Suspensión de antirresortivos en osteonecrosis asociada a medicamentos: revisión de la literatura / Suspension of antiresorptive drugs in medication-related osteonecrosis of the jaws: a review of the literature

La suspensión de antirresortivos en el contexto de cuadros de osteonecrosis asociada a medicamentos (ONAM) es controversial. Aunque la evidencia de ca-lidad al respecto es insuficiente, múltiples socieda-des profesionales y grupos de trabajo han sugerido emplear este recurso. Recientemente la Sociedad Americana de Cirujanos Orales y Maxilofaciales ha puesto en duda sus beneficios. En el presente estudio abordamos esta temática en dos situaciones clínicas diferentes. Por un lado, analizamos la suspensión de los antirresortivos en pacientes asintomáticos an-tes de llevar a cabo procedimientos invasivos en los maxilares para disminuir el riesgo de desarrollo de ONAM. Por otro lado, evaluamos la suspensión de los antirresortivos en pacientes con ONAM establecida para mejorar el pronóstico de la enfermedad (AU)

The suspension of antiresorptive drugs in the context of medication-related osteonecrosis of the jaws (MRONJ) is controversial. Despite the lack of quality evidence, several professional associations and working groups have made suggestions in using this resource. Recently the American Association of Oral and Maxillofacial Surgeons has questioned its benefits. In the present study we address this issue in two different clinical situations. On the one hand, we analyzed the suspension of antiresorptive agents in asymptomatic patients before carrying out invasive procedures in the jaws to reduce the risk of developing MRONJ. On the other hand, we evaluated the suspension of antiresorptive drugs in patients actually presenting MRONJ to improve the prognosis of the disease (AU)

Osteonecrosis maxilar asociada con altas dosis de antirresortivos en paciente oncolólgico adulto mayor: resolución interdisciplinaria de caso clínico / Osteonecrosis of the jaw associated with high doses of antiresorptive in an elderly cancer patient: interdisciplinary resolution of a clinical case

La osteonecrosis maxilar relacionada con medicamentos (ONMM) es una patología de características clínicas objetivas con signo-sintomatología patogno-mónica. 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 sema-nas, 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 situa-ción se torna más compleja en pacientes oncológicos con altas dosis de antirresortivos para tratamiento de metástasis ósea. Varios informes de casos des-criben cuadros de ONMM en pacientes con cáncer que reciben terapias dirigidas, específicamente TKI (inhibidores de tirosina kinasa) y anticuerpos mo-noclonales-VEGF (anticuerpos dirigidos al factor de crecimiento del endotelio vascular). La ONMM afecta negativamente la calidad de vida del paciente onco-lógico y produce comorbilidad significativa. Resulta imperioso identificar los pacientes en riesgo y dise-ñar un protocolo de atención odontológica específico para estos casos. En este artículo, se presenta un caso de ONMM asociado con altas dosis de Deno-sumab y administración simultánea de anticuerpos monoclonales específicos. El caso sorprende por la magnitud de la necrosis y su cuadro insidioso. El pro-tocolo 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 cu-ración total de la lesión (AU)

Medication-related osteonecrosis of the jaws (MRONJ) is a pathology with objective clinical characteristics with pathognomonic signs and symp-toms. 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 re-ceive 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 nega-tively affects the quality of life in cancer patients and produces significant comorbidity. It is imperative to identify patients at risk and design a specific den-tal care strategy for these cases. In this article, we present a case of MRONJ associated with high doses of Denosumab and simultaneous administration of specific monoclonal antibodies. The case is surpris-ing due to magnitude of the 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 heal-ing of the lesion (AU)

The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence

ABSTRACT It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.

Conhecimento dos graduandos em odontologia sobre osteonecrose dos maxilares: da etiologia ao manejo / Knowledge of undergraduates in dentistry about osteonecrosis of the jaws: from etiology to management / Conocimientos de los estudiantes de odontología sobre osteonecrosis de los maxilares: de la etiología a la gestión

O objetivo foi avaliar o nível de conhecimento dos discentes do último ano do curso de odontologia da Universidade de Pernambuco, acerca da etiológia e manejo da osteonecrose dos maxilares. Metodologia: Trata-se de um estudo transversal realizado com os alunos do 9° e 10° períodos, onde 45 alunos responderam voluntariamente, após firmarem o aceite do termo de Consentimento Livre e Esclarecido, questionário estruturado mediante informações básicas sobre drogas antirreabsortivas e antiangiogênicas, além do manejo de pacientes com osteonecrose dos maxilares. Resultados: Dos 45 discentes que aceitaram responder o questionário 22 (48,8%) eram do 9° período e 23 (51,11%) do 10° período; 82% relataram que não aprenderam sobre medicamentos antirreabsortivos e antiangiogênicos; 84,4% tiveram informações sobre a osteonecrose durante a formação acadêmica. Em relação à possibilidade terapêutica 43,6% indicaram o tratamento cirúrgico (desbridamento); 20,5% laser de baixa intensidade e antibiótico; 12,8% ressecção cirúrgica; 10,3% laser de baixa intensidade; 7,7% oxigenação hiperbárica; (5,12%) infusão de PRP (plasma rico em plaquetas). Conclusão: O atual padrão de conhecimento passado sobre a etiologia e manejo da osteonecrose dos maxilares, induzida por fármacos, não está dando o suporte necessário para a tomada de decisão ao término do processo formal de ensino e aprendizagem no curso de odontologia... (AU)

The objective was to evaluate the level of knowledge of the final-year dental students of the Universidade de Pernambuco about the etiology and management of osteonecrosis of the jaws. Methodology: This is a cross-sectional study carried out with students from the 9th and 10th periods. Informed Consent, a structured questionnaire with basic information about antiresorptive and antiangiogenic drugs, besides the management of patients with osteonecrosis of the jaws. Results: Of the 45 students who agreed to answer the questionnaire, 22 (48.8%) were from the 9th period and 23 (51.11%) from the 10th period; 82% reported that they did not learn about antiresorptive and antiangiogenic drugs; 84.4% had information about osteonecrosis during their academic training. Regarding the therapeutic possibility 43.6% indicated surgical treatment (debridement); 20.5% low intensity laser and antibiotic; 12.8% surgical resection; 10.3% low intensity laser; 7.7% hyperbaric oxygenation; (5.12%) infusion of PRP (platelet rich plasma). Conclusion: The current pattern of past knowledge on the etiology and management of drug-induced osteonecrosis of the jaws is not providing the necessary support for decision making at the end of the formal teaching and learning process in the dental course... (AU)

El objetivo es evaluar el nivel de conocimiento de los estudiantes del último año del curso de odontología de la Universidad de Pernambuco, sobre la etiología y el manejo de la osteonecrosis de los maxilares. Metodología: Se trata de un estudio transversal realizado con los estudiantes de los periodos 9° y 10°, en el que 45 estudiantes respondieron voluntariamente, tras firmar el término de Consentimiento Livre y Esclarecido, a un cuestionario estructurado mediante información básica sobre drogas antirreabsortivas y antiangiogénicas, además del manejo de pacientes con osteonecrosis de los maxilares. Resultados: De los 45 estudiantes que accedieron a contestar el cuestionario, 22 (48,8%) eran del 9º periodo y 23 (51,11%) del 10º periodo; el 82% informó de que no había aprendido sobre los fármacos antirresortivos y antiangiogénicos; el 84,4% tuvo información sobre la osteonecrosis durante su formación académica. En cuanto a la posibilidad terapéutica, el 43,6% indicó tratamiento quirúrgico (desbridamiento); el 20,5%, láser de baja intensidad y antibiótico; el 12,8%, resección quirúrgica; el 10,3%, láser de baja intensidad; el 7,7%, oxigenación hiperbárica; el 5,12%, infusión de PRP (plasma rico en plaquetas). Conclusión: El modelo actual de conocimientos previos sobre la etiología y el tratamiento de la osteonecrosis de los maxilares inducida por fármacos no está proporcionando el apoyo necesario para la toma de decisiones al final del proceso formal de enseñanza y aprendizaje en el curso de odontologia... (AU)

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)

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)

Pharmacological Therapy for Postmenopausal Osteoporosis

Osteoporosis, now defined as a disease characterized by a low bone mass and a microarchitectural deterioration of bone tissue leading to an enhanced bone fragility and fracture risk, is a major public health problem, affecting 200 million individuals worldwide. Optimal treatment and prevention of osteoporosis require modification of risk factors, particularly smoking cessation, adequate physical activity, and attention to diet, in addition to pharmacologic intervention. A number of pharmacologic options are now available to health care providers. The estrogens and raloxifene both prevent bone loss in postmenopausal women, and the estrogens probably also decrease the risk of first fracture. There is a good evidence that raloxifene prevents further fractures in postmenopausal women who already have had fractures and some evidence that estrogen does as well. Bisphosphonate alendronate prevents bone loss and reduces fractures in healthy and osteoporotic postmenopausal women, and in osteoporotic men as well. Risedronate is more potent and has fewer upper gastrointestinal side effects than alendronate, and reduces the incidence of fractures in osteoporotic women. An intermittent use of potent bisphosphonate zoledronate also increases bone mineral density and may become an alternative in the prevention and treatment of osteoporosis. Calcitonin increases bone mineral density in early postmenopausal women and men with idiopathic osteoporosis, and also reduces the risk of new fractures in osteoporotic women. All of the agents discussed above prevent bone resorption, whereas teriparatide increases bone formation and is effective in the treatment of osteoporotic women and men. Bisphosphonates are also effective in the treatment of secondary osteoporosis associated with the use of glucocorticoids to treat inflammation or prevent rejection after transplantation. New avenues for targeting osteoporosis will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may remain to be solved.