Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Patient preferences for lifestyle behaviours in osteoporotic fracture prevention: a cross-European discrete choice experiment.

Using a discrete choice experiment, we aimed to assess patients' preferences with regard to adopting lifestyle behaviours to prevent osteoporotic fractures. Overall, the 1042 patients recruited from seven European countries were favourable to some lifestyle behaviours (i.e., engaging in moderate physical activity, taking calcium and vitamin D supplements, reducing their alcohol consumption and ensuring a normal body weight). INTRODUCTION: Alongside medical therapy, healthy lifestyle habits are recommended for preventing osteoporotic fractures. In this study, we aimed to assess patients' preferences with regard to adopting lifestyle changes to prevent osteoporotic fractures. METHODS: A discrete choice experiment was conducted in seven European countries. Patients with or at risk of osteoporosis were asked to indicate to what extent they would be motivated to adhere to 16 lifestyle packages that differed in various levels of 6 attributes. The attributes and levels proposed were physical activity (levels: not included, moderate or high), calcium and vitamin D status (levels: not included, taking supplements, improving nutrition and assuring a minimal exposure to sunlight daily), smoking (levels: not included, quit smoking), alcohol (levels: not included, moderate consumption), weight reduction (levels: not included, ensure a healthy body weight) and fall prevention (levels: not included, receiving general advice or following a 1-day fall prevention program). A conditional logit model was used to estimate a patient's relative preferences for the various attributes across all participants and per country. RESULTS: In total, 1042 patients completed the questionnaire. Overall, patients were favourable to lifestyle behaviours for preventing osteoporotic fractures. However, among the lifestyle behaviours proposed, patients were consensually not prone to engage in a high level of physical activity. In addition, in Ireland, Belgium, the Netherlands and Switzerland, patients were also not inclined to participate in a 1-day fall prevention program and Belgian, Swiss and Dutch patients were not prone to adhere to a well-balanced nutritional program. Nevertheless, we observed globally that patients felt positively about reducing their alcohol consumption, engaging in moderate physical activity, taking calcium and vitamin D supplements and ensuring a normal body weight, all measures aimed at preventing fractures. CONCLUSIONS: In a patient-centred approach, fracture prevention should take these considerations and preferences into account.

Persistencia a los inhibidores de la aromatasa en la cohorte SIDIAP: mortalidad e influencia de los bifosfonatos / Persistence to aromatase inhibitors in the SIDIAP cohort: mortality and influence of bisphosphonates

OBJETIVO: Evaluar la persistencia a la terapia con inhibidores de la aromatasa (IA), la mortalidad asociada a la discontinuidad al tratamiento y la influencia de los bifosfonatos (BF) orales, en la práctica clínica habitual. MATERIAL Y MÉTODOS: Estudio prospectivo observacional de mujeres con cáncer de mama en tratamiento con IA entre enero de 2006 y diciembre de 2015, registradas en la base de datos SIDIAP. Se excluyeron aquellas tratadas previamente con tamoxifeno. Se estudió la persistencia al tratamiento con IA con un análisis de supervivencia: se calculó el estimador de Kaplan-Meier, y se realizó un modelo de los riesgos proporcionales (regresión de Cox) entre usuarias y no usuarias de BF ajustando por edad. Se llevó a cabo un análisis de sensibilidad teniendo en cuenta la mortalidad como riesgo competitivo (modelos de Fine y Gray). Se comparó la diferencia de mortalidad entre grupos mediante una prueba Chi cuadrado. RESULTADOS: Se observó una persistencia a los IA del 87% a 5 años de tratamiento, con una mortalidad global del 19,75%. Se registró un 7,7% menos de mortalidad en aquellas pacientes que completaron los 5 años de tratamiento respecto a las que no. Las pacientes con BF mostraron una disminución de la mortalidad (6,6%) y una disminución del riesgo de abandono de la terapia (SHR ajustado: 0,62 [IC 95%: 0,55 a 0,70]) respecto a las no usuarias. CONCLUSIONES: La permanencia a los IA y el uso de BF está asociada a una disminución de la mortalidad global. Además, el uso de BF resulta en un aumento de la adherencia al tratamiento con IA

OBJETIVE: To assess the persistence of aromatase inhibitor (AI) therapy, mortality associated with treatment discontinuation and the influence of oral bisphosphonates (BP) in routine clinical practice. MATERIAL AND METHODS: Prospective observational study of women with breast cancer undergoing AI treatment between January 2006 and December 2015, registered in the SIDIAP database. Those previously treated with tamoxifen were excluded. AI persistence was studied with a survival analysis: the Kaplan-Meier estimator was calculated, and a proportional hazards model (Cox regression) was performed between users and non-users of BP adjusting for age. A sensitivity analysis was carried out taking into account mortality as a competitive risk (Fine and Gray models). The difference in mortality between groups was compared using a Chi square test. RESULTS: A persistence to AI of 87% was observed after 5 years of treatment, with an overall mortality of 19.75%. There was 7.7% less mortality in those patients who completed the 5 years of treatment compared to those who did not. Patients with BP showed a decrease in mortality (6.6%) and a decrease in the risk of discontinuing therapy (adjusted SHR: 0.62 [95% CI: 0.55 to 0.70]) compared to non-users. CONCLUSIONS: Persistence to AI and BP use are associated with a decrease in overall mortality. Furthermore, the use of BP increases adherence to AI treatment

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Determinants, consequences and potential solutions to poor adherence to anti-osteoporosis treatment: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF).

Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions. INTRODUCTION: Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication. METHODS: A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken. RESULTS: Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few interventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it. CONCLUSION: These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions.

The association between type 2 diabetes mellitus, hip fracture, and post-hip fracture mortality: a multi-state cohort analysis.

Type 2 diabetes mellitus (T2DM) is associated with an excess risk of fractures and overall mortality. This study compared hip fracture and post-hip fracture mortality in T2DM and non-diabetic subjects. The salient findings are that subjects in T2DM are at higher risk of dying after suffering a hip fracture. INTRODUCTION: Previous research suggests that individuals with T2DM are at an excess risk of both fractures and overall mortality, but their combined effect is unknown. Using multi-state cohort analyses, we estimate the association between T2DM and the transition to hip fracture, post-hip fracture mortality, and hip fracture-free all-cause death. METHODS: Population-based cohort from Catalonia, Spain, including all individuals aged 65 to 80 years with a recorded diagnosis of T2DM on 1 January 2006; and non-T2DM matched (up to 2:1) by year of birth, gender, and primary care practice. RESULTS: A total of 44,802 T2DM and 81,233 matched controls (53% women, mean age 72 years old) were followed for a median of 8 years: 23,818 died without fracturing and 3317 broke a hip, of whom 838 subsequently died. Adjusted HRs for hip fracture-free mortality were 1.32 (95% CI 1.28 to 1.37) for men and 1.72 (95% CI 1.65 to 1.79) for women. HRs for hip fracture were 1.24 (95% CI 1.08 to 1.43) and 1.48 (95% CI 1.36 to 1.60), whilst HRs for post-hip fracture mortality were 1.28 (95% CI 1.02 to 1.60) and 1.57 (95% CI 1.31 to 1.88) in men and women, respectively. CONCLUSION: T2DM individuals are at increased risk of hip fracture, post-hip fracture mortality, and hip fracture-free death. After adjustment, T2DM men were at a 28% higher risk of dying after suffering a hip fracture and women had 57% excess risk of post-hip fracture mortality.

The impact of hip fracture on health-related quality of life and activities of daily living: the SPARE-HIP prospective cohort study.

PURPOSE: The medical morbidity and mortality associated with neck of femur fractures is well-documented, whereas there is limited data for patient-reported outcomes. The aim of this study was to characterize the impact of neck of femur fractures on activities of daily living and patient-reported health-related quality of life. METHODS: Design and participants: Multicentric prospective cohort study. Consecutive sample patients with fragility hip fracture over 50 years old admitted in 48 hospitals in Spain. OUTCOMES: daily living activity function (Barthel Index) and health-related quality of life (EQ-5D) pre-fracture, admission to hospital and at 1- and 4-month follow-up post-fracture. STATISTICS: Barthel and EQ-5D over time are described as mean (SD) and median (interquartile range). RESULTS: A total of 997 patients were recruited at baseline with 4-month outcomes available for, and 856 patients (89.5%). Barthel Index fell from 78.77 (23.75) at baseline to 43.62 (19.86) on admission to hospital with the fracture. Scores partially recovered to 54.89 (25.40) and 64.09 (21.35) at 1- and 4-month post-fracture, respectively. EQ-5D fell from a median of 0.75 (0.47-0.91) to - 0.01 (- 0.03 to 0.51) on admission. Partial recovery was observed again to (0.51 (- 0.06 to 0.67)) and (0.60 (0.10 to 0.80)) at 1- and 4-month post-fracture, respectively. CONCLUSIONS: Hip fracture results in a large decline in the ability to perform activities of daily living and patient-reported health-related quality of life with only partial recovery amongst survivors 4-month post-fracture.

Spanish National Hip Fracture Registry (RNFC): analysis of its first annual report and international comparison with other established registries.

Hip fracture registries have helped improve quality of care and reduce variability, and several audits exist worldwide. The results of the Spanish National Hip Fracture Registry are presented and compared with 13 other national registries, highlighting similarities and differences to define areas of improvement, particularly surgical delay and early mobilization. INTRODUCTION: Hip fracture audits have been useful for monitoring current practice and defining areas in need of improvement. Most established registries are from Northern Europe. We present the results from the first annual report of the Spanish Hip Fracture Registry (RNFC) and compare them with other publically available audit reports. METHOD: Comparison of the results from Spain with the most recent reports from another ten established hip fracture registries highlights the differences in audit characteristics, casemix, management, and outcomes. RESULTS: Of the patients treated in 54 hospitals, 7.208 were included in the registry between January and October 2017. Compared with other registries, the RNFC included patients ≥ 75 years old; in general, they were older, more likely to be female, had a worse prefracture ambulation status, and were more likely to have extracapsular fractures. A larger proportion was treated with intramedullary nails than in other countries, and spinal anesthesia was most commonly used. With a mean of 75.7 h, Spain had by far the longest surgical delay, and the lowest proportion of patients mobilized on the first postoperative day (58.5%). Consequently, development of pressure ulcers was high, but length of stay, mortality, and discharge to home remained in the range of other audits. CONCLUSIONS: National hip fracture registries have proved effective in changing clinical practice and our understanding of patients with this condition. Such registries tend to be based on an internationally recognized common dataset which would make comparisons between national registries possible, but variations such as age inclusion criteria and follow-up are becoming evident across the world. This variation should be avoided if we are to maximize the comparability of registry results and help different countries learn from each other's practice. The results reported in the Spanish RNFC, compared with those of other countries, highlight the differences between countries and detect areas of improvement, particularly surgical delay and early mobilization.

El papel de la determinación de un marcador de resorción, el telopéptido carboxiterminal del colágeno I, en la valoración del cumplimiento terapéutico en pacientes tratadas con bifosfonatos orales / The determining role of a resorption marker,carboxyterminal telopeptide of collagen I,in assessing therapeutic compliance inpatients treated with oral bisphosphonates

Objetivo: Se estima que al año entre el 50-60% de los pacientes tratados con fármacos para la osteoporosis son incumplidores. Disponemos de diferentes métodos indirectos de valoración del cumplimiento. Nuestro objetivo es testar una única determinación del telopéptido carboxiterminal del colágeno tipo I (CTX) para valorar el cumplimiento en pacientes tratadas con bifosfonatos, de forma aislada o junto al cuestionario de Morinsky-Green. Material y método: Estudio de validación diagnóstica realizado en 10 centros de Cataluña. Mediante muestreo consecutivo se seleccionaron mujeres postmenopáusicas con osteoporosis y tratadas con un mismo fármaco antirresortivo en el último año; se excluyeron aquellas tratadas con un fármaco diferente a bifosfonato, con deterioro cognitivo, enfermedad terminal, o insuficiencia renal avanzada, o fractura en el año previo. Se recogieron datos sobre el diagnóstico de osteoporosis y tipo de tratamiento. Se solicitó analítica con determinación del CTX. Como gold-standard se utilizó la tasa de posesión de medicación (Medication Possession Ratio, MPR). Mediante metodología de la curva ROC se estableció el punto de corte teórico del CTX. Se calculó la sensibilidad, la especificidad y los valores predictivos positivos para estimar el cumplimiento terapéutico. Resultados: Se incluyeron 100 pacientes, de las cuales más de la mitad recibían alendronato. Según la MPR, un 70% eran cumplidoras. El valor medio del CTX fue de 0,193±0,146 ng/ml, siendo inferior en las pacientes cumplidoras. Se estableció como punto de corte para valorar el cumplimiento un valor de 0,196 ng/ml. La valoración conjunta del CTX junto al cuestionario de Morinsky-Green presentó mayor capacidad discriminativa. Conclusiones: La realización de una única determinación del CTX (<0,196 ng/ml) junto al cuestionario de Morinsky-Green permite valorar mejor el cumplimiento terapéutico en pacientes tratadas con bifosfonatos

Objective:It is estimated that in one year between 50‐60% of patients treated with osteoporosis drugs are non‐com‐pliant. There are different indirect methods of assessing compliance. Our objective is to test a single determination ofthe carboxyterminal telopeptide of type I collagen (CTX) to assess compliance in patients treated with bisphosphonates,either on its own or together with the Morinsky‐Green questionnaire.Material and method:A diagnostic assessment study was carried out in 10 centers in Catalonia. Through consecutivesampling, postmenopausal women with osteoporosis were selected and treated with the same antiresorptive drug inthe last year. Those treated with a drug other than bisphosphonate, with cognitive impairment, terminal illness, advancedrenal failure or fracture in the previous year, were excluded. Data were collected on the diagnosis of osteoporosis andtype of treatment. Analysis was requested with CTX determination. As a gold standard, the medication possession rate(MPR) was used. Using the ROC curve methodology, the theoretical CTX cut‐off point was established. Sensitivity, spe‐cificity and positive predictive values were calculated to estimate therapeutic compliance.Results:100 patients were included, of which more than half were being treated with alendronate. According to theMPR, 70% were compliant. The mean CTX value was 0.193±0.146 ng/ml. It was lower in the compliant patients. A valueof 0.196 ng/ml was established as a cut‐off point to assess compliance. The joint assessment of the CTX together withthe Morinsky‐Green questionnaire showed greater discriminatory capacity.Conclusions:Carrying out a single determination of CTX (<0.196 ng/ml) along with the Morinsky‐Green questionnaireallows us to more accurately assess the therapeutic compliance in patients treated with bisphosphonates

Inflammation status in HIV-positive individuals correlates with changes in bone tissue quality after initiation of ART.

BACKGROUND: The mechanisms behind ART-induced bone changes in HIV-infected patients are poorly known. We aimed to analyse changes in inflammatory and bone markers in HIV after tenofovir disoproxil fumarate initiation, and the associations with changes in the bone strength parameters. METHODS: HIV-positive participants starting tenofovir disoproxil fumarate-based ART underwent dual-energy X-ray absorptiometry (QDR 4500 SL®, Hologic, Waltham, MA, USA) for bone mineral density (BMD), a microindentation test (OsteoProbe®, Active Life Scientific, Santa Barbara, CA, USA) for bone quality [bone material strength index (BMSi)] and phlebotomy at baseline and 48 weeks after ART. A panel of inflammatory biomarkers and bone turnover markers were measured by ELISA. HIV-negative controls underwent identical procedures once. Values are expressed as medians and IQRs, and non-parametric tests were used to perform the analysis. RESULTS: Twenty HIV-infected individuals and 20 HIV-negative control individuals were matched in terms of age and gender. HIV individuals showed higher levels of inflammatory markers. We found no differences in bone turnover markers. HIV-positive individuals presented lower BMSi values at baseline compared with controls [86 (83-90) versus 89 (88-93), respectively; P = 0.034]. We found no difference in BMD (at either of the sites evaluated). BMSi tended to increase with treatment. IL-1ß at baseline was positively correlated with changes in BMSi after ART (rho = 0.564, P = 0.014). Baseline levels of sclerostin tended to be negatively correlated with changes in BMSi (rho = -0.402, P = 0.097). We found a negative correlation between time since HIV diagnosis and changes in BMSi (rho = -0.466, P = 0.04). CONCLUSIONS: We observed a correlation between changes in bone quality and the inflammatory environment in HIV-positive individuals. Moreover, among the underlying mechanisms we highlight the Wnt pathway as having a potentially significant role in ART bone quality recovery.

Estudio genético de la fractura femoral atípica mediante la secuenciación del exoma en tres hermanas afectas y tres pacientes no relacionadas / Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients

Objetivos: Las fracturas atípicas de fémur (FAF) son un tipo de fracturas poco frecuentes, a menudo relacionadas con un tratamiento prolongado con bisfosfonatos (BPs). Actualmente no se conocen con exactitud sus mecanismos patogénicos y no hay pruebas para identificar aquellos pacientes con un alto riesgo de sufrir una FAF. El objetivo de este trabajo es investigar las bases genéticas de las FAFs. Material y métodos: Se secuenció el exoma completo de 3 hermanas y de 3 pacientes adicionales no relacionadas, todas tratadas con BPs durante más de 5 años. Se seleccionaron variantes compartidas por las hermanas, de baja frecuencia y potencialmente patogénicas, y se construyó una red de interacciones de genes y proteínas con los datos hallados. Resultados: Identificamos 37 variantes raras (en 34 genes) compartidas por las 3 hermanas, algunas de ellas no descritas anteriormente. La variante más llamativa fue la mutación p.Asp188Tyr en el enzima geranilgeranil pirofosfato sintasa (codificada por el gen GGPS1), de la vía del mevalonato y esencial para la función del osteoclasto. Otro hallazgo interesante fueron dos mutaciones (una en las 3 hermanas y una en una paciente no relacionada) en el gen CYP1A1, implicado en el metabolismo de los esteroides. Identificamos otras variantes que también podrían estar involucradas en la susceptibilidad a las FAFs o en el fenotipo osteoporótico subyacente, tales como las presentes en los genes SYDE2, NGEF, COG4 y la FN1. Conclusiones: Nuestros datos son compatibles con un modelo donde la acumulación de variantes de susceptibilidad podría participar en la base genética de las FAF

Objectives: Atypical femoral fractures (AFF) are rare, often related to long-term bisphosphonate (BPs) treatment. Their pathogenic mechanisms are not precisely known and there is no evidence to identify patients with a high risk of AFF. The aim of this work is to study the genetic bases of AFFs. Material and methods: Whole-exome sequencing was carried out on 3 sisters and 3 unrelated additional patients, all treated with BPs for more than 5 years. Low frequency, potentially pathogenic variants shared by the 3 sisters, were selected, were selected and a network of gene and protein interactions was constructed with the data found. Results: We identified 37 rare variants (in 34 genes) shared by the 3 sisters, some not previously described. The most striking variant was the p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase (encoded by the GGPS1 gene), from the mevalonate pathway and essential for osteoclast function. Another noteworthy finding was two mutations (one in the 3 sisters and one in an unrelated patient) in the CYP1A1 gene, involved in the metabolism of steroids. We identified other variants that could also be involved in the susceptibility to AFFs or in the underlying osteoporotic phenotype, such as those present in the SYDE2, NGEF, COG4 and FN1 genes. Conclusions: Our data are compatible with a model where the accumulation of susceptibility variants could participate in the genetic basis of AFFs

Estudios funcionales de variantes de DKK1 presentes en la población general / Functional studies of DKK1 variants present in the general population

Objetivo: En las últimas décadas se han identificado genes asociados a la masa ósea y al riesgo de fractura osteoporótica, varios de los cuales pertenecen a la vía de Wnt. En este proyecto se estudió la funcionalidad de 7 mutaciones de cambio de sentido del gen DKK1 -un inhibidor de la vía de Wnt- presentes en la población general. Material y métodos: Se realizaron estudios in vitro del gen reportero luciferasa para medir la actividad de la vía de Wnt en presencia o ausencia de DKK1 silvestre o mutada, y estudios de western blot, para evaluar si las distintas mutaciones afectan a su síntesis y/o a su estabilidad. Resultados: La proteína DKK1 con la variante p.Ala41Thr presenta menor actividad inhibidora de la vía en comparación con la proteína silvestre. También se observaron diferencias significativas entre los experimentos realizados en ausencia de DKK1 y los que incluyen DKK1 con la mutación p.Ala41Thr. Los western blots mostraron que la cantidad de proteína era similar para todas las variantes, tanto las mutadas como la silvestre, por lo que la pérdida de actividad de p.Ala41Thr no parecía deberse a falta de proteína. El resto de las mutaciones no presentaron un comportamiento diferente al de la proteína DKK1 silvestre. Conclusiones: La variante de cambio de sentido p.Ala41Thr de la proteína DKK1, con una frecuencia poblacional de 0,013%, presenta una pérdida parcial de su función inhibidora, que no es debida a la falta de expresión de ésta. Esta variante génica podría conllevar un aumento de la densidad mineral ósea en las personas de la población general portadoras de esta mutación

Objective: In recent decades, genes associated with bone mass and osteoporotic fracture risk have been identified, several of which belong to the Wnt pathway. In this project, the functionality of 7 missense mutations of the gene DKK1-an inhibitor of the Wnt pathway- present in the general population was studied. Material and methods: In vitro studies of the luciferase reporter gene were carried out to measure Wnt pathway activity in the presence or absence of wild-type or mutated DKK1, and western blot studies, to evaluate if the different mutations affect its synthesis and/or stability. Results: The DKK1 protein with the p.Ala41Thr variant shows lower pathway inhibitory activity compared to the wild-type protein. Significant differences were also observed between the experiments performed in the absence of DKK1 and those that include DKK1 with the p.Ala41Thr mutation. Western blots showed that the amount of protein was similar for all variants, both mutated and "wild-type, so the loss of p.Ala41Thr activity did not seem to be due to a lack of protein. The rest of the mutations did not show different behavior from that of the wild DKK1 protein. Conclusions: The missense variant p.Ala41Thr of the DKK1 protein, with a population frequency of 0.013%, shows a partial loss of its inhibitory function, which is not due to the lack of expression. This gene variant could lead to an increase in bone mineral density in those people in the general population who carry this mutation

La resistencia mecánica tisular ósea es independiente de la edad en individuos sanos / Bone tissue mechanical strength is in dependent of age in healthy individuals

Objetivo: La microindentación de impacto (MII) es una técnica que permite medir in vivo la resistencia tisular mecánica ósea. Se ha demostrado que la MII proporciona información útil sobre la evaluación de enfermedades esqueléticas, pero se desconoce el efecto que la edad puede ejercer sobre la propiedad ósea medida. El objetivo del estudio es analizar la relación entre la edad y la MII. Material y métodos: El índice de Resistencia Mineral Ósea (BMSi), la variable de medición de MII, se midió en 69 mujeres (mediana de edad: 49 años; rango: 30-81 años) y 19 varones (mediana de edad: 34 años; rango: 24-98 años) sanos. La correlación entre BMSi y la edad se analizó mediante regresión lineal. La asociación entre BMSi y edad se evaluó mediante ANOVA tras ajustar por el índice de masa corporal. El posible efecto de depleción estrogénica postmenopáusica sobre el BMSi se estudió comparando el subgrupo de mujeres más jóvenes con las más mayores mediante la prueba t de Student. Resultados: Los análisis de regresión lineal mostraron que la BMSi no se correlaciona con la edad en varones (R2=0,0016, p=0,74) ni en mujeres (R2=0,076, p=0,25). Asimismo, el análisis ajustado de ANOVA no demostró asociación entre la BMSi y la edad ni en varones (p=0,78) ni en mujeres (p=0,73). Finalmente, no se encontraron diferencias entre la BMSi entre las mujeres más jóvenes y las mayores (p=0,8). Conclusiones: La resistencia tisular mecánica ósea en individuos sanos es independiente a la edad y a la depleción estrogénica postmenopáusica

Objective: Impact microindentation (IMI) is a technique that allows the measurement of mechanicalbone tissue resistance in vivo. IMI has proven to provide useful information on the evaluation of skeletal diseases, but the effect of age on the bone property that is measured by this technique is unknown. This study aims to analyzethe relationship between age and MIH. Material and methods: Bone Material Strength index (BMSi), IMI’s output variable, was measured in 69 healthy women (median age: 49 years, range: 30-81 years) and 19 healthy men median age: 34 years, range: 24-98 years). The correlation between BMSi and age was analyzed by linear regression. The association between BMSi and age was evaluated by ANOVA after adjusting for body mass index. The potential effect of postmenopausal estrogenic depletion on BMSi was studied by comparing the younger vs the older subset of women through a t-student test. Results: Linear regression analysis showed that BMSi was not correlated with age in either men (R2=0.0016, p=0.74) or women (R2=0.076, p=0.25). Similarly, the BMI-adjusted ANOVA model revealed a lack of asso-ciation of BMSi with age in men (p=0.78) and women (p=0.73). Finally, there were not significant differences on BMSi detected between the younger and the older subset of women (p=0.8). Conclusions: Bone tissue mechanical resistance in healthy individuals is independent of age and postmenopausal estrogenic depletion

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation / Registro Nacional Español de Fracturas de Cadera (RNFC): descripción de sus objetivos, metodología e implementación

Objective: To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality. Design: Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. Study scope and subjects: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible. Results: It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition

Objetivo: Conocer la situación actual y la variabilidad clínica del proceso asistencial a la Fractura de Cadera (FC) en España y los factores relacionados con la misma mediante la utilización de un Registro Nacional (RNFC) con elevada casuística y representación territorial RNFC, así como comparar resultados en el ámbito nacional e internacional y proponer estándares y criterios para mejorar la calidad asistencial. Diseño: Registro continuo durante al menos tres años de una muestra representativa de los pacientes ingresados por FC en los hospitales españoles mediante el Minimum Common Dataset - MCD internacional de la Fragility Fracture Network (FFN) adaptado al castellano. Ámbito y sujetos del estudio: se incluirán todos los pacientes mayores de 74 años hospitalizados con el diagnóstico de FC por fragilidad en los hospitales participantes repartidos por el territorio español. Inicialmente están incluidos 48 hospitales, a los que se espera que se vayan incorporando el mayor número posible de centros. Resultados: Se pretende conocer la situación actual de la atención a este proceso en España Se ofrecerá a cada hospital la información de sus resultados y su situación en relación al resto, se compararán los resultados de los hospitales nacionales entre sí y con los hospitales extranjeros incluidos en registros que usan la misma base de datos. Se estudiará la variabilidad, se establecerán estándares asistenciales y se plantearán objetivos para la mejora continua del proceso en la atención a esta patología

Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case-control study.

We conducted a nested case-control study to study the association between antidiabetic treatments (alone or in combination) use and fracture risk among incident type 2 Diabetes mellitus patients. We found an increased risk of bone fracture with insulin therapy compared to metformin monotherapy. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures, to which antidiabetic therapies may contribute. We aimed to characterize the risk of fracture associated with different antidiabetic treatments as usually prescribed to T2DM patients in actual practice conditions. METHODS: A case-control study was nested within a cohort of incident T2DM patients registered in 2006-2012 in the Information System for Research Development in Primary Care (Catalan acronym, SIDIAP), a database which includes records for > 5.5 million patients in Catalonia (Spain). Each case (incident major osteoporotic fracture) was risk-set matched with up to five same-sex controls by calendar year of T2DM diagnosis and year of birth (± 10 years). Study exposure included previous use of all antidiabetic medications (alone or in combination), as dispensed in the 6 months before the index date, with metformin (MTF) monotherapy, the most commonly used drug, as a reference group (active comparator). RESULTS: Data on 12,277 T2DM patients (2049 cases and 10,228 controls) were analyzed. Insulin use was associated with increased fracture risk (adjusted OR 1.63 (95% CI 1.30-2.04)), as was the combination of MTF and sulfonylurea (SU) (adjusted OR 1.29 (1.07-1.56)), compared with MTF monotherapy. Sensitivity analyses suggest possible causality for insulin therapy but not for the MTF + SU combination association. No significant association was found with any other antidiabetic medications. CONCLUSIONS: Insulin monotherapy was associated with an increased fracture risk compared to MTF monotherapy in T2DM patients. Fracture risk should be taken into account when starting a glucose-lowering drug as part of T2DM treatment.

Estudio de la base genética de la reducción del Trabecular Bone Score relacionada con los inhibidores de la aromatasa / Study of the genetic basis of Trabecular Bone Score reduction related to aromatase inhibitors

Objetivos: Los inhibidores de la aromatasa (AI) son terapias endocrinas adyuvantes eficaces para pacientes con cáncer de mama, aunque se han asociado a un mayor riesgo de fractura osteoporótica. Previamente se ha demostrado una pérdida en el Trabecular Bone Score (TBS) que puede variar entre las pacientes tratadas con IA. El estudio pretendió identificar la base genética asociada al cambio en el TBS mediante el estudio de genes de la vía esteroidogénica. Material y métodos: La cohorte B-ABLE estudia de forma prospectiva a mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. Se calculó el TBS a partir de los datos adquiridos en la densitometría mediante absorciometría radiológica dual (DXA) realizada al inicio y al final del tratamiento con IA. El cambio relativo del TBS se calculó como la variación porcentual del valor de TBS al final de tratamiento respecto al TBS basal. Para estudiar la posible asociación genética se genotiparon los polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR y CYP24A1. Se estudió mediante regresión lineal múltiple la posible relación entre genes y cambios en TBS contemplando los modelos de herencia genética dominante, recesivo y aditivo. Resultados: Se incluyeron en el estudio un total de 212 mujeres no tratadas con bisfosfonatos en las que pudo calcularse el TBS. La mitad de las pacientes habían recibido tratamiento previo con tamoxifeno. El porcentaje de cambio intra-individual del TBS fue del -0,04% [IC del 95%: -0,05 a -0,03; p<0,001] al final de tratamiento con IA. El SNP rs6013897 en el gen CYP24A1 mostró una asociación significativa con la reducción del TBS [p=0,03565; coeficiente Beta (IC del 95%) = -1,55 (-2,98 a -0,11)]. Conclusiones: El gen CYP24A1 podría estar implicado en la variabilidad fenotípica encontrada en el deterioro de la microarquitectura ósea durante el tratamiento con IA

Objectives: Aromatase inhibitors (AI) are effective adjuvant endocrine therapies for breast cancer patients, although they have been associated with an increased risk of osteoporotic fracture. Trabecular Bone Score (TBS) loss has been previously demonstrated, although it may vary among AI-treated patients. This study aims to identify the genetic basis associated with TBS change by studying steroidogenic pathway genes. Material and methods: The B-ABLE cohort studies prospectively postmenopausal women with breast cancer under treatment with AI. TBS is calculated from the raw data acquired in dual-energy x-ray absorptiometry (DXA) scan at the outset of the study and at the end of AI-treatment. The relative TBS change was calculated as the percentage variation of the TBS value at the end of treatment from baseline. To study the possible genetic association, nucleotide polymorphisms (SNPs) were genotyped in genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR and CYP24A1. The possible relationship between genes and TBS changes was studied by multiple linear regression, considering models of dominant, recessive and additive genetic inheritance. Results: The study included 212 women that had not been treated with bisphosphonates and had available TBS data. Half of the patients had been treated previously with tamoxifen. The percentage of intra-individual TBS change was -0.04% [95% CI: -0.05 to -0.03; p<0.001] at the end of AI treatment. The SNP rs6013897 in the gene CYP24A1 showed a significant association with TBS reduction [p=0.03565; coefficient Beta (95% CI) = -1.55 (-2.98 to -0.11)]. Conclusions: The CYP24A1 gene could be involved in the phenotypic variability found in bone microarchitecture deterioration during AI treatment

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation.

OBJECTIVE: To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality. DESIGN: Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. STUDY SCOPE AND SUBJECTS: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible. RESULTS: It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition.

Uso de fármacos para la osteoporosis en pacientes con diabetes mellitus tipo 2: estudio de cohortes de base poblacional / Use of drugs for osteoporosis treatment in patients with type 2 diabetes mellitus: population-based cohort study

Objetivo: Determinar si existen diferencias en la prevalencia del uso de fármacos para la osteoporosis entre pacientes diabéticos tipo 2 (DM2) y no diabéticos. Material y método: Estudio de cohortes retrospectivas con datos del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP), que contiene información clínica anonimizada de más de 5 millones de pacientes de Cataluña. Se seleccionaron todos los pacientes de ≥50 años de edad con diagnóstico de DM2, que fueron apareados con dos sujetos sin diabetes. Se recogió información sobre variables descriptivas, fracturas prevalentes y el uso de fármacos para la osteoporosis agrupados en bifosfonatos (BF), suplementos calcio y vitamina D (CaD), y cualquier fármaco para la osteoporosis (FPO). Mediante regresión logística se calculó la asociación entre la presencia de DM2 y el uso de FPO, ajustando por variables confusoras. Resultados: Se identificaron 166.106 pacientes con DM2 y 332.212 no diabéticos. Los DM2 tenían mayor prevalencia de fractura que los no diabéticos (1,3% vs. 0,3%). El uso de BF en los pacientes con DM2 era del 6,6%, frente al 9,3% en los no diabéticos (p<0,001); de CaD, 9,7% vs. 12,3% (p<0,001); y de FPO, 7,6% vs. 10,7% (p<0,001). Tras ajustar por variables confusoras, los pacientes con DM2 presentaban menor probabilidad de ser tratados con BF (OR=0,67; IC95%: 0,64-0,68), con CaD (OR=0,71; IC95%: 0,70-0,73) o con FPO (OR=0,66; IC95%: 0,64-0,67) que los no diabéticos. Conclusiones: A pesar de presentar una mayor prevalencia de fracturas previas, los pacientes con DM2 tienen más del 30% de probabilidad de no recibir un FPO que los no diabéticos. Esto podría ser debido a una infravaloración del riesgo en estos pacientes (AU)

Objective: Ascertain whether there are differences in the prevalence of osteoporosis drugs in patients with type 2 diabetes (DM2) and non-diabetic patients. Material and methods: Retrospective cohort study with data from the Information System for the Development of Primary Care Research (SIDIAP), which contains anonymous clinical information from more than 5 million patients in Catalonia. All 50-year-old patients diagnosed with DM2, who were matched with two subjects without diabetes, were selected. Information on descriptive variables, prevalent fractures and the use of osteoporosis drugs grouped in bisphosphonates (BF), calcium and vitamin D supplements (CaD), and any osteoporosis drug (OD) were collected. Through logistic regression, the association between the presence of DM2 and the use of OD was calculated, adjusting for confounding variables. Results: A total of 166,106 patients with DM2 and 332,212 non-diabetics. The DM2 group presented a higher prevalence of fracture than did diabetics (1.3% vs 0.3%). The use of BF in patients with DM2 was 6.6%, compared to 9.3% in non-diabetics (p<0.001). Of CaD, 9.7% vs 12.3% (p<0.001) and OD, 7.6% vs 10.7% (p<0.001). After adjusting for variable confounders, the patients with DM2 presented a lower probability of being treated with BF (OR=0.67, 95% CI: 0.64-0.68), with CaD (OR=0.71, 95% CI: 0.70-0.73) or with OD (OR=0.66, 95% CI: 0.64-0.67) than non-diabetics. Conclusions: Despite having a higher prevalence of fractures in patients with DM2, they have more than 30% chance of not having received an OD than non-diabetic patients. This may be attributed to an underestimation of risk in these patients (AU)

Self-perception of fracture risk: what can it tell us?

In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.