Efectividad y seguridad de los bisfosfonatos en el tratamiento de la osteoporosis infantil secundaria

Bisfosfonatos; Efectividad; NiñoBisfosfonats; Efectivitat; NenBisphosphonates; Effectiveness; ChildIntroduction There are few studies on effectiveness and safety of bisphosphonate therapy in secondary osteoporosis in children. The aim of this research was to analyse effectiveness and safety of bisphosphonates in secondary osteoporosis in children. Patients and methods Multicentre retrospective study in patients younger than 18 suffering from secondary osteoporosis and who have received bisphosphonates. Clinical data were recorded. Bone mineral density (BMD) was assessed in terms of BMD Z-score in lumbar spine (ZBMDls) measured by dual-energy X-ray absorptiometry (DXA). Effectiveness was valued at changes in ZBMDls one and two years after the onset of bisphosphonates and at the decrese in the number of fractures a year. Adverse events reported were recorded. Descriptive and bivariant analysis was performed. Results 32 patients were recruited. ZBMDls increased one year after the onset of treatment ((−2.46 ± 0.96) vs. (−1.54 ± 1.38); p < .001). Fractures a year dicreased significantly (1 (1–2) vs. 0 (0–0.61); p < .001). ZBMDls increase was higher in patients who were able to walk (1.88 ± 0.72 vs. 0.55 ± 0.82; p = .07) and correlated positively with body mass index (BMI)- for- age percentile (rho: 0.564; p < .001). The decrease in the number of fractures a year was higher in patients with lower initial fracture rate (rho: −0,47; p = .006) and with higher initial ZBMDls (rho: −0.47; p = .07). 10 adverse events were reported in 7 patients (22%), all of them intravenous bisphosphonates related. No association was found between adverse events and studied variables. Conclusions Bisphosphonates are effective in secondary osteoporosis in children. Response seems to be better in patients who are able to walk, well-nourished and in the early stages of the disease. Adverse events were frequent but mild.Introducción Los estudios sobre efectividad y seguridad de los bisfosfonatos en osteoporosis infantil secundaria (OIS) son escasos. El objetivo fue analizar efectividad y seguridad de los bisfosfonatos en OIS. Pacientes y métodos Estudio multicéntrico retrospectivo en <18 años afectos de OIS tratados con bisfosfonatos. Se recogieron variables clínicas. Se valoró densidad mineral ósea (DMO) mediante el Z-score de DMO en columna lumbar (ZDMOcl) medido por absorciometría de rayos X de doble energía (DXA). Valoramos efectividad en función del cambio del ZDMOcl al año y a los dos años de su inicio y del descenso del número de fracturas/año. Los eventos adversos reportados fueron recogidos. Se realizó análisis descriptivo y bivariante. Resultados Se reclutaron 32 pacientes. El ZDMOcl se incrementó al año del inicio del tratamiento ((−2,46 ± 0,96) vs. (−1,54 ± 1,38); p < 0,001). El número de fracturas/año disminuyó significativamente (1 (1–2) vs. 0 (0–0,61); p < 0,001). El cambio en el ZDMOcl fue mayor en los pacientes deambulantes (1,88 ± 0,72 vs. 0,55 ± 0,82; p = 0,07) y se correlacionó positivamente con el percentil del IMC (rho: 0,564; p < 0,001). El descenso del número de fracturas/año fue mayor en los pacientes con menor tasa inicial de fracturas (rho: −0,47; p = 0,006) y cuanto mayor era el Z-score inicial (rho: −0,47; p = 0,07). Se reportaron 10 eventos adversos leves en 7 pacientes (22%), todos con bisfosfonatos intravenosos. No se halló relación entre eventos adversos y las variables estudiadas. Conclusiones Los bisfosfonatos son efectivos en OIS. La respuesta parece ser mejor en pacientes deambulantes, bien nutridos y en estadios precoces de la enfermedad. Resultan seguros, siendo los efectos adversos leves, aunque frecuentes

Comparative effectiveness of Tocilizumab with either Methotrexate or Leflunomide in the treatment of rheumatoid arthritis

Objective: In agreement with EULAR recommendations, a DMARD in combination with a biotherapy is the reference treatment because of the superior long-term clinical and radiographic outcomes. Methotrexate (MTX) is the cornerstone of combination therapy but is in some cases contra-indicated or poorly tolerated. This observational study aimed to compare the effectiveness and safety of TCZ in combination with either MTX or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs and/or biological agents in a real-world setting. Methods: We performed an ambispective review of 91 patients with active RA who were routinely treated with TCZ plus MTX or LEF. A comparative study between the two combinations of treatment was performed at 6 months of follow-up considering 3 outcomes: improvement of RA disease activity, evolution of functional disability, and tolerability and side effect profile. Results: Of the 91 patients, 62 received TCZ with MTX and 29 received TCZ with LEF. Eighty-one patients were followed for 6 months, and the remaining 10 patients discontinued treatment due to serious adverse events. At baseline, there were no significant differences between the groups in terms of the main clinical and laboratory data or in the number of previous DMARDs and biological agents used. At 6 months, there were no significant differences between the combinations in terms of disease activity and functional disability. Serious adverse events occurred in 11% and 10% of the patients treated in combination with MTX and LEF, respectively. Conclusion: Our preliminary data support the argument that LEF is an effective and safe (equivalent) alternative to MTX for combination treatment with TCZ

Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children

Background: Osteoporosis incidence in children is increasing due to the increased survival rate of patients suffering from chronic diseases and the increased use of drugs that can damage bones. Recent changes made to the definition of childhood osteoporosis, along with the lack of guidelines or national consensuses regarding its diagnosis and treatment, have resulted in a wide variability in the approaches used to treat this disease. For these reasons, the Osteogenesis Imperfecta and Childhood Osteoporosis Working Group of the Spanish Society of Pediatric Rheumatology has sounded the need for developing guidelines to standardize clinical practice with regard to this pathology. Methods: An expert panel comprised of 6 pediatricians and 5 rheumatologists carried out a qualitative literature review and provided recommendations based on evidence, when that was available, or on their own experience. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A Delphi survey was conducted for those recommendations with an evidence level of IV or V. This survey was sent to all members of the SERPE. All recommendations that had a level of agreement higher or equal to 70% were included. Results: Fifty-one recommendations, categorized into eight sections, were obtained. Twenty-four of them presented an evidence level 4 or 5, and therefore a Delphi survey was conducted. This was submitted electronically and received a response rate of 40%. All recommendations submitted to the Delphi round obtained a level of agreement of 70% or higher and were therefore accepted. Conclusion: In summary, we present herein guidelines for the prevention, diagnosis and treatment of secondary childhood osteoporosis based on the available evidence and expert clinical experience. We believe it can serve as a useful tool that will contribute to the standardization of clinical practice for this pathology. Prophylactic measures, early diagnosis and a proper therapeutic approach are essential to improving bone health, not only in children and adolescents, but also in the adults they will become in the future

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Introduction: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. Conclusion: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes

Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA

Estudio de fragilidad ósea en población pediátrica con factores de riesgo

La presente tesis doctoral aborda el problema de la Baja Masa Ósea para la edad cronológica (BMOec) y la Osteoporosis infantil (OPi), situaciones que pueden ser silentes y que requieren de una investigación activa para llegar a su diagnóstico en edad pediátrica. El objetivo principal de esta tesis es estimar la prevalencia de dichas enfermedades en los pacientes con riesgo de presentarlas, así como evaluar las características densitométricas de los mismos, tanto la cantidad ósea mediante Densidad Mineral Ósea, como la calidad ósea mediante Trabecular Bone Score. Los objetivos secundarios han sido describir las características clínicas de esta población y comparar los hallazgos densitométricos con los de población sana sin factores de riesgo. Se incluyeron 103 pacientes con edades comprendidas entre los 2 y los 20 años de edad. Todos ellos con al menos un factor de riesgo: entre los más prevalentes la presencia de un diagnóstico potencialmente osteopenizante y la ingesta inadecuada de calcio. Entre el 6 y el 10% de la muestra presentaba BMOec, que variaba según la región de interés estudiada y el ajuste de talla. Cinco sujetos presentaban criterios de OPi por presencia de fracturas vertebrales, en 4 de ellos las fracturas fueron silentes y descubiertas mediante técnicas de imagen. TBS resultó inferior en los sujetos con BMOec medida en cuerpo entero. La DMO de adolescentes y jóvenes fue menor en población con factores de riesgo frente a la población sana de la misma edad y género. TBS fue menor en adolescentes y jóvenes femeninas pero mayor en el resto de grupos estudiados.This doctoral thesis deals with Low Bone Mass for chronological age (LBMca) and infantile Osteoporosis (iOP), both can be asymptomatic and may require an extra effort to get to their diagnosis in pediatric age. The main objective of this work is to estimate the prevalence of these diseases in patients at risk of presenting them, as well as to evaluate these patient’s densitometric characteristics, both quantity through Bone Mineral Density, and quality through Trabecular Bone Score. Secondary objectives include the description of the clinical characteristics of our sample, as well as the comparison of the densitometric findings with those of healthy peers without risk factors. We included 103 patients aged between 2 and 20 years of age. All of them with at least one risk factor. The presence of a potentially osteopening diagnosis and the inadequate calcium intake that did not reach the daily recommendations were the most prevalent risks factors. Between 6 and 10% of the sample presented LBMca, which varied according to the regions of interest studied and the height adjustment. 5 subjects met iOP criteria for the presence of vertebral fractures. In 4 of them, these fractures were silent and were localized by imaging techniques. TBS was lower in subjects with LBMca measured in the whole body region. Adolescents and young people BMD was lower in the population with risk factors compared to the healthy population of the same age and gender. TBS was lower in adolescents and young women but higher in the rest of the groups

Estudio de fragilidad ósea en población pediátrica con factores de riesgo

La presente tesis doctoral aborda el problema de la Baja Masa Ósea para la edad cronológica (BMOec) y la Osteoporosis infantil (OPi), situaciones que pueden ser silentes y que requieren de una investigación activa para llegar a su diagnóstico en edad pediátrica. El objetivo principal de esta tesis es estimar la prevalencia de dichas enfermedades en los pacientes con riesgo de presentarlas, así como evaluar las características densitométricas de los mismos, tanto la cantidad ósea mediante Densidad Mineral Ósea, como la calidad ósea mediante Trabecular Bone Score. Los objetivos secundarios han sido describir las características clínicas de esta población y comparar los hallazgos densitométricos con los de población sana sin factores de riesgo. Se incluyeron 103 pacientes con edades comprendidas entre los 2 y los 20 años de edad. Todos ellos con al menos un factor de riesgo: entre los más prevalentes la presencia de un diagnóstico potencialmente osteopenizante y la ingesta inadecuada de calcio. Entre el 6 y el 10% de la muestra presentaba BMOec, que variaba según la región de interés estudiada y el ajuste de talla. Cinco sujetos presentaban criterios de OPi por presencia de fracturas vertebrales, en 4 de ellos las fracturas fueron silentes y descubiertas mediante técnicas de imagen. TBS resultó inferior en los sujetos con BMOec medida en cuerpo entero. La DMO de adolescentes y jóvenes fue menor en población con factores de riesgo frente a la población sana de la misma edad y género. TBS fue menor en adolescentes y jóvenes femeninas pero mayor en el resto de grupos estudiados.This doctoral thesis deals with Low Bone Mass for chronological age (LBMca) and infantile Osteoporosis (iOP), both can be asymptomatic and may require an extra effort to get to their diagnosis in pediatric age. The main objective of this work is to estimate the prevalence of these diseases in patients at risk of presenting them, as well as to evaluate these patient’s densitometric characteristics, both quantity through Bone Mineral Density, and quality through Trabecular Bone Score. Secondary objectives include the description of the clinical characteristics of our sample, as well as the comparison of the densitometric findings with those of healthy peers without risk factors. We included 103 patients aged between 2 and 20 years of age. All of them with at least one risk factor. The presence of a potentially osteopening diagnosis and the inadequate calcium intake that did not reach the daily recommendations were the most prevalent risks factors. Between 6 and 10% of the sample presented LBMca, which varied according to the regions of interest studied and the height adjustment. 5 subjects met iOP criteria for the presence of vertebral fractures. In 4 of them, these fractures were silent and were localized by imaging techniques. TBS was lower in subjects with LBMca measured in the whole body region. Adolescents and young people BMD was lower in the population with risk factors compared to the healthy population of the same age and gender. TBS was lower in adolescents and young women but higher in the rest of the groups

Estudio de fragilidad ósea en población pediátrica con factores de riesgo /

La presente tesis doctoral aborda el problema de la Baja Masa Ósea para la edad cronológica (BMOec) y la Osteoporosis infantil (OPi), situaciones que pueden ser silentes y que requieren de una investigación activa para llegar a su diagnóstico en edad pediátrica. El objetivo principal de esta tesis es estimar la prevalencia de dichas enfermedades en los pacientes con riesgo de presentarlas, así como evaluar las características densitométricas de los mismos, tanto la cantidad ósea mediante Densidad Mineral Ósea, como la calidad ósea mediante Trabecular Bone Score. Los objetivos secundarios han sido describir las características clínicas de esta población y comparar los hallazgos densitométricos con los de población sana sin factores de riesgo. Se incluyeron 103 pacientes con edades comprendidas entre los 2 y los 20 años de edad. Todos ellos con al menos un factor de riesgo: entre los más prevalentes la presencia de un diagnóstico potencialmente osteopenizante y la ingesta inadecuada de calcio. Entre el 6 y el 10% de la muestra presentaba BMOec, que variaba según la región de interés estudiada y el ajuste de talla. Cinco sujetos presentaban criterios de OPi por presencia de fracturas vertebrales, en 4 de ellos las fracturas fueron silentes y descubiertas mediante técnicas de imagen. TBS resultó inferior en los sujetos con BMOec medida en cuerpo entero. La DMO de adolescentes y jóvenes fue menor en población con factores de riesgo frente a la población sana de la misma edad y género. TBS fue menor en adolescentes y jóvenes femeninas pero mayor en el resto de grupos estudiados.This doctoral thesis deals with Low Bone Mass for chronological age (LBMca) and infantile Osteoporosis (iOP), both can be asymptomatic and may require an extra effort to get to their diagnosis in pediatric age. The main objective of this work is to estimate the prevalence of these diseases in patients at risk of presenting them, as well as to evaluate these patient's densitometric characteristics, both quantity through Bone Mineral Density, and quality through Trabecular Bone Score. Secondary objectives include the description of the clinical characteristics of our sample, as well as the comparison of the densitometric findings with those of healthy peers without risk factors. We included 103 patients aged between 2 and 20 years of age. All of them with at least one risk factor. The presence of a potentially osteopening diagnosis and the inadequate calcium intake that did not reach the daily recommendations were the most prevalent risks factors. Between 6 and 10% of the sample presented LBMca, which varied according to the regions of interest studied and the height adjustment. 5 subjects met iOP criteria for the presence of vertebral fractures. In 4 of them, these fractures were silent and were localized by imaging techniques. TBS was lower in subjects with LBMca measured in the whole body region. Adolescents and young people BMD was lower in the population with risk factors compared to the healthy population of the same age and gender. TBS was lower in adolescents and young women but higher in the rest of the groups