Frailty has become a major challenge for health systems, but it also presents a window of opportunity to fight disability through preventive strategies focused on the detection and treatment of frailty across all care settings. However, no systematic strategies for screening and early detection are currently available in clinical practice. This project aims to identify clinical and biological phenotypic clusters that drive progression through the different stages of frailty, and to describe the underlying mechanisms of the trajectories leading to disability and potential treatment interventions. In addition, the Frailty Trait Scale 5 (FTS5) will be validated as a practical tool for implementation in both primary care and hospital settings. A prospective, population-based cohort (CohorFES) will be established for frailty phenotyping. A CIBERFES Biobank will also be created to store blood and urine samples from CohorFES participants for future research. Demographic and clinical history data, anthropometric measurements, the PREDIMED questionnaire, peripheral blood biochemical variables, and metabolomics data will be collected at baseline and annually until participants develop frailty. Cluster partition models (k-means and hierarchical clustering) will be used to group individuals with similar deficits and characteristics (frailty phenotypes). Then, by using pre-established criteria (gap and silhouette), the proposed clustering solution (belonging to given clusters) will be evaluated. We will also assess, in a longitudinal manner, the emergence and accumulation of deficits over time, identifying subgroups with more rapid progression. The results will be used to define and compare clusters and progression trajectories. Finally, frailty phenotypes and patient clusters will be correlated with health outcomes such as healthcare utilization (primary and secondary care), hospital admissions, and mortality. Information on clinical and biological phenotypic clusters involved in the progression of frailty may help identify potential therapeutic targets to improve the management of these patients. In summary, from a research perspective, this project aims to improve our understanding of the interindividual variability in clinical trajectories that lead to frailty, dependence, and ultimately, death. Protocol Registration: NCT06965972 (date 05/02/2025).

Anticancer therapies frequently compromise skeletal health and increase fracture risk. This narrative review synthesizes information and provides guidance on assessment, prevention, and management of therapy-related bone loss in adults with cancer. Major contributors to bone loss in this population include aromatase inhibitors, androgen deprivation therapy, systemic glucocorticoids, chemotherapy, and selected targeted or immune agents. Recommended assessments include clinical evaluation, laboratory tests (calcium, vitamin D, and renal function), and bone mineral density by dual-energy X-ray absorptiometry with vertebral fracture assessment and, when acute vertebral fracture is suspected, magnetic resonance imaging. Prevention measures include exercise, adequate calcium and vitamin D intake, and fall-reduction strategies. Pharmacological treatment options include bisphosphonates and denosumab. Selection of treatment should consider skeletal efficacy and potential oncological benefits, while ongoing care includes repeat bone density testing at 12–24 months and vigilance for osteonecrosis of the jaw and atypical femoral fractures.

Frailty is defined by the World Health Organization as a state of increased vulnerability in older adults, characterized by a decline in physiological functions across multiple systems and heightened sensitivity to external stressors. The global prevalence of frailty is expected to rise due to population ageing, highlighting the need for effective preventive strategies. However, while diet can play a crucial role in this context, their relationship is complex and potentially bidirectional: unhealthy dietary patterns may contribute to the onset of frailty, whereas early stages of frailty may influence food choices through limitations in meal preparation, and appetite. Hence, identifying biomarkers associated with frailty phenotypes may help clarify these mechanisms and improve prevention strategies. This systematic review aims to summarize current evidence on metabolomics-derived biomarkers potentially involved in the relationship between dietary patterns and frailty. A comprehensive literature search was conducted across three electronic databases (PubMed, Web of Science, Scopus) in accordance with the PRISMA guidelines, yielding 1661 studies, of which five met the inclusion criteria. Three dietary exposures were identified and analyzed: fruit and vegetable, plant/animal protein intake, and adherence to the Mediterranean diet. The findings suggest that specific metabolites, such as hippuric acid, different amino acids, and lipid derived compounds may represent potential candidates for establishing a metabolic signature of frailty. Nevertheless, current evidence remains limited and unclear about the direction of associations. Further research is needed, particularly in healthy populations, to validate the effectiveness of these biomarkers, and tailor guidelines specific for older adults.

3D-DXA provides volumetric and compartment-specific hip measurements from standard DXA scans. However, for reliable longitudinal interpretation, establishing scanner-specific short-term precision data is essential. This study assessed the short-term precision of 3D-DXA-derived parameters using repeated acquisitions from five clinical Hologic DXA scanner datasets. Duplicate hip DXA acquisitions were collected at five clinical centers using two Horizon Wi scanners, two Horizon A scanners, and one Discovery W scanner. Each subject was scanned twice with complete repositioning between acquisitions. Conventional total hip and femoral neck aBMD were obtained using APEX software, and 3D-Shaper software was used to derive integral vBMD, trabecular vBMD, and cortical sBMD. Precision error was expressed as RMS-SD and RMS-CV, and LSC was calculated at the 95

Background: This 1-year cohort study aimed to track long COVID prevalence, identify associated risk factors, and assess its association with hospitalization. Methods: The GINA-COVID cohort study included 2698 COVID-19 patients from Spain, who reported persistent symptoms spontaneously mentioned in an open questionnaire one year after infection. We recorded symptom onset, duration, and recovery rates at 12 months. Hospitalization data were collected from the Catalan Health System. We performed descriptive statistics and logistic regression models stratified by sex to identify factors associated with long COVID, using multiple imputation for missing values and model selection via stepwise regression based on the Akaike Information Criterion. Results: Significant sex differences appeared, with females showing a two-fold higher risk of developing long COVID compared to males (OR=1.95; 95% CI, 1.68-2.29). Females reported higher prevalence and a greater number of persistent symptoms, with fatigue being the most common in both sexes (36% in females, 26% in males at 3 months). The recovery rate at 12 months was lower in females (23% vs. 34%, p<0.001). Hypertension emerged as the most significant protective factor for long COVID in females (OR=0.64; 95% CI, 0.48-0.84), whereas COVID-19 severity was the most influential risk factor in males (OR=2.34; 95% CI, 1.79-3.08). Despite these differences, the trajectory of persistent symptoms over time was similar between the sexes. Importantly, long COVID did not increase hospital admissions. Conclusion: Findings underscore the importance of sex-specific approaches in managing long COVID and suggest further investigation into hypertension's protective role in females and disease severity's impact in males.

Background: Three-dimensional dual-energy X-ray absorptiometry reconstructs three-dimensional maps of the proximal femur's density distribution from standard hip scans, enabling the estimation of trabecular and cortical bone parameters. The aim of this study was to assess the agreement of these three-dimensional cortical and trabecular femur parameters across different series and models of Hologic densitometers. Methodology: The study cohort was composed of 103 women and men recruited from four clinical centers in Spain and France. Subjects had duplicated hip scans using different Hologic scanners from the Horizon, Discovery, and QDR4500 series. Analyses were performed using 3D-Shaper software. Inter-scanner agreement was evaluated using Deming regression and Bland-Altman analysis. Results: The parameters demonstrated strong inter-device agreement across all clinical centers and scanner models, with coefficients of determination greater than 0.91. Absolute biases were less than 2.5 mg/cm^3 for integral volumetric bone mineral density, less than 2.9 mg/cm^3 for trabecular volumetric bone mineral density, and less than 1.7 mg/cm^2 for cortical surface bone mineral density. No statistically significant bias was found between parameters obtained from different scanners. Furthermore, the observed bias was lower than the expected least significant change, indicating that inter-scanner variability across these devices is not clinically significant. Conclusions: This study demonstrated excellent agreement for standard and three-dimensional derived bone parameters at the hip across Hologic densitometers. These findings support their suitability for clinical use.

Background: The lack of a universally accepted definition, a gold-standard assessment tool, and sufficient evidence-based interventions has hindered the integration of frailty into routine clinical practice, particularly outside geriatric medicine. For clinicians, health professionals, policymakers, and aging researchers, a unified framework based on robust evidence has become essential. Objectives: To provide a consensus on relevant aspects of frailty, including definition, attributes, misunderstandings, pathophysiology, phenotypes, assessment, biomarkers, management, stigmas and future challenges, useful for epidemiological, clinical and research application across Europe. Design: Consensus document. Setting: 25 research centers on frailty and healthy aging. Measurements: Relevant aspects on frailty. Results: In this document we present a consensus regarding what frailty is, what frailty is not, what is aging, which are the most common misunderstandings related to frailty, which is the pathophysiology and which are the biomarkers of frailty, how should frailty be assessed and who should assess frailty, how should frailty be managed, the presence or absence of frailty subphenotypes or subtypes, how is the stigma of been considered frail, which are the gender considerations, and which are the current challenges and future directions. We support that frailty is the expression of an age-associated clinical phenotypic syndrome driven by the biology of aging, life-course environmental exposures, and disease burden. Its physiological basis lies in a heterogeneous decline of functional reserve across organ systems, accompanied by impaired homeostasis and reduced capacity to respond to stressors, ultimately predisposing to adverse health outcomes, mainly disability. Conclusions: We present a consensus document on frailty, useful for epidemiological, clinical and research application across Europe.

OBJECTIVES:This observational prospective study evaluated bone changes using 3D-DXA in the B-ABLE cohort of postmenopausal women with early breast cancer receiving aromatase inhibitors (AI). STUDY DESIGN:Hip DXA scans were performed before initiating AI therapy and on a yearly basis until its completion: 5 years of AI therapy (5y-AI group) or 2-3 years of AI therapy after switching from 2 or 3 years of tamoxifen (pTMX-AI group). 3D-DXA analysis was performed using 3D-Shaper® software. Patients with osteoporosis or high fracture risk at baseline started antiresorptive treatment (ARP). MAIN OUTCOME MEASURES:Cumulative changes in areal bone mineral density (aBMD) and 3D-DXA-derived parameters, including cortical surface BMD, cortical thickness, and integral, cortical, and trabecular volumetric BMD (vBMD), were evaluated by linear mixed models considering ARP and previous tamoxifen treatment. RESULTS:Of a total of 785 women included, 191 (24.3 %) started ARP at baseline. Non-ARP-treated patients had a decrease of more than 4 % in all bone parameters at the end of AI treatment, except cortical thickness, which displayed minimum changes. Women previously treated with TMX had significantly greater losses in most parameters, which occurred mainly during the first year of AI treatment. In ARP-treated patients, a significant increase was detected in all bone parameters, especially in the 5y-AI group. Denosumab showed greater efficacy than bisphosphonate in improving most bone parameters. CONCLUSIONS:3D-DXA provides deeper insights into the detrimental changes in the cortical and trabecular bone compartment caused by AI, and how ARP can prevent these effects.

A 29-year-old Spanish Caucasian man, without relevant family history, was attended in our unit due to an undiagnosed skeletal dysplasia associated with low bone mass and several fragility fractures throughout his childhood and adolescence. DXA exams throughout his life showed very low BMD values; currently, his spinal and femoral neck T-scores were − 4.3 and − 3.5, respectively. Blood and urinary tests were normal. Other relevant features included right hand and foot syndactyly, aplasia cutis, right hemibody hypoplasia, vertebral malformations, abnormal-looking humerii, and Asperger’s syndrome among others. Whole exome sequencing retrieved a highly probable pathogenic variant in the PORCN gene p.(Arg296Pro) in mosaicism. PORCN mutations cause focal dermal hypoplasia (FDH), an X-linked ultra-rare ecto-mesodermal disorder characterized by several of the findings the patient presented. However, low BMD has not been classically associated with the disease. Noteworthy, PORCN is key for canonical Wnt signaling. Literature scrutiny has yielded other cases of FDH with skeletal fragility during childhood. In addition, preclinical studies with PORCN inhibitors, currently under development as an antitumoral therapy, have shown rapid detrimental effects on bone mass. Collectively, these findings indicate that FDH is probably an underrecognized monogenic cause of low bone mass due to defective Wnt signaling.

Osteoporosis and fragility fractures are among the most prevalent and clinically significant complications in patients with chronic kidney disease (CKD), particularly in stages G4-G5 and in those undergoing dialysis (G5D). These skeletal disorders are associated with markedly increased morbidity and mortality, including a 2- to 9-fold higher risk of hip fractures compared to the general population, prolonged hospitalization, functional decline, and excess postoperative mortality. Despite this substantial burden, CKD-associated osteoporosis remains underrecognized and undertreated. Limited inclusion of CKD patients in pivotal osteoporosis trials and the absence of high-evidence guidance in clinical guidelines have contributed to a persistent therapeutic gap. PTH analog agents such as teriparatide and abaloparatide have demonstrated robust efficacy in increasing bone mass and reducing fracture risk in the general population. However, their use in CKD remains limited. PTH analog are poorly prescribed in patients with CKD stage G3 and remain off-label for stages G4-G5D, despite the high prevalence of adynamic bone disease across all stages of CKD. Abaloparatide, a selective PTH1 receptor agonist, exerts potent anabolic effects with a lower incidence of hypercalcemia than teriparatide and may offer a favourable safety profile in carefully selected patients. Preliminary data suggest preservation of bone microarchitecture and potential benefits in low-turnover bone disease, although evidence in CKD is still limited. This narrative review examines current evidence on abaloparatide's potential role in CKD, emphasizing its mechanism of action, efficacy, safety, and relevance for patients with low bone turnover and high fracture risk.

Post-Acute COVID Syndrome (PACS) is a complex disorder that currently lacks effective evidenced-based therapies to manage it. This randomized controlled trial aims to evaluate the effects of balneotherapy (BT) on PACS symptomatology. Ninety-eight adults with PACS visited at Hospital del Mar Research Institute, Barcelona (Spain) were included to the study. Participants in the intervention group (n = 51) were allocated to 12 sessions of BT and aquatic exercises delivered in one month while the control group (n = 47) did not. The primary outcome was to evaluate the absolute change in questionnaire scores between baseline and two follow-up points: immediately after balneotherapy (or one-month post-baseline for the control group) and 2 months post-baseline. The following scales/questionnaires were employed: Post-COVID-19 functional status scale, mMRC dyspnea Scale, SF-36, Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Memory failures in everyday life following severe head injury, and Visual Analogic Scale (VAS). Forty-seven patients in the BT group and 43 in the control group completed the study. The majority of participants were middle-aged women (> 84

We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition. Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses. When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men. Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID.

Pre-existing coronary artery disease (CAD), and thrombotic, inflammatory, or virus infectivity response phenomena have been associated with COVID-19 disease severity. However, the association of candidate single nucleotide variants (SNVs) related to mechanisms of COVID-19 complications has been seldom analysed. Our aim was to test and validate the effect of candidate SNVs on COVID-19 severity. CARGENCORS (CARdiovascular GENetic risk score for Risk Stratification of patients positive for SARS-CoV-2 [COVID-19] virus) is an age- and sex-matched case-control study with 818 COVID-19 cases hospitalized with hypoxemia, and 1636 controls with COVID-19 treated at home. The association between severity and SNVs related to CAD (n = 32), inflammation (n = 19), thrombosis (n = 14), virus infectivity (n = 11), and two published to be related to COVID-19 severity was tested with adjusted logistic regression models. Two external independent cohorts were used for meta-analysis (SCOURGE and UK Biobank). After adjustment for potential confounders, 14 new SNVs were associated with COVID-19 severity in the CARGENCORS Study. These SNVs were related to CAD (n = 10), thrombosis (n = 2), and inflammation (n = 2). We also confirmed eight SNVs previously related to severe COVID-19 and virus infectivity. The meta-analysis showed five SNVs associated with severe COVID-19 in adjusted analyses (rs11385942, rs1561198, rs6632704, rs6629110, and rs12329760). We identified 14 novel SNVs and confirmed eight previously related to COVID-19 severity in the CARGENCORS data. In the meta-analysis, five SNVs were significantly associated to COVID-19 severity, one of them previously related to CAD.

BACKGROUND:Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture. RESULTS:Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria. CONCLUSIONS:Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

This study aims to understand how osteoporosis medication acceptance varies across countries with differing guidance on treatment threshold and influence of clinical and demographic factors. A total of 79.2

Williams–Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.

The RICO study indicated that most patients would like to receive information regarding their fracture risk but that only a small majority have actually received it. Patients globally preferred a visual presentation of fracture risk and were interested in an online tool showing the risk. The aim of the Risk Communication in Osteoporosis (RICO) study was to assess patients’ preferences regarding fracture risk communication. To assess patients’ preferences for fracture risk communication, structured interviews with women with osteoporosis or who were at risk for fracture were conducted in 11 sites around the world, namely in Argentina, Belgium, Canada at Hamilton and with participants from the Osteoporosis Canada Canadian Osteoporosis Patient Network (COPN), Japan, Mexico, Spain, the Netherlands, the UK, and the USA in California and Washington state. The interviews used to collect data were designed on the basis of a systematic review and a qualitative pilot study involving 26 participants at risk of fracture. A total of 332 women (mean age 67.5 ± 8.0 years, 48