y curativa, la ozonioterapia fue un importante agente terapéutico para mejorar la calidad de vida del paciente.

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