Ozonotherapy for Treatment of Radiation Therapy-induced Jaw Osteonecrosis and Bisphosphonates: Case Report / Ozonioterapia para o Tratamento de Osteonecrose em Mandíbula Induzida pela Radioterapia Associada com Bisfosfonato: Relato de Caso / Ozonoterapia para el Tratamiento de la Osteonecrosis de la Mordaza Inducida por Terapia de Radiación y Bisfosfonatos: Relato de Caso

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

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

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

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)

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

Medication-related osteonecrosis of the jaw, osteoradionecrosis, and osteomyelitis: A comparative histopathological study

Abstract It is largely known that some oral diseases can be diagnosed based upon their clinical manifestation combined with the patient's medical history and generally not depending on examination. This is the case of some bone diseases such as osteoradionecrosis of the jaw (ORNJ), osteomyelitis of the jaw (OMJ), and medication-related osteonecrosis of the jaw (MRONJ). The present study aimed to analyze the histopathological features of these specific bone diseases in order to evaluate similarities and differences. Forty-four bone specimens resected from each bone disease (22 cases of ORNJ, 6 cases of OMJ, and 16 cases of MRONJ) were analyzed by two experienced oral pathologists without prior knowledge of the diagnosis, considering bone tissue condition, inflammation, vascularization, and the presence of microorganisms. In addition, the examiners formulated a diagnostic hypothesis for each specimen. Many histopathological similarities were found among the diseases, especially considering the presence of necrotic bone, inflammation, and microorganisms. Statistically significant differences were detected in empty bone lacunae, which was decreased in ORN (p = 0.042), and considering neutrophil count, which was low in the MRONJ group (p ≤ 0.001). The Kappa coefficient was calculated and agreement was detected based on the histopathological parameters, but not for diagnostic suggestion (p=0.23). In conclusion, histopathological aspects of ORNJ, OMJ, and MRONJ do not permit a conclusive diagnosis, emphasizing the necessity of a detailed clinical report.

Osteonecrosis de los maxilares asociada al uso de bifosfonatos / Bisphosphonate-related osteonecrosis of the jaws

Los bifosfonatos (BP) son fármacos análogos a la molécula del pirofosfato que inhiben la reabsorción ósea. Estos medicamentos son usados en la prevención y tratamiento de enfermedades que involucran procesos de reabsorción ósea, como la osteoporosis y algunas formas de cáncer. En 2003 el Dr. Robert Marx encendió la alarma mundial al comunicar 36 casos de pacientes con exposiciones óseas sintomáticas en sus maxilares, secundarias a procedimientos quirúrgicos bucales e incluso de aparición espontánea, estando todos estos enfermos bajo tratamiento con bifosfonatos, como zoledronato o pamidronato. Esto se explica porque los maxilares son los únicos huesos que tienen interacción con el ambiente mediante vía dentaria, siendo más propensos a sufrir alteraciones que otros huesos del cuerpo. Desde entonces han existido múltiples estudios respecto al desarrollo de osteonecrosis de los maxilares asociados al uso de bifosfonatos (BRONJ). El propósito de esta comunicación es realizar una puesta al día sobre este tema, entregando información actualizada sobre los riesgos a que están expuestos los pacientes que usan BP, la forma de prevenir su aparición en los maxilares y su tratamiento...

Bisphosphonates (BP) are a group of drugs like phirosphate molecule that inhibit bone resorption. Bisphosphonates are commonly prescribed for prevention and treatment of disease whit bone loss caused by osteoporosis and some types of cancer. In 2003, Dr. Robert Marx, turned on the world alarm, reporting 36 diagnosed cases whit painful bone exposure in the mandible and maxilla, after bucal surgery treatment or spontaneously, all the patients receiving the biphosphonates pamidronato and zoledronato. The maxilla and mandible were the only bones involved in this exposure, because they are more exposed to enviroment throw de teeth, been more susceptible to disease than other bones of the body. Since then so many reports have been published about bisphosphonate-related osteonecrosis of the jaws (BRONJ). The purpose of this article is communicate about the risk, prevention and treatment of osteonecrosis of the jaws in all the patients who have taken bisphosphonates...

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.

Osteonecrose maxilar associada ao uso de bisfosfonatos / Bisphosphonate-related osteonecrosis of the jaw

Os bisfosfonatos (BFs) têm sido indicados para o tratamento de doenças do metabolismo ósseo. Atualmente, seu emprego terapêutico aumentou e, com ele, os efeitos adversos, dos quais um dos mais importantes é a indução da osteonecrose dos maxilares, uma complicação de difíceis tratamento e solução. Até o presente, não se sabe ao certo qual é o mecanismo de desenvolvimento da osteonecrose dos maxilares induzida por bisfosfonatos (ONMB), nem qual deve ser o tratamento estabelecido perante essa manifestação. Apesar de a literatura apresentar formas variadas de tratamento, não existe um protocolo definido. Apresentamos uma revisão sobre a ONMB, enfocando sua etiopatogenia e as formas reportadas de tratamento.

Bisphosphonates (BPs) have been used for the management of bone metabolic diseases. Currently their therapeutic use has increased, as also have their adverse effects, one of the most important being the bisphosphonate-related osteonecrosis of the jaw (BRONJ), a complication of difficult treatment and solution. Until now, the physiopathology of BRONJ remains unclear, and its treatment is uncertain. Although the literature provides several treatment options, there is no defined protocol. We present a review about BRONJ, focusing on its pathogenesis and its reported forms of treatment.

Osteonecrosis mandibular y maxilar secundaria a bifosfonatos: presentación de tres nuevos casos / Mandibular and maxilar osteonecrosis secondary to bisphosphonates: introduction of three new cases

El empleo de los bifosfonatos supone en la actualidad una herramienta de especial relevancia para el manejo terapéutico de diversas patologías, en tanto que forman parte del tratamiento estándar. Sin embargo, y de un modo casi paralelo, se han documentado un amplio número de casos en los que el paciente, secuencialmente a su tratamiento con bifosfonatos, ha desarrollado un cuadro de necrosis avascular en región maxilar y/o mandibular. Cuadro éste, de complejo abordaje, que tiende a comprometer y mermar la calidad de vida de nuestros pacientes. No obstante, la posible aparición de esta complicación, no debe por otra parte, implicar reticencias en cuanto a su uso en la terapéutica, sino más bien constituir un aspecto a vigilar durante el tiempo de terapia. El objetivo de este trabajo es alertar sobre las posibles complicaciones en pacientes que reciben terapia con bifosfonatos a través de la revisión de la literatura y la presentación de tres nuevos casos clínicos.

The use of bisphosphonates is now particularly important in the therapeutic management of various pathologies, as an integral part of standard therapy. However, in an almost parallel form, a large number of cases have been documented in which the patient following treatment with bisphosphonates, developed a vascular necrosis event in the maxillary and/or mandibular region. This is an event of complex approach which tends to compromise and undermine the quality of life for our patients. However the possible occurrence of this complication should not on the other hand, imply misgivings about their use in therapy, but rather constitute an event to be monitored during the time of therapy.The aim of this paper is to advise about possible complications in patients receiving bisphosphonate therapy through literature review and the presentation of these three new clinical cases.