Search Results (77)

Background: Inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), may impair bone metabolism, particularly in children. The RANKL/OPG axis, as a key regulator of bone turnover, may contribute to these disturbances. However, data in the pediatric population remain limited. Methods: A single-center, prospective observational study included 100 children aged 4–18 years, with a comparable number of girls and boys. Among them, 72 had IBD (27 CD, 45 UC) and 28 were healthy controls. Anthropometric, biochemical, and densitometric assessments were performed, including serum levels of RANKL and OPG, and markers of inflammation and bone turnover. Results: Children with CD had significantly lower height and weight percentiles compared to UC and controls. Serum RANKL and the RANKL/OPG ratio were significantly elevated in IBD patients, particularly in CD (p < 0.01). Total body BMD Z-scores were lower in IBD compared to controls (p = 0.03). Low BMD was found in 14.7% of UC and 26.3% of CD patients. In both groups, over 30% had values in the “gray zone” (−1.0 to −2.0). A positive correlation was observed between height and weight and bone density (p < 0.01). Higher OPG was associated with lower body weight (p < 0.001), while increased RANKL correlated with osteocalcin (p = 0.03). Patients receiving biological therapy had significantly lower BMD. Conclusions: Pediatric IBD is associated with significant alterations in the RANKL/OPG axis and reduced bone density. These findings support early screening and suggest RANKL/OPG as a potential biomarker of skeletal health. Full article

Background/Objective: In patients with acute lymphoblastic leukemia (ALL), it has been demonstrated that the treatment has a negative effect on bone health. The n-3 polyunsaturated fatty acids (LCPUFAs-ω3) may attenuate bone resorption. We evaluated the effects of LCPUFAs-ω3, vitamin D, and calcium supplementation on bone turnover markers and changes in vitamin D concentrations during 6 weeks of supplementation and during 6 weeks of post-intervention follow-up in pediatric patients with ALL. Methods: Thirty-six pediatric patients with ALL were randomly assigned to the ω-3VDCa group (100 mg/kg/d LCPUFAs-ω3 + 4000 IU vitamin D + 1000 mg calcium) or the VDCa group (4000 IU vitamin D + 1000 mg calcium) for 6 weeks. Blood samples were collected to determine 25(OH)D, PTH, ICTP, and TRAP-5b (biomarkers of bone resorption) and osteocalcin (OC, a biomarker of bone production) levels at baseline, 6 weeks, and 12 weeks after supplementation. The 25(OH)D analysis was performed using ultra-high-performance liquid chromatography coupled to a mass spectrometer, and PTH and bone turnover markers were measured by ELISA. Results: The 25(OH)D concentration increased in both groups (ω3VDCa group: 19.4 ng/mL vs. 44.0 ng/mL, p < 0.0001; VDCa group: 15.3 ng/mL vs. 42.8 ng/mL, p = 0.018) and remained significantly higher at 12 weeks. At 12 weeks, ICTP showed lower concentrations in the ω-3VDCa group than in the VDCa group (0.74 ng/mL vs. 1.05 ng/mL, p = 0.024). Conclusions: Combined omega-3 and 4000 IU vitamin D supplementation for 6 weeks had a positive effect on bone health, as indicated by serum ICTP, with no effect on serum 25(OH)D levels over vitamin D supplementation alone. Full article

Introduction: Celiac disease (CD) impairs bone development in children through inflammation and nutrient malabsorption. Osteoprotegerin (OPG), a decoy receptor for RANKL, plays a role in bone remodeling and is increasingly recognized as a potential biomarker of bone metabolism and inflammation. However, its clinical significance in pediatric CD remains unclear. Aim: To evaluate the relationship between OPG levels, growth parameters, and delayed bone age in children with CD, and to assess OPG’s potential as a biomarker of bone health and disease activity. Methods: This three-year case–control study included 146 children: 25 with newly diagnosed CD (Group A), 54 with established CD on a gluten-free diet (Group B), and 67 healthy controls (Group C). Participants underwent clinical, anthropometric, and laboratory assessments at baseline and after 6 months (Groups A and B). OPG and osteocalcin were measured, and bone age was assessed radiologically. Statistical analyses included ANOVA, Spearman’s correlations, and binomial logistic regression. Results: OPG levels were highest in newly diagnosed children (Group A), showing a non-significant decrease after gluten-free diet initiation. OPG correlated negatively with age and height in CD patients and controls, and positively with hemoglobin and iron in Group B. Logistic regression revealed no significant predictive value of OPG for delayed bone age, although a trend was observed in Group B (p = 0.091). Children in long-term remission exhibited bone maturation patterns similar to healthy peers. Conclusions: OPG levels reflect disease activity and growth delay in pediatric CD but lack predictive power for delayed bone age. While OPG may serve as a secondary marker of bone turnover and inflammatory status, it is not suitable as a standalone biomarker for skeletal maturation. These findings highlight the need for integrative biomarker panels to guide bone health monitoring in children with CD. Full article

Musculoskeletal (MSK) disorders remain a major global cause of disability, with diagnostic complexity arising from their heterogeneous presentation and multifactorial pathophysiology. Recent advances across imaging modalities, molecular biomarkers, artificial intelligence applications, and point-of-care technologies are fundamentally reshaping musculoskeletal diagnostics. This review offers a novel synthesis by unifying recent innovations across multiple diagnostic imaging modalities, such as CT, MRI, and ultrasound, with emerging biochemical, genetic, and digital technologies. While existing reviews typically focus on advances within a single modality or for specific MSK conditions, this paper integrates a broad spectrum of developments to highlight how use of multimodal diagnostic strategies in combination can improve disease detection, stratification, and clinical decision-making in real-world settings. Technological developments in imaging, including photon-counting detector computed tomography, quantitative magnetic resonance imaging, and four-dimensional computed tomography, have enhanced the ability to visualize structural and dynamic musculoskeletal abnormalities with greater precision. Molecular imaging and biochemical markers such as CTX-II (C-terminal cross-linked telopeptides of type II collagen) and PINP (procollagen type I N-propeptide) provide early, objective indicators of tissue degeneration and bone turnover, while genetic and epigenetic profiling can elucidate individual patterns of susceptibility. Point-of-care ultrasound and portable diagnostic devices have expanded real-time imaging and functional assessment capabilities across diverse clinical settings. Artificial intelligence and machine learning algorithms now automate image interpretation, predict clinical outcomes, and enhance clinical decision support, complementing conventional clinical evaluations. Wearable sensors and mobile health technologies extend continuous monitoring beyond traditional healthcare environments, generating real-world data critical for dynamic disease management. However, standardization of diagnostic protocols, rigorous validation of novel methodologies, and thoughtful integration of multimodal data remain essential for translating technological advances into improved patient outcomes. Despite these advances, several key limitations constrain widespread clinical adoption. Imaging modalities lack standardized acquisition protocols and reference values, making cross-site comparison and clinical interpretation difficult. AI-driven diagnostic tools often suffer from limited external validation and transparency (“black-box” models), impacting clinicians’ trust and hindering regulatory approval. Molecular markers like CTX-II and PINP, though promising, show variability due to diurnal fluctuations and comorbid conditions, complicating their use in routine monitoring. Integration of multimodal data, especially across imaging, omics, and wearable devices, remains technically and logistically complex, requiring robust data infrastructure and informatics expertise not yet widely available in MSK clinical practice. Furthermore, reimbursement models have not caught up with many of these innovations, limiting access in resource-constrained healthcare settings. As these fields converge, musculoskeletal diagnostics methods are poised to evolve into a more precise, personalized, and patient-centered discipline, driving meaningful improvements in musculoskeletal health worldwide. Full article

Prostate cancer with bone metastasis exhibits significant heterogeneity, complicating prognosis, and treatment. This study explores the potential of plasma, serum, and urine biomarkers to stratify patients and evaluate their prognostic value. Using two-step clustering, we analyzed baseline levels of Platelet-derived growth factor-BB (PDGF-BB), Insulin-like growth factor-binding protein 1 (IGFBP-1), Bone Morphogenetic Protein 2 (BMP-2), Vascular endothelial growth factor (VEGF) (plasma and urine), prostate-specific antigen (PSA), neuron-specific enolase (NSE), chromogranin A (CgA) and bone-specific alkaline phosphatase (BAP) (serum) and creatinine (Cr), and type I collagen-cross-linked N telopeptide (NTx) (urine) in 29 patients with prostate cancer and bone metastasis. Longitudinal biomarker dynamics were assessed at baseline, 6 months, and 12 months. Clinical outcomes were evaluated using Kaplan–Meier and multivariate analyses. Three distinct groups (C1, C2, and C3) were identified. C1 exhibited elevated pPDGF-BB and pVEGF levels, C3 had increased pBAP and uNTx/Cr, and C2 showed lower biomarker levels. Prior treatments influenced biomarker levels, with bisphosphonates reducing bone turnover markers and radiotherapy correlating with long-term changes in growth factors. Longitudinal analysis revealed unique biomarker dynamics within each group, with a tendency for pPDGF-BB and pVEGF levels to decrease over time in C1, and distinct trends in uNTx/Cr between groups. Despite individual biomarkers failing to predict survival, C3 patients demonstrated significantly worse survival than C1 and C2. Molecular clustering of peripheral blood and urinary biomarkers identifies distinct subgroups with metastatic castration-resistant prostate cancer patients outperforming traditional models in outcome prediction and supporting its potential for personalized treatment and prognosis. Full article

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article

Background and Objectives: Aging-related bone loss still lacks interventions. As bone marrow-derived mesenchymal stem cells (BMSCs) undergo aging, R-loop-induced DNA replication stress impairs the osteogenic ability of BMSCs. High-mobility group A-2 (Hmga2) acts as a DNA-binding protein, and the understanding of its underlying mechanisms is crucial for developing effective preventive and therapeutic strategies. Materials and Methods: Aging mice were used as the experimental model, and mouse BMSCs were isolated from their femurs. Hmga2 was achieved through specific gene delivery methods. R-loop formation was detected using dot blotting, chromatin immunoprecipitation (ChIP), and DNA–RNA immunoprecipitation (DRIP) assays. Osteogenic differentiation was evaluated. Results: R-loops were highly accumulated in aging BMSCs. Notably, the key regulator Hmga2 reversed the accumulation of R-loops in aging BMSCs. Hmga2 overexpression significantly decreased the senescence and improved the osteogenic differentiation of aging mBMSCs. Mechanistically, R-loop-forming sequence (RLFS) regions were confirmed in key osteogenesis-related genes, including runt-related transcription factor 2 (Runx2). Hmga2 bound to the RLFS region of Runx2 and promoted its expression by reducing the R-loop level. More, Hmga2 treatment delivered via the AAV system effectively decreased bone loss in aging mice and increased the serum bone turnover biomarkers and collagen remodeling. Conclusions: Our study demonstrates that Hmga2 acts as an activator of aging BMSCs, significantly promoting their osteogenic ability by eliminating the aging-induced DNA replication stress caused by R-loops. Our findings provide new insights into the mechanisms of aging-related bone loss, suggesting that Hmga2 may be a new strategy for alleviating the bone loss phenotype in aging individuals. Full article

Twin pregnancies, with higher incidences of preterm birth, are becoming more prevalent. Progesterone has shown effectiveness in the prevention of preterm labour, though other factors related to pregnancy and neonatal health may be affected by this hormone and have not been previously addressed. This study aims to evaluate the impact of progesterone administration on oxidative stress and bone turnover during twin gestation and investigate associations with some maternal/neonatal variables of interest. Women pregnant with twins were recruited in the “Virgen de la Arrixaca” University Hospital and randomly assigned to two groups: control (n = 49) and progesterone (n = 50). A total of 600 mg/day of progesterone was vaginally administered from 11 to 14 to 34 weeks of gestation. Blood samples were taken in the first (T1) and third trimester (T3), analyzing biomarkers related to oxidative stress and bone turnover. Most bone turnover and oxidative markers experiment with significant changes during gestation. Progesterone administration significantly increased (p < 0.05) the levels of osteocalcin in T3 and decreased (p < 0.05) the levels of sclerostin. Regarding oxidative stress, the progesterone group, unlike the control group, showed no significant increase in oxidative stress between T1 and T3. In conclusion, results show that progesterone administration could increase maternal bone formation and modulate oxidative stress. Full article

Introduction: This study aimed to capture the early metabolic changes before osteoporosis occurs and identify metabolomic biomarkers at the osteopenia stage for the early prevention of osteoporosis. Materials and Methods: Metabolomic data were generated from normal, osteopenia, and osteoporosis groups with 320 participants recruited from the Nicheng community in Shanghai. We conducted individual edge network analysis (iENA) combined with a random forest to detect metabolomic biomarkers for the early warning of osteoporosis. Weighted Gene Co-Expression Network Analysis (WGCNA) and mediation analysis were used to explore the clinical impacts of metabolomic biomarkers. Results: Visual separations of the metabolic profiles were observed between three bone mineral density (BMD) groups in both genders. According to the iENA approach, several metabolites had significant abundance and association changes in osteopenia participants, confirming that osteopenia is a critical stage in the development of osteoporosis. Metabolites were further selected to identify osteopenia (nine metabolites in females; eight metabolites in males), and their ability to discriminate osteopenia was improved significantly compared to traditional bone turnover markers (BTMs) (female AUC = 0.717, 95% CI 0.547–0.882, versus BTMs: p = 0.036; male AUC = 0.801, 95% CI 0.636–0.966, versus BTMs: p = 0.007). The roles of the identified key metabolites were involved in the association between total fat-free mass (TFFM) and osteopenia in females. Conclusion: Osteopenia was identified as a tipping point during the development of osteoporosis with metabolomic characteristics. A few metabolites were identified as candidate early-warning biomarkers by machine learning analysis, which could indicate bone loss and provide new prevention guidance for osteoporosis. Full article

Background/Objectives: Bone turnover markers (BTMs) can provide information on the bone growth of apparently healthy children and adolescents or useful results in the diagnosis and monitoring of the disease condition, comparing them with appropriate reference intervals (RIs). The aim of this study was to establish the RI for the BTM [specific bone alkaline phosphatase (BALP), carboxy-terminal cross-linked collagen type I telopeptide (CTX), N-terminal propeptide pro-collagen type I (PINP), osteocalcin (OC), resistant to acid tartrate phosphatase isoform 5b (TRAcP-5b)] on serum samples from children and adolescents. Method: 202 samples from children and adolescents (ages 1–18 years) (51.48% male), considered apparently healthy. The biomarker was analyzed on automatic immunometric equipment (TGSTA Technogenetics) and the IDS-iSYS automated system kits The RI of the studied parameters was calculated according to CLSI Guideline C28-A3 with stratification by age and sex. Evaluation of the distribution of values and the meaning of the biomarker concentrations were used to calculate general and specific RI for an age group. Results: BTM concentrations vary with pubertal growth. The pattern of change differs for each bone marker. General and age-specific RI were calculated: 1–14 years, 15–18 years for BALP and CTX; 1–13 years, 14–18 years for Oc and PINP and 1–12 years, 13–18 years for TRAcP. Discussion and Conclusions: Concentrations for biomarker studied vary with age and gender. The proof of concentrations with insignificant changes until puberty led to identification of two groups of RI relating to the covariables (age and sex) for each biomarker. Full article

Renal osteodystrophy (ROD) represents histological bone changes in patients with chronic kidney disease and is classified according to turnover and mineralization. This cross-sectional study evaluates several bone biomarkers and their ability to discriminate turnover and mineralization defects in hemodialysis (HD) patients. Bone-specific [BSAP] and total [tAP] alkaline phosphatase, procollagen-1 N-terminal propeptide [P1NP], C-terminal cross-linking telopeptide [CTX], intact [iPTH] and whole [wPTH] parathyroid hormone, sclerostin [SOST], fibroblast growth factor 23 [FGF-23], vitamin D, osteoprotegerin [OPG], and receptor activator of nuclear factor κB ligand [RANKL] were collected before the bone biopsy. Thirty-two patients were evaluated by bone histomorphometry, which identified mineralization defects and low and high turnover in 47%, 50%, and 41% of patients, respectively. Bone biomarkers (tAP, BSAP, CTX, P1NP) and hormones (iPTH, wPTH, and SOST) were capable of identifying low and high turnover (AUC > 0.877 and >0.857, respectively, p < 0.001). PTH plus AP had the best accuracy for identifying high turnover. BSAP > 2x, iPTH > 8x, and wPTH > 6x upper limit of normal range identified high turnover. Lower calcium values (Ca < 8.7 mg/dL) were correlated with mineralization defects. On the other hand, FGF-23, OPG, and RANKL did not impact the turnover and mineralization. While bone histomorphometry is not widely available, bone biomarkers such as BSAP, P1NP, PTH, and calcium allow the assessment of turnover and mineralization defects in HD patients. Then, using bone biomarkers may help clinicians define treatments for ROD and osteoporosis and monitor therapeutic response. Full article

Background/Objectives: Patients with Gaucher disease have a high risk of bone disease, with osteonecrosis representing the most debilitating complication. The pathogenesis of osteonecrosis has not been fully elucidated yet, and there is an unmet need for predictive biomarkers of bone complications. We aimed to assess the utility of angiogenesis and bone turnover biomarkers as predictors of osteonecrosis in Gaucher disease. Methods: Angiogenesis and bone turnover biomarkers were measured in 146 Gaucher disease patients (70M:76F, median age 49.5 [IQR 36.7 to 61]) with/without osteonecrosis enrolled in the UK-based registry GAUCHERITE [enrolment 2015–2017]. Receiver-operating characteristic curve analysis was used to compare the osteonecrosis predictive value of angiogenesis and bone turnover biomarkers and determine the optimal cut-off values for each biomarker. Results: Sixty-two patients had osteonecrosis before study enrolment, 11 had osteonecrosis during follow-up, and 73 remained osteonecrosis-free. Patients with osteonecrosis showed increased osteopontin and matrix metalloproteinase (MMP)-2 levels and decreased MMP-9 and vascular endothelial growth factor (VEGF)-C compared with those free from osteonecrosis. MMP-9 predicted future osteonecrosis with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC] 0.84 [95% CI 0.84–0.99]; sensitivity/specificity 82%/75%; cutoff value ≤ 72,420 pg/mL) than osteopontin, MMP-2 and VEGF-C when taken alone. The combination of MMP-9 and VEGF-C further increased the discriminating accuracy. Conclusions: The osteopontin–MMPs–VEGF axis is dysregulated in Gaucher disease patients with osteonecrosis. The combination of MMP-9 and VEGF-C circulating levels may serve to identify Gaucher disease patients at risk of osteonecrosis. Full article

Gingival crevicular fluid (GCF) and oral fluid have emerged as promising diagnostic tools for detecting biomarkers. This review aimed to evaluate the existing literature on using oral fluids as a source of biomarkers for bone turnover diseases affecting the jawbone. A comprehensive search strategy was executed between August 2014 and August 2024 across five major databases (Web of Science, EBSCOhost Dentistry & Oral Sciences Source, Cochrane Library, Scopus, and PubMed) and grey literature sources. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) was applied. The screening was facilitated using Rayyan at rayyan.ai and Endnote X20 software tools, culminating in the evaluation of 14,965 citations from databases and 34 from grey literature. Following rigorous scrutiny, 37 articles were selected for inclusion in this review, encompassing diseases such as periodontitis, medication-related osteonecrosis of the jaw (MRONJ), and osteoporosis. The quality of the included observational studies was assessed using the Revised Risk of Bias Assessment Tool for Non-Randomized Studies (RoBANS 2). Interleukin-1 beta (IL-1β), sclerostin, osteoprotegerin (OPG), and interleukin-34 (IL-34) emerged as significant biomarkers in GCF, and they were mainly from periodontitis and osteoporosis. Osteocalcin (OC), IL-1β, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), OPG, and matrix metalloproteinase-9 (MMP-9) were significant in oral fluid or saliva, and they were from periodontitis, MRONJ, and osteoporosis. These findings underscore the potential use of oral fluids, which are regarded as non-invasive tools for biomarker identification in bone turnover. Many biomarkers overlap, and it is important to identify other specific biomarkers to enable accurate diagnosis of these conditions. Full article

Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression. Full article

Osteoarthritis (OA) is a chronic degenerative disease leading to articular cartilage destruction. Menopausal and postmenopausal women are susceptible to both OA and osteoporosis. S-equol, a soy isoflavone-derived molecule, is known to reduce osteoporosis in estrogen-deficient mice, but its role in OA remains unknown. This study aimed to explore the effect of S-equol on different degrees of menopausal OA in female Sprague–Dawley (SD) rats induced by estrogen deficiency caused by bilateral ovariectomy (OVX) combined with intra-articular injection of mono-iodoacetate (MIA). Knee joint histopathological change; serum biomarkers of bone turnover, including N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX-I) and N-terminal telopeptide of type I collagen (NTX-I); the cartilage degradation biomarkers hyaluronic acid (HA) and N-terminal propeptide of type II procollagen (PIINP); and the matrix-degrading enzymes matrix metalloproteinases (MMP)-1, MMP-3 and MMP-13, as well as the oxidative stress-inducing molecules nitric oxide (NO) and hydrogen peroxide (H₂O₂), were assessed for evaluation of OA progression after S-equol supplementation for 8 weeks. The results showed that OVX without or with MIA injection induced various severity levels of menopausal OA by increasing pathological damage, oxidative stress, and cartilage matrix degradation to various degrees. Moreover, S-equol supplementation could significantly reduce these increased biomarkers in different severity levels of OA. This indicates that S-equol can lessen menopausal OA progression by reducing oxidative stress and the matrix-degrading enzymes involved in cartilage degradation. Full article