Eficácia e segurança de romosozumabe para o tratamento de osteoporose grave em mulheres na pós-menopausa: revisão sistemática e meta-análise em rede / Efficacy and safety of romosozumab for the treatment of severe osteoporosis in postmenopausal women: systematic and network meta-analysis

Introdução: A osteoporose é uma das principais causas de morbimortalidade, principalmente em idosos e mulheres na pós-menopausa, devido ao aumento da fragilidade óssea e maior suscetibilidade a fraturas. Objetivo: Avaliar a eficácia e segurança do romosozumabe, comparado aos tratamentos farmacológicos atualmente disponíveis no Sistema Único de Saúde para o manejo de mulheres na pós-menopausa com osteoporose grave e alto risco de fraturas. Métodos: Foi realizada uma busca seguida por meta-análises indiretas, por ensaios clínicos randomizados (ECR) nas bases PubMed Central e Medline, Embase e Cochrane Library e por busca manual. O risco de viés (RoB 2.0) e a qualidade da evidência (GRADE) foram analisados. Meta-análises indiretas foram realizadas para desfechos de fraturas, densidade mineral óssea e eventos adversos. Resultados: Sete ECR (n= 19.951 mulheres) foram incluídos nesta revisão. Romosozumabe seguido de alendronato reduziu risco de fraturas não vertebrais em 12 meses (RR: 0,64, IC 95%: 0,49-0,84; alta certeza de evidência) e em 24 meses (RR: 0,52, IC 95%: 0,43-0,64; (alta certeza de evidência) na comparação ao alendronato. Achados semelhantes foram identificados para outros desfechos. Ácido zoledrônico foi associada a maior risco de descontinuação por evento adverso que placebo (RR: 1,02, IC 95%: 1,01-1,03). Conclusão: Foi identificado que romosozumabe ou romosozumabe seguido por alendronato são eficazes e seguros na comparação com alendronato.

Background: Osteoporosis is a major cause of morbidity and mortality, especially in the elderly and postmenopausal women, due to increased bone fragility and greater susceptibility to fractures. Objective: To evaluate the efficacy and safety of romosozumab, compared to pharmacological treatments currently available in the Unified Health System of Brazil for the management of postmenopausal women with severe osteoporosis and high risk of fractures. Methods: A search was carried out followed by indirect meta-analyses, randomized controlled trials (RCTs) in PubMed Central and Medline, EMBASE, and Cochrane Library databases and manual search. Risk of bias (RoB 2.0) and quality of evidence (GRADE) were assessed. Indirect frequentist meta-analyses were carried out for outcomes related to fractures, bone mineral density, and adverse events. Results: Seven RCTs (n= 19,951 woman) were included in this review. Romosozumab followed by alendronate reduced the risk of non-vertebral fractures at 12 months (RR: 0.64, 95% CI: 0.49-0.84; high certainty of evidence) and at 24 months (RR: 0.52, CI 95 %: 0.43-0.64; (high certainty of evidence) in comparison to alendronate. Similar findings were identified for other outcomes. Zoledronic acid was associated with a higher risk of discontinuation due to adverse events than placebo (RR: 1.02, 95% CI: 1.01-1.03). Conclusion: This review identified that romosozumab or romosozumab followed by alendronate are effective and safe compared to alendronate.

Avaliação da resposta óssea de uma superfície de implante revestida com odanacatib em ratas ovariectomizadas: estudo experimental in vivo / Evaluation of the bone response of an odanacatib coated implant surface in ovariectomized rats: in vivo experimental study

Atualmente novos princípios ativos de função reabsortiva têm ganhado campo de estudo para avaliar seus mecanismos e comportamento biológico. Com isso, um novo antirreabsortivo, inibidor da catepsina K tem apresentado efeito positivo na osseointegração. Este estudo tem como objetivo avaliar a resposta óssea da superfície de implantes revestida por duplo ataque ácido e Odanacatib (MK-0822) em ratas ovariectomizadas. Neste estudo foram utilizadas ratas (Albinus, Wistar) ovariectomizadas ou sham (placebo). Cinquenta e dois (52) tiveram as superfícies revestidas por duplo ataque ácido e MK-0822 a 0,06 mg/ml através do método biomimético, e 48 implantes foram instalados em tíbias de ratas ovariectomizadas ou sham. Microscopia eletrônica de varredura (MEV) e energia dispersiva de raios-x (EDS) foram realizadas em 4 implantes após tratamento de superfície, para análise da topografia e composição química, além da realização da análise do ângulo de contato em 16 discos de titânio comercialmente puro tratados com as mesmas superfícies. Aos 15 e 40 dias após instalação de implantes (n=6), foi realizada microtomografia computadorizada. Dados quantitativos foram avaliados adotando-se o nível de significância p< 0,05. Além dos resultados topográficos favoráveis para os grupos tratados com MK-0822, os resultados microtomográficos apresentaram diferença estatisticamente significante entre os grupos SHAM e OVX na maioria dos parâmetros (p< 0,05). Ainda assim, os grupos tratados com MK-0822 apresentaram resultado semelhante ou maior, porém sem diferença estatística, em relação ao grupo controle em todos os parâmetros (TV, BV, BV ̸TV, Tb.Sp e Tb.N)(AU)

Currently new active principles of resorptive function have gained field of study to evaluate their mechanisms and biological behavior. Thereby a new anti-absorbent, cathepsin K inhibitor has had a positive effect on osseointegration. This study aims to evaluate the bone response of the surface of implants coated by double acid-etched and Odanacatib (MK-0822) in ovariectomized rats. In this study, either ovariectomized rats (Albinus, Wistar) or sham (placebo) have been used. Fifty-two (52) implants had the surfaces coated with double acid-etched and MK-0822 at 0,06 mg/ml by the biomimetic method and 48 implants were installed on sham or ovariectomized rat tibias. Scanning electron microscopy (SEM) and X-ray dispersive energy (EDS) were performed in 4 implants after surface treatment for analysis of topography and chemical composition, in addition to performing contact angle analysis on 16 commercially pure titanium discs treated with the same surfaces. At 15 and 40 days after implant installation, microcomputer tomography was performed. Quantitative data was evaluated by adopting the significance level of p< 0.05. Besides the favorable topographic results to MK-0822 coated implants group, the microtomographic results presents statistically significant differences between the SHAM and OVX groups at most of the parameters (p< 0,05). Nevertheless, the MK-0822 coated group presents similar or higher values, although without statistic differences related to the control group in all parameters (TV, BV, BV ̸TV, Tb.Sp and Tb.N)(AU)

Analysis of the Degree of Information of Dental Surgeons about Antiresorptive Drugs According to the Time Since Graduation in Dentistry

ABSTRACT Objective: To determine the level of scientific information of dental surgeons who carry out their professional activities in Brazil about antiresorptive drugs and indicated pharmacological procedures aiming at the prevention of osteonecrosis of the jaws and the therapy of drug sequelae that may occur, considering the time since graduation in Dentistry. Material and Methods: This is a quantitative cross-sectional study in which 339 dentists were consulted using the virtual questionnaire containing topics of personal nature, elements contained in the anamnesis carried out and knowledge about antiresorptive drugs, including indications, adverse effects and treatments applied. Chi-square and Fisher's exact tests were performed to analyze associations of data described by absolute and relative frequencies with professionals' time since graduation. All analyses were performed using the R software, with a 5% significance level. Results: Those who revealed to have graduated for more than five years with the highest academic degree were those who demonstrated maximum knowledge of antiresorptive drugs or revealed that, somehow, they had information about them (p<0.05). Conclusion: Dental surgeons in Brazil who have more than five years since graduation have more scientific information about antiresorptive drugs and pharmacological procedures, which can positively contribute to the prevention of osteonecrosis of the jaws and treatment of drug sequelae that may occur.

[Therapeutic alternatives for drug-associated maxillary osteonecrosis (MRONJ): reports of two clinical cases and review of the literature]. / Alternativas terapéuticas de osteonecrosis maxilar asociada a medicamentos (ONMAM): reportes de dos casos clínicos y revisión de la literatura.

Introduction: Drug-associated Maxillary Osteonecrosis is one of the most relevant adverse effects in treatment with antiresorptive drugs such as bisphosphonates and denosumab. Oncological conditions such as multiple myeloma, breast cancer, prostate, and bone-metabolic disorders such as osteoporosis lead the indications for these antiresorptive therapies. Treatment is complex because the disease is often refractory. Pharmacological, conservative and surgical treatments are described. Objective: The aim of this study is to report two clinical cases of MRONJ treated with two different therapeutic protocols and the analysis of the available literature on these aspects based on the clinical classification defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Conclusion: Patients who develop clinical signs of great morbidity associated with MRONJ, may see their quality of life conditioned and suffer a worsening of their underlying pathology. MRONJ treatment is conditioned by the stage of the disease, its success depends on interdisciplinary management and strict medical and dental clinical follow-up, as well as rigorous monitoring to prevent or detect future recurrences early.

Introducción: La Osteonecrosis Maxilar asociada a Medicamentos (ONMAM) constituye uno de los efectos adversos más relevantes en el tratamiento con drogas antirresortivas como bifosfonatos y denosumab. Patologías oncológicas como mieloma múltiple, cáncer de mama, próstata, y alteraciones óseas-metabólicas como la osteoporosis lideran las indicaciones para estas terapias antirresortivas. El tratamiento es complejo debido a que muchas veces, la enfermedad es refractaria a la terapéutica aplicada. Se describen tratamientos farmacológicos, conservadores y quirúrgicos. Objetivo: El objetivo de este trabajo es reportar dos casos clínicos de ONMAM tratados con dos protocolos terapéuticos diferentes y el análisis de la literatura disponible en la actualidad sobre estos aspectos en base a la clasificación clínica definida por la American Association of Oral and Maxillofacial Surgeons (AAOMS). Conclusión: Los pacientes que desarrollan cuadros clínicos bucales de gran morbilidad como lo es ONMAM, pueden ver condicionada su calidad de vida y sufrir un agravamiento de su patología de base. El tratamiento de ONMAM está condicionado al estadio de la enfermedad, el éxito del mismo depende del manejo interdisciplinario y de un estricto seguimiento clínico médico y odontológico, así como también un riguroso monitoreo para evitar o detectar precozmente futuras recurrencias.

A systematic review assessing occurrence of medication-related osteonecrosis of the jaw following dental procedures

Aim: This study aimed to systematically review existing literature regarding the association between dental procedures­such as tooth extractions and periodontal therapy­and occurrence of medication-related osteonecrosis of the jaw (MRONJ) in individuals using bone-modifying drugs. Methods: Search strategies were performed in PubMed, Scopus, Web of Science and Cochrane Library for a timeframe ending in December 2021. Study selection, data extraction and risk of bias were analyzed independently by two researchers. Three meta-analyses were performed, estimating the crude risk ratio (RR), the adjusted odds ratio (OR) and the adjusted hazard ratio (HR) for the association between tooth extraction and MRONJ. Results: Of the 1,654 studies initially retrieved, 17 were ultimately included. The majority of patients with MRONJ in these studies were female, with a mean age of 64 years. Zoledronic acid was the most commonly used drug among patients with MRONJ, and cancer was the most frequent underlying health condition. Regarding the performed meta-analyses, crude and adjusted analyses demonstrated that tooth extraction increased the risk for MRONJ by 4.28 (95% confidence interval [95%CI]: 1.73­10.58), the OR for MRONJ by 26.94 (95%CI: 4.17­174.17), and the HR for MRONJ by 9.96 (95%CI: 4.04­24.55). Conclusion: It was concluded that performing dental procedures, especially tooth extraction, in patients using bone-modifying drugs increased the risk of MRONJ occurrence and, therefore, should be avoided. Further studies, using adjusted data, are warranted

Impact of Antiresorptive Agents on Maxillary Bones: a Narrative Literature Review / Impacto dos Agentes Antirreabsortivos nos Ossos Maxilares: uma Revisão de Literatura narrativa

Abstract Antiresorptive drugs operate in the bone metabolism modulation and are widely used in the treatment of bone metastases and bone losses related to hormonal deficiency. Although this therapy shows satisfactory results, there are adverse effects associated with its use, such as osteonecrosis of the jaws. Medication-related osteonecrosis of the jaws (MRONJ) is, therefore, a serious and challenging condition with important implications in dentistry. The aim was to conduct a narrative literature review on anti-resorptive drugs and their latest repercussions on the maxillary bones. The review was carried out through a bibliographic search using Decs/Mesh descriptors of interest, in Portuguese and English, in the PubMed, Virtual Health Library (VHL) and Scielo databases. After applying the inclusion and exclusion criteria, a total of 33 studies were selected for analysis. It can be noticed that therapy with anti-resorptive agents is complex, especially in dental practice, since MRONJ is a complication that is difficult to manage. Regarding the therapeutic options, these are divided into conservative, surgical or adjuvant therapy, however, there are no protocols in the literature, and there is no consistency regarding the indication of the suspension of the drug administration - "Drug Holiday". Thus, it is important that the multidisciplinary team seeks strategies that minimize complications and promote control over the use of these drugs. In addition, there is a need for investigations that contribute with guidelines for the management and control of adverse effects resulting from therapy with antiresorptive drugs. (AU)

Resumo As drogas antirreabsortivas atuam na modulação do metabolismo ósseo e são indicadas para o tratamento de metástases ósseas e perdas ósseas relacionadas à deficiência hormonal. Ainda que esta terapia apresente resultados satisfatórios, observam-se efeitos adversos associados ao seu uso, como a osteonecrose dos maxilares. A osteonecrose dos maxilares associada ao uso de medicamentos (OMAM) é, portanto, uma condição séria e desafiadora com implicações importantes na Odontologia. O objetivo foi realizar uma revisão narrativa de literatura sobre as drogas antirreabsortivas e suas respectivas repercussões nos ossos maxilares. A revisão foi realizada através de busca bibliográfica utilizando descritores Decs/Mesh de interesse, em português e inglês, nas bases de dados PubMed, Biblioteca Virtual de Saúde (BVS) e Scielo. Após aplicação dos critérios de inclusão e exclusão, um total de 33 trabalhos foram selecionados para análise. Pode-se constatar que a terapia com agentes antirreabsortivos é complexa, sobretudo na prática odontológica, visto que a OMAM é uma complicação de difícil manejo. Em relação às condutas terapêuticas para esta condição, divide-se em terapia conservadora, cirúrgica ou adjuvante, todavia, não existem protocolos validados na literatura, bem como não há consistência quanto à indicação do intervalo de suspensão da administração da droga - "Drug Holiday". Desse modo, é importante que a equipe multidisciplinar busque estratégias que minimizem as complicações e promovam o controle no uso dessas drogas. Além disso, nota-se a necessidade de realizar investigações que contribuam com diretrizes para o manejo e controle dos efeitos adversos decorrentes da terapia com medicamentos antirreabsortivos. (AU)

Clinical and demographic characterization of the population with osteoporosis in two reference medical centres in Colombia / Caracterización clínica y demográfica de la población con osteoporosis en 2 centros médicos de referencia en Colombia

ABSTRACT Introduction: Osteoporosis is a public health problem. However, there is still a lack of data in Colombia on the characteristics of patients with osteoporosis. Objectives: This study aims to characterize the population with osteoporosis without previous diagnosis. Materials and methods: Observational, retrospective, descriptive study in patients with osteoporosis. Patients diagnosed between 2014 and 2017 were included. The information was obtained from the patient medical records and the densitometry results. Results: Most (92.2%) of the patients came from Medellín, and the rest from Cali. The mean age of the population was 65.1 years (SD: 9.97). As regards the history of fracture, it was reported that 12.0% had suffered from vertebral fractures, 2.3% had a history of fracture in the distal radius, 2.8% in the femoral neck, and 1.4% had had femoral shaft fracture. Bone densitometry showed a mean T-score of -2.90 in the femoral neck; -3.02 in total hip; -3.03 in the lumbar spine, and -3.42 in the 33% radius. In the 602 patients who had a control bone densitometry, an average BMD gain was seen in all the evaluated regions. Conclusions: The present study has enabled the characterizing of patients from 2 Colombian cities with a diagnosis of osteoporosis. The 2 most frequently reported locations for the diagnosis of osteoporosis were lumbar spine and femoral neck. An average BMD gain was also observed.

RESUMEN Introducción: La osteoporosis es un problema de salud pública, sin embargo, en Colombia en la actualidad faltan datos sobre las características de los pacientes con esta enfermedad. Objetivos: Este estudio pretende caracterizar la población con osteoporosis sin diagnóstico previo. Materiales y métodos: Estudio observacional, retrospectivo, descriptivo en pacientes con osteoporosis. Incluyó a pacientes diagnosticados entre el 2014 y el 2017. La información fue obtenida a partir de las historias clínicas de los pacientes y el resultado de la densitometría. Resultados: El 92,2% de los pacientes provenía de Medellín y los restantes de Cali. La edad promedio ± desviación estándar de la población fue 65,1 ± 9,97 arios. En cuanto al antecedente de fractura, se reportó que el 12,0% había presentado fracturas vertebrales, el 2,3% tenía antecedente de fractura en radio distal, el 2,8% en cuello femoral y el 1,4% había tenido fractura de diáfisis femoral. La densitometría ósea (DMO) mostró un T-score promedio de -2,90 en cuello femoral, -3,02 en cadera total, -3,03 en columna lumbar y-3,42 en radio 33%. En los 602 pacientes que contaban con DMO de control se vio una ganancia de la DMO promedio en todas las regiones evaluadas. Conclusiones: El presente estudio permitió caracterizar a pacientes con diagnóstico de osteoporosis en 2 ciudades de Colombia. Las 2 localizaciones más reportadas para el diagnóstico de osteoporosis fueron columna lumbar y cuello femoral; adicionalmente, se observó una ganancia de la DMO promedio.

Diagnostic, treatment, and follow-up of osteoporosis-position statement of the Latin American Federation of Endocrinology.

The Latin American Federation of Endocrinology position statement on osteoporosis was developed by endocrinologists from 9 countries. It encompasses the definition, diagnosis, treatment, and follow-up of the disease, the identification of barriers to healthcare, and proposals to improve the disease care in the region. INTRODUCTION: There is a gap in the understanding of osteoporosis in Latin America. The objective of this work is to state the position of the Latin American Federation of Endocrinology on osteoporosis care in postmenopausal women to better bridge this gap. METHODS: An experts' panel was formed comprising of 11 endocrinologists from 9 countries. A data search was conducted with a conceptual approach and data selection was based on the hierarchy of the EBHC pyramid. Unpublished data was considered for local epidemiological data and expert opinion for the identification of barriers to healthcare. An expert consensus based on the Delphi methodology was carried out. Experts were asked to respond on a 5-point Likert Scale to two provided answers to guiding questions. RESULTS: Consensus was agreed on the answer for the questions with the higher median on the Likert scale and synthetized on 16 statements covering the definition of osteoporosis, diagnostic approach, treatment options, and follow-up. Besides clinical topics, unmet needs in osteoporosis were identified in relation to local epidemiological data, barriers to treatment, and misclassification of programs within health systems. CONCLUSIONS: Through a process based on recognized methodological tools, FELAEN's position on osteoporosis was developed. This made it possible to state an optimum scenario for the care of the disease and helped to identify knowledge gaps. There is great variability in the approach to osteoporosis in Latin America and barriers in all the stages of healthcare persist.

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

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

Avaliação do efeito do tratamento com alendronato na artrodese lombar em ratas osteoporóticas / Evaluation of alendronate treatment on lumbar arthrodesis in osteoporotic rats

A osteoporose é um distúrbio osteometabólico caracterizado pela redução da densidade mineral óssea. Estima-se que 200 milhões de pessoas possuam osteoporose no mundo. A doença é fator de risco para falha do processo de fusão vertebral, que consiste na consolidação de vértebras adjacentes através da colocação de enxertia óssea e estabilização mecânica, fundamental para o sucesso das cirurgias da coluna vertebral. O alendronato é um medicamento antirreabsortivo utilizado no tratamento da osteoporose. Apesar de sua eficácia, sugere-se que retarda o processo de remodelamento no sítio cirúrgico da fusão vertebral, atrasando a osteointegração do enxerto aos corpos vertebrais. Ainda não há consenso sobre a melhor abordagem medicamentosa para os pacientes osteoporóticos que se encontram em uso crônico de alendronato e que serão submetidos ao procedimento cirúrgico de fusão vertebral. Este estudo avaliou o efeito do alendronato na consolidação óssea do procedimento de fusão vertebral em ratas osteoporóticas. Quinze ratas da linhagem Sprague Dawley foram divididas em três grupos: Grupo Não-OVX (n=3) - ratas não submetidas a ooforectomia e submetidas a fusão espinhal; Grupo OVX (n=5) - ratas submetidas a ooforectomia entre 8 a 12 semanas de vida e à fusão vertebral 12 semanas após a ooforectomia e Grupo ALN (n=7) - ratas ooforectomizadas e submetidas a fusão vertebral que receberam semanalmente 70µg/kg de alendronato iniciado 5 semanas antes da fusão vertebral e mantido até a eutanásia. Foram coletadas amostras de sangue semanalmente e os animais foram submetidos a eutanásia 8 semanas após a fusão vertebral. A condição osteoporótica foi confirmada através da dosagem por ELISA dos níveis plasmáticos de CTX-I 12 semanas após ooforectomia, que foi maior no grupo OVX em relação ao grupo Não-OVX (p=0,0086). Os parâmetros da microestrutura do corpo vertebral medidos através da microtomografia computadorizada (µCT) denotam redução na fração de volume ósseo (BV/TV) (p=0,116), no número de trabéculas (Tb.N) (p=0,116), na espessura das trabéculas (Tb.Th) (p=0,033), e leve aumento na desconexão entre as trabéculas (Tb.pf p = 0,086). Quanto à eficiência da fusão, a avaliação radiográfica do segmento lombar revelou taxa de fusão de 75% (3/4) no grupo Não-OVX, 100% (3/3) no grupo OVX e nenhuma fusão no grupo ALN. Pela avaliação manual, os resultados foram semelhantes para os grupos Não-OVX e OVX e de 57,1% (4/7) no grupo ALN. A avaliação dos aspectos estruturais da massa da fusão por µCT revelou maior BV/TV (p ≤ 0,05), maior Tb.N (p ≤ 0,01), maior espaçamento entre as trabéculas (Tb.Sp) (p ≤ 0,01) e Conn.Den (p = 0,02) no grupo ALN em relação aos grupos OVX e não OVX. O grupo ALN também apresentou maior Tb.Th (p = 0,04) e menor Tb.pf (p = 0,03) do que o grupo OVX. As ratas osteoporóticas submetidas a cirurgia de fusão vertebral e tratadas com alendronato apresentaram menor taxa de fusão vertebral, apesar de possuir melhor qualidade da massa de fusão. Imaginavamos que o tratamento crônico com alendronato, assim como o tratamento iniciado após a cirurgia, leve à formação de massas de fusão com maior qualidade trabecular e mais exuberantes, porém, diferente do observado quando o tratamento é iniciado após a cirurgia, não resulta em aumento na taxa de fusão

Osteoporosis is an osteometabolic disorder characterized by reduced bone mineral density. About 200 million people are affected in the world and the disease is a risk factor for pseudoarthrosis in spinal fusion. Alendronate is a bisphosphonate medication that inhibits bone resorption and is used to treat osteoporosis. Despite its effectiveness, it is suggested that`s impairs bone remodeling at the surgical site of spinal fusion, delaying the osteointegration of the bone graft to the vertebral bodies. There is still no consensus on the best approach for osteoporotic patients who are in chronic use of alendronate and who will undergo surgical procedure for spinal fusion. This study sought to examine the effect of the chronic use of alendronate on bone formation of spinal fusion in osteoporotic rats. Fifteen Sprague Dawley adult female rats were divided into three groups: Non-OVX (n=3) ­ non-ovariectomized rats submitted to posterolateral lumbar spinal fusion; OVX (n=5) - rats submitted to ovariectomy at 8 ­ 12 weeks of age and to posterolateral lumbar spinal fusion 12 weeks later; and ALN (n = 7) ­ ovariectomized rats submitted to spinal fusion in which weekly subcutaneous injections of Alendronate (70µg/kg) were administered from 5 weeks before the spinal fusion until euthanasia. Blood samples were collected weekly and euthanasia was performed 8 weeks after the spinal fusion procedure. Development of osteoporosis was evaluated through the plasmatic dosage of CTX-I, in which we observed a significant increase in the OVX group (p=0.0086). Bone loss was confirmed by micro-CT analysis of the fourth lumbar vertebra, with slightly reduction in the bone volume (BV/TV) (p=0.116), trabecular number (Tb.N) (p=0.116), significantly reduction in the trabecular tickness (Tb.Th) (p=0.033), and slightly increase in the trabecular bone pattern factor (TB.pf) (p = 0.086). Radiographic evaluation of the lumbar spine revealed fusion rate of 75% (3/4) in Non-OVX, 100% (3/3) in OVX, and no fusion in ALN. According to manual palpation, we observed similar results for the non-OVX and OVX goup, while in the ALN group we observed 57.1% (4/7) of fusion rate. New bone formation identified on µCT imaging of bilaterally fused specimens demonstrated a higher BV/TV (p ≤ 0.05), Tb.N (p ≤ 0.01), Tb.Sp (p ≤ 0.01), and connective density (Conn.Den, p = 0.02) in ALN than in nonOVX and OVX groups. The alendronate also improved the Tb.Th (p = 0.04) and Tb.pf (p = 0.03) in comparisson to OVX group. This study demonstrates that, despite the better quality of new bone formation after long term administration of alendronte in osteoporotic rats submitted to posterolateral spinal fusion, the treatment does not improve the fusion rates

Nitrogen-containing bisphosphonate therapy-Part II: Assessment of alveolar bone tissue inflammatory response in rats-A blind randomized controlled trial.

This study aimed to evaluate the alveolar bone tissue inflammatory response in rats undergoing zoledronic acid therapy. The study sample was composed of 28 Wistar rats. Animals from the test group GTa received a weekly intraperitoneal dose of 0.2 mg/kg of zoledronic acid for 3 weeks, while test group GTb received the same dose for 8 weeks. A physiological saline dose, equivalent to that of the medication, was administered to the controls in groups GCa and GCb. A defect was created in the dental crown of the lower first molars using a drill to simulate pulp and periapical injury. Data were evaluated regarding image grey levels by cone-beam computed tomography and histologically by assigning scores for the presence of inflammatory infiltrate, type of infiltrate, vascularization, bone necrosis and dental resorption. Grey levels in the 3-week therapy group (GTa) showed more pronounced changes in comparison with those seen in the GCa group (P < 0.05). Evaluation of the scores demonstrated no association between any of the variables amongst the groups (>0.05). However, bone remodelling decreased in the groups receiving the medication. Bone necrosis was present more frequently in group GTb than in the control group GCb. The results suggest that the drug interfered in the reaction capacity of the alveolar bone tissue as test group GTa showed higher grey levels in comparison to the control group GCa. In addition, there was less bone remodelling activity, with the appearance of bone necrosis zones and intense acute inflammatory infiltrate associated with the 8-week therapy group GTb.

Biomateriais de substituição óssea para procedimentos de reconstrução alveolar em implantodontia / Bone replacement biomaterials for alveolar reconstruction procedures in implantology

Introdução: a reconstrução do processo alveolar para a reabilitação de pacientes edêntulos com implantes dentários vem se tornando uma realidade segura e previsível. Desta forma, conhecer as características destes tecidos e biomateriais é fundamental para o sucesso. Contudo, a diversidade de marcas e produtos presentes no mercado geram dúvidas na seleção do biomaterial. Objetivo: este estudo tem como objetivo caracterizar os biomateriais disponíveis no mercado brasileiro para procedimentos de reconstrução óssea em implantodontia. Metodologia: Foram incluídos 18 biomateriais de substituição óssea disponíveis no mercado nacional (Brasil), registrados e regulamentados pela agência nacional de vigilância sanitária (ANVISA). As empresas fabricantes foram contatadas para fornecer as informações dos seus respectivos produtos. Resultados: Após a análise dos 18 biomateriais encontrados no mercado nacional, as informações obtidas segundo os fabricantes foram classificadas nos seguintes itens: produto e empresa, granulometria, porosidade, forma de apresentação, composição, origem, propriedade biológica e se for fe procedência nacional ou importado. Discussão: conforme as propriedades de cada tecido ou material, ele pode possuir um ou mais mecanismos de formação óssea. A composição química, forma física e as diferenças de superfície resultam em diferentes níveis de reabsorção. Dessa forma, é importante para o clínico conhecer a natureza variada dos biomateriais disponíveis que vão determinar a velocidade e sua forma de reabsorção. Conclusão: Este estudo tabulou os biomateriais estudados, quanto suas principais características biológicas, visando orientar os profissionais da saúde na escolha do biomaterial mais adequado para alcançar seus objetivos no tratamento

Concordancia de la utilización de teriparatide o ácido zoledrónico en pacientes con osteoporosis con recomendaciones internacionales, en una empresa de salud de Colombia / Concordance in the use of teriparatide or zoledronic acid in patients with osteoporosis with international recommendations, in a health company of Colombia

RESUMEN Introducción: Los bifosfonatos son la primera línea de tratamiento para la osteoporosis; siendo el zolendronato el más efectivo. La teriparatide (agente anabólico), dado su alto costo, debería restringirse al tratamiento de pacientes más afectados y luego de un adecuado tratamiento con bifosfonatos. Objetivo: Establecer el porcentaje de pacientes con osteoporosis, en tratamiento con teriparatide o ácido zoledrónico en Colombia, que se ajusta a recomendaciones de organizaciones internacionales. Método: Estudio de utilización de medicamentos retrospectivo, enero 2012-diciembre 2015, en pacientes con osteoporosis y en tratamiento con teriparatide o ácido zoledrónico. Se revisó información sociodemográfica y clínica, y el grado de concordancia del uso de teriparatide o ácido zoledrónico con recomendaciones de tres guías clínicas internacionales: National Osteoporosis Foundation, National Institute for Health and Clinical Excellence y Scottish Intercollegiate Guidelines Network. Resultados: Se incluyeron 103 pacientes, edad promedio en años (desviación estándar) 78 (10,4), 74,8% mujeres. La osteoporosis posmenopáusica (61,2%) y osteoporosis no especificada (20,4%), ambas con o sin fractura patológica, fueron los diagnósticos principales. En el 36,9%, la utilización de teriparatide y ácido zoledrónico fue acorde a las recomendaciones de las guías revisadas. La utilización de estos medicamentos en diagnósticos diferentes a osteoporosis posmenopáusica (43,7%) o como farmacoterapia inicial (36,9%) fueron las principales causas para ausencia de concordancia. Conclusiones: Sólo en el 36,9% de los casos revisados, la utilización de teriparatide o ácido zoledrónico se ajusta a las guías de organizaciones internacionales. La ausencia de concordancia se debe, especialmente a uso en diagnósticos diferentes a osteoporosis posmenopáusica y como farmacoterapia inicial.

ABSTRACT Introduction: Bisphosphonates are the first-line treatment of osteoporosis in which zoledronate is the most effective. Teriparatide (anabolic agent), due to high cost, should be restricted to the treatment of the most affected patients and after adequate treatment with bisphosphonates. Objective: To establish the percentage of patients with osteoporosis, in treatment with teriparatide or zoledronic acid in Colombia, that meet international organizations recommendations. Method: Retrospective drug utilization study, January 2012-December 2015, in patients with osteoporosis and treatment with teriparatide or zoledronic acid. The socio-demographic and clinical information and the degree of concordance of teriparatide or zoledronic acid use with recommendations from three international clinical guidelines were reviewed: National Osteoporosis Foundation, National Institute for Health and Clinical Excellence, and Scottish Intercollegiate Guidelines Network. Results: 103 patients were included, average age in years (standard deviation) 78 (10.4), 74.8% women. Postmenopausal osteoporosis (61.2%) and unspecified osteoporosis (20.4%), both with or without pathological fracture, were the main diagnoses. In 36.9%, the use of teriparatide and zoledronic acid was accord with the guidelines recommendations revised. The use of these drugs in diagnoses different to postmenopausal osteoporosis (43.7%) or initial pharmacotherapy (36.9%) were the main causes for concordance absence. Conclusions: Only 36.9% of the reviewed cases, the use of teriparatide or zoledronic acid was accord with international organizations guideliness. Concordance absence is due especially both to the use in diagnoses different to postmenopausal osteoporosis and initial pharmacotherapy.

Nitrogen-containing bisphosphonate therapy: assessment of the alveolar bone structure in rats - a blind randomized controlled trial.

This study aimed to assess the effect of zoledronic acid exposure on structures of the alveolar bone of rats. The sample was composed of 42 male Wistar rats. Animals in the T1 and T2 groups received weekly doses of 0.2 mg/kg intraperitoneal zoledronic acid for 3 weeks, while animals in the T3 group received the same treatment for 8 weeks. The control groups C1, C2 and C3 received equivalent doses of saline. The first upper molars of Wistar rats in the C2, T2, C3 and T3 groups were extracted. Cone-beam computerized tomography scans were performed, and the image density was analysed by grey levels. The presence and type of inflammatory infiltrate, vascularization and bone necrosis were assigned by histological qualitative scores. Histomorphometric analysis of bone density was performed in the groups without extraction. No significant differences were found in the bone grey density estimated by grey-level value and histomorphometric analysis between the C1 and T1 groups (P > 0.05). The grey levels in the T3 group were lower (P < 0.05) than in the C3 group, corresponding to the bone defect. Histological assessments showed the presence of bone necrosis in the T3 group and lower levels of bone remodelling in the test groups (T2 and T3) compared to the control groups (C2 and C3). The results of qualitative analyses did not differ significantly between the groups (P > 0.05). Zoledronic acid-exposed animals showed maxillary changes including reduced grey levels, the presence of bone necrosis and a higher prevalence of inflammatory signs.

Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence.

Human bones are in a continuous process of remodeling that ensures renovation and maintenance of the skeletal mass. Bone remodeling has two phases that are normally coupled and balanced: bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. An increase in bone resorption over bone formation results in a progressive loss of bone mass and impairment of bone microarchitecture leading to osteoporosis and its associated fractures. Recent advances in the understanding of the molecular and cellular mechanisms involved in the remodeling process have allowed the development of new targets for osteoporosis treatment. Cathepsin K, a cysteine protease, is found in osteoclasts along the bone resorption surfaces and very efficiently degrades type I collagen, the major component of the organic bone matrix. Inhibition of cathepsin K reduces bone resorption but does not impair bone formation particularly at cortical sites. Odanacatib, a potent and highly selective cathepsin K inhibitor, showed prevention of bone loss without reduction of bone formation in preclinical and clinical trials (phase I and II). Odanacatib is currently in a phase III fracture outcome international trial for the treatment of postmenopausal osteoporosis.

Moduladores seletivos do receptor estrogênico: novas moléculas e aplicações práticas / Selective estrogen receptor modulators: new molecules and practical uses

Os moduladores seletivos do receptor de estrogênio são moléculas que se ligam ao receptor estrogênico com ações agonistas e antagonistas, em tecidos específicos. Eles apresentam efeitos estrogênicos e antiestrogênicos em vários órgãos, o que lhes permite diferentes atuações clínicas específicas. As diferenças nas estruturas moleculares conferem propriedades diferentes de ligação ao receptor-alvo, resultando em diferenças nos efeitos terapêuticos e adversos. Desde a descoberta dos primeiros compostos, há 50 anos, vários outros têm sido estudados e são usados frequentemente por ginecologistas, oncologistas e mastologistas. O raloxifeno é aprovado para a prevenção e o tratamento de osteoporose na pós-menopausa e para o câncer de mama receptor de estrogênio positivo; o tamoxifeno, para prevenção e tratamento do câncer de mama receptor de estrogênio positivo na pós-menopausa; e o clomifeno, primeiro modulador seletivo com receptor de estrogênio a ser estudado e empregado clinicamente, para infertilidade. Outras moléculas como bazedoxifeno, lasofoxifeno e arzoxifeno vêm sendo estudadas e vêm se mostrando como alternativas eficazes, algumas com menos efeitos colaterais

Selective estrogen receptor modulators are molecules that bind to estrogen receptor with agonistic and antagonistic actions in specific tissues. They exert estrogenic and anti-estrogenic effects in several organs, allowing them to perform differently in specific clinical situations. The differences in molecular structures provide different binding properties to the target receptor, resulting in differences in therapeutic and adverse effects. Since the discovery of the first compounds 50 years ago, several others have been studied and are often used by gynecologists and oncologists, and mastologists. Raloxifene is approved for preventing and treating osteoporosis in postmenopausal women and for treating estrogen receptor-positive breast cancer; tamoxifen is used for preventing and treating estrogen receptor-positive postmenopausal breast cancer; and clomiphene, the first selective estrogen receptor modulator to be studied and clinically employed, is used for infertility treatment. Other molecules such as bazedoxifene, lasofoxifene and arzoxifene have been studied and shown to be effective alternatives, some with fewer side effects

Effects of D-003 (10 mg/day) on bone mineral density of the lumbar spine and femoral neck in postmenopausal women: a randomized, double-blinded study.

BACKGROUND/AIMS: Increased osteoclast activity is a pivotal finding in osteoporosis. This increase is mediated via the mevalonate-to-cholesterol pathway, which is involved in producing the intermediates required for osteoclast activity. D-003, a mixture of high molecular weight sugarcane wax acids, has been shown to inhibit cholesterol synthesis prior to mevalonate production, resulting in a reduction of bone loss and resorption in ovariectomized rats. Moreover, previous studies have demonstrated that short-term D-003 treatment reduces urinary excretion of deoxypyridinoline/creatinine in postmenopausal women. METHODS: We performed a double-blinded, placebo-controlled study to investigate the effects of D-003 (10 mg/day) treatment for 3 years on bone mineral density (BMD) in 83 postmenopausal women with low BMD. RESULTS: Over 3 years, D-003 treatment increased lumbar spine BMD (5.1%, p < 0.01) and improved osteoporosis-related quality of life scores as compared with placebo-treated controls. D-003 was also well tolerated; the frequency of adverse events in the bone, joints, or muscle with D-003 treatment (p < 0.05) was lower than in the placebo group. CONCLUSIONS: D-003 treatment (10 mg/day) for 3 years increased lumbar spine BMD and produced clinical improvements in postmenopausal women with low BMD. Further studies, however, will be required to confirm these results.