Uso de denosumab en quiste óseo aneurismático: revisión de la literatura / Use of denosumab in aneurysmatic bone cyst: literature review

INTRODUCCIÓN Los quistes óseos aneurismáticos (QOAs) son tumores benignos, localmente agresivos, y con importante potencial de recidiva, que representan aproximadamente el 1% de todos los tumores óseos. Se describen múltiples tratamientos, como: escisión intralesional, embolización arterial selectiva, inyección de agentes esclerosantes, y radiación. Estos tratamientos tienen una tasa variable de eficacia, ya que la recurrencia puede llegar al 20% y puede estar asociada a comorbidades graves como la pérda funcional de la extremidad. OBJETIVO Realizar una revisión integradora de la literatura sobre el uso de denosumab para el tratamiento de QOAs, describiendo el perfil epidemiológico, la dosis utilizada, y las complicaciones. MÉTODO Se recopilaron artículos publicados en los últimos cinco años en la base de datos PubMed. La información recogida de los casos reportados fue la edad, el sexo, la ubicación del tumor, la realización de cirugía antes y/o después del tratamiento con denosumab, la dosis utilizada, las complicaciones, y la recurrencia. RESULTADOS Se analizaron 7 artículos, 4 reportes de casos y 3 series de casos, escritos en inglés, y publicados de 2014 a 2019. La mayoría de los pacientes eran del sexo femenino, con una edad promedio de 14 años, y el tumor localizado en la columna. CONCLUSIÓN El uso de denosumab en el tratamiento de QOAs ha tenido una buena respuesta, ya que tiene bajas tasas de recurrencia y complicaciones; sin embargo, hacen falta más estudios para definir el protocolo de tratamiento.

INTRODUCTION Aneurysmal Bone Cysts (ABCs) are locally-aggressive benign tumors with relevant potential for recurrence, representing approximately 1% of all bone tumors. Multiple treatments are described for them, such as: intralesional excision, selective arterial embolization, injection of sclerosing agents, and radiation. These treatments have a variable efficacy rate, can reach 20% and may be associated with serious comorbidities such as functional loss of the limb. OBJETIVE To perform an integrative review of the literature on the use of denosumab in the treatment of ABCs, describing the epidemiological profile, the dosage used, and the complications. METHODOLOGY Articles published in the past five years were retrieved from the PubMed database. The information collected from the cases reported was age, gender, tumor location, the performance of surgery before and/or after the denosumab treatment, the dose used, the complications, and recurrence. RESULTS We analyzed 7 articles, 4 case reports and 3 case series, written in English, and published from 2014 to 2019. Most patients were female, with an average age of 14 years, with the tumor located in the spine. CONCLUSION The use of denosumab in the treatment of ABCs yielded good results, with low rates of recurrence and complications. However, further studies are needed to define a treatment protocol.

Which is the best antiresorptive treatment after finishing teriparatide? / ¿Cuál es el mejor tratamiento antirresortivo luego de terminar con teriparatide?

Abstract Anabolic drugs are the treatment of choice for osteoporotic patients with very high risk of fractures. Post anabolic treatment with an antiresorptive drug maintains the bone mineral density (BMD) gained. The recommendations regarding the ideal antiresorptive drug are not precise. The aim of this paper is to compare the usefulness of zoledronate and denosumab in a group of 28 women with very high risk of fractures. All of them completed at least one year of treatment with teripatide and latter 14 received zolendronate and 14 denosumab for another year. We retrospectively review their biochemical and densitometric changes. Both treat ment groups experienced a reduction in bone turnover markers of the same magnitude at the end of the second year. In Lumbar Spine BMD increase of 3.96 ± 8.56% Median (Me) 2.54 p = 0.21 in zolendronate group and 3.55 ± 5.36% (Me 5.14) p = 0.07 in denosumab group. Femoral Neck BMD changed -0.09 ± 6.50% (Me 0.29) p = 0.85 in zolendronate group, and - 3.41 ± 5.08% (Me 5.35) p = 0.59 in denosumab group, with no difference between both groups. In Total Hip BMD an increase of 0.55 ± 4.20% (Me 0.43) p = 0.70 in zoledronate group, and 4.53 ± 5.13% (Me 0.64) p = 0.04 with denosumab. We conclude that both antiresortive treatments have a similar effect in biochemical markers after one year of treatment. BMD increase significantly in total hip and changed with a trend toward in lumbar spine with denosumab, but without differences between both groups of treatment.

Resumen Los anabólicos son el tratamiento de elección en la osteoporosis con muy alto riesgo de fracturas. Después del tratamiento anabólico un fármaco antirresortivo mantiene la densidad mineral ósea (DMO) ganada. Las reco mendaciones sobre el fármaco antirresortivo ideal no son precisas. El objetivo de este trabajo es comparar la utilidad de zoledronato y denosumab en un grupo de 28 mujeres con muy alto riesgo de fracturas. Todas ellas completaron al menos un año de tratamiento con teripatide y luego 14 recibieron zolendronato y 14 denosumab durante un año. Revisamos retrospectivamente sus cambios bioquímicos y densitométricos. Ambos grupos de tratamiento experimentaron una reducción de los marcadores de recambio óseo de la misma magnitud al final del segundo año. En columna lumbar la DMO aumentó 3.96 ± 8.56% Mediana (Me) 2.54, p = 0.21 en el grupo zolendronato y 3.55 ± 5.36% (Me 5.14) p = 0.07 en el grupo denosumab. La DMO del cuello femoral cambió -0.09 ± 6.50% (Me 0.29) p = 0.85 en el grupo zolendronato y - 3.41 ± 5.08% (Me 5.35) p = 0.59 en el grupo de denosumab, sin diferencias entre ambos grupos. En la Cadera Total la DMO aumentó 0.55 ± 4.20% (Me 0.43) p = 0.70 con zoledronato y 4.53 ± 5.13% (Me 0.64) p = 0.04 con denosumab. Concluimos que ambos tratamien tos antiresortivos tuvieron un efecto similar en los marcadores bioquímicos después de un año de tratamiento. La DMO aumentó significativamente en la cadera total y mostró una tendencia similar en columna lumbar con denosumab, sin diferencias entre ambos tratamientos.

Eficácia e segurança da Teriparatida comparada aos bifosfonados orais e Raloxifeno para prevenção de fraturas em osteoporose: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of Teriparatide compared to oral biposphonates or Raloxifene for osteoporotic fracture prevention: rapid review of evidence

Tecnologia: Teriparatida, comparada a bifosfonados orais ou Raloxifeno. Indicação: prevenção de fraturas em pessoas com osteoporose. Pergunta: A Teriparatida é mais eficaz e segura que os bifosfonados orais ou o Raloxifeno para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Resultados: Foram selecionadas 2 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: Para a população em geral com osteoporose, a Teriparatida evita mais fraturas vertebrais que o Alendronato de sódio ou Risedronato de sódio, mas efeito similar para fraturas não vertebrais. Teriparatida previne mais fraturas vertebrais e não vertebrais que Raloxifeno. Teriparatida tem maior efeito sobre a massa óssea corporal que o Risedronato de sódio e o Raloxifeno, mas tem efeito similar ao Alendronato de sódio. Na população masculina com osteoporose, a terapia com bifosfonados orais é mais eficaz que suplementação nutricional ou placebo para prevenir fraturas. Já o tratamento com Teriparatida não é mais eficaz que a suplementação nutricional ou placebo

Teriparatide compared to oral bisphosphonates or Raloxifene. Indication: prevention of fractures in people with osteoporosis. Question: Is Teriparatide more effective and safer than oral bisphosphonates or Raloxifene for treating osteoporosis and preventing fractures secondary to osteoporosis? Methods: Bibliographic survey was carried out in the PUBMED database, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the tool Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Results: Two systematic reviews were selected, which met the inclusion criteria. Conclusion: For the general population with osteoporosis, Teriparatide prevents more vertebral fractures than Alendronate or Risedronate sodium, but has similar effect for non-vertebral fractures. Teriparatide prevents more vertebral and non-vertebral fractures than Raloxifene. Teriparatide has a greater effect on body bone mass than Risedronate sodium and Raloxifene, but it has a similar effect to Alendronate sodium. In the male population with osteoporosis, oral bisphosphonates is more effective than nutritional supplementation or placebo to prevent fractures. Treatment with teriparatide is no more effective than nutritional supplementation or placebo

Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism

SUMMARY Severe hypercalcemia is a medical emergency that requires immediate and aggressive management. Primary hyperparathyroidism (PHPT) often causes severe hypercalcemia. Volume resuscitation, parenteral salmon calcitonin, and administration of intravenous bisphosphonates are common measures used to stabilize patients. However, the use of these measures is inadequate in several patients and may even be contraindicated in individuals with renal insufficiency or severe systemic illness. This study demonstrated the efficacy and safety of denosumab in patients with severe hypercalcemia due to PHPT, when immediate surgery was not feasible. We present four patients with severe hypercalcemia due to PHPT. Immediate surgery was not feasible because the patients had severe systemic illness, such as seizures and altered sensorium (case 1); acute severe pancreatitis (cases 2 and 3); or coronavirus disease 2019 pneumonia (case 4). Intravenous normal saline and parenteral salmon calcitonin were inadequate for controlling hypercalcemia. Intravenous bisphosphonates were avoided because of severe systemic illness in all cases and impaired renal function in three cases. Denosumab was administered to control hypercalcemia and allow the stabilization of patients for definitive surgical management. Following denosumab administration, serum calcium levels normalized, and general condition improved in all patients. Three patients underwent parathyroidectomy after two weeks and another patient after eight weeks. The use of denosumab for the management of severe hypercalcemia due to PHPT is efficacious and safe in patients when immediate surgical management is not feasible due to severe systemic illness.

Nuevos avances en el conocimiento de la historia natural de la displasia fibrosa / News advances in the knowledge of natural history of the fibrous dysplasia

La displasia fibrosa (DF) es una enfermedad infrecuente del hueso, no hereditaria, producida por una mutación activadora del gen GNAS, responsable de codificar la unidad a-estimuladora de la proteína G (Gsa). La presentación clínica de la enfermedad es muy variada, pues adopta desde formas asintomáticas hasta otras marcadamente sintomáticas. En los últimos años, el análisis exhaustivo de bases de datos de pacientes con DF ha permitido conocer más sobre su historia natural. En este artículo se revisa la información actualmente disponible sobre algunos aspectos que ayudarán al mejor enfoque clínico del paciente, como son: la utilidad clínica de los marcadores óseos, los factores pronósticos para el desarrollo de fracturas, la DF como condición predisponente para el desarrollo de tumores específicos, nuevas perspectivas sobre la fisiopatología del dolor óseo y nuevas estrategias terapéuticas. Un mayor conocimiento sobre la historia natural de esta enfermedad finalmente redundará en la mejor calidad de vida de los pacientes con DF. (AU)

Fibrous dysplasia (FD) is an infrequent, non-hereditary bone disease caused by a somatic mutation of the GNAS gene, responsible for encoding the a-subunit of the G-protein (Gsa). The clinical presentation of the disease varies greatly, with some patients being asymptomatic and others markedly symptomatic. The exhaustive analysis of the database from patients with FD has allowed to learn more about the natural history of this disease. This article reviews the current information available on the clinical utility of bone markers, the prognostic factors for the occurrence of fractures, the evidence supporting as a predisposing condition for the development of specific tumors, new perspectives on the pathophysiology of bone pain, and emerging therapeutic strategies. A greater understanding of the natural history of this disease will allow to make better medical decisions, which will ultimately contribute to improve FD patients' quality of life. (AU)

Eficácia e segurança do denosumabe comparado aos bifosfonados orais para tratamento de osteoporose e prevenção de fraturas: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of denosumab compared to oral biposphonates for treating osteoporosis and fracture prevention: rapid review of evidence

Tecnologia: Denosumabe e bifosfonados. Indicação: tratamento de osteoporose para prevenção de fraturas. Pergunta: O denosumabe é mais eficaz e seguro que os bifosfonados orais para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico realizado na PUBMED seguindo estratégia de busca predefinida. Avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foram selecionadas e incluídas 3 revisões sistemáticas, com pontuação de 9 a 11 no AMSTAR. Conclusão: Denosumabe tem menor risco relativo que alendronato e risedronato de sódio para fraturas vertebrais e maior efeito sobre densidade óssea mineral femoral, com risco similar de outros tipos de fratura e eventos adversos (infecções, transtornos cardiovasculares, óbito por infecção, morte cardiovascular ou por qualquer causa). Denosumabe evita 0,00154 fraturas, previne 0,00025 institucionalizações (ou cuidados permanentes de enfermagem no domicílio) e promove um ganho de 0,0018 anos de vida a mais que o alendronato de sódio por paciente tratado. Denosumabe é um pouco mais eficaz e tão seguro quanto os bifosfonados, mas a diferença de eficácia é mínima

Technology: Denosumab and bisphosphonates. Indication: osteoporosis treatment for fracture prevention. Question: Denosumab is more effective and safer than oral bisphosphonates for treating osteoporosis and preventing fractures related to osteoporosis? Methods: Bibliographic search was performed on PUBMED, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. Results: We selected and included 3 systematic reviews. Their scores ranged from 9 to 11 on AMSTAR. Conclusion: Denosumab has a lower relative risk than sodium alendronate and risedronate for vertebral fractures and greater effect on femoral mineral bone density, with a similar risk for non-vertebral fractures and adverse events (infections, cardiovascular disorders, death caused by infection, cardiovascular death or any cause mortality). Denosumab avoids 0.00154 fractures, prevents 0.00025 nursing home/ residential care admissions and get 0.0018 years of life gained per treated patient more than sodium alendronate. Denosumab is slightly more effective and as safe as bisphosphonates, but the effectiveness difference is minimal

Debería usarse Denosumab para la prevención y tratamiento de fracturas osteoporóticas en la mujer postmenopáusica? / Should Denosumab be used for the prevention and treatment of osteoporotic fractures in postmenopausal women?

CONTEXTO: La osteoporosis es un trastorno esquelético caracterizado por resistencia óssea comprometida, predisposición pacientes a un mayor riesgo de fractura. La prevalência aumenta del 6% de las mujeres de edad 50 a 59 años a más del 40% de las mujeres de edad 80 años y mayores.1 Consecuencias de mantener una fractura puede ser grave e incluir un aumento riesgo de fracturas posteriores, hospitalización o institucionalización, disminución de la calidad de vida, y mortalidad prematura, con una carga relacionada com el sistema de salud. DESCRIPCIÓN DE LA TECNOLOGÍA: El denosumab es un anticuerpo monoclonal que inhibe la resorción ósea producida por los osteoclastos. Fue comercializado en 2010 para el tratamiento de la osteoporosis. En estos años se han identificado varios efectos adversos potencialmente graves: predisposición a infecciones, cáncer, reacciones de hipersensibilidad, transtornos autoinmunes, e incremento de la incidencia de múltiples fracturas vertebrales espontáneas al suspender el tratamiento. En este número revisamos estas novedades. TECNOLOGÍAS ALTERNATIVAS: Los agentes antirresortivos como los bifosfonatos orales son el estándar tratamiento para la osteoporosis posmenopáusica, en conjunto con medidas no farmacológicas y sobre todo el énfasis en la prevención de las caídas. Otras opciones de tratamiento incluyen un bisfosfonatos intravenoso (ácido zoledrónico), un agente formador de hueso (teriparatida) y un modulador selectivo del receptor de estrógeno (raloxifeno). MÉTODOS: Se realizó una búsqueda bibliográfica utilizando las siguientes bases de datos bibliográficas: MEDLINE, EMBASE, The Cochrane Library, y PubMed. Aplicaron filtros metodológicos para evaluaciones de tecnología sanitaria, estudios económicos, revisiones sistemáticas, metanálisis, y ensayos controlados aleatorios (ECA). La búsqueda también se limitó a Idioma en Inglés y humanos. Se excluyeron los resúmenes de congresos en los resultados de búsqueda. Se identificó la literatura gris (literatura que no se publica comercialmente) fue identificado mediante la búsqueda de secciones relevantes de la Lista de verificación de Grey Matters (http://www.cadth.ca/en/resources/grey-matters). Google y otros motores de búsqueda de internet fueron se utiliza para buscar en la web adicional materiales Estas búsquedas se complementaron con revisar las bibliografías de documentos clave y a través de contactos con expertos apropiados. ESTRATEGIA DE BÚSQUEDA: Se realizó una búsqueda con última fecha 26/08/2019 en diversas bases de datos, incluidas PubMed y Embase, así como la biblioteca Cochrane, ClinicalTrials.gov y bases de datos de revisiones sistematicas Epistemonikos. La búsqueda sólo incluyó documentos escrito en ingles y espanol. RESULTADOS: Denosumab comparado con placebo para pacientes con osteoporosis. El riesgo en el grupo de intervención (y su intervalo de confianza del 95%) se basa en el riesgo asumido en el grupo de comparación y en el efecto relativo de la intervención (y su intervalo de confianza del 95%). Eficacia frente a bifosfonatos: comparaciones directas. Se evalúa el perfil de evidencia GRADE donde se evidencia el metaanálisis entre cuatro ECA 5-8 que comprendieron 2071 participantes con un rango de seguimiento de 12 a 24 meses y compararon el uso de Denosumab con bifosfonatos orales (Alendronato,Etidronato). Existe incertidumbre en el efecto de denosumab sobre el riesgo de fracturas en comparación con bifosfonatos. La certeza em la evidencia va desde BAJA A MUY BAJA considerando la presencia de imprecisión muy seria y el potencial riesgo de sesgo de publicación. Eficacia frente a bifosfonatos: comparaciones indirectas. No se han encontrado en la literatura comparaciones directas entre Denosumab y otros fármacos distintos. Esta recomendación de cobertura otorga más peso a la incertidumbre en la eficacia comparada con bifosfonatos, al potencial impacto presupuestario de su uso y la potencial reducción de la equidad; que a la preferencia de los pacientes respecto de la forma de administración de las drogas para osteoporosis.

Osteoactivos en insuficiencia renal crónica avanzada: a propósito de un caso / Osteoactive in advanced chronic renal failure: a case report

El propósito de la terapia en el desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica (IRC) consiste en restaurar el balance mineral, y, en la osteoporosis, mantener o aumentar la masa ósea. Ambas terapias tratan de evitar la fractura ósea. La mayoría de los osteoactivos están contraindicados en la insuficiencia renal crónica avanzada (estadios 4 y 5), y las terapias son empíricas. Algunos autores opinan que sin anomalías bioquímicas del desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica avanzada se podría intentar el tratamiento estándar para la osteoporosis. Antes de intentar la terapia osteoactiva se debe corregir el desorden mineral óseo que pudiera presentarse asociado a la IRC, y en la indicación del tipo de osteoactivo se sugiere seleccionar al paciente según su estado óseo. Se aconseja que la administración de los antirresortivos se realice a dosis menores con respecto a los que tienen mejor función renal junto con aportes adecuados de calcio y vitamina D, antes y durante el tratamiento para prevenir el riesgo de severas hipocalcemias y un efecto óseo excesivo. Se presenta el caso clínico de una mujer de 65 años, con diagnóstico de osteoporosis de etiología multifactorial, fractura de pelvis, múltiples fracturas vertebrales e insuficiencia renal crónica avanzada, entre otras comorbilidades, y probable enfermedad ósea adinámica. Recibió inicialmente terapia con teriparatide y luego con denosumab, complicándose con hipocalcemia asintomática. (AU)

The purpose of therapy for the bone mineral metabolism disorder associated with chronic kidney disease is to restore the mineral balance; and to maintain or increase bone mass in osteoporosis. The goal of both types of therapy is to avoid bone fractures. Most antiosteoporotic drugs are contraindicated in advanced chronic renal failure (CRF) stages 4 and 5, and the therapies are empirical. Some authors believe that without biochemical abnormalities of the mineral bone metabolism disorder associated with advanced chronic kidney disease, standard treatment for osteoporosis could be attempted. Before attempting antiosteoporotic therapy, the bone mineral disorder that may be associated with CRF must be corrected, and in the indication of the type drug it is suggested that the patient be selected according to their bone status. It is advised that the administration of anti-resorptives be performed at lower doses in individuals with poor renal function compared to those with better renal function together with adequate calcium and vitamin D, before and during treatment to prevent the risk of severe hypocalcemia, and an excessive bone effect. We present the clinical case of a 65-year-old woman with a diagnosis of osteoporosis of multifactorial etiology, pelvic fracture, multiple vertebral fractures and advanced chronic renal failure, among other comorbidities and probable adynamic bone disease. The patient received initial therapy with teriparatide and followed by denosumab administration and exhibited asymptomatic hypocalcemia. (AU)

Denosumab, tratamiento alternativo en tumor óseo de células gigantes / Denosumab, an alternative treatment for giant cell tumor of bone

Introducción: el tumor óseo de células gigantes (TOCG) es un tumor benigno pero localmente agresivo. Se presenta en población joven y a nivel epifiso-metafisario. Está compuesto por una población celular estromal y otra multinucleada similar a los osteoclastos, donde se destaca la interacción RANK-RANKL (receptor del activador del factor nuclear kappa-B y su ligando, respectivamente). El anticuerpo monoclonal humano denosumab actúa inhibiendo específicamente RANKL, lo que evita la formación y activación de células multinucleadas. En la bibliografía se evidencia que denosumab tiene resultados alentadores como tratamiento adyuvante de algunos TOCG, generando planes terapéuticos con una menor morbimortalidad que los planteados previamente a la administración del anticuerpo. Material y método: se describe la primera experiencia terapéutica en Uruguay con dos pacientes menores de 40 años que consultaron por gonalgia de larga data, realizándose diagnóstico de TOCG estadio III de Campanacci, donde se realiza tratamiento con denosumab de forma protocolar valorando respuesta clínica, imagenológica, efectos adversos y modificación en plan terapéutico inicial. Resultados: se evidenció una respuesta clínica e imagenológica en los pacientes valorados. No se reportaron efectos adversos, logrando preservar la articulación afectada. Conclusiones: los resultados obtenidos son alentadores respecto al uso terapéutico de denosumab en los pacientes seleccionados. Esto permite considerar a denosumab dentro de las opciones terapéuticas de determinados pacientes con diagnóstico de TOCG.

Introduction: giant cell tumor of bone (GCTB) is a benign tumor, although it is locally aggressive. It arises mainly in young people at the epi-metaphyseal level. It consists of stromal cells and osteoclasts-like populations, where the RANK-RANKL (receptor activator of nuclear factor kappa-B and its ligand, respectively) stands out. Denosumab, the human monoclonal antibody, acts by specifically inhibiting RANKL, what prevents the formation and activation of multinucleate cells. The existing bibliography indicates denosumab has obtained encouraging results as adjuvant treatment for some GCTB, enabling therapeutic plans that have lower morbi-mortality rates than those applied prior to administration of the antibody. Method: the study describes the therapeutic experience of two patients younger than 40 years old, who consulted in Uruguay for long standing gonalgia. Campanacci Stage III GCTB was diagnosed, and denosumab treatment was initiated. Clinical response was assessed, as well as imaging response, adverse side effects and the modification of initial treatment. Results: clinical and imaging response was seen in the assessed patients. No adverse side effects were reported, and the affected joint was preserved. Conclusions: the results obtained are encouraging with regard to the therapeutic use of denosumab in the selected patients. This allows for denosumab to be regarded within the therapeutic options for certain patients with a diagnosis of GCTB.

Introdução: O tumor de células gigantes ósseo (TOCG) é um tumor benigno, porém agressivo. Apresenta-se em jovens localizando-se na metáfise e epífise dos ossos; compõe-se de uma população celular estromal e outra multinucleada similar aos osteoclastos, donde se destaca a interação RANK-RANKL (receptor do ativador do fator nuclear kappa-B e seu ligando, respectivamente). O anticorpo monoclonal humano denosumab age inibindo especificamente o RANKL, evitando a formação e a activação de células multinucleadas. A bibliografia mostra que o denosumab tem resultados animadores como tratamento adjuvante de alguns TOCG, com planos terapêuticos com menor morbimortalidade que os utilizados antes da administração do anticorpo. Material e método: descreve-se a primeira experiencia terapêutica no Uruguai com dois pacientes com menos de 40 anos que consultaram por gonalgia de longa data, realizando-se diagnóstico de TOCG estádio III de Campanacci; realizou-se tratamento com denosumab de acordo com o protocolo e avaliando a resposta clínica, a imagenología, os efeitos adversos e a modificação no esquema terapêutico inicial. Resultados: evidenciou-se uma resposta clínica e na imagenología nos pacientes avaliados. Não se informaram efeitos adversos, sendo possivel preservar a articulação afetada. Conclusões: os resultados obtidos são animadores com relação ao uso terapêutico do denosumab nos pacientes selecionados. Isto permite considerar o denosumab como opção terapêutica para determinados pacientes com diagnóstico de TOCG.

Osteoporose: seleção de medicamentos e avanços no manejo clínico / Osteoporosis: medication selection and advances in the clinical management

Osteoporose é um problema de saúde pública importante que acomete mais de metade das mulheres com idade superior a 50 anos. Doença com um enorme impacto sobre a saúde pública, através da morbidade e mortalidade aumentadas, com custos econômicos associados resultantes das fraturas. O objetivo é avaliar e identificar as pessoas de risco para desenvolver fraturas osteoporóticas de fragilidade que necessitam ser tratadas. A abordagem de mulheres com baixa massa óssea e aumento do risco de fraturas deve ser multidisciplinar. A farmacoterapia é apenas uma Steiner ML, Strufaldi R, Fernandes CE das possíveis intervenções. Aspectos como a nutrição orientada, fortalecimento muscular, prevenção de quedas, suplementos vitamínicos e minerais devem ser considerados. O tratamento farmacológico permite a prevenção da perda óssea, a prevenção primária e secundária de fragilidade óssea e deve ser baseado na avaliação do risco de fratura do indivíduo e na relação custo-benefício do medicamento escolhido.

Osteoporosis is a significant public health problem that affects more than half of women aged over 50. This disease has a huge impact on public health through morbidity and increased mortality, and economic costs associated with the resulting fractures. The goal is to assess and identify risk people to develop osteoporotic fragility fractures that need to be addressed. The approach of women with low bone mass and increased risk of fractures should be multidisciplinary. Pharmacotherapy is just one of the possible interventions. Aspects such as the guidance nutrition, muscle strengthening, prevention of falls, mineral and vitamin supplements should be considered. Pharmacological treatment allows preventing bone loss and primary and secondary prevention of osteoporosis and should be based on risk factors and pharmaceutical cost benefit analysis.

Evaluación de la respuesta densitométrica en pacientes con osteoporosis posmenopáusica tratadas con ranelato de estroncio o denosumab / Densitometric response in postmenopausal osteoporosis treated with strontium ranelate or denosumab

Tanto el ranelato de estroncio (RSr) como el denosumab (Dmab) son eficaces en el tratamiento de la osteoporosis (OP) posmenopáusica (PM). El efecto de cada fármaco por separado sobre la densidad mineral ósea (DMO) ha sido estudiado recientemente. Con ambas drogas se observó, al año de tratamiento, un aumento significativo de la DMO en columna lumbar (CL), cuello femoral (CF) y cadera total (CT). En este trabajo comparamos la respuesta densitométrica al año de tratamiento con una y otra droga. Utilizamos los registros de 425 pacientes PMOP tratadas con Dmab y 441 tratadas con RSr. En cada paciente analizamos el porcentaje de cambio; se clasificaron como respondedoras aquellas que mostraron un cambio ≥3%. Adicionalmente se comparó la respuesta en pacientes no previamente tratadas con bifosfonatos (BF-naïve) en comparación con pacientes que habían recibido previamente un BF. Al analizar el grupo completo para Dmab, el porcentaje de pacientes respondedoras fue de 68,4% en CL, 63,3% en CF y 49,3% en CT. Por otro lado, en el grupo de pacientes tratadas con RSr, el porcentaje de respondedoras (53,8% en CL, 40,0% en CF y 35,6% en CT) fue estadísticamente menor. Cuando comparamos la respuesta entre las pacientes BF-naïve que recibieron RSr o Dmab, el Dmab indujo mayor respuesta en CL y CF que el grupo RSr, sin diferencias en CT. Cuando se analizaron los subgrupos BF-previo, las tratadas con Dmab mostraron mayor respuesta en todas las regiones. Conclusión: en pacientes con OP-PM, el tratamiento con Dmab produjo mayores incrementos densitométricos que el RSr, siendo el porcentaje de pacientes respondedoras mayor con Dmab que con RSr. (AU)

Both strontium ranelate (SrR) and denosumab (Dmab) are effective in the treatment of postmenopausal osteoporosis (PMOP). The effect of each drug on bone mineral density (BMD) has been studied separately by us. With both treatments, there was a significant increase after one year of treatment at the lumbar spine (LS) and hip. In this paper we compared the densitometric response after one year of treatment with both drugs used separately. We used the clinical records of 425 PM patients treated with Dmab and 441 treated with SrR. For each patient we analyzed the percentage of change; those who showed a change ≥3% were classified as responders. Additionally, the response was compared in patients not previously treated with bisphosphonates (BP-naïve) compared to patients who had previously received a BP. When analyzing the complete group for Dmab, the percentage of "responders" was 65.2% at the LS, 62.9% at the femoral neck (FN) and 47.4% at the total hip (TH). On the other hand, in the group of patients treated with SrR the percentage of responders (53.8% at the LS, 40.0% at the FN and 35.6% at the TH) was statistically lower. When comparing the response between in BF-naïve patients receiving RSr or Dmab, Dmab induced a greater response at the LS and FN than the RSr group, with no statistical differences at the TH. When the subgroups with prior BP treatment were analyzed, those treated with Dmab showed greater response in all regions. Conclusion: in patients with PMOP treatment with Dmab produced greater densitometric increments than SrR, and the percentage of responders was higher with Dmab than with SrR. (AU)

Assessment of Denosumab in Korean Postmenopausal Women with Osteoporosis: Randomized, Double-Blind, Placebo-Controlled Trial with Open-Label Extension

PURPOSE: The efficacy and safety of denosumab was compared with placebo in Korean postmenopausal women with osteoporosis in this phase III study. MATERIALS AND METHODS: Women aged 60 to 90 years with a T-score of <-2.5 and ≥-4.0 at the lumbar spine or total hip were randomized to a single 60 mg subcutaneous dose of denosumab or placebo for the 6-month double-blind phase. Eligible subjects entered the 6-month open-label extension phase and received a single dose of denosumab 60 mg. RESULTS: Baseline demographics were similar in the 62 denosumab- and 64 placebo-treated subjects who completed the double-blind phase. Treatment favored denosumab over placebo for the primary endpoint {mean percent change from baseline in lumbar spine bone mineral density (BMD) at Month 6 [3.2% (95% confidence interval 2.1%, 4.4%; p<0.0001)]}; and secondary endpoints (mean percent change from baseline in lumbar spine BMD at Month 1, total hip, femoral neck, and trochanter BMD at Months 1 and 6, and median percent change from baseline in bone turnover markers at Months 1, 3, and 6). Endpoint improvements were sustained over 12 months in the open-label extension (n=119). There were no new or unexpected safety signals. CONCLUSION: Denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a 12-month period in Korean postmenopausal women. The findings of this study demonstrate that denosumab has beneficial effects on the measures of osteoporosis in Korean postmenopausal women.

Bone health in cerebral palsy and introduction of a novel therapy / A saúde do osso na paralisia cerebral e a introdução de uma nova terapia

ABSTRACT Objective To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. Methods Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. Results Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. Conclusion Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms.

RESUMO Objetivo Avaliar o estado de saúde dos ossos em crianças com paralisia cerebral e o efeito terapêutico do denosumabe em um subgrupo de crianças com paralisia cerebral e redução da massa óssea. Métodos Crianças com paralisia cerebral foram avaliadas de acordo com seu escore de incapacidade motora (sistema de classificação para funções motoras grossas, de III a V), e marcadores de turnover ósseo. Dual de absorção de energia de raios X foi utilizado para medir a coluna lombar e total do corpo menos cabeça. Posteriormente, um grupo de crianças com paralisia cerebral e osteoporose foi tratado com denosumabe, um anticorpo monoclonal totalmente humano. Marcadores de remodelação óssea foram medidos antes e três meses após o tratamento. Resultados Houve uma redução da densidade óssea, particularmente em crianças com maior comprometimento do escore motor; os marcadores de remodelação óssea diminuíram em um grupo selecionado de crianças três meses depois de terem sido expostas ao denosumabe. Conclusão A perda óssea esteve presente em crianças com importante comprometimento das funções motoras, além da redução nos níveis séricos de marcadores de reabsorção óssea com novos tratamentos.