Revista de Osteoporosis y Metabolismo Mineral

Musculoskeletal disorders and bisphosphonates: a disproportionality analysis within the Spanish pharmacovigilance database

Abstract Background: several musculoskeletal adverse effects associated with the use of bisphosphonates have been identified, although their frequency, severity and risk factors are still unknown. The aim of our study is to determine the possible causal relationship between the most widely used bisphosphonates in Spain and the occurrence of musculoskeletal adverse events. Material and methods: we conducted a retrospective, observational, analytical, case/non-case study using the database of the Spanish Pharmacovigilance System. The bisphosphonates selected were alendronic acid, ibandronic acid and risedronic acid. The adverse reactions studied according to MedDRA terminology were SOC musculoskeletal and connective tissue disorders and PTs myalgia, arthralgia, bone pain, paresthesia, musculoskeletal pain, musculoskeletal stiffness, arthritis, muscle weakness and pain in an extremity. Results: the ROR values obtained for the SOC were > 1 for all 3 drugs studied. These reactions occur mostly in those over 65 years of age, women and that most of them are classified as serious. For the 9 PTs studied (myalgia, arthralgia, bone pain, paresthesia, musculoskeletal pain, musculoskeletal stiffness, arthritis, muscle weakness and pain in a limb), ROR values > 1 were found for all three drugs, except for the PT paresthesia and PT pain in a limb. Conclusion: musculoskeletal adverse reactions not listed in the official information have been detected. The information provided by this work could recommend for a re-evaluation and update of the benefit-risk ratio of these drugs.

Identification in silico of miRNAs and their targets involved in the development of osteoarthritis

Abstract Introduction: osteoarthritis is considered the main cause of joint pain in older people, affecting four core tissues: cartilage, bone, joint capsule, and joint apparatus. In recent years, microRNAs have been described to play a vital role in the development of bone metabolism diseases, including osteoarthritis, since they can have an inhibitory effect or a promoting effect on disease progression. Objective: through microarray analysis and bioinformatics tools, miRNAs and their potential target genes involved in signaling pathways associated with the development of osteoarthritis are identified. Methods: the microRNAs were selected through microarray expression analysis from the "Gene Expression Omnibus" database, and through literature search, their target genes were obtained by integrating different databases. This set of genes was compared with a set of differentially expressed genes from expression microarray analysis of samples from patients with osteoarthritis. The shared gene set was subjected to signaling pathway enrichment analysis. Results: a total of 4 miRNAs were identified, miR-485, miR-940, miR-107, and miR-142-5p, that regulate 185 genes involved in 9 signaling pathways in which CSF1, CXCL3, FOS, IL6, IL6R, NFATC1, NFKB1, NFKB2, PPARG, THBS1 and TNF genes play a crucial role in bone and immune system-associated processes and their deregulation may favor the progression of osteoarthritis. Conclusions: the microRNAs identified in this study could be used as biomarkers for the timely diagnosis and monitoring of osteoarthritis treatment.

Las vesículas extracelulares circulantes modifican la diferenciación de células estromales mesenquimales y angiogénesis. Potencial uso en regeneración ósea

Resumen Introducción: el uso de vesículas extracelulares (VE) tiene un alto potencial en medicina regenerativa. Aunque principalmente se han estudiado las derivadas de células estromales mesenquimales (MSC), las VE circulantes de sangre de cordón umbilical (veCU) o de adultos jóvenes sanos (veAD), también contienen factores que pueden favorecer la regeneración tisular. Este estudio evalúa el efecto de veCU y veAD sobre la diferenciación de MSC a osteoblastos y adipocitos, y la angiogénesis de células endoteliales. Material y métodos: las VE fueron aisladas por cromatografía de exclusión de tamaño, caracterizadas y cuantificadas. Cultivos de MSC fueron tratados con veCU y veAD durante la diferenciación a osteoblastos o adipocitos. En ellas se estudió la expresión de genes osteoblásticos o adipogénicos, la mineralización y la formación de vesículas de grasa. Fueron evaluadas células endoteliales de vena de cordón umbilical (HUVEC) en ensayos de angiogénesis. Resultados: VeCU y veAD no afectaron a la viabilidad de las MSC, pero veAD aumentó la de HUVEC. En osteoblastos, aumentó la expresión de colágeno alfa-1 tipo I (COL1A1) con veAD, pero la mineralización no se afectó. En adipocitos se inhibió la expresión de adipo-triglicérido-lipasa (ATGL) y la proteína 4 de unión a ácido graso (FABP4), y disminuyó la formación de vesículas de grasa con ambos tipos de VE. En HUVEC, veCU y veAD indujeron la angiogénesis. Conclusión: los resultados sugieren que ambos tipos de VE, procedentes de fuentes abundantes, sin aspectos éticos importantes y fáciles de aislar, tienen un alto potencial en medicina regenerativa aplicada al hueso, inhibiendo la adiposidad de la médula ósea y favoreciendo la angiogénesis.

Abstract Introduction: the use of extracellular vesicles (EVs) has a high potential in regenerative medicine. Although mainly those derived from mesenchymal stromal cells (MSC) have been studied, circulating EVs from umbilical cord blood (UCBEV) or from healthy young adults (peEV) also contain factors that can favor tissue regeneration. This study evaluates the effect of UCBEV and peEV on MSC differentiation to osteoblasts and adipocytes, and endothelial cell angiogenesis. Material and methods: MSC cultures were treated with UCBEV and peEV during differentiation into osteoblasts or adipocytes. The expression of osteoblastic or adipogenic genes was studied. Mineralization and lipid droplet formation were quantified. Umbilical cord vein endothelial cells (HUVEC) were evaluated in angiogenesis assays. Results: UCBEV and peEV did not affect MSC viability, but peEV increased HUVEC viability. In osteoblasts, collagen type I alpha 1 (COL1A1) expression was increased by peEV, but mineralization was not affected. In adipocytes, adipose triglyceride lipase (ATGL) and fatty acid-binding protein 4 (FABP4) expression was inhibited, and lipid droplet formation was decreased with both types of EV. In HUVEC, UCBEV and peEV induced angiogenesis. Conclusion: the results suggest that both types of EVs, from abundant sources, without major ethical issues and easy to isolate, have high potential in regenerative medicine applied to bone, inhibiting bone marrow adiposity and favoring angiogenesis.

Biogénesis de RNA circulares, funciones biológicas y su papel en el desarrollo de la osteoartritis

Resumen La osteoartritis (OA) es la enfermedad articular más común en todo el mundo y su progresión es irreversible. Actualmente los procesos que conducen al desarrollo de esta condición no son del todo comprendidos. Sin embargo, la evidencia sugiere que mecanismos epigenéticos podrían desempeñar un papel clave en el desarrollo de esta patología. Entre estos mecanismos se encuentran los RNA no codificantes (ncRNA), que incluyen a los RNA circulares (circRNA), una clase de RNA con una estructura de bucle cerrado covalentemente que es altamente estable y conservada. La mayoría de los circRNA presentan características de abundancia, estabilidad, conservación y, a menudo, exhiben una manera específica de tejido o etapa de desarrollo con estructuras únicas, su desregulación se ha asociado con la alteración de diversos procesos biológicos como la tumorigénesis, el crecimiento, la invasión, la metástasis, apoptosis y vascularización, favoreciendo el desarrollo de distintas enfermedades incluida la OA. Estudios recientes sugieren que los circRNA desempeñan papeles clave al actuar como esponjas de microRNA (miRNA) o andamios proteicos, lo que los propone como prometedores biomarcadores con potencial para la prevención, diagnóstico y blancos terapéuticos en el tratamiento de la OA. Por lo tanto, en esta revisión se presenta el concepto, las características principales de los circRNA y se describen las principales funciones biológicas y la relevancia clínica de este tipo de RNA, así como las expresiones y sus mecanismos reguladores, lo cual proporciona evidencia de las posibles utilidades en el diagnóstico y tratamiento de la OA.

Abstract Osteoarthritis (OA) is the most common joint disease worldwide, and its progression is irreversible. Currently, the processes that lead to the development of this condition are not fully understood. However, evidence suggests that epigenetic mechanisms could play a key role in the development of this disease. Among these mechanisms are non-coding RNAs (ncRNA), which include circular RNAs (circRNAs), a class of RNA with a covalently closed loop structure that is highly stable and conserved. Most circRNAs present characteristics of abundance, stability, and conservation and often exhibit a tissue- or stage-specific manner of development with unique structures, and their deregulation has been associated with changes to various biological processes such as tumorigenesis, growth, invasion, metastasis, apoptosis, and vascularization, favoring the development of different diseases including OA. Recent studies suggest that circRNAs play key roles by acting as microRNA (miRNA) sponges or protein scaffolds, proposing them as promising biomarkers with potential for prevention, diagnosis, and therapeutic targets for the treatment of OA. Therefore, this review presents the concept and the main characteristics of circRNAs and describes the main biological functions and clinical relevance of this type of RNA, as well as their expressions and regulatory mechanisms, which provide evidence of the possible uses in the diagnosis and treatment of OA.

Consenso Delphi sobre el manejo de pacientes con osteoporosis en atención primaria

Resumen Introducción: existen numerosas guías clínicas sobre la identificación, tratamiento y seguimiento de pacientes con osteoporosis, pero presentan diferencias significativas en sus recomendaciones, lo que a menudo genera confusión e incertidumbre entre los profesionales sanitarios. Objetivo: consensuar y unificar criterios en torno a la identificación, evaluación, tratamiento, seguimiento y papel de pacientes con osteoporosis. Métodos: tras la revisión de las principales guías sobre el manejo de la osteoporosis, un comité de expertos identificó aquellos aspectos con mayor controversia o menor evidencia y elaboró un cuestionario Delphi con 92 aseveraciones agrupadas en los siguientes bloques: 1. Identificación y evaluación; 2. Tratamiento; 3. Monitorización y seguimiento; 4. Criterios de derivación; y 5. Punto de vista del paciente. Resultados: se alcanzó consenso en 77 aseveraciones (83,7 %). Los panelistas coincidieron en la importancia de identificar adecuadamente esta condición, estratificando a los pacientes según su riesgo de fractura, para lo que se ha de tener en cuenta factores como la densidad mineral ósea, edad, sexo, riesgo de caídas, antecedentes familiares y personales de fractura, y otros factores clínicos. También se hizo hincapié en la importancia del ejercicio y la nutrición, así como el momento de inicio, duración y posibles vacaciones terapéuticas del tratamiento farmacológico, individualizando cada caso según sea necesario. Conclusiones: los médicos de familia son conscientes de identificar, evaluar, tratar y monitorizar adecuadamente los pacientes con osteoporosis para poder reducir el riesgo de fracturas por fragilidad. Sin embargo, todavía existen aspectos que generan confusión en los que es necesaria una mayor evidencia científica.

Abstract Introduction: numerous clinical guidelines exist on the identification, treatment, and follow-up of patients with osteoporosis, but they show significant differences in their recommendations, often leading to confusion and uncertainty among healthcare professionals. Objective: to reach a consensus and unify criteria regarding the identification, evaluation, treatment, follow-up, and role of patients with osteoporosis. Methods: after reviewing major guidelines on osteoporosis management, an expert committee identified aspects with the most controversy or the least evidence and developed a Delphi questionnaire with 92 statements grouped into the following sections: 1. Identification and evaluation; 2. Treatment; 3. Monitoring and follow-up; 4. Referral criteria; and 5. Patient perspective. Results: consensus was reached on 77 statements (83.7 %). Panelists agreed on the importance of properly identifying this condition by stratifying patients according to their fracture risk, considering factors such as bone mineral density, age, sex, fall risk, family and personal history of fractures, and other clinical factors. Emphasis was also placed on the importance of exercise and nutrition, as well as the timing, duration, and potential treatment holidays of pharmacological therapy, with individualization as needed. Conclusions: family physicians recognize the importance of identifying, evaluating, treating, and monitoring patients with osteoporosis to reduce the risk of fragility fractures. However, some aspects still cause confusion and require further scientific evidence.