Osteonecrosis mandibular: hallazgos clínicos e imagenológicos en un paciente tratado con denosumab / Mandibular osteonecrosis: clinical and imaging findings in a patient treated with denosumab

Introducción: La administración de bifosfonatos y medicamentos antiangiogénicos en pacientes con cáncer es un esquema terapéutico usual en oncología. Existen reportes de osteonecrosis de los maxilares en pacientes sometidos a este esquema de tratamiento, luego de realizar un procedimiento dental invasivo. Objetivo: A partir de las características clínicas e imagenológicas de la patología, ilustrar al odontólogo sobre los medicamentos para el tratamiento del cáncer, susceptibles de generar osteonecrosis de los maxilares. Presentación de caso: Paciente masculino de 89 años, con cáncer de próstata tratado con denosumab, que desarrolló osteonecrosis del maxilar inferior posterior a una extracción dental. Es de vital importancia que el odontólogo identifique los medicamentos, factores de riesgo y las medidas para minimizar el riesgo de osteonecrosis de los maxilares en pacientes susceptibles(AU)

Introduction: The administration of bisphosphonates and antiangiogenic drugs in cancer patients is a usual therapeutic scheme in oncology. There are reports of osteonecrosis of the jaws in patients undergoing this treatment scheme, after performing an invasive dental procedure. Objective: Show the dentist from the clinical and imaging characteristics of the pathology on the drugs for the treatment of cancer sensitivity to generate osteonecrosis of the jaws. Case presentation: An 89-year-old male patient with prostate cancer treated with denosumab developed osteonecrosis of the lower jaw after tooth extraction. It is vitally important that the dentist identifies medications, risk factors and measures to minimize the risk of osteonecrosis of the jaws in sensitivy patients(AU)

Osteonecrosis de los Maxilares, Puesta al Día

RESUMEN: La osteonecrosis también conocida como una necrosis avascular del hueso, es una condición degenerativa producida por la pérdida en la irrigación sanguínea, debido a la toxicidad directa en los tejidos óseos provocadas por quimioterapia, radioterapia, daño térmico, fumar y en la última década con la aparición de medicamentos como los bifosfonatos (BF), denosumab y medicamentos antigiogénicos, con los cuales hemos ido conociendo más sobre esta patología. La principal hipótesis de la fisiopatología de esta enfermedad es la inhibición de la angiogénesis, pero también se considera como hipótesis la toxicidad de los tejidos blandos o la disfunción adquirida de la inmunidad. En el año 2003 fue relatada por primera vez la relación entre BF y osteonecrosis maxilar (ONM). Ese mismo año fue descrito que pacientes con mieloma múltiple que recibían pamidronato podrían desarrollar necrosis avascular de los maxilares. Otras publicaciones informaban sobre pacientes que requerían tratamiento para necrosis ósea intra-oral de ocurrencia espontánea después de extracciones dentales o trauma oral. La primera denominación a esta patología fue (BRONJ) por sus siglas en inglés, se refería a ONM relacionada a BF. En 2014 la Asociación Americana de Cirujanos Orales y Maxilofaciales (AAOMS) publicó una nueva definición (position paper) renombrándolo como MRONJ (osteonecrosis de los maxilares relacionada a medicamentos) ONMRM. El rol en la identificación de pacientes con riesgo de ONMRM es fundamental. Los estudios han demostrado que el riesgo de desarrollar la afección se puede reducir sustancialmente si los pacientes son evaluados por un profesional dental y se toman medidas preventivas. La presente revisión narrativa realiza un recorrido desde la historia, los medicamentos involucrados, y diferentes estrategias de tratamientos propuestos, haciendo hincapié en la conducta que debemos seguir los cirujanos dentistas para enfrentar estos casos de forma temprana y prevenir su evolución.

ABSTRACT: Osteonecrosis is also known as avascular necrosis of the bone, it is a degenerative condition produced by the loss of blood flow, due to direct toxicity in the bone tissues caused by chemotherapy, radiotherapy, thermal damage, smoking and in the last decade with the arrival of drugs such as bisphosphonates (BP), denosumab and antigiogenic drugs we have been learning more about this pathology. The main hypothesis of the pathophysiology of this disease is the inhibition of angiogenesis, but soft tissue toxicity or acquired immunity dysfunction are also considered as hypotheses. In 2003, the relationship between BP and osteonecrosis of the jaws (ONJ) was reported for the first time. In the same year it was described that multiple myeloma patients receiving pamidronate could develop avascular necrosis of the jaws. Other publications reported about patients requiring treatment for spontaneously intra-oral bone necrosis after dental extractions or oral trauma. The first name for this pathology was (BRONJ) for its English acronym, it referred to ONJ related to BF. In 2014 the American Association of Oral and Maxillofacial Surgeons (AAOMS) published a new definition (position paper) renaming it MRONJ (drug-related osteonecrosis of the jaws) ONMRM. The role of identifying patients at risk of ONMRM is fundamental. Studies have shown that the risk of developing the condition can be substantially reduced if patients are evaluated by a dental professional and preventive measures are taken Exposure of bone or fistula that can be probed down to the bone in the maxillofacial region that persists for more than 8 weeks, with these conditions it is considered that there is a diagnosis of ONMRM This narrative review takes a journey from history, the drugs involved, and different proposed treatment strategies, emphasizing the behavior that dental surgeons must follow to face these cases early and prevent their evolution.

Caracterización clínico-terapéutica de pacientes diagnosticados con Osteonecrosis en los maxilares relacionada con medicación / Clinical and therapeutic characterization of patients diagnosed with medication-related osteonecrosis of the jaws

Introducción: La osteonecrosis en los maxilares por medicación es una afección asociada al tratamiento con bifosfonatos, antireabsortivos y antiangiogénicos. Objetivo: Caracterizar clínica y terapéuticamente los pacientes diagnosticados de Osteonecrosis en los Maxilares relacionada con medicación. Material y Método: Se realizó una serie de casos de 19 pacientes, la totalidad de los diagnosticados con la entidad en el Servicio de Cirugía Maxilofacial. Facultad de Estomatología Raúl González Sánchez, enero 2018-enero 2019. Se identificó severidad, factores de riesgo y se estandarizó tratamiento que incluyó la curación con aceite ozonizado y la aplicación de láser infrarrojo. Se evaluó el tratamiento a los 90 días. Se operacionalizaron las variables: sexo, tipo de medicación, vía y tiempo de administración, localización y evaluación al tratamiento. Resultados: La edad promedio de los pacientes fue 69±8,5 años, un 52,63 por ciento fueron masculinos, el zolendronato fue el agente mas asociado en el 78,95 por ciento de los casos, la enfermedad periodontal fue el factor local preponderante (57,89 por ciento), la localización mandibular postero lateral y el estadio evolutivo 2 predominaron en el 63,16 por ciento y 52,63 por ciento de las lesiones. El 78,94 por ciento de los casos presentó evolución satisfactoria a los 90 días. Conclusiones: La medicación con bifosfosfonatos parenterales predominantemente con el zolendronato, fue la causa principal de las osteonecrosis, las cuales prevalecieron en el sector postero lateral de mandíbula y con el estadio 2. La variante de tratamiento de curación con aceite ozonizado e irradiación con láser fue la más implementada. Los valores de lesiones resueltas y mejoradas a los 90 días fueron satisfactorios(AU)

Introduction: Medication-related osteonecrosis of the jaws is an affection associated with the treatment with bisphosphonates, antiresorptive agents or antiangiogenic medications. Objective: To perform a clinical and therapeutic characterization of patients with the diagnosis of medication-related osteonecrosis of the jaws. Material and Method: A case series of a total of 19 patients with the diagnosis of medication-related osteonecrosis of the jaws was carried out in the Department of Dental and Maxillofacial Surgery of ¨Raúl González Sánchez¨ Dental School of Havana from January 2018 to January 2019. The severity and risk factors were identified and the treatment including the healing with ozone oil and the application of infrared laser was standardized. The patients were evaluated in the 90 days after treatment. The operationalization of variables included: sex, type of medications, ways and time of administration, localization, and evaluation of treatment. Results: The average age of patients was 69±8,5 years and 52,63 percent of them were male. Zolendronate was the most associated agent in 78,95 percent of cases. Periodontal disease was the most identified local factor (57, 89 percent). The posterolateral area of the mandible and stage 2 disease evolution predominated in 63,16 percent and 52, 63 percent of lesions, respectively. Also 78, 94 percent of cases had a satisfactory evolution in the 90 days after treatment. Conclusions: The administration of intravenous bisphosphonates, particularly Zolendronate, was the main cause of osteonecrosis. These lesions were mainly located in the posterior lateral area of the mandible and presented stage 2 disease evolution. Healing with ozone oil and application of infrared laser was the most implemented alternative treatment. The values of resolved and improved lesions were satisfactory in the 90 days after treatment(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.

Fundamentos de elección terapéutica: osteonecrosis maxilar asociada a drogas antirresortivas (MRONJ) / Fundamentals of therapeutic choice: anti-resorptive drug-related maxillary osteonecrosis (MRONJ)

La acción terapéutica favorable que los antirresortivos (bifosfonatos BPs, denosumab DS) y drogas antiangiogénicas ocasionan en el tejido óseo en aquellos pacientes que presentan como causa etiológica cáncer o discrasias óseas incluyen hipercalcemias malignas o ­si requieren el consumo de dicha droga a baja concentración­ como ser: osteoporosis, osteopenia, enfermedad de Paget, displasia fibrosa, Osteogénesis Imperfecta. (1) La presente actualización pretende relacionar el tratamiento odontológico con prescripción crónica y drogas antirresortivas, para lo cual American Association of Oral and Maxillofacial Surgeons AAOMS: define el concepto de Osteonecrosis Maxilar Asociada a drogas Antirresortivas (MRONJ) como: «Área ósea necrótica expuesta al medio bucal con más de ocho semanas de permanencia, en presencia de tratamiento crónico con bifosfonatos en ausencia de radioterapia en cabeza y cuello¼. La AAOMS estableció los siguientes grupos de acuerdo con sus características clínicas en 4 estadios (0, 1 ,2 y 3) de acuerdo con el aspecto clínico y radiológico de la lesión osteonecrótica. Estadío 0: lesión osteonecrótica sin evidencia de hueso necrótico en pacientes bajo consumo de drogas antirresortivas. Estadío 1: lesión osteonecrótica con signos clínicos y ausencia de sintomatología clínica. Estadío 2: lesión osteonecrótica con signo y sintomatología clínica evidente. Estadío 3: lesión osteonecrótica con signo y sintomatología evidente que compromete a estructuras nobles: fracturas patológicas, anestesia del nervio dentario inferior, comunicación buco-nasal, comunicación buco-sinusal, fístulas cutáneas (2) (AU)

It is known the favourable action which antiresorptive (Bisphosphonates BPs, Denosumab: DS) and Antiangiogenic drugs produce in bone tissue. High concentrations are primarily used as an effective treatment in the management of cancer-related disorders, including hypercalcemia of malignant. Besides, low concentrations are used for other metabolic bone diseases including Osteoporosis, Osteopenia, Paget's Disease, Fibrous Dysplasia, Imperfect Osteogenesis. (1) The update relate relationship between dentistry and chronic treatment with antiresorptive drugs. According to the American Association of Oral and Maxillofacial Surgeons (AAOMS), MRONJ is defined as exposed or necrotic bone in the maxillofacial region that has persisted for more than 8 weeks in association with current or previous BPs or DS therapy and with a lack of head and neck radiotherapy. AAOMS divided the MRONJ into 4 stages (0,1, 2 and 3) according to the clinical and radiological aspect of the osteonecrotic lesion: Stage 0: osteonecrotic lesion without sign-pathognomonic evidence of osteonecrosis. Stage 1: osteonecrotic lesion with clinical signs and absence of clinical symptoms. Stage 2: osteonecrotic lesion with sign and evident clinical symptoms. Stage 3: osteonecrotic lesion with signs and evident symptoms that involve noble structures: pathological fractures, anaesthesia of the lower dental nerve, oral-nasal communication, oral-sinus communication, skin fistulas (2) (AU)

Knowledge, attitudes, and practices of dentists in Colombia regarding bisphosphonate-induced osteonecrosis of the jaws / Conhecimento, atitudes e práticas de dentistas na Colômbia sobre osteonecrose dos maxilares induzida por bisfosfonatos / Conocimientos, actitudes y prácticas de los odontólogos en Colombia respecto a la osteonecrosis de las mandíbulas inducida por bisfosfonatos

Abstract Introduction and objective: In order to provide proper dental management to patients who are under bisphosphonate therapy it is of critical importance that dentists perform a good anamnesis, a comprehensive clinical examination to asses for possible risk factors for bisphosphonate-induced osteonecrosis of the jaws (BIONJ). Although this issue has been explored in other parts of the world, in Colombia there is currently no scientific evidence to support it. Thus, the aim of this study was to compare knowledge, attitudes, and practices (domains) of general and specialist dentists regarding BIONJ. Materials and methods: Paper/online surveys that included questions about knowledge, attitudes, and practices regarding BIONJ were distributed and completed by 228 general dentists and 114 dental specialists in Colombia. Student's t-test was used to determine statistical difference between groups of dentists (P < 0.05). Results: The attitudes domain was removed from the analysis as it did not meet statistical criteria. Overall rate of BIONJ knowledge was 55.8%, being 65.3% and 50.7% for specialists and general dentists respectively. The difference between these groups was statistically significant (P = 0.0004). Overall rate of adequate practices was 38.4%, being 44.6% for dental specialists, and 35.1% for general dentists. The difference between these groups was statistically significant (P = 0.023). Conclusion: The level of knowledge and good practices regarding BIONJ in Colombia was greater and better in dental specialists than in general dentists. Those with higher knowledge scores suggested greater educational efforts to spread knowledge among dentists about BIONJ.

Resumen Introducción y objetivo: Para proporcionar un tratamiento odontológico adecuado a los pacientes que están bajo terapia con bisfosfonatos, es importante que los odontólogos realicen una buena anamnesis, un examen clínico integral para evaluar los posibles factores de riesgo de osteonecrosis de las maxilares inducida por bisfosfonatos (BIONJ). Aunque este tema ha sido explorado en otras partes del mundo, en Colombia actualmente no hay evidencia científica que lo respalde. Así, el objetivo de este estudio fue comparar el conocimiento, las actitudes y prácticas (dominios) de los odontólogos generales y especialistas con respecto a la BIONJ. Materiales y métodos: Encuestas físicas y digitales que incluían preguntas sobre conocimientos, actitudes y prácticas con respecto a BIONJ fueron distribuidas y llenadas por 228 odontólogos generales y 114 especialistas en Colombia. La prueba t de Student se usó para determinar la diferencia estadística entre grupos de odntólogos (P <0.05). Resultados: El dominio de actitudes se eliminó del análisis ya que no cumplía con los criterios estadísticos. La tasa general de conocimiento de BIONJ fue de 55,8%, siendo 65,3% y 50,7% para especialistas y odontólogos generales, respectivamente. La diferencia entre estos grupos fue estadísticamente significativa (P = 0,0004). La tasa general de prácticas decuadas fue del 38.4%, siendo 44.6% para los especialistas y 35.1% para los odontólogos generales. La diferencia entre estos grupos fue estadísticamente significativa (P = 0.023). Conclusión: El nivel de conocimiento y buenas prácticas con respecto a BIONJ en Colombia fue mayor y mejor en los odontólogos especialistas que en los generales. Aquellos con puntajes altos de conocimiento sugirieron mayores esfuerzos educativos en la difusión del conocimiento sobre BIONJ entre los odontólogos generales.

Resumo Introdução e objetivo: A fim de fornecer tratamento odontológico adequado aos pacientes sob terapia com bifosfonatos, é de importância crítica que os dentistas realizem uma boa anamnese, um exame clínico abrangente para avaliar possíveis fatores de risco para osteonecrose dos maxilares induzida por bisfosfonatos (BIONJ). Embora essa questão tenha sido explorada em outras partes do mundo, atualmente na Colômbia não há evidências científicas para apoiá-la. O objetivo deste estudo foi comparar conhecimentos, atitudes e práticas (domínios) de dentistas gerais e especialistas em osteonecrose dos maxilares induzida por bisfosfonatos (BIONJ). Materiais e métodos: Pesquisas em papel / on-line que incluíam perguntas sobre conhecimentos, atitudes e práticas relacionadas ao BIONJ foram distribuídas e concluídas por 228 dentistas gerais e 114 especialistas em odontologia na Colômbia. O teste t de Student foi utilizado para determinar a diferença estatística entre os grupos de dentistas (P <0,05). Resultados: O domínio de atitudes foi retirado da análise por não atender aos critérios estatísticos. A taxa geral de conhecimento do BIONJ foi de 55,8%, sendo 65,3% e 50,7% para especialistas e dentistas, respectivamente. A diferença entre esses grupos foi estatisticamente significante (P = 0,0004). A taxa geral de práticas adequadas foi de 38,4%, sendo 44,6% para especialistas em odontologia e 35,1% para dentistas em geral. A diferença entre esses grupos foi estatisticamente significante (P = 0,023). Conclusão: O nível de conhecimento e boas práticas sobre o BIONJ na Colômbia foi maior e melhor em especialistas em odontologia do que em dentistas em geral. Aqueles com maior pontuação de conhecimento sugeriram maiores esforços educacionais para difundir conhecimento entre os dentistas sobre o BIONJ.

Análise do processo de reparo alveolar em camundongos fêmeas senescentes 129/Sv-WT e 129/Sv 5-LOKO sob terapia com bifosfonato de alta potência / Alveolar bone repair of 129/Sv WT and 129/Sv 5LOKO female senescent mice under therapy with high potency bisphosphonate

O processo de senescência acarreta uma série de modificações fisiológicas com declínio das funções das atividades celulares e sistêmicas que se manifestam de maneira mais importante na população feminina pelo evento da menopausa, como a osteoporose. A fim de se minimizar tais efeitos, há a possibilidade de se utilizar medicamentos que diminuem o processo de remodelação óssea como os bifosfonatos nitrogenados (BF). Entretanto, o uso dessas drogas está intimamente relacionado ao desenvolvimento de osteonecrose dos maxilares (OM), principalmente quando associado a outros fatores de risco como as cirurgias bucais. Sabe-se que fisiologicamente a dinâmica do tecido ósseo depende também de eicosanóides derivados do metabolismo do ácido araquidônico (AA), como as enzimas cicloxigenase (COX) e 5 lipoxigenase (5LO). Deste modo, o objetivo do presente trabalho foi analisar o efeito BF ácido zoledrônico (ZL) e sua relação com o desenvolvimento da OM em camundongos fêmeas senescentes 129/Sv com e sem modificação genética para a enzima 5LO. Para tanto, foram utilizados 40 camundongos fêmeas senescentes 129/Sv, sendo 20 WT e 20 com alteração no gene 5LO (129 Alox5tm1Fun/J) (5LOKO), divididas em grupos: WT, tratadas com 0,01 ml de solução salina 0,9% estéril (SS) via intraperitoneal (IP) e ZL, tratadas com 250µg/Kg de ácido zoledrônico (ZL) IP diluído em solução salina estéril, ambas administradas 1 vez/semana por 7 semanas. Os grupos foram compostos por 5 animais cada (WT Controle ­ 7 e 21dias, WT ZL ­ 7 e 21 dias, 5LOKO Controle ­ 7 e 21 dias, 5LOKO ZL ­ 7 e 21dias), sendo as maxilas coletadas para análises em microCT, histopatológica, birrefringência, técnica imunohistoquímica e histomorfométricas. De modo geral, a microCT revelou deficiência significativa na microarquitetura óssea nos animais WT ZL em comparação com os demais. Do mesmo modo, a partir da análise histopatológica e de birrefringência da matriz colagenosa, observou-se padrão compatível com o desenvolvimento de OM no grupo WT ZL, com presença de infiltrado inflamatório intenso, atraso na neoformação óssea, presença de fraturas patológicas, e deficiência da matriz colagenosa e de células Runx-2+, TRAP+ e F4/80+. Os animais 5LOKO ZL apresentaram alterações compatíveis com atraso no processo de reparo especialmente no período de 7 dias, com menor quantidade de células Runx-2+ em comparação com o grupo 5LOKO Controle e pela qualidade da matriz óssea colagenosa com menor quantidade de fibras do espectro vermelho neste período, se igualando, porém, aos 21 dias. Deste modo, concluiu-se que o processo de reparo em camundongos fêmeas senescentes da linhagem 129/Sv WT e 5LOKO associados ao uso do BF ZL ocorreu de modo distinto, levando a quadro de OM nos animais WT e atraso nos animais 5LOKO, sem sinais histopatológicos que caracterizassem a doença. Deste modo, a inibição da enzima 5LO parece influenciar de maneira positiva o processo de reparo ósseo intramembranoso alveolar, mesmo na presença de fenótipo esqueletal osteopetrótico, sugerindo outros fatores relacionados à droga que favoreçam o desenvolvimento da OM no presente modelo animal(AU)

Senescence brings a number of physiological modifications with the decrease of cell and systemic activities and function that manifest in an important way in female population due to the event of menopause, as osteoporosis. In order to diminish these effects, there is the possibility of taking medication that decrease bone remodeling process, as the bisphosphonates containing nitrogen (BF). However, the use of these drugs is intimate related with the development of the osteonecrosis of the jaws (ON), especially when associated to other risk factors as oral surgery. It is known that physiologically, the dynamics of bone tissue also depends on the eicosanoids derivate from the arachidonic acid metabolism (AA), such as cyclooxygenase (COX) and 5 lipoxygenase (5LO) enzymes. In this way, the aim of the present study was to analyze the effects of the BF zoledrônico acid (ZL) and its relation with de development of ON in 129/SV old female mice with or without genetic modification for 5LO. Forty animals, 20 WT and 20 with 5LO gene alteration (129 Alox5tm1Fun/J) (5LOKO) were divided in groups: WT, treated with 0.01 ml of sterile 0.9% saline solution (SS) intraperitoneal (IP), and ZL, treated with 250µg/Kg of ZL IP diluted in SS, both administered once a week for 7 weeks. Groups contained 5 animals each (WT Control ­ 7 and 21 days, WT ZL ,7 and 21 days, 5LOKO Control, 7 and 21 days, and 5LOKO ZL, 7 and 21 days), and the maxillae removed for microCT, histopathology, birefringence, immunohistochemistry, and histomorphometric analysis. In general, microCT revealed significant deficiency in bone microarchitecture in WT ZL group in comparison to the other groups. In the same way, histopathological and birefringence analysis revealed histological pattern compatible with ON development in WT ZL group, presenting intense inflammatory infiltrate, late new bone formation, presence of pathological fractures, and deficiency in collagenous matrix, and also in Runx-2+, TRAP+, and F4/80. 5LOKO ZL animals presented alterations compatible with a late bone repair, especially at day 7, with decreased number of Runx-2+ cells in comparison to 5LOKO Control, and by the quality of collagenous bone matrix with decreased number of red spectra fibers in this period, however, being similar at day 21. From this, it could be concluded that alveolar bone repair of 129/SV WT and 5LOKO old female mice associated with the administration of ZL occurred in different ways, leading to a picture of ON in the WT animals, and late bone repair in the 5LOKO animals, without histopathological signs that could characterize the disease. In this way, inhibition of 5LO seems to influence intramembranous alveolar bone repair in a positive way, even in the presence of osteopetrotic skeletal phenotype, suggesting other factors related to the drug that favors the development of the ON in the present animal model(AU)

Osteonecrosis mandibular secundaria al uso de bisfosfonatos. Reporte de un caso / Jaw secondary osteonecrosis to bisphosphonates. Case report

RESUMEN Fundamento: La osteonecrosis de los maxilares secundaria a la administración de bisfosfonatos es una patología que se ha ido incrementando a partir del aumento del uso de esta droga, ya sea por vía oral o endovenosa. Objetivo: Ofrecer una enseñanza clínico-quirúrgica y crear conciencia entre los profesionales de la salud sobre la osteonecrosis mandibular por bisfosfonatos. Presentación de caso: Se reportó un caso de una paciente de 74 años de edad, con osteonecrosis mandibular secundaria al uso de bifosfonatos, localizada en cuerpo mandibular derecho; se le realizó mandibulectomía segmentaria intraoral. Conclusiones: La osteonecrosis de los maxilares asociada al uso de bisfosfonatos es una complicación que repercute en la calidad de vida de estos pacientes. La paciente de este caso, un mes después del tratamiento, se encontraba bien clínicamente y con buenos resultados en los exámenes imaginológicos.

ABSTRACT Background: Osteonecrosis of the jaws, secondary to the administration of bisphosphonates is a pathology that has been increasing from the use of this drug, either orally or intravenously. Objective: To offer clinical-surgical education and raise awareness among health professionals concerning jaw osteonecrosis to bisphosphonate. Case report: A 74-year-old patient with jaw secondary Osteonecrosis to bisphosphonates, located in the right mandibular body was reported; and intraoral segmental mandibulectomy performed. Conclusions: Osteonecrosis of the jaws associated with the use of bisphosphonates is a complication that affects the life quality of these patients. The patient in this case, one month after the treatment, was well clinically and with good results in the imaging tests.

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)

Osteonecrose dos maxilares relacionada ao uso de medicações: Diagnóstico, tratamento e prevenção / Medication-Related Osteonecrosis of the Jaw: Diagnosis, treatment and prevention / Osteonecrosis de los maxilares relacionados con el uso de medicamentos: Diagnóstico, tratamiento y prevención

Resumo A osteonecrose dos maxilares é uma alteração óssea que pode ser induzida pelo uso de drogas indicadas para o tratamento de pacientes com osteoporose e tumores malignos. Inicialmente acreditava-se estar associada apenas ao uso de bisfosfonatos, atualmente sabe-se que também está vinculada ao uso de outro antirresorptivo (denosumabe) e de antiangiogênico (bevacizumabe). Não se sabe ao certo qual é o mecanismo de desenvolvimento e ainda não existe um protocolo único de tratamento definido, mas existem diversos trabalhos sendo publicados sobre o tema. Com a crescente quantidade de casos relatados é de suma importância que o profissional de saúde saiba diagnosticar, identificar os riscos e tratar essa condição.

Abstract Osteonecrosis of the jaws is a bone alteration that can be induced using drugs indicated for the treatment of patients with osteoporosis and malignant tumors. Initially it was believed to be associated only with the use of bisphosphonates, currently it is known that it is also linked to the use of other antiresorptive (denosumab) and antiangiogenic (bevacizumab). It is not known what the development mechanism is and there is still no single defined treatment protocol, but there are several papers being published on the topic. With the increasing number of cases reported, it is extremely important that the health professional can diagnose, identify the risks and treat this condition.

Resumen La osteonecrosis de los maxilares es una alteración ósea que puede ser inducida por el uso de drogas indicadas para el tratamiento de pacientes con osteoporosis y tumores malignos. Inicialmente se creía estar asociada sólo al uso de bisfosfonatos, actualmente se sabe que también está vinculada al uso de otro antirresorptivo (denosumab) y de antiangiogénico (bevacizumabe). No se sabe con certeza cuál es el mecanismo de desarrollo y aún no existe un protocolo único de tratamiento definido, pero existen diversos trabajos siendo publicados sobre el tema. Con la creciente cantidad de casos reportados es de suma importancia que el profesional de salud pueda diagnosticar, identificar los riesgos y tratar esa condición.

Effects of Zoledronic Acid in Experimental Periapical Lesions in Rats: An Imaging and Histological Analysis

Abstract The aim of this study was to assess the imaging and histological features of experimental periapical lesions, including the adjacent alveolar bone, in rats under zoledronic acid treatment. The study used 40 male Wistar rats distributed into 8 groups of 5 animals each: G1: induction of periapical lesion (PL) and weekly intraperitoneal administration (WIPA) of saline solution (0.9% NaCl) for 4 weeks; G2: PL induction and WIPA of zoledronic acid (0.15 mg/kg/week) for 4 weeks; G3: PL induction and WIPA of saline solution for 8 weeks; G4: PL induction and WIPA of zoledronic acid for 8 weeks; G5:WIPA of saline solution for 4 weeks and subsequent PL induction; G6: WIPA of zoledronic acid for 4 weeks and subsequent PL induction; G7: WIPA of saline solution for 8 weeks and subsequent PL induction; G8: WIPA of zoledronic acid for 8 weeks and subsequent PL induction. The administration of zoledronic acid or saline solution continued after PL induction until the euthanasia. Thus, cone beam computed tomography and histological analysis were performed. Statistical analyzes were performed by ANOVA and Kruskal-Wallis test. Groups treated with zoledronic acid showed significantly smaller size of PL than the groups treated with 0.9% NaCl (p<0.05). PLs were formed by chronic inflammation ranging from mild to moderate, with no difference between groups. In all specimens, no mandibular necrosis was observed. In conclusion, the presence of PLs apparently does not represent an important risk factor for the development of bisphosphonate-related osteonecrosis of the jaws.

Resumo O objetivo deste estudo foi avaliar as características histológicas e de imagem de lesões periapicais experimentais, incluindo o osso alveolar adjacente, em ratos sob tratamento com ácido zoledrônico. O estudo utilizou 40 ratos Wistar, machos, distribuídos em 8 grupos de animais cada: G1: indução de lesão periapical (LP) e administração intraperitoneal semanal (AIS) de solução salina (NaCl 0.9%) por 4 semanas; G2: indução de LP e AIS de ácido zoledrônico (0,15 mg/kg/week) por 4 semanas; G3: indução de LP e AIS de solução salina por 8 semanas; G4: indução de LP e AIS de ácido zoledrônico por 8 semanas; G5- AIS de solução salina por 4 semanas e subsequente indução de LP; G6- AIS de ácido zoledrônico por 4 semanas e subsequente indução de LP; G7: AIS de solução salina por 8 semanas e subsequente indução de LP; G8: AIS de ácido zoledrônico por 8 semanas e subsequente indução de LP. A administração de ácido zoledrônico ou solução salina continuou após indução de LP até a eutanásia. Após isso, tomografia computadorizada de feixe cônico e análise histológica foram realizadas. Análises estatísticas foram realizadas por ANOVA e teste de Kruskal-Wallis. Os grupos tratados com ácido zoledrônico mostraram LPs significativamente menores que os grupos tratados com NaCl 0.9% (p <0.05). LPs eram formadas por inflamação crônica variando de leve a moderada, sem diferença entre os grupos. Em todos os espécimes, necrose mandibular não foi observada. Em conclusão, a presença de LPs aparentemente não representa um fator de risco importante para o desenvolvimento de osteonecrose relacionada ao uso de bisfosfonatos.

Osteonecrosis de los maxilares inducida por bifosfonatos

La osteonecrosis de los maxilares inducida por bifosfonatos es una reacción adversa asociada al uso a largo plazo de estos fármacos; se caracteriza por la presencia de hueso expuesto o necrótico en la región maxilar, y/o mandibular la cual se desarrolla en la gran mayoría de los casos posterior a la realización de un tratamiento dental invasivo. No se conocen aún detalles importantes sobre su etiopatogenia; sin embargo, se ha logrado establecer asociaciones con ciertos factores de riesgo. Uno de los aspectos más relevantes en relación con la osteonecrosis de los maxilares inducida por bifosfonatos es su prevención, la cual actualmente en Costa Rica es muy escasa, por lo que existe una necesidad manifiesta de capacitación en el tema para los profesionales del área de la salud.

Osteonecrosis of the jaw induced by bisphosphonates is an undesirable effect associated with long term use of these drugs, is characterized by the presence of exposed and/or necrotic bone in the maxillar and/or mandibular region, which develops in the majority of cases after performing an invasive dental treatment. Many important details about its pathogenesis are still unknown, however there have been established partnerships with certain risk factors. One of the most important aspects related to osteonecrosis of the jaws induced by bisphosphonate is prevention, which currently in Costa Rica is low, therefore there is a clear need for training health professionals in the subject.

Surgical Treatment of Bisphosphonate-Related Osteonecrosis of the Jaws with the Use of Buccal Fat Pad: Case Report

Bisphosphonate-related osteonecrosis of the jaws (BROJ) has been described since 2003 as an adverse effect of bisphosphonate medications. These drugs act on the vasculature and bone remodeling, mainly on osteoclastic activity and can cause areas of necrotic bone exposure. Treatment for the BROJ is not yet defined, but surgical treatment is one of the forms proposed, which may cause oral deformities like sinus communication in some cases. In situations like this the buccal fat pad is an important alternative for coating nasal-oral communications, due its large blood supply, elasticity, absence of restriction by age and safety. This paper presents the case of a 58-year-old woman with BROJ in the left maxilla caused by the use of zoledronic acid for metastatic breast cancer. The extensive necrotic bone area was surgically removed resulting in oral sinus communication. A buccal fat pad was used to cover the defect. More studies should be performed regarding the treatment of BROJ but, if necessary, a buccal fat pad flap could be an alternative to solve nasal-oral communications related to BROJ.

Osteonecrose dos maxilares por bifosfonatos (OMB) tem sido descrita desde 2003 como um efeito adverso dos medicamentos bifosfonatos. Essas drogas atuam sobre a vascularização e remodelação óssea, principalmente na atividade osteoclástica, podendo gerar áreas de exposição óssea necrótica. O tratamento para a doença ainda não é definido, mas o tratamento cirúrgico é uma das formas preconizadas que, em algumas situações podem ocasionar deformações orais como as comunicações buco-sinusais. Em situações como esta o tecido adiposo bucal é uma alternativa importante para o recobrimento da comunicação oro-nasal, devido ao seu grande suprimento sanguíneo, elasticidade, ausência de restrição pela idade e segurança. Este trabalho apresenta um caso clínico de paciente de 58 anos do sexo feminino, portadora de OMB em maxila esquerda pelo uso de ácido zoledrônico para câncer metastático. A extensa remoção da porção óssea necrótica resultou em fístula buco-sinusal. O retalho do tecido adiposo bucal foi utilizado para cobrir o defeito. Mais estudos devem ser realizados com relação ao tratamento de OMB, no entanto, se necessário, o retalho de tecido adiposo bucal poderia ser uma alternativa para resolver a comunicação oro-nasal relacionada à OMB.

O efeito do ácido zoledrônico na microestrutura óssea analisado pela micro-CT em mandíbulas de ratos wistar / Zoledronic acid effect on the bone microarchitecture of the jaw of rats by Micro-CT

Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações...

Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The "t-student" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae...

Spontaneous bisphosphonate-related osteonecrosis of the left hemi-mandible: Similarities with phossy jaw.

Intravenous bisphosphonates (BP) play a key role in the treatment of bone metastases. As a long-term side effects BP, a form of avascular osteonecrosis of the jaw has been reported. Although, invasive oral local procedures are often present in clinical history of patients suffering from bisphosphonates-related osteonecrosis of the jaws (BRONJ), about up to 50% of BRONJ are spontaneous. We report a case of a 68-year-old female with a spontaneous wide bone sequestration of the left mandibular body onset after infusion of zoledronic acid for 18 cycles for osseous metastasis due to metastatic anaplastic thyroidal carcinoma. Surprisingly the clinical aspects of the patient initially reminded us of the famous pathology described in 1899 called phossy jaw. This case is remarkable not only for the spontaneity of the osteonecrosis, but, above all, for the clinical similarity with cases of phossy jaw, described for the first time in the literature, thereby suggesting a potential common pathogenesis.

Clinical study of correlation between C-terminal cross-linking telopeptide of type I collagen and risk assessment, severity of disease, healing after early surgical intervention in patients with bisphophonate-related osteonecrosis of the jaws

INTRODUCTION: The utility of the C-terminal cross-linking telopeptide test (CTX) as a method for staging Bisphosphonate-related osteonecrosis of the jaws (BRONJ) and its healing process was examined. MATERIALS AND METHODS: A total 19 patients who were diagnosed with BRONJ underwent a fasted morning CTX test, were enrolled in this study. The serum CTX values ranged from 50 to 630 pg/mL (mean 60). The risk assessment was rated according to the CTX values of the individual patient (minimal risk, > or =150 pg/mL, moderate, 100 to 150 pg/mL, high, < or =100 pg/mL). The BRONJ scores were then calculated according to the number of BRONJ lesions and their stage. The operation was done as soon as possible, regardless of BORNJ stage. RESULTS: The mean duration of bisphosphonate therapy was 4.1 years. Of the 19 patients, 15, 2 ans 2 received alendronate, risedronate and zoledronate, respecively. Of the 19 patients who underwent a sequestrectomy, saucerization and smoothing, 15 healed after the initial surgery, 1 patient healed after one more surgical procedure, 3 patients did not heal completely but showed improvement in symptoms. Therefore, 17 out of the 19 patients healed completely with complete mucosal coverage and the elimination of pain. The risk assessment using the CTX value and disease severity were not correlated (r=-0.264, P=0.275). In addition, the risk assessment using CTX value and healing after surgery were not correlated (r=-0.147, P=0.547). CONCLUSION: The serum CTX should be considered carefully by clinicians as part of overall management. Early surgical intervention is of benefit in the treatment of stage II BRONJ.