Search Results (314)

Osteoarthritis (OA) and other rheumatic diseases are among the leading causes of chronic pain, disability, and reduced quality of life worldwide. Increasing evidence indicates that disturbances in metal homeostasis contribute to the pathogenesis of these disorders through their effects on oxidative stress, immune regulation, cartilage metabolism, bone remodeling, and extracellular matrix degradation. This review summarizes current knowledge regarding the role of essential metals and trace elements, including zinc, iron, copper, magnesium, selenium, and manganese, as well as toxic metals such as cadmium, lead, mercury, and arsenic, with primary emphasis on their involvement in the development and progression of osteoarthritis. Other rheumatic diseases are discussed briefly to provide a comparative perspective. Particular attention is given to the molecular mechanisms underlying metal-mediated pathology, including oxidative stress, ferroptosis, mitochondrial dysfunction, activation of intracellular signaling pathways, and inflammasome activation. The diagnostic and therapeutic potential of metal-related biomarkers, metalomics, and targeted interventions aimed at restoring metal homeostasis are also discussed. Furthermore, current limitations of available studies and emerging research directions, including single-cell technologies, spatial transcriptomics, multi-omics approaches, and personalized medicine, are highlighted. A better understanding of metal homeostasis may improve the identification of novel biomarkers and therapeutic targets, ultimately contributing to more precise diagnosis and individualized treatment strategies for osteoarthritis and other rheumatic diseases. Full article

The dysregulation of immune homeostasis and the persistence of chronic, low-grade inflammation represent core pathophysiological drivers governing the onset and progression of metabolic and cardiovascular disorders. Myeloid-derived suppressor cells (MDSCs) comprise a highly heterogeneous population of immature myeloid cells that are rapidly mobilized from the bone marrow in response to biological stressors, such as sustained tissue injury and chronic inflammatory signaling. Historically evaluated within oncology and infectious disease frameworks, accumulating evidence highlights the pivotal, context-dependent roles of MDSCs in cardiometabolic environments. In conditions of obesity and type 2 diabetes (T2D), MDSCs undergo substantial expansion and accumulation within peripheral tissues, including adipose tissue and the liver. Functionally, MDSCs act as dynamic immunoregulators that can either buffer metabolic inflammation, via the secretion of interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and nitric oxide (NO) or, conversely, reflect and exacerbate disease progression depending on specific cellular subsets, glycemic control, and tissue localization. Within the vascular system, specific monocytic MDSC subsets demonstrate significant atheroprotective and cardioprotective capabilities by dampening Th1/Th17-mediated arterial wall inflammation, stabilizing atherosclerotic plaques, and preserving cardiac structural architecture during heart failure. However, phenotypic and functional heterogeneity poses a critical clinical challenge, as certain persistent or altered subsets correlate with heightened cardiovascular risk and adverse cerebrovascular outcomes. This review delivers a comprehensive synthesis of contemporary insights into MDSC biology at the intersection of obesity-associated diabetes and cardiovascular disease, characterizing their dualistic mechanisms, distinguishing preclinical causal mechanisms from human observational data. Moreover, we have established a comprehensive framework to reconcile the conflicting protective versus detrimental effects of MDSCs. And finally, we have also evaluated their potential clinical utility as candidate biomarkers, delineating the safety imperatives essential for translating MDSC-targeted therapeutic interventions into clinical practice. Full article

Background: Osteoporosis is a multifactorial skeletal disorder characterized by reduced bone mass, impaired bone remodeling, and an increased risk of fractures, particularly under estrogen-deficient conditions. Artocarpus integer (Thunb.) Merr. contains prenylated flavonoids and chalcone derivatives with diverse biological activities; however, its anti-osteoporotic potential remains largely unexplored. This study investigated the phytochemical composition, molecular mechanisms, and anti-osteoporotic effects of A. integer leaf extract in an ovariectomized (OVX) rat model. Methods: Phytochemical profiling was performed using liquid chromatography–high-resolution mass spectrometry (LC–HRMS). Network pharmacology was employed to identify potential osteoporosis-related targets and signaling pathways. The anti-osteoporotic activity of the extract was evaluated in OVX rats through physiological and biochemical assessments, including body weight gain, uterine weight, serum biomarkers, femoral calcium content, and RT-PCR analysis of genes associated with osteogenesis, osteoclastogenesis, and estrogen signaling. Results: LC–HRMS analysis identified several bioactive compounds, including isobavachalcone, artocarpesin, morachalcone A, genistein, apigenin, luteolin, naringenin, catechin derivatives, and mangiferin. Network pharmacology revealed 96 overlapping targets between A. integer phytochemicals and osteoporosis-related genes, highlighting pathways involved in estrogen signaling, PI3K–Akt signaling, osteoclast differentiation, inflammation, and metabolic regulation. In vivo, OVX rats exhibited increased body weight gain, uterine atrophy, elevated leptin levels, reduced adiponectin concentrations, and decreased femoral calcium content. Treatment with A. integer attenuated OVX-induced metabolic alterations, improved adipokine profiles, and increased femoral calcium content, particularly in the medium-dose group. RT-PCR analysis demonstrated the upregulation of the osteogenic markers Runx2 and Osx, together with the downregulation of the osteoclastogenic markers TRAP. Conclusions: Artocarpus integer leaf extract exhibited promising anti-osteoporotic activity through the coordinated regulation of osteogenesis, osteoclastogenesis, estrogen-related signaling, and bone mineral preservation. These findings support the potential development of A. integer as a nutraceutical candidate for the prevention or management of postmenopausal osteoporosis. Full article

Acute myeloid leukemia (AML) represents a heterogeneous group of hematological malignancies characterized by uncontrolled proliferation of myeloid progenitors and accumulation of immature blasts in the bone marrow. Metabolic reprogramming is now recognized as a core hallmark of AML, generating dependencies that distinguish leukemic cells from normal hematopoietic stem and progenitor cells and that can be exploited therapeutically. In this review we follow a single connected line of argument: we first place metabolic rewiring within the broader hallmarks of cancer, then describe the principal metabolic programs altered in AML and the specific features that distinguish AML from other malignancies. We next examine the inhibitors and drugs that target each of these pathways, linking every drug class to its mechanism of synergy with chemotherapy, the preclinical and clinical evidence available, and its association with outcome in AML. We then consider multi-target (combination) therapy as a distinct opportunity, and finally the principal challenges that remainsafety and tolerability, the metabolic heterogeneity and plasticity of AML, and the design of biomarker-guided trials. Multiple classes of metabolic drugs are discussed, including glycolysis inhibitors, oxidative phosphorylation inhibitors, glutamine metabolism antagonists, fatty acid oxidation modulators, and redox-active compounds. Despite significant challenges, targeting cellular metabolism represents a promising strategy to enhance therapeutic outcomes in patients with AML. Full article

Background: Fibroblast growth factor 23 (FGF23) and α-Klotho are key regulators of mineral metabolism and bone homeostasis; however, their combined diagnostic value in postmenopausal osteoporosis remains incompletely understood. This study investigated the associations of serum FGF23, α-Klotho, and the FGF23/α-Klotho ratio with bone mineral density (BMD), bone turnover markers, and their diagnostic performance for postmenopausal osteoporosis. Methods: This cross-sectional study included 165 women divided into three groups: premenopausal healthy controls (n = 55), postmenopausal non-osteoporotic women (n = 55), and postmenopausal women with osteoporosis (n = 55). Serum FGF23 and α-Klotho concentrations were measured by enzyme-linked immunosorbent assay. Bone mineral density was assessed by dual-energy X-ray absorptiometry. Correlation analyses, age- and BMI-adjusted partial correlations, multivariable linear and logistic regression analyses, receiver operating characteristic (ROC) analyses, and incremental diagnostic models were performed. Diagnostic ROC and incremental model analyses were restricted to postmenopausal women (n = 110). Results: Serum FGF23 concentrations and the FGF23/α-Klotho ratio increased progressively across the study groups, whereas α-Klotho levels decreased (all p < 0.001). FGF23 was inversely correlated with lumbar spine, femoral neck, and total hip BMD and T-scores (all p < 0.001), whereas α-Klotho demonstrated positive correlations with all BMD parameters (all p < 0.001). These associations remained significant after adjustment for age and BMI. In multivariable linear regression analyses, the FGF23/α-Klotho ratio showed the strongest independent association with skeletal T-scores (standardized β = −0.379 to −0.404; all p < 0.001). Multivariable logistic regression identified lower 25-hydroxyvitamin D, higher parathyroid hormone, higher FGF23, and lower α-Klotho as independent factors associated with osteoporosis. In analyses restricted to postmenopausal women, the FGF23/α-Klotho ratio showed the highest numerical discriminative performance for osteoporosis (AUC = 0.832, 95% CI: 0.755–0.901), followed by α-Klotho (AUC = 0.793) and FGF23 (AUC = 0.697). The ratio significantly outperformed FGF23 alone (ΔAUC = 0.135, p = 0.001), whereas its performance did not differ significantly from that of α-Klotho (ΔAUC = 0.038, p = 0.270). Adding FGF23 and α-Klotho to age, BMI, and 25-hydroxyvitamin D increased the AUC from 0.743 to 0.882. Conclusions: Serum FGF23 and α-Klotho are independently associated with bone mineral density and are linked to bone turnover markers in postmenopausal women. The FGF23/α-Klotho ratio showed the highest numerical discriminative performance among the evaluated biomarkers, although its performance was not significantly different from that of α-Klotho alone. The combined assessment of FGF23 and α-Klotho provided additional discriminatory information beyond the measured clinical variables. Given the cross-sectional design and lack of external validation, these findings should be considered exploratory and require validation in prospective independent cohorts. Full article

Background: The stability of the musculoskeletal axis is crucial for maintaining mobility in women, yet the impact of controlled thyroid dysfunction on this system remains ambiguous. Objectives: The aim of this cross-sectional study was to compare the body composition and functional performance of women with Hashimoto’s thyroiditis, women with hypothyroidism, and healthy controls in the context of the role of parathyroid hormone (PTH) as a potential comorbid factor. Methods: The study included 70 women divided into three groups: Hashimoto’s thyroiditis (n = 27), hypothyroidism (n = 15), and control (n = 28). Anthropometric parameters, including limb muscle mass (ALM) and bone mineral density (BMD), were assessed using X-ray absorptiometry (DXA). Physical performance was assessed using handgrip strength (HGP) and Timed Up and Go (TUG) tests, supplemented by ELISAs for metabolic and neurotrophic biomarkers (BDNF, irisin, GDF-15, P3NP). Results: The results showed no statistically significant differences between groups in muscle mass (ALM: p = 0.13; ALMI: p = 0.27) or bone density (BMD: p = 0.82). Functional performance outcomes were also comparable between groups (HGP: p = 0.71; TUG: p = 0.143). The levels of the analyzed biomarkers did not differ significantly by thyroid status (BDNF: p = 0.91; irisin: p = 0.85; GDF-15: p = 0.96). Furthermore, correlation analysis revealed that PTH showed a moderate, negative correlation with P3NP in the total population (r = −0.44, p = 0.003). In contrast, its association with muscle mass index (ALM) was attenuated after FDR correction. Conclusions: These preliminary results indicate no detectable deterioration in musculoskeletal and functional parameters in women with managed thyroid dysfunction. However, due to the small sample size of the hypothyroidism subgroup and low statistical power, these findings cannot establish physiological equivalence and must be interpreted with caution, as they do not confirm a direct protective effect of levothyroxine therapy against muscle mass decline. Full article

The heart–kidney axis has emerged as a central framework for understanding the bidirectional interactions that drive cardiorenal syndrome and broader cardiovascular–kidney–metabolic (CKM) disease. However, existing interpretations have often emphasized hemodynamic and neurohormonal mechanisms without fully integrating the growing evidence for endocrine, inflammatory, and metabolic mediators that coordinate injury across organs. This Review was therefore undertaken to provide an updated and clinically relevant synthesis of the physiological basis of heart–kidney communication, the mechanisms underlying its disruption, and the therapeutic implications of these insights. To achieve this aim, we performed a systematic narrative review of the literature using PubMed, Embase, Web of Science, and Scopus for studies, supplemented by manual screening of reference lists. Priority was given to original studies, large cohort analyses, randomized controlled trials, meta-analyses, and authoritative reviews. We integrated evidence spanning physiological regulation, maladaptive signaling pathways, emerging mediators, experimental models, and evolving treatment strategies. The reviewed evidence indicates that heart–kidney crosstalk is driven not only by altered perfusion and venous congestion, but also by sustained activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), inflammation, oxidative stress, mitochondrial dysfunction, anemia, uremic toxins, and disordered mineral metabolism. Among novel mediators, fibroblast growth factor 23 (FGF23) emerges as a major bone-derived, chronic kidney disease (CKD)-associated endocrine mediator linking renal injury to cardiac hypertrophy, fibrosis, calcium mishandling, and diastolic dysfunction, whereas Klotho appears to exert counter-regulatory protective effects. Heart-derived natriuretic peptides, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), remain important modulators of renal blood flow, natriuresis, and volume homeostasis. We further highlight the translational relevance of newer biomarkers and therapies, including sodium–glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), and mineralocorticoid receptor antagonists (MRAs), which may help address cardiac and renal dysfunction in parallel. Overall, this Review supports a revised conceptual model in which the heart–kidney axis is governed by multidirectional hemodynamic, neurohormonal, immune, and endocrine signaling networks. A more integrated understanding of these mechanisms may improve biomarker discovery, refine risk stratification, and promote therapies that target both organs simultaneously. Full article

Frailty is a multidimensional syndrome of reduced physiological reserve that is particularly prevalent in individuals with type 2 diabetes. Identifying objective biochemical markers to complement clinical screening tools, such as the FRAIL scale, is an increasingly important unmet need. Periostin, a matricellular protein involved in tissue remodeling, bone metabolism, and chronic complications of diabetes, has emerged as a potential candidate. In this cross-sectional study of 137 adults with type 2 diabetes (65 ± 8 years), participants were classified as robust, pre-frail, or frail according to FRAIL scores. Frailty correlated positively with age (p < 0.001), BMI (p = 0.006), waist circumference (p = 0.01), and diabetes duration (p = 0.040), and negatively with TBS (p = 0.001), HDL-c (p = 0.040), and eGFR (p = 0.009). A stronger positive correlation was observed with serum periostin (p < 0.001). Frail individuals showed higher periostin levels than pre-frail (p = 0.006) and robust participants (p = 0.008), independent of age. Periostin demonstrated moderate discriminatory capacity for frailty status (AUC = 0.710; p < 0.001), while adding periostin to clinical variables resulted in a numerical increase in overall model discrimination (AUC = 0.900 vs. 0.858). A threshold of >1307 pmol/L yielded 77.8% sensitivity and 66.7% specificity. These preliminary findings indicate that periostin is significantly associated with frailty in type 2 diabetes and may represent a complementary biochemical biomarker of frailty status, warranting further validation in longitudinal studies. Full article

Background: Fragility fractures of the pelvis (FFP) are increasingly encountered in older adults, yet early deterioration is difficult to anticipate because fracture instability interacts with frailty and systemic vulnerability. We developed and validated an admission-based multimodal framework to predict 90-day treatment failure (TF90) before definitive management. Methods: This multicentre retrospective prediction study included 1684 consecutive patients aged ≥65 years with FFP treated at five tertiary hospitals. TF90 was defined as persistent fracture-related pain or immobility, delayed conversion to operative stabilisation, secondary displacement, FFP-related unplanned readmission, revision or unplanned reoperation, or all-cause mortality within 90 days. Only predictors available within 24 h of admission and before the definitive treatment decision were eligible, including CT-defined fracture morphology, frailty, clinical characteristics and routine laboratory biomarkers; DXA and specialised bone metabolism measurements were evaluated separately in an extended model. Four prespecified models were developed in 985 patients, temporally validated in 520 patients and evaluated in a completely held-out Centre E internal–external validation cohort of 179 patients, with additional leave-one-centre-out internal–external cross-validation. Results: TF90 occurred in 307 patients (18.2%) and increased from 8.1% in FFP I to 37.1% in FFP IV. Higher risk was associated with advanced age, greater frailty, impaired prefracture mobility, bilateral posterior ring injury, greater displacement, systemic inflammation, hypoalbuminaemia and renal dysfunction. In temporal validation, AUROCs were 0.732 for the simple logistic model, 0.763 for the core logistic model, 0.759 for the core random forest and 0.755 for the extended random forest. Neither greater algorithmic complexity nor specialised skeletal measurements provided reproducible incremental value. A development-derived high-risk stratum had a TF90 incidence of 32.2% and contained 70.0% of all events. At the fixed threshold of 0.209, sensitivity was 71.3%, specificity 70.0% and negative predictive value 93.1%. Conclusions: Pretreatment integration of pelvic ring mechanics, frailty and routinely available systemic biomarkers enables clinically relevant enrichment of older patients at risk of TF90. The model is best positioned to support intensified surveillance and structured reassessment rather than determine operative treatment. Independent prospective external validation, recalibration and clinical impact evaluation are required before routine implementation. Full article

Background/Objectives: Temporomandibular joint (TMJ) abnormalities are a common finding in the general adult population, but they have been rarely investigated in people receiving chronic dialysis. The TMJ is a unique synovial joint that can be altered by either inflammatory or degenerative processes, both of which are amenable to ultrasound (US) assessment. The aim of this study was to describe the pattern of TMJ involvement in a cohort of hemodialysis patients using TMJ ultrasound (TMJ US). Methods: This cross-sectional, single-center study evaluated the clinical utility of TMJ US to detect inflammatory and degenerative changes in patients undergoing chronic hemodialysis and was carried out between June and December 2025. Demographic data, dialysis vintage, the Controlling Nutritional Status (CONUT) score and the Charlson Comorbidity Index (CCI) were collected and related to TMJ US findings and to bone-metabolism biomarkers (calcium, phosphate, parathyroid hormone). Results: 100 hemodialysis patients were included (65 male, 65%; mean age 71.6 ± 13.1 years). Comorbidity and undernutrition were frequent findings (CCI ≥ 4 in 63%; CONUT ≥ 3 in 68%). TMJ US revealed that degenerative indicators were more common than inflammatory ones: calcifications (36%), condylar irregularities (33%) and enthesophytes (25%) were the most prevalent degenerative findings, whereas joint effusion (16%), synovial hypertrophy (15%) and cartilage changes (15%) were the leading inflammatory findings; a positive power Doppler signal was rare (1%). Cortical/condylar irregularity was significantly more prevalent in patients with a dialysis vintage of less than 30 months (43.8% vs. 23.1%, p = 0.034), who also had lower serum calcium levels. No other TMJ US finding showed a significant association with age, sex, comorbidity burden, nutritional status, or bone-metabolism parameters on univariate. Conclusions: TMJ US demonstrated a substantial burden of subclinical degenerative and, to a lesser extent, inflammatory TMJ findings in this cohort of hemodialysis patients; none of these abnormalities were spontaneously reported as symptomatic, and their prevalence was independent of age, dialysis vintage, comorbidity, nutritional status and classical bone-metabolism parameters. These findings cannot be directly attributed to the dialysis/uremic environment rather than to age-related degeneration; they support the concept that the TMJ warrants further investigation as a potentially under-recognized target within the broader systemic metabolic derangement of end-stage kidney disease, and suggest that TMJ US is a feasible, accessible technique for detecting subclinical TMJ involvement in this population, pending confirmation of clinical utility in controlled studies. Full article

Background: The contribution of specific nutritional biomarkers to skeletal fragility remains poorly understood, in part because most studies include participants with metabolic conditions that obscure nutrient-specific effects. We aimed to examine incremental contribution of six pathway-specific nutritional biomarkers. Methods: In a prospective cross-sectional case–control design, 108 patients undergoing arthroplasty were enrolled (hip-fracture, n = 63; non-fracture, n = 45), and bone biopsies and blood specimens were collected intraoperatively. Circulating biomarkers reflecting vitamin K, one-carbon metabolism, antioxidant nutrients (vitamins E and C), protein and zinc status were measured. Bone outcomes included remodelling markers, trabecular microarchitecture and bone strength. Hierarchical regression was used to quantify the incremental contribution of nutritional biomarkers beyond clinical covariates with a priori outcome selection. Results: Bone remodelling markers did not differ between groups after covariate adjustment, indicating that fractures in this cohort were characterised by deficits in bone strength and quality rather than elevated systemic remodelling activity. Among six nutritional pathways tested, only vitamin K-dependent biomarkers showed consistent independent associations with bone outcomes, suggesting a degree of pathway specificity. Critically, carboxylated (cOC), undercarboxylated (ucOC) and fully uncarboxylated (unOC) osteocalcin fractions showed differential associations reflecting their distinct biological roles: cOC was independently associated with greater bone strength (section modulus, femoral neck width and cortical shaft thickness; p < 0.05) and lower trabecular separation (Tb.Sp); ucOC was associated with higher Tb.Sp (p = 0.004); and unOC was positively associated with cortical bone instability (buckling ratio, p = 0.003) and explained 17% of the variance in the bone resorption marker (p < 0.001), consistent with a shift towards bone loss. Vitamin K2-7 was negatively associated with hip axis length (p = 0.021). Conclusions: These findings identify vitamin K-dependent carboxylation as a mechanistically specific and modifiable factor associated with skeletal fragility beyond bone mineral density, with distinct skeletal consequences across osteocalcin carboxylation states. Full article

Individuals with overweight and obesity consistently demonstrate lower circulating concentrations of serum 25-hydroxyvitamin D (25OHD), the primary biomarker of vitamin D status. Additionally, they exhibit an attenuated response to conventional vitamin D supplementation and may require doses approximately 2–3 times higher than those recommended for individuals with normal body weight to achieve equivalent serum 25OHD concentrations. However, accumulating evidence from randomized controlled trials raises concerns regarding the safety of high-dose vitamin D supplementation, with some studies reporting increased risks of falls and fractures, as well as potential adverse effects on bone mineral density and cognitive outcomes. Magnesium is an essential cofactor in vitamin D metabolism, participating in enzymatic processes required for the hepatic and renal hydroxylation of vitamin D into its active forms. Inadequate Magnesium status may therefore influence vitamin D status and response to vitamin D treatment. Previous randomized clinical trials suggest that Magnesium supplementation, administered either alone or in combination with moderate doses of vitamin D, can effectively increase serum 25OHD concentrations, particularly among individuals with overweight or obesity. Collectively, these findings suggest that optimizing Magnesium status may improve the response to vitamin D supplementation and potentially reduce the need for high-dose vitamin D therapy in obese individuals. Physicians treating overweight or obese patients for vitamin D deficiency should consider co-supplementation with Magnesium and/or encourage intake of Magnesium-rich foods to improve vitamin D status and supplementation outcomes in this population. Full article

Objective: To investigate the effect of milk minerals on bone mineral density (BMD) and bone quality in growing rats and explore the underlying mechanisms related to calcium absorption, bone metabolism, and the gut–bone axis. Methods: Sixty healthy 4-week-old male Sprague-Dawley (SD) rats were randomly divided to five groups based on their body weight: Low-Calcium Control Group (Control), Low-Dose milk mineral Group (Low), Medium-Dose milk mineral Group (Medium), High-Dose milk mineral Group (High) and Calcium Carbonate Control Group (CaCO₃), which received the same dose level (elemental calcium) as the High group. The milk mineral dosage was set at 5, 10, and 15 times the human recommended intake of elemental calcium. After 12 weeks of intervention, femurs were collected for analysis of BMD, bone microstructure, and bone mechanical strength. Additionally, analyses included calcium levels in the femur, feces, and diet; serum bone metabolism biomarkers; tissue protein expression; as well as gut microbiota composition and short-chain fatty acid content. Result: Milk mineral exhibited non-inferior efficacy to CaCO₃ in increasing femoral calcium content, enhancing BMD, and improving bone microarchitecture. Notably, the Medium group achieved comparable bone-protective effects to the CaCO₃ group despite a 20.8% lower calcium content, which was accompanied by a relatively high calcium absorption rate (90.9% vs. 86.5%). With respect to serum markers, milk mineral maintained bone formation while suppressing bone resorption, resulting in a net anabolic state comparable to that of CaCO₃. Milk mineral significantly upregulated the protein expression of renal CYP27B1 and intestinal calcium ion transporters, and increased serum IGF-I levels. Furthermore, milk mineral promoted the enrichment of certain specific gut microbial genera, which showed a significant positive correlation with IGF-I, bone calcium content and BMD. Conclusions: Milk mineral supplementation appears to promote bone formation and mineralization in growing rats, accompanied by enhanced intestinal calcium absorption, enrichment of characteristic gut microbes and elevated microbial metabolite concentrations. Full article

Osteosarcopenia—defined as the coexistence of sarcopenia and osteoporosis—is increasingly recognized as a clinically important geriatric syndrome associated with falls, fractures, frailty, disability, and mortality. Beyond the simple coexistence of bone and muscle loss, emerging data suggest that osteosarcopenia may reflect systemic dysregulation of the bone–muscle–immune–metabolic network. In this narrative review, we synthesize evidence linking inflammaging, immune-cell polarization, mitochondrial dysfunction, nutrient metabolic dyshomeostasis, and gut-derived metabolites to the pathogenesis of osteosarcopenia. Multiple pathological processes—including chronic low-grade inflammation, Th17/Treg imbalance, macrophage polarization, oxidative stress, impaired mitophagy, insulin resistance, ectopic fat accumulation, and altered microbial metabolites—may converge to disrupt bone–muscle crosstalk. Notably, direct evidence from osteosarcopenic populations remains limited, and many mechanistic insights are extrapolated from osteoporosis, sarcopenia, and aging models. We further discuss current and emerging therapeutic strategies, including exercise, nutritional interventions, anti-osteoporotic agents, metabolic modulators, mitochondrial-targeted therapies, and gut-directed approaches. Longitudinal cohorts, multi-omics studies, and randomized controlled trials are urgently required to validate immunometabolic biomarkers and develop integrated interventions for osteosarcopenia. Full article

Background/Objectives: Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) is a frequent complication of chronic kidney disease, characterized by altered bone mineral density and mineral–hormonal metabolism. Therapeutic exercise may help attenuate these alterations, but evidence remains limited. This systematic review and meta-analysis evaluated the effects of therapeutic exercise on bone mineral density and mineral–bone and hormonal biomarkers in adults with CKD, focusing on CKD-MBD-related outcomes. Methods: Following a PROSPERO-registered protocol (CRD420251245021), Scopus, PubMed, Cochrane Central Register of Controlled Trials CENTRAL, and Web of Science were searched from inception to January 2026. Randomized controlled trials, including pilot randomized controlled trials, comparing therapeutic exercise with usual care or non-exercise control conditions in adults with CKD were included. Methodological quality and risk of bias were assessed with the PEDro scale and RoB 2, respectively. Results: Six studies involving 398 participants were included. Most interventions lasted 22 to 24 weeks and used resistance or combined aerobic and resistance exercise across inpatient and outpatient settings. Qualitative synthesis suggested improvements in femoral neck and lumbar spine bone mineral density and favorable biomarker changes. The assessed outcomes included femoral neck and lumbar spine BMD, calcium, phosphorus, sclerostin, PTH, FGF23, and klotho. Meta-analysis showed significant effects favoring therapeutic exercise for bone mineral density (MD = 0.05; 95% CI: 0.03 to 0.06; p < 0.00001; I² = 39%), mineral and bone-related biomarkers (SMD = 0.71; 95% CI: 0.42 to 0.99; p < 0.00001; I² = 75%), and hormonal biomarkers (SMD = 1.32; 95% CI: 0.88 to 1.77; p < 0.00001; I² = 85%). Conclusions: Therapeutic exercise may have beneficial effects on bone mineral density and selected mineral and hormonal biomarkers in adults with CKD. However, confidence in these findings is limited by the small number of studies, differences in CKD stage and exercise protocols, methodological limitations, risk of bias, and substantial heterogeneity in several pooled analyses. No definitive conclusions can currently be drawn regarding the optimal exercise modality, dose, or effects across CKD stages. Full article