Osteonecrosis maxilar inferior asociado a bifosfonatos / Lower jaw osteonecrosis associated with bisphosphonates / Osteonecrose do maxilar inferior associada a bisfosfonatos

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.

Osteonecrosis de los maxilares: reacción medicamentosa / Osteonecrosis of the jaws: drug reaction

La osteonecrosis de los maxilares (ONM) secundaria al consumo de medicamentos antirresortivos y antiangiogénicos es una patología oral que afecta el funcionamiento del organismo de los seres humanos no sólo a nivel bucal, sino que disminuye su calidad de vida y aumenta su morbilidad. La ONM se define como la presencia de hueso necrótico expuesto que puede ser explorado mediante una fístula en el territorio maxilofacial, que se mantiene durante un periodo mínimo de ocho se- manas. Los fármacos antirresortivos y antiangiogénicos son indicados a pacientes que presentan patologías osteometabólicas, cáncer, entre otras, de ahí la importancia de mantener una estrecha relación entre médico tratante-odontólogo-paciente. El propósito de este artículo es establecer un protocolo de cuidado oral básico y definir las funciones del médico tratante, cirujano dentista y cirujano maxilofacial mediante una revisión bibliográfica con el fin de crear una propuesta preventiva para el tratamiento de estos pacientes (AU)

Medication-related osteonecrosis of the jaw (MRONJ), secondary to the consumption of antiresorptive and antiangiogenic drugs is an oral pathology that affects the functioning of the human body, not only at the oral level, but also decreasing their quality of life and increasing their morbidity. MRONJ is defined as the presence of exposed necrotic bone that can be explored through a fistula in the maxillofacial territory, which is maintained for a minimum period of eight weeks. Antiresorptive and antiangiogenic drugs are indicated for patients with osteometabolic pathologies, cancer, among others. For the same reasons, the importance of maintaining a close relationship between the treating physician, dentist and patient. The purpose of this article is to establish a clinical guide for basic oral care and define the functions of the treating physician, dental surgeon and maxillofacial surgeon through a bibliographic review; in order to create a preventive proposal for the treatment of these patients (AU)

Tetrahedral framework nucleic acid carrying angiogenic peptide prevents bisphosphonate-related osteonecrosis of the jaw by promoting angiogenesis / 国际口腔科学杂志·英文版

The significant clinical feature of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the exposure of the necrotic jaw. Other clinical manifestations include jaw pain, swelling, abscess, and skin fistula, which seriously affect the patients' life, and there is no radical cure. Thus, new methods need to be found to prevent the occurrence of BRONJ. Here, a novel nanoparticle, tFNA-KLT, was successfully synthesized by us, in which the nanoparticle tetrahedral framework nucleic acid (tFNA) was used for carrying angiogenic peptide, KLT, and then further enhanced angiogenesis. TFNA-KLT possessed the same characteristics as tFNA, such as simple synthesis, stable structure, and good biocompatibility. Meanwhile, tFNA enhanced the stability of KLT and carried more KLT to interact with endothelial cells. First, it was confirmed that tFNA-KLT had the superior angiogenic ability to tFNA and KLT both in vitro and in vivo. Then we apply tFNA-KLT to the prevention of BRONJ. The results showed that tFNA-KLT can effectively prevent the occurrence of BRONJ by accelerating angiogenesis. In summary, the prepared novel nanoparticle, tFNA-KLT, was firstly synthesized by us. It was also firstly confirmed by us that tFNA-KLT significantly enhanced angiogenesis and can effectively prevent the occurrence of BRONJ by accelerating angiogenesis, thus providing a new avenue for the prevention of BRONJ and a new choice for therapeutic angiogenesis.

Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice / 国际口腔科学杂志·英文版

Bacterial infection is a common finding in patients, who develop medication-related osteonecrosis of the jaw (MRONJ) by the long-term and/or high-dose use of anti-resorptive agents such as bisphosphonate (BPs). However, pathological role of bacteria in MRONJ development at the early stage remains controversial. Here, we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model. C57/BL6 female mice were treated with intragastric broad-spectrum antibiotics for 1 week. Zoledronic acid (ZOL) through intravenous injection and antibiotics in drinking water were administered for throughout the experiment. Pulp was exposed on the left maxillary first molar, then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal. All mice were harvested, and cecum, maxilla, and femurs were collected. ONJ development was assessed using μCT and histologic analyses. When antibiotic was treated in mice, these mice had no weight changes, but developed significantly enlarged ceca compared to the control group (CTL mice). Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics, which was confirmed by decreased osteoclasts and inflammation. ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount. Furthermore, antibiotics treatment could further exacerbate bone necrosis, with increased osteoclast number. Our findings suggest that the commensal microbiome may play protective role, rather than pathological role, in the early stages of MRONJ development.

Osteonecrosis maxilar relacionada con medicamentos en pacientes oncológicos con metástasis óseas: resolución de dos casos / Medication-related osteonecrosis of the jaw in oncological patients with bone metastases: resolution of two cases

La osteonecrosis maxilar relacionada con medicamentos (ONMM) es una patología de características clínicas objetivas con signo-sintomatología patognomónica. El criterio clínico aceptado es la presencia de hueso necrótico expuesto y visible sobre el reborde óseo maxilar que no ha cicatrizado luego de 8 semanas, en pacientes con antecedentes de tratamiento antirresortivo. La denominación "relacionada con medicamentos" se utiliza por el creciente número de casos asociados con otros fármacos antirresortivos como denosumab y con terapias antiangiogénicas, más allá de la conocida relación con bifosfonatos.Si bien la incidencia de ONMM en pacientes tratados por osteopatías metabólicas es muy baja, la situación se torna más compleja en pacientes oncológicos con altas dosis de antirresortivos para tratamiento de metástasis ósea. Varios in-formes de casos describen cuadros de ONMM en pacientes con cáncer que reciben terapias dirigidas, específicamente TKI (inhibidores de tirosina quinasa) y anticuerpos monoclonales-VEGF (anticuerpos dirigidos al factor de crecimiento del endotelio vascular). La ONMM afecta negativamente la calidad de vida del paciente oncológico y produce comorbilidad significativa. Resulta imperioso identificar a los pacientes en riesgo y diseñar un protocolo de atención odontológica específico para estos casos. En este artículo se presentan dos casos de ONMM asociado con altas dosis de denosumab y administración simultánea de anticuerpos monoclonales específicos para el tratamiento del cáncer. Ambos casos sorprenden por la prematura instalación de la necrosis y su cuadro insidio-so. El protocolo de tratamiento descripto permitió controlar el cuadro inicial, limitar el avance de la lesión, asegurar el control del dolor y la infección, y finalmente, la curación total de la lesión. (AU)

Medication-related osteonecrosis of the jaws (MRONJ) is a pathology with objective clinical characteristics, with pathognomonic signs and symptoms. The accepted clinical criterion is the presence of exposed and visible necrotic bone on the maxillofacial region that has not healed after 8 weeks, in patients with history of antiresorptive treatment.The name "medication-related" is justified by the growing number of cases associated with other antiresorptive drugs such as denosumab and antiangiogenic therapies, beyond the known relationship with bisphosphonates. Although the incidence of MRONJ in patients treated for metabolic osteopathies is very low, the situation becomes more complex in cancer patients who receive high doses of antiresorptives for the treatment of skeletal metastases. Several case reports describe the presence of MRONJ in cancer patients receiving targeted therapies, specifically TKI (tyrosine kinase inhibitors) and monoclonal antibodies-targeting VEGF (vascular endothelial growth factor). MRONJ negatively affects the quality of life in cancer patients and produces significant comorbidity. It is imperative to identify patients at risk and design a specific dental care strategy for these cases.In this article, we present two cases of MRONJ associated with high doses of Denosumab and simultaneous administration of specific monoclonal antibodies. Both cases are surprising due to premature onset of necrosis. The described treatment strategies made it possible to control the initial symptoms, limit the lesion progression, ensure pain and infection control, and finally, the total healing of the lesion. (AU)

Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws / 华西口腔医学杂志

The morbidity rate of medication-related osteonecrosis of the jaws (MRONJ) increased rapidly in recent years. Thusfar, the mechanism of MRONJ has no consensus. The possible mechanisms may include bone remodeling inhibition theory, angiogenesis inhibition theory, oral microorganism infection theory, immunosuppression theory, cytotoxicity-targeted oral epithelial cells, microcrack formation of maxillary or mandibular bone, and single nucleotide polymorphism. However, the efficacy of prevention and treatment based on a single mechanism is not ideal. Routine oral examination before MRONJ-related drug treatment, treatment of related dental diseases, and regular oral follow-up during drug treatment are of great significance for the prevention of MRONJ. During the treatment of MRONJ, the stage of MRONJ must be determined accurately, treatment must be standardized in accordance with the guidelines, and personalized adjustments must be made considering the specific conditions of patients. This review aimed to combine the latest research and guidelines for MRONJ and the experiences on the treatment of MRONJ in the Maxillofacial Surgery Department of West China Hospital of Stomatology, Sichuan University, and discuss the strategies to improve the clinical process.

Efetividade da terapia fotodinâmica antimicrobiana utilizando butil azul de toluidina e laser de baixa potência na prevenção da osteonecrose dos maxilares associada à terapia medicamentosa / Effectiveness of antimicrobial photodynamic therapy using butyl toluidine blue and low-level laser in preventing the occurrence of medicationrelated osteonecrosis of the jaws

O presente estudo teve como objetivo avaliar a efetividade e a segurança do emprego de múltiplas sessões de aPDT, utilizando o butil azul de toluidina (BuAT) e a irradiação com laser de baixa potência (LBP), no sítio de extração dental de ratas com os principais fatores de risco para a ocorrência da osteonecrose dos maxilares associada à terapia medicamentosa (ONM-M). Vinte e oito ratas senescentes foram distribuídas em quatro grupos experimentais: VEI, VEI-aPDT, ZOL e ZOL-aPDT. O protocolo de tratamento teve duração de 7 semanas. Um dia antes do início deste protocolo foi instalada uma ligadura de algodão ao redor do primeiro molar inferior esquerdo para indução da periodontite experimental (PE). Nos grupos VEI e VEI-aPDT, as ratas receberam injeções intraperitoneais de 0,45ml de solução de cloreto de sódio 0,9% (veículo) a cada três dias. Nos grupos ZOL e ZOL-aPDT, as ratas receberam 0,45ml do veículo acrescido de 100µg/Kg do zoledronato a cada três dias. Após três semanas do início do protocolo de tratamento a ligadura foi removida e foi realizada a exodontia do primeiro molar inferior esquerdo. Nos grupos VEI e ZOL não foi efetuado nenhum tratamento local no sítio de extração dental. Nos grupos VEI-aPDT e ZOL-aPDT foram realizadas sessões de aPDT aos 0, 2, e 4 dias pós exodontia. Para a aPDT depositouse sobre o sítio de extração dental 300µl de BuAT (concentração: 0,5mg/ml; tempo de pré-irradiação, 60s) em seguida foi realizada a irradiação com laser de baixa potência (laser: InGaAIP; 660nm; 35mW; 74,2J/cm²; 60s) emissor: InGaAlP; comprimento de onda: 660 nm, laser visível - vermelho; potência: 35 mW; densidade energética por ponto: 74,2 J/cm2 ; tempo de aplicação: 60s). Decorridos 28 dias pós-operatórios foi realizada a eutanásia. As hemimandíbulas foram devidamente processadas para assegurar que no sítio de extração dental fossem efetuadas: 1) análise clínica; 2) análise histológica da reparação tecidual; 3) análise histométrica da Porcentagem de Tecido Ósseo Neoformado (PTOnf); 4) análise histométrica da Porcentagem de Tecido Ósseo Não Vital (PTOnv) e; análise imunoistoquímica de células TRAPpositivas. Os dados foram submetidos à análise estatística com nível de significância de 5%. Os grupos ZOL e ZOL-aPDT apresentaram menor quantidade de células TRAP-positivas quando comparados com os grupos VEI e VEI-aPDT. O grupo ZOL apresentou grande comprometimento do processo de reparação tecidual, condizentes com um quadro de ONM-M. Os grupos VEI, VEI-aPDT e ZOL-aPDT apresentaram um processo de reparação tecidual favorável do sítio de extração dental. No grupo ZOL a PTOnf no sítio de extração dental se mostrou menor que nos grupos VEI, VEI-aPDT e ZOL-aPDT. No grupo ZOL a PTOnv se mostrou maior que nos grupos VEI, VEIaPDT e ZOL-aPDT. No grupo ZOL-aPDT a PTOnv se apresentou maior que nos grupos VEI e VEI-aPDT. O emprego de múltiplas sessões de aPDT, utilizando o BuAT e LBP, no sítio de extração dental de ratas senescentes tratadas com alta dose de zoledronato se mostrou uma estratégia terapêutica segurança e efetiva para evitar a ocorrência da ONM-M pós exodontia(AU)

The present study aimed to evaluate the effectiveness and safety of using multiple aPDT sessions, using butyl toluidine blue (BuTB) and low-level laser irradiation (LLL), at the dental extraction site of rats with the main risk factors for the occurrence of medication-related osteonecrosis of the jaws (MRONJ). Twenty-eight senescent rats were distributed in four experimental groups: VEH, VEH-aPDT, ZOL and ZOL-aPDT. The treatment protocol lasted 7 weeks. One day before the beginning of this protocol, a cotton ligature was installed around the mandibular first molar left to induce experimental periodontitis (EP). In the VEH and VEH-aPDT groups, the rats received intraperitoneal injections of 0.45 ml of 0.9% sodium chloride solution (vehicle) every three days. In the ZOL and ZOL-aPDT groups, the rats received 0.45 ml of the vehicle plus 100 µg / Kg of zoledronate every three days. Three weeks after the beginning of the treatment protocol, the ligature was removed and extraction of the mandibular first molar left was performed. In the VEH and ZOL groups, no local treatment was performed at the tooth extraction site. In the VEH-aPDT and ZOL-aPDT groups, aPDT sessions were performed at 0, 2, and 4 days after extraction. For aPDT, 300µl of BuTB was deposited on the dental extraction site (0.5mg / ml; pre-irradiation time, 60s), followed by irradiation with low-level laser (laser: InGaAIP; 660nm; 35mW; 74.2J / cm²; 60s). After 28 postoperative days, euthanasia was performed. The hemimandibles were properly processed to ensure that at the tooth extraction site: 1) clinical analysis; 2) histological analysis of tissue repair; 3) histometric analysis of the Percentage of Neoformed Bone Tissue (PNFBT); 4) histometric analysis of the Percentage of NonVital Bone Tissue (PNVBT) and; immunohistochemical analysis of TRAP-positive cells. The data were submitted to statistical analysis with a 5% significance level. The ZOL and ZOL-aPDT groups showed less TRAP-positive cells when compared with the VEH and VEH-aPDT groups. The ZOL group showed great compromise in the tissue repair process, consistent with MRONJ. The groups VEH, VEH-aPDT and ZOL-aPDT presented a favorable tissue repair process at the dental extraction site. In the ZOL group, the PNFBT at the tooth extraction site was lower than in the VEH, VEH-aPDT and ZOL-aPDT groups. In the ZOL group, PNVBT was higher than in the VEH, VEHaPDT and ZOL-aPDT groups. In the ZOL-aPDT group, PNVBT was higher than in the VEH and VEH-aPDT groups. The use of multiple aPDT sessions, using BuTB and LLL, at the dental extraction site of senescent rats treated with a high dose of zoledronate proved to be a safe and effective therapeutic strategy to prevent the occurrence of MRONJ after tooth extraction(AU)

Prevention and treatment of oral adverse effects of antiresorptive medications for osteoporosis - A position paper of the Brazilian Society of Endocrinology and Metabolism (SBEM), Brazilian Society of Stomatology and Oral Pathology (Sobep), and Brazilian Association for Bone Evaluation and Osteometabolism (Abrasso)

ABSTRACT Antiresorptive therapy is the main form of prevention of osteoporotic or fragility fractures. Medication-related osteonecrosis of the jaw (MRONJ) is a relatively rare but severe adverse reaction to antiresorptive and antiangiogenic drugs. Physicians and dentists caring for patients taking these drugs and requiring invasive procedures face a difficult decision because of the potential risk of MRONJ. The aim of this study was to discuss the risk factors for the development of MRONJ and prevention of this complication in patients with osteoporosis taking antiresorptive drugs and requiring invasive dental treatment. For this goal, a task force with representatives from three professional associations was appointed to review the pertinent literature and discuss systemic and local risk factors, prevention of MRONJ in patients with osteoporosis, and management of established MRONJ. Although scarce evidence links the use of antiresorptive agents in the context of osteoporosis to the development of MRONJ, these agents are considered a risk factor for this complication. Despite the rare reports of MRONJ in patients with osteoporosis, the severity of symptoms and impact of MRONJ in the patients' quality of life make it imperative for health care professionals to consider this complication when planning invasive dental procedures.

Osteonecrosis de los maxilares asociada a medicamentos: revisión de la literatura y propuesta para la prevención y manejo / Osteonecrosis of the jaws

Medication-related osteonecrosis of the jaw is a disease where there is necrotic bone exposed or that can be explored by means of a fistula in the maxillofacial region. It has been associated with the use Biphosphonates and denosumab for osteoporosis. Although its etiology is unclear, it may be related to a decrease in bone turnover produced by these drugs, rendering the bone more prone to generate cell necrosis during invasive dental procedures, especially in the posterior region of the jaw. There is no consensus about the prevention and treatment of this condition. The aim of this paper is to present a review of the literature with the main characteristics of osteonecrosis of the jaws associated with drugs, together with a proposal for prevention and treatment for these patients.

Osteonecrosis de los maxilares asociada a medicamentos (ONMM): guía redactada por expertos invitados por la Asociación Argentina de Osteología y Metabolismo Mineral y por la Sociedad Argentina de Osteoporosis / Medication-related osteonecrosis of the jaw (MRONJ): guideline prepared by experts invited by the Argentine Association of Osteology and Mineral Metabolism, and the Argentine Society for Osteoporosis

La osteonecrosis maxilar asociada a medicamentos (ONMM=MRONJ como se conoce en la literatura en inglés) se define como un área ósea expuesta al medio bucal con más de ocho semanas de permanencia, en pacientes tratados con antirresortivos y/o antiangiogénicos y sin antecedentes de radioterapia en cabeza y cuello. Las fracturas ocasionan una morbimortalidad significativa y los antirresortivos son drogas eficaces y seguras para prevenirlas. Se utilizan principalmente en osteoporosis, pero también en enfermedades oncológicas como mieloma múltiple o metástasis óseas de tumores sólidos. La posología varía según el contexto clínico, siendo mayor la dosis y frecuencia de administración en oncología. Los antirresortivos actualmente más utilizados son los bifosfonatos (BF) y el denosumab (Dmab). Si bien los BF persisten largo tiempo en el tejido óseo, el Dmab tiene un mecanismo de acción reversible y su suspensión abrupta conlleva importante pérdida de masa ósea y riesgo aumentado de fracturas vertebrales múltiples. Ninguna droga puede ser suspendida ni espaciada sin autorización médica, dado que no es de competencia del odontólogo. El diagnóstico presuntivo de ONMM debe ser confirmado clínicamente por un odontólogo, quien solicitará imágenes radiológicas para establecer el estadio de la lesión. La anamnesis correcta permite establecer un diagnóstico diferencial entre ONMM, osteomielitis y osteorradionecrosis. La presentación clínica es variable y puede mostrar distintos estadios. La mayoría de los casos están precedidos por un procedimiento quirúrgico odontológico. Suele ser asintomática, aunque puede haber dolor si se localiza cerca de una estructura neuronal. La localización es variable: 62,3% se produce en el maxilar inferior. La incidencia de ONMM es baja, en un rango de 0,001 a 0,01% y tiene relación con las dosis y el tiempo de administración. La remoción de caries, la operatoria dental, la endodoncia y la rehabilitación protética fija o removible no se asocian a riesgo de ONMM. Con menos de 3 años de tratamiento antirresortivo se pueden efectuar terapéuticas quirúrgicas como exodoncias, apicectomías, cistectomías, tratamientos periodontales de raspaje y alisado subgingival sin riesgo. Con más de 3 años se aconseja evitar la realización de exodoncias y manipulación de tejido óseo. Ante la necesidad de realizar un procedimiento odontológico, no hay evidencia que avale que la suspensión transitoria del tratamiento antirresortivo pueda reducir el riesgo. Tampoco la medición de marcadores de remodelado óseo aporta datos de utilidad. Existen pocos datos en la literatura sobre la colocación de implantes dentales en pacientes que reciben drogas antirresortivas en dosis bajas; si bien existe ONMM asociada, su incidencia sería baja. Antes de iniciar un tratamiento antirresortivo se recomienda realizar interconsulta con el odontólogo para evaluar potenciales necesidades quirúrgicas. Quienes reciben antirresortivos deben realizar controles orales periódicos (semestrales) y, ante cualquier síntoma compatible con un estadio incipiente de ONMM, deben consultar a su odontólogo. El trabajo conjunto del médico y el odontólogo puede prevenir la aparición de la ONMM, un evento infrecuente, pero que puede generar elevada morbilidad en los pacientes. La comunicación fluida entre profesionales tenderá a evitar no solo la incertidumbre y desconfianza de los pacientes, sino también que se produzcan lesiones con la consecuente necesidad de tratamientos de mayor complejidad. (AU)

Medication-Related Osteonecrosis of the Jaw (MRONJ) is defined as a bone area exposed to the oral environment lasting more than eight weeks, in patients treated with antiresorptive and/or antiangiogenic drugs and without a history radiation therapy to the head and neck. Fractures cause significant morbidity and mortality, and antiresorptives are effective and safe drugs to prevent them. They are used to treat not only osteoporosis but also oncological diseases such as multiple myeloma or bone metastases from solid tumors. The dosage varies according to the clinical context; doses and frequencies of administration are higher in oncology. The most commonly used antiresorptive medications are bisphosphonates (BP) and denosumab (Dmab). Whereas BP persist for a long time in bone tissue, Dmab has a reversible mechanism of action and its discontinuation leads to significant loss of bone mass and an increased risk of multiple vertebral fractures. No drug can be suspended or spaced without medical authorization. Dentists should not take decisions about antiresorptive prescription. The presumptive diagnosis of MRONJ must be clinically confirmed by a dentist, who will order radiological studies to establish the stage of the injury. The correct anamnesis helps differentiate MRONJ from osteomyelitis and osteoradionecrosis. Clinical presentation is variable and can present different stages. Most of the cases are preceded by a dental surgical procedure. Usually MRONJ is asymptomatic although patients may feel pain if it is located near a neuronal structure. The location is variable: 62.3% occurs in the lower jaw. The incidence of MRONJ is low, in the range of 0.001 to 0.01%, and is related to the dose and time of administration. Caries removal, dental surgery, endodontics, fixed or removable prosthetic rehabilitation are not associated with risk of MRONJ. With less than 3 years of antiresorptive treatment, surgical therapies such as extractions, apicectomies, cystectomies, periodontal scaling treatments and subgingival smoothing can be performed without risk. With more than 3 years, it is advisable to avoid performing extractions and manipulating bone tissue. Given the need to perform a dental procedure, there is no evidence to support that the temporary suspension of antiresorptive treatment can reduce the risk. Nor does the measurement of bone turnover markers provide useful information. There are few data in the literature on the placement of dental implants in patients receiving antiresorptive drugs at low doses; although there might be an associated risk of MRONJ, its incidence appears to be low. Before starting antiresorptive treatment, consultation with the dentist is recommended to evaluate potential surgical needs. Patients receiving treatment with antiresorptive agents should undergo periodic oral controls (every six months) and in the event of any symptoms compatible with an early MRONJ stage, they should consult their dentists. The collaboration between physician and dentist can prevent the appearance of MRONJ, that is an infrequent event, but can generate high morbidity in patients. Fluid communication between professionals will tend to avoid, not only the uncertainty and distrust of patients, but also the occurrence of injuries needing complex treatments. (AU)

Pathogenesis and multidisciplinary management of medication-related osteonecrosis of the jaw / 国际口腔科学杂志·英文版

Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of bone-modifying agents and inhibits angiogenesis agents. Although the pathogenesis of MRONJ is not entirely clear, multiple factors may be involved in specific microenvironments. The TGF-β1 signalling pathway may have a key role in the development of MRONJ. According to the clinical stage, multiple variables should be considered when selecting the most appropriate treatment. Therefore, the prevention and management of treatment of MRONJ should be conducted in patient-centred multidisciplinary team collaborative networks with oncologists, dentists and dental specialists. This would comprise a closed responsibility treatment loop with all benefits directed to the patient. Thus, in the present review, we aimed to summarise the pathogenesis, risk factors, imaging features, clinical staging, therapeutic methods, prevention and treatment strategies associated with MRONJ, which may provide a reference that can inform preventive strategies and improve the quality of life for patients in the future.

Preventive and therapeutic effects of relaxin on bisphosphonate related osteonecrosis of the jaw: an experimental study in rats / Efeitos preventivos e terapêuticos da relaxina na osteonecrose da mandíbula relacionada a bisfosfonatos: um estudo experimental em ratos

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)

Agentes antirresortivos y antiangiogénicos y su relación con la osteonecrosis de los maxilares asociada a medicamentos / Antiresorptive and antiangiogenic agents and their relationship with osteonecrosis of the jaws related to medication

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)

Les ostéonécroses maxillo-mandibulaires induites par les bisphosphonates : à propos de 36 cas

L'ostéonécrose maxillo-mandibulaire induite par les bisphosphonates (ONBP) est un effet indésirable décrit pour la 1 ère fois en 2003. La gestion de cette pathologie reste difficile compte tenu de la gravité de cette pathologie et la complexité de ses lésions. A travers une étude marocaine sur 36 cas, les auteurs soulignent l'intérêt des mesures préventives et l'importance d'études prospectives avec un échantillonnage significatif, afin de mieux préciser les facteurs de risque associés à la survenue d'une ONBP et de déterminer les catégories des patients à risque nécessitant une adaptation de la prise en charge

Prevención de osteonecrosis asociada a medicamentos y ensayo clínico multicéntrico, Facultad de Odontología, Universidad de Buenos Aires / Prevention of drug-related osteonecrosis and multicentric clinical trial, School of Dentistry, University of Buenos Aires

La osteonecrosis asociada a medicamentos (ONAM) es un efecto adverso poco frecuente pero potencialmente serio que afecta a pacientes que reciben o recibieron tratamiento con drogas antirresortivas o antiangiogénicas. A partir de una revisión narrativa de la literatura, el presente artículo aporta conceptos básicos e información actualizada acerca de incidencia, factores de riesgo y prevención de ONAM desde la perspectiva de la Práctica Basada en la Evidencia. Además pone en conocimiento a la comunidad profesional de la Facultad de Odontología de la Universidad de Buenos Aires acerca de las actividades de investigación clínica llevadas a cabo en este área en la Cátedra de Cirugía y Traumatología Buco-Máxilo-Facial I de nuestra casa de estudios (AU)

Medicine related osteonecrosis of the jaws (MRONJ) is a rare but potentially serious side effect experienced by patients receiving treatment with antiresorptive or antiangiogenic drugs. Through a narrative review of the literature, this paper provides basic concepts and updated data about incidence, risk factors and prevention of MRONJ from the Evidence Based Practice perspective. It also informs the professional community of the School of Dentistry of the University of Buenos Aires about the clinical research activities carried out in this area in the Oral and Maxillofacial Surgery I Department (AU)

Protocolo clínico de pacientes con historia de uso de bifosfonatos / Clinical protocol for patients with history of use of biphosphonates

Los bifosfonatos son un grupo de medicamentos que se han estadoutilizando en los últimas décadas para el tratamiento de padecimientos que se caracterizan por destrucción o pérdida ósea, cáncer, menopausiay enfermedades óseas no malignas por lo cual es muy importante realizar una amplia y correcta historia clínica para evitar las posibles complicaciones en la fase de cicatrización de los procedimientos quirúrgicos odontológicos. Al atender a un paciente con antecedentes de haber usado este medicamento, se debe conocer la farmacocinética y farmacodinamia para poder planificar el tratamiento pre-, trans- y postoperatorio de los pacientes que serían sometidos principalmente a extracciones dentarias, por lo cual actualmente se puede clasificar a este tipo de pacientes de acuerdo a los resultados de la prueba de laboratorio de la proteína C-telopéptido. Una vez determinado el riesgo del paciente de acuerdo a los resultados de dicha prueba se puede realizar un plan de tratamiento más seguro y eficaz para el paciente en donde se tomen las precauciones necesarias para no evitar una osteonecrosis mandibular o maxilar. Se presenta un caso clínico de un paciente con historia de bifosfonatos en donde se hace el tratamiento de acuerdo a los lineamientos actuales para tratar a este tipo de pacientes.

Bisphosphonates are a group medications that have been used for the last decades for the treatment of conditions that are characterized bybone loss or destruction, cancer, menopause and non-malignant bone diseases, which is why it is very important to make a broad and correctmedical history to avoid the possible complications in the healing phaseof dental surgical treatments. When treating a patient with a history of this drug we should know the pharmacokinetics and pharmacodynamics to be able to plan the pre, trans and postoperative treatment of patientsmainly subject to dental extractions, which is why currently this type ofpatients can be classified according to the results of the laboratory testof the C-Telopeptide protein. Once the patient’s risk has been determined according to the results of this test, an effective and safe treatmentplan can be started for the patient in which the necessary precautionsare taken to not develop a mandibular or maxillary osteonecrosis. We present a case of a patient with a history of bisphosphonates wherethe treatment is done according to the current guidelines for treatingthis type of patients.

Desarrollo de un modelo experimental de osteonecrosis de maxilar asociada al tratamiento crónico con aminobisfosfonatos / Experimental model of osteonecrosis of the jaw associated to chronic treatment with aminobisphosphonates

La osteonecrosis de maxilar asociada a aminobisfosfonatos (BRONJ) constituye un efecto secundario del tratamiento crónico con los más potentes. Un modelo experimental permitiría determinar la patogenia de dicha alteración. La oveja presenta características orales y del metabolismo óseo similar al humano y permite realizar manipulaciones bucales. Se evaluaron cambios clínicos, remodelación ósea y masa ósea maxilar en ovejas hembras adultas tratadas con zolendronato (ZOL), durante 22 meses y utilizando dosis equivalente al tratamiento de neoplasias. Seis ovariectomizadas (OVX) recibieron ZOL; 5 OVX y 4 SHAM (control) recibieron solución fisiológica. Al inicio, 4 y 22 meses se evaluó calcemia, fosfatemia, crosslaps (CTX) y fosfatasa alcalina ósea. Al final, se evaluó contenido mineral óseo de la hemimandíbula superior (CMO: mg/cm2). Al final del estudio, CTX disminuyó significativamente en ZOL (p<0,05) sin diferencias entre SHAM y OVX. En maxilar, los contenidos de Ca y P (g/g tejido) y CMO (g/cm2 ) disminuyeron en OVX vs. SHAM (p<0,05) y solo Ca y CMO respecto de ZOL (p<0,05). ZOL incrementó el contenido de Ca y CMO, mientras que el de P permaneció significativamente disminuido respecto de SHAM. La sobrevida en SHAM y OVX fue del 100% y en ZOL 77% (2 muertes); 2 ovejas del grupo ZOL presentaron necrosis de maxilar. Conclusiones: fue posible obtener desarrollo de BRONJ por tratamiento crónico con ZOL, el cual redujo notablemente la resorción y, según la relación Ca/P, posiblemente haya afectado la mineralización ósea. (AU)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of chronic treatment with the most powerful aminobisphosphonates (BPs). An experimental animal model would allow to determine the pathogenesis of this complication. Ewes exhibit similar oral cavity characteristics and bone metabolism as humans, and they are suitable for oral cavity interventions. We examined herein the clinical manifestations, bone remodeling status, and maxillary bone mass in adult female ewes treated with zoledronate (ZOL) for 22 months. Six ovariectomized (OVX) ewes received ZOL; and 5 OVX and 4 SHAM animals received saline solution. At the start of the experiment, and at the 4 and 22 month-time points serum Ca, P, crosslaps (CTX), and bone alkaline phosphatase were measured. Bone mineral content (BMC) of the superior hemimandible was measured at the end of the experiment. At this time point, CTX was significantly decreased only in the ZOL group (p<0.05). Ca and P content (g/g tissue) and BMC in the mandible were significantly decreased in the OVX group compared to SHAM animals (p<0.05) and only Ca content and BMC were decreased when compared to ZOL (p<0.05). ZOL treatment increased the Ca content and BMC, whereas the P content remained low compared to the SHAM group (p<0.05). All ewes from the SHAM and OVX groups and 77% of the animals from the ZOL group survived until the end of the experiment, whereas two ewes of ZOL group exhibited BRONJ. Conclusion: under our experimental conditions, it was possible to induce BRONJ by the chronic ZOL administration, which in turn induced a high reduction in bone resorption as well as possibly impaired bone mineralization, based on the Ca/P ratio in the mandible. (AU)

Treatment of postmenopausal osteoporosis: a literature-based algorithm for use in the public health care system / Tratamento da osteoporose pós-menopáusica: um algoritmo baseado na literatura para uso no sistema público de saúde

ABSTRACT Bisphosphonates are considered first-line agents in the treatment of postmenopausal osteoporosis based on extensive experience of use, safety, and proven efficacy in reducing vertebral, non-vertebral and femur fractures. However, post-marketing reports based on the treatment of millions of patients/year over lengthy periods of time have revealed the occurrence of initially unexpected adverse effects, such as osteonecrosis of the jaw and atypical femoral fracture, leading to the restriction of treatment duration with bisphosphonates by global regulatory agencies. However, despite the association between these effects and bisphosphonates, this risk should be analyzed in the context of osteoporosis treatment, alongside the benefit of preventing osteoporotic fractures and their clinical consequences. Therefore, we consider it plausible to discuss the restriction to the use of bisphosphonates, possible indications for prolonged treatment and alternative therapies following the suspension of this drug class for patients with persistent high risk of fracture after initial treatment, especially considering the problems of public health funding in Brazil and the shortage of drugs provided by the government. Thus, to standardize the treatment of osteoporosis in the public health care system, we aim to develop a proposal for a scientifically-based pharmacological treatment for postmenopausal osteoporosis, establishing criteria for indication and allowing the rational use of each pharmacological agent. We discuss the duration of the initial bisphosphonate treatment, the therapeutic options for refractory patients and potential indications of other classes of drugs as first-choice treatment in the sphere of public health, in which assessing risk and cost effectiveness is a priority.

RESUMO Com base na vasta experiência de uso, segurança e eficácia comprovada na redução de fraturas vertebrais, não vertebrais e femorais, os bisfosfonatos são considerados agentes de primeira linha no tratamento da osteoporose pós-menopáusica. No entanto, os relatos pós-venda baseados no tratamento de milhões de pacientes/ano durante períodos prolongados de tempo revelaram a ocorrência de efeitos adversos inicialmente inesperados, como osteonecrose da mandíbula e fratura atípica do fêmur. Isso levou as agências reguladoras globais a restringirem a duração do tratamento com bisfosfonatos. No entanto, apesar da associação entre esses efeitos e os bisfosfonatos, esse risco deve ser analisado no contexto do tratamento da osteoporose, paralelamente ao benefício na prevenção de fraturas osteoporóticas e suas consequências clínicas. Portanto, considera-se plausível discutir a restrição ao uso dos bisfosfonatos, possíveis indicações para o tratamento prolongado e terapias opcionais após a suspensão dessa classe de fármaco para pacientes com alto risco persistente de fratura após o tratamento inicial, especialmente se considerarmos os problemas financeiros de saúde pública no Brasil e a escassez de fármacos fornecidos pelo governo. Assim, para padronizar o tratamento da osteoporose no sistema público de saúde pretende-se desenvolver uma proposta de tratamento farmacológico cientificamente fundamentada para a osteoporose pós-menopáusica, estabelecer critérios de indicação e permitir o uso racional de cada agente farmacológico. Discutem-se a duração do tratamento inicial com bisfosfonatos, as opções terapêuticas para pacientes refratários e potenciais indicações de outras classes de medicamentos como tratamento de primeira linha na esfera da saúde pública, em que a avaliação do risco e custo-efetividade é uma prioridade.

Collagen sponge and rhBMP-2 improve socket healing in rats treated with zoledronic acid

Abstract The aim of the present study was to evaluate the possible use of a commercial absorbed collagen sponge and bone morphogenetic protein (BMP) for the prevention of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in rats. Twenty rats received intraperitoneal injections of 0.1-mg/kg of zoledronic acid three times a week for eight weeks before the extraction of both maxillary first molars after eight weeks. A collagen sponge (experimental group 1) and a collagen sponge with recombinant human BMP-2 (experimental group 2) were applied to the right extraction sockets of ten rats each. The 20 left extraction sockets (control groups 1 and 2) were left unprotected. After eight weeks, all rats were euthanized. Macroscopic analysis, micro-computed tomography (CT) analysis, and histological analysis were performed. There was a significant difference in the bone density between the control and experimental groups on micro-CT analysis. Impaired healing of the extraction sockets, indicating BRONJ, was observed in 80% of control group 1, 90% of control group 2, 30% of experimental group 1, and 20% of experimental group 2. The collagen sponge with/without BMP used for protecting the extraction socket had the potential for a positive effect in reducing the incidence of bisphosphonate-related osteonecrosis of the jaw in rats.

Bisphosphonate associated osteomyelitis of the jaw in patients with bony exposure: prevention, a new way of thinking

Objective There is strong evidence of a link between the use of systemic bisphosphonates (BPs) and osteonecrosis of the jaw, especially in cancer patients. Among risk factors for BRONJ, tooth extraction and immune suppressive drugs seem to have significant role on bone healing. Therefore, the importance of these parameters in development of BRONJ was reviewed in this retrospective study in two maxillofacial surgery units. Material and Methods From 2007 to 2012, 46 patients on bisphosphonate who had developed oral bony lesions participated in this study. The pharmacological exposure, comorbidities, maxillofacial findings, types of treatment and outcome data were collected from clinical and radiological records. Results The most frequently used BP was alendronate (67%). Tooth extraction was reported in 61% of patients with BRONJ. Systemic corticosteroids were prescribed in 35 cases (76%) as an adjuvant for BP. Patients on corticosteroids had a lower probability of bony lesion healing (p<0.05) than patients without corticosteroids. Of the 46 patients who underwent conservative treatments, only ten were completely healed (21%). Conclusions Beside tooth extraction, corticosteroids were shown to be an implant risk factor for low rate of bone healing and hence the development of BRONJ. The outcome of conservative treatment was uncertain and this emphasizes the importance of prevention. .