Bone [JOURNAL]
Sun
200 papers
TGF-β1-regulation of bone formation via the miR-3064-3p/HDAC4/Runx2 axis: In vitro and in vivo studies.
Saranya I, Preetha D, Nivruthi S … +1 more , Selvamurugan N
Bone · 2026 Jun · PMID 42302905 · Publisher ↗
Transforming growth factor-beta1 (TGF-β1) regulates bone formation through Runx2, a bone transcription factor, and Runx2 activity is regulated by several coactivators and corepressors. Histone deacetylase 4 (HDAC4) funct...
Transforming growth factor-beta1 (TGF-β1) regulates bone formation through Runx2, a bone transcription factor, and Runx2 activity is regulated by several coactivators and corepressors. Histone deacetylase 4 (HDAC4) functions as a transcriptional corepressor, and it downregulates Runx2 activity in osteoblastic cells. Emerging evidence suggests that non-coding RNAs, particularly microRNAs (miRNAs), significantly influence normal and abnormal bone homeostasis. In this study, we identified miR-3064-3p, which targets HDAC4 in osteoblasts. Our findings demonstrated that TGF-β1 upregulates miR-3064-3p, which in turn downregulates HDAC4, leading to increased acetylation of Runx2 in osteoblastic cells. Conversely, inhibition of miR-3064-3p restored HDAC4 levels and reduced Runx2 acetylation. Inhibition of miR-3064-3p also decreased the expression of osteogenic transcription factors in differentiating osteoblasts. miR-3064-3p directly targeted the 3' untranslated region of HDAC4 in osteoblasts. In vivo analyses using a rat femoral defect model demonstrated that TGF-β1 significantly enhances bone regeneration, and the miR-3064-3p inhibitor markedly impaired this regenerative process, indicating its essential role in mediating TGF-β1-driven bone regeneration. Collectively, these findings highlight the pivotal role of the TGF-β1/miR-3064-3p/HDAC4/Runx2 axis as a positive regulator of bone formation.
Metabolic flexibility secures skeletal progenitor function upon reduced glycolysis driven by PFKFB3 loss.
Rosseels L, Stockmans I, Moermans K … +7 more , Blockx L, Coolen PJ, Ferrari G, Dmitriev RI, Carmeliet P, Carmeliet G, Stegen S
Bone · 2026 Jun · PMID 42302904 · Publisher ↗
Glycolysis is widely considered as a major metabolic pathway in several bone-residing cell types, including skeletal stem and progenitor cells (SSPCs) that are essential for bone development, maintenance, and regeneratio...
Glycolysis is widely considered as a major metabolic pathway in several bone-residing cell types, including skeletal stem and progenitor cells (SSPCs) that are essential for bone development, maintenance, and regeneration. However, the contribution of glycolysis to the in vivo function of SSPCs remains unknown. To examine how reduced glycolysis affects SSPC biology, we conditionally deleted phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of glycolytic flux. PFKFB3 deletion decreased glycolytic flux by at least 30%, but also reduced glucose‑carbon incorporation into glycolysis-branching pathways and tricarboxylic acid (TCA) cycle intermediates. Despite this overall attenuation of glucose metabolism, PFKFB3-deficient SSPCs maintained metabolic homeostasis and their functional properties. Bone mass was also preserved in mutant mice, even under anabolic conditions that are associated with increased glycolytic demand. Mechanistically, metabolic profiling revealed that PFKFB3 knockout SSPCs compensated for reduced glucose utilization by increasing the uptake of amino acids and pyruvate, with pyruvate‑carbon contributing to TCA cycle anaplerosis and amino acid synthesis. Together, these findings demonstrate that SSPCs possess substantial metabolic flexibility, allowing them to adapt to reductions in glucose metabolism by rerouting alternative nutrients to biosynthetic and bioenergetic pathways. This metabolic reprogramming likely represents an adaptive mechanism that helps preserve bone formation under metabolic stress.
Partial lumbar spine response in hip non-responders to romosozumab: Baseline bone mineral density as the principal determinant in a multi-center real-world Japanese cohort (n = 398).
Nakano R, Suzuki A, Iwasaki H … +1 more , Fukuda A
Bone · 2026 Jun · PMID 42289221 · Publisher ↗
Romosozumab produces substantially greater bone mineral density (BMD) gains at the lumbar spine than at the total hip, with approximately half of treated patients failing to achieve a least significant change of +3% at t...
Romosozumab produces substantially greater bone mineral density (BMD) gains at the lumbar spine than at the total hip, with approximately half of treated patients failing to achieve a least significant change of +3% at the hip - the priority site in contemporary treat-to-target frameworks. The determinants of this site-discordant response and its clinical interpretation remain incompletely characterized in real-world Japanese practice. We retrospectively analyzed 398 Japanese patients (mean age 76.7 ± 8.7 years; 94.5% female) who completed 12 monthly doses of romosozumab at Mutsu General Hospital (n = 305) and Towada City Hospital (n = 93) between April 2019 and April 2025. The ±3% least significant change threshold was applied separately to the lumbar spine and total hip BMD changes to define four response patterns. Three parallel multivariable logistic regression analyses identified independent predictors of (i) non-response, (ii) full versus partial response, and (iii) partial versus bilateral non-response. Twenty-four-month outcomes were assessed in 202 patients. Hip non-response occurred in 196 patients (49.2%); among them, 169 (86.2%) demonstrated a partial response with concomitant lumbar spine gain ≥ + 3%, while only 27 patients (6.8% of the full cohort) exhibited bilateral non-response. In the multivariable analyses, the principal independent predictors of hip non-response were baseline total hip BMD (odds ratio 1.04 per %YAM; 95% CI 1.02-1.07; p = 0.001), baseline lumbar spine BMD (OR 1.02; p = 0.020), age (OR 1.04; p = 0.020), and body mass index (OR 0.93; p = 0.033), collectively consistent with a baseline-BMD ceiling effect. Baseline 25-hydroxyvitamin D levels and prior denosumab exposure were not independent predictors (p = 0.218 and p = 0.391, respectively). Among 85 patients with 12-month partial response who completed the 24-month follow-up, hip BMD recovered to ≥ + 3% in 39 (45.9%). In this real-world, multi-center Japanese cohort, the principal determinants of hip non-response to romosozumab were baseline BMD, age, and BMI, consistent with a ceiling effect, rather than prior anti-resorptive exposure. Most hip non-responders nonetheless gained BMD at the lumbar spine, and approximately half subsequently recovered at the hip by 24 months, supporting the interpretation of hip non-response as predominantly delayed rather than absent.
Trends in anti-osteoporosis pharmacotherapy and pharmacological initiation for secondary fracture prevention in Japan, 2017-2023.
Hatano M, Okada A, Kimura Y … +5 more , Ishikura H, Tanaka T, Saito T, Tanaka S, Yasunaga H
Bone · 2026 Jun · PMID 42288172 · Publisher ↗
In this study, we aimed to describe the national trends in anti-osteoporosis pharmacotherapy in Japan and assess whether introducing the April 2022 management fee for post hip fracture care was accompanied by changes in...
In this study, we aimed to describe the national trends in anti-osteoporosis pharmacotherapy in Japan and assess whether introducing the April 2022 management fee for post hip fracture care was accompanied by changes in pharmacological secondary fracture prevention after hip and vertebral fractures. We conducted a nationwide cross-sectional study using data from the DeSC database. The annual hip and vertebral fracture cohorts included adults aged ≥50 years with an incident fracture without recorded prior anti-osteoporosis prescriptions. In these fracture cohorts, we estimated the proportion of patients who initiated anti-osteoporosis medication within 3 months after fracture, as well as agent-specific initiation proportions. The proportion of patients initiating anti-osteoporosis medication within 3 months of a hip fracture increased starting in 2022, reaching 29.5% in 2023. The corresponding proportion following a vertebral fracture increased slightly, reaching 35.7% in 2023. After hip fracture, the initiation of oral bisphosphonates increased, whereas that of teriparatide declined starting in 2022. In addition, the initiation of other anti-osteoporosis medications declined. After vertebral fracture, the initiation of teriparatide remained stable but that of other anti-osteoporosis medications declined. Initiation of romosozumab following both fractures increased following its market entry. These findings describe changes in post-fracture anti-osteoporosis pharmacotherapy in Japan, including increased treatment initiation after hip fracture, smaller changes after vertebral fracture, and shifts in agent-specific initiation patterns. Further research and longer follow-up are needed to assess whether these patterns are sustained and to clarify their implications for post-fracture osteoporosis care.
Multimorbidity, physical function, and risk of falls in middle-aged adults.
George P, Bharat C, Murray K … +3 more , Hunter M, Hoey MA, Zhu K
Bone · 2026 Jun · PMID 42288171 · Publisher ↗
BACKGROUND: Physical function and multimorbidity are key risk factors for falls in middle-aged adults, but few studies have evaluated these associations in a longitudinal manner. In 3561 participants (1968 females, aged...
BACKGROUND: Physical function and multimorbidity are key risk factors for falls in middle-aged adults, but few studies have evaluated these associations in a longitudinal manner. In 3561 participants (1968 females, aged 45-69 years) from the Busselton Healthy Ageing Study, a longitudinal cohort study, we studied the associations of baseline multimorbidity count and patterns with physical function and the subsequent risk of falls at six years. METHOD: At baseline, 21 morbidities were assessed and four multimorbidity patterns were identified using latent class analysis. Physical function tests including hand grip-strength (HGS), timed up and go (TUAG) and five times sit to stand (5TSTS) were performed at Phase 1 (baseline) and Phase 2 (average six years) and falls occurring in the previous 12 months were captured through self-report at Phase 2. General linear models and logistic regression were used to evaluate associations, adjusting for sex and baseline covariates. RESULTS: Mean physical function measures worsened by 6.0% to 23.7% between phases; 950 (26.7%) participants reported at least one fall and 383 (10.7%) reported multiple falls. Increasing multimorbidity count was associated with lower physical function at both phases, greater decline over time (HGS: -0.13 kg, TUAG: +0.08 s, 5TSTS: +0.14 s per unit increase), and greater risk of falling and among fallers having multiple falls (odds ratio (OR): 1.14 and 1.15 per unit increase, respectively). Among the multimorbidity classes, the "cardiometabolic" class had the lowest physical function at both phases and the greatest decline over time (2.8-8.8% greater vs "healthy"), whereas the "non-cardiometabolic" class showed the highest risk of falling and having multiple falls (OR: 1.79 and 2.16 vs "healthy", respectively). Associations with falls risk remained significant after further adjustment of physical function measures of either phase. CONCLUSION: Our study underscores the importance of identifying multimorbidity as a risk factor for physical function decline and fall risk in middle-age.
Vital bone and increased osteoid in equine osteochondrosis dissecans of the proximal phalanx: A controlled study indicating a mineralization deficit rather than vascular failure.
Leuffert SI, von Brackel FN, Cardinaux EM … +4 more , Alimy AR, Windels O, Geburek F, Amling M
Bone · 2026 Jun · PMID 42285242 · Publisher ↗
Osteochondrosis and osteochondrosis dissecans (OCD) are among the most common orthopaedic disorders in young horses. Although traditionally explained by vascular failure and ischaemic necrosis, recent findings in human j...
Osteochondrosis and osteochondrosis dissecans (OCD) are among the most common orthopaedic disorders in young horses. Although traditionally explained by vascular failure and ischaemic necrosis, recent findings in human juvenile OCD suggest that impaired bone mineralization may play an important role. Horses are known to have relatively low circulating vitamin D metabolites, raising the question of whether insufficient mineralization contributes to equine OCD. This study investigated the bone vitality and mineralization status of osteochondrosis dissecans fragments (OCDFs) collected from the dorsomedioproximal aspect of the proximal phalanx and compared them with control bone from the corresponding anatomic region in non-affected horses. Micro-CT, undecalcified histology, histomorphometry, and quantitative backscattered electron imaging (qBEI) were used to assess bone vitality, osteoid accumulation, and mineral content. All OCDFs showed vital bone tissue without any evidence of osteonecrosis. Histomorphometry revealed a pronounced accumulation of osteoid by means of osteoid per tissue volume (control: 0.49% ± 0.36% vs. OCD: 2.85% ± 1.45%, p = 0.0001). Micro-CT demonstrated reduced bone tissue mineral density in OCD (control: 843.7 mgHA/cm ± 31.3 mgHA/cm vs. OCD: 779.0 mgHA/cm ± 37.0 mgHA/cm, p < 0.0001) confirmed by qBEI. Our results indicate that equine OCDFs contain vital bone with impaired mineralization rather than necrotic tissue. This pattern mirrors findings in human juvenile OCD and supports the hypothesis that a metabolic mineralization disorder contributed to the pathogenesis of equine OCD.
Can proton density-weighted MRI-based finite element models predict bone strength?
Olowu BD, Auger JD, Morgan EF
Bone · 2026 Jun · PMID 42285241 · Publisher ↗
Hip fractures are a major clinical concern, and patient-specific finite element (FE) modeling of the proximal femur is increasingly used to assess bone strength and fracture risk at the hip. Although most patient-specifi...
Hip fractures are a major clinical concern, and patient-specific finite element (FE) modeling of the proximal femur is increasingly used to assess bone strength and fracture risk at the hip. Although most patient-specific FE models rely on computed tomography (CT) imaging, CT requires relatively high doses of radiation, limiting its application. Magnetic resonance imaging (MRI)-based FE models present a radiation-free alternative that could expand clinical applicability. This study evaluated the predictive capability of proton density (PD)-weighted MRI-based FE models of the proximal femur under sideways fall. Cadaveric femora (n = 14) were imaged using MRI (n = 10) and CT (n = 14) to construct patient-specific FE models, and then mechanically tested to obtain experimental measures of stiffness and failure load. Existing relationships between image voxel intensity and tissue modulus were used; in the case of the MRI models, the relationship was based on a BV/TV-modulus equation previously applied in a T2-weighted MRI-FE study. Digital image correlation (DIC) was used to measure full-field strain distributions during mechanical testing to compare with FE predictions. Values of the whole-bone stiffness and failure load predicted by the MRI-based models showed poor agreement with experimentally measured values and paired CT-based FE predictions. However, when homogeneous material properties were assigned to the FE models, predicted stiffness and failure load no longer differed between MRI and CT. Notably, both MRI- and CT-based FE models qualitatively approximated the spatial distribution of principal strain patterns measured experimentally using DIC. These results indicate that the femoral geometry is captured well by PD-weighted MRI, but the appropriate material mapping relationship to use with this imaging sequence is unknown. Thus, future work should explore the relationship between PD-weighted MRI signal values and measures of modulus or density to advance an MRI-based FE framework for fracture risk assessment.
PTH treatment is effective in the Aga2/+ mouse model of moderate to severe osteogenesis imperfecta.
Kot A, Wachtell D, Wight C … +3 more , Bagheri R, Zieba J, Krakow D
Bone · 2026 Jun · PMID 42285240 · Publisher ↗
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by brittle bone and recurrent fractures. The majority of OI is clinically categorized into mild, moderate, severe, and perinatal lethal fo...
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by brittle bone and recurrent fractures. The majority of OI is clinically categorized into mild, moderate, severe, and perinatal lethal forms. A clinical study on the use of intermittent parathyroid hormone (PTH) as an anabolic therapy for OI found PTH was effective in mild, but not in individuals with moderate/severe OI. However, this sub-group analysis was relatively small and considered preliminary by the authors. Since then, research on PTH therapy in OI has focused on mild OI and no studies of PTH use in moderate/severe OI patients or animal models have been reported. In this work, we used the Aga2/+ mouse, an established autosomal dominant model of moderate/severe OI, to investigate whether PTH treatment has an effect on bone. In vitro, Aga2/+ osteoblasts were sensitive to PTH and exhibited similar transcriptional changes compared to WT. In vivo, PTH treatment improved lumbar trabecular bone, increased cortical bone area fraction in the mid-femur, and, in females, led to improved biomechanical properties. These results demonstrate the Aga2/+ model responded to PTH and support further investigation into whether PTH is effective in adult individuals with moderate/severe OI who have limited treatment options.
MASH-induced elevation of FGF23 promotes hepatic osteodystrophy.
Okamoto Y, Tsuru Y, Nonoshita Y … +3 more , Kurosawa T, Mihara T, Hori M
Bone · 2026 Jun · PMID 42276403 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease characterized by hepatic steatosis and inflammation that can progress to severe conditions. MASH affects systemic organs, leading to hepatic oste...
Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease characterized by hepatic steatosis and inflammation that can progress to severe conditions. MASH affects systemic organs, leading to hepatic osteodystrophy with bone weakness and an increased risk of fractures. Although calcium supplementation is commonly used to alleviate hepatic osteodystrophy, it often has no effect. Therefore, we focused on fibroblast growth factor 23 (FGF23) as a potential causative factor for hepatic osteodystrophy, given its critical role in regulating phosphorus, another key component of bone. MASH mouse models were generated using a choline- and methionine-deficient high-fat diet. Histological and biochemical analyses confirmed severe hepatic steatosis and inflammation in the MASH mice. Micro-computed tomography analysis revealed decreased bone mineral density and trabecular number, with increased trabecular separation, indicating weakened bones in MASH mice. Although serum FGF23 levels were elevated in MASH mice, serum phosphorus levels remained unchanged. This led us to examine the effects of FGF23 on bone remodeling by osteoblasts and osteoclasts, and we found that FGF23 promoted osteoclast differentiation and suppressed osteoblast differentiation. Our findings suggest that MASH-induced elevation of FGF23 contributes to an imbalance in bone remodeling, leading to hepatic osteodystrophy.
Roles of Del-1 in effects of hyponatremia on muscle and bone in mice.
Kawao N, Nishikawa A, Aoyama A … +6 more , Matsuoka M, Mizukami Y, Kishigami R, Muratani M, Ono Y, Kaji H
Bone · 2026 Jun · PMID 42276402 · Publisher ↗
Hyponatremia induces both osteoporosis and sarcopenia. Although interactions between muscle and bone have been extensively examined, the myokines affecting bone in the hyponatremic state remain unclear. Therefore, we her...
Hyponatremia induces both osteoporosis and sarcopenia. Although interactions between muscle and bone have been extensively examined, the myokines affecting bone in the hyponatremic state remain unclear. Therefore, we herein investigated myokines linking muscle to bone in the hyponatremic state using mice treated with 1-desamino-8-D-arginine vasopressin (dDAVP) and furosemide for 8 weeks. An RNA-sequencing analysis showed that the expression of developmental endothelial locus-1 (Del-1), a humoral factor, was down-regulated by hyponatremia in the gastrocnemius muscles of mice. dDAVP and furosemide significantly reduced Del-1 expression in the gastrocnemius and soleus muscles as well as circulating Del-1 levels in mice. Low sodium concentrations also decreased Del-1 expression in mouse myoblasts and myotubes. Del-1 significantly suppressed osteoclast formation in mouse bone marrow cells. A simple regression analysis revealed that serum Del-1 levels and Del-1 mRNA levels in the gastrocnemius muscle were positively correlated with trabecular bone volume fraction and cortical bone mineral density in mice. In conclusion, we herein identified Del-1 as a myokine linking muscle to bone in hyponatremia. The present results suggest that decreased expression of Del-1 in skeletal muscles might contribute to hyponatremia-induced bone loss in mice.
Insulin therapy improves bone microstructure and material properties without restoring whole-bone strength in male insulin-deficient Akita mice.
Toillon I, Badoud I, Ferrari S … +1 more , Gerbaix M
Bone · 2026 Jun · PMID 42269903 · Publisher ↗
Type 1 diabetes is associated with increased fracture risk, yet the respective contributions of insulin deficiency and replacement to skeletal fragility remain poorly understood. Using insulin-deficient male Akita mice,...
Type 1 diabetes is associated with increased fracture risk, yet the respective contributions of insulin deficiency and replacement to skeletal fragility remain poorly understood. Using insulin-deficient male Akita mice, we characterized skeletal alterations and assessed the effects of early insulin therapy. Untreated male Akita mice displayed severe hyperglycemia, impaired growth, low bone formation, and marked trabecular and cortical deficits, resulting in reduced whole-bone structural mechanical properties. Insulin therapy initiated at early diabetes onset normalized glycemia, restored bone formation, and fully recovered cortical material properties. However, cortical porosity remained elevated, cortical geometry was not fully restored, and whole-bone structural mechanical properties did not improve. Gene expression profiling showed downregulation of osteoblast, osteocyte, mechanosensing, and Wnt-related genes in male Akita mice. Notably, Sp7 (Osterix) and Ostn (Osteocrin), key regulators of osteocyte dendrite formation, were downregulated in male Akita mice, suggesting disrupted osteocyte network development. Insulin upregulated osteogenic and Wnt signaling targets but incompletely restored mechanosensing pathways. Importantly, expression of the Wnt inhibitors Sost (Sclerostin) and Dkk1 (Dickkopf-1) remained elevated despite insulin treatment, potentially maintaining an inhibitory environment that limits the anabolic response to mechanical loading. These findings show that early insulin therapy improves bone health in type 1 diabetes, including turnover, trabecular structure, and cortical tissue material properties, but fails to fully rescue cortical integrity and whole-bone structural mechanical properties. This incomplete recovery likely reflects persistent defects in osteocyte function and mechanosensing in insulin-deficient bone and highlights potential therapeutic targets beyond glycemic control to reduce fracture risk in type 1 diabetes.
Belt electrode-skeletal muscle electrical stimulation-induced attenuation of aromatase inhibitor-induced bone loss in ovariectomized rats.
Tsubouchi Y, Kataoka T, Takase R … +3 more , Hamanaka R, Kataoka M, Kaku N
Bone · 2026 Jun · PMID 42259425 · Publisher ↗
Cancer treatment-induced bone loss (CTIBL) is a clinically significant adverse effect of endocrine therapy in hormone-related cancers, including breast cancer. Pharmacological interventions, including antiresorptive agen...
Cancer treatment-induced bone loss (CTIBL) is a clinically significant adverse effect of endocrine therapy in hormone-related cancers, including breast cancer. Pharmacological interventions, including antiresorptive agents, are widely used; however, few nonpharmacological interventions ensure preservation of bone health without imposing excessive physical burden. We investigated the preventive effects of belt electrode-skeletal muscle electrical stimulation (B-SES) on aromatase inhibitor (AI)-induced bone loss in a letrozole-administered ovariectomized rat model. Twenty-two 12-week-old female Sprague-Dawley rats were ovariectomized and allocated to a control group (n = 8) or a letrozole-administered group (n = 14); treatment administration was initiated 4 weeks post-ovariectomy, and 6-week B-SES was initiated 6 weeks post-ovariectomy in the right hindlimb of letrozole-administered rats. Tibial bone microarchitecture was evaluated using micro-computed tomography, biomechanical properties were assessed using a three-point bending test, and gene expression in tibial bone marrow fluid and gastrocnemius muscle was analyzed using real-time RT-PCR. Letrozole administration worsened trabecular bone microarchitecture and reduced biomechanical strength, consistent with skeletal deterioration associated with aromatase inhibitor administration under estrogen-deficient conditions. Prophylactic B-SES significantly improved trabecular bone volume fraction, trabecular thickness, and yield stress compared with those in the non-stimulated limbs (all p < 0.05), whereas cortical bone parameters were only modestly improved. At the molecular level, B-SES suppressed skeletal muscle myostatin expression and reduced receptor activator of nuclear factor kappa-B ligand expression in tibial bone marrow fluid. Thus, B-SES mitigated aromatase inhibitor-induced skeletal fragility predominantly through favorable effects on trabecular bone, potentially through mechanically mediated loading and muscle-bone crosstalk. B-SES may represent a feasible nonpharmacological adjunct for preserving bone health under endocrine therapy-associated skeletal conditions.
Proteomics-driven discovery of intervention windows and risk subtypes in osteoporosis: A prospective cohort study.
Zheng Y, Li J, Li Y … +6 more , Wang J, Suo C, Jiang Y, Jin L, Xu K, Chen X
Bone · 2026 Jun · PMID 42252044 · Publisher ↗
Given the limited feasibility of population-wide bone mineral density screening and the infrequency of long-term monitoring in healthy individuals, identifying the window for early intervention and the populations to be...
Given the limited feasibility of population-wide bone mineral density screening and the infrequency of long-term monitoring in healthy individuals, identifying the window for early intervention and the populations to be prioritized for screening is critical. This study aimed to identify intervention windows for osteoporosis and to determine potential high-risk subtypes within the healthy population. Based on proteomic data from 41,408 healthy adults, we conducted the DE-SWAN method to identify change peaks in plasma protein during the pre-diagnostic osteoporosis phase, and employed finite Gaussian mixture model-based clustering to delineate high-risk subtypes of osteoporosis. We identified 122 protein biomarkers significantly associated with osteoporosis risk throughout the follow-up period. Importantly, we identified two critical peaks occurring approximately 10 and 6 years before diagnosis, with the former enriched in immune-related pathways and the latter prominently involving responses to retinoic acid and glucocorticoids. Furthermore, one high-risk subtype for osteoporosis was identified in both males and females, termed the Frailty and Obesity Subtype. This subtype is characterized by a high degree of frailty and obesity, accompanied by a significantly elevated risk of both osteoporosis and fractures. Finally, we developed a predictive model comprising 10 proteins for identifying high-risk subtypes of osteoporosis, which demonstrated better performance than the traditional risk factor model (AUC: 0.743 vs. 0.680). Our findings demonstrate that proteomic profiling can reveal early molecular changes and identify high-risk subtypes years before clinical onset, providing a foundation for screening and precision prevention of osteoporosis.
Prediction of compressive strength of vertebral body with metastatic lesions based on quantitative computed tomography-based subject-specific finite element models.
Ghosh R, Shearman E, Roger R … +3 more , Palanca M, Dall'Ara E, Lacroix D
Bone · 2026 Jun · PMID 42252043 · Publisher ↗
Pathologic vertebral fractures are a major complication in metastatic spine disease. However, current clinical scores, such as Spinal Instability Neoplastic Score (SINS), show limited predictive capability, particularly...
Pathologic vertebral fractures are a major complication in metastatic spine disease. However, current clinical scores, such as Spinal Instability Neoplastic Score (SINS), show limited predictive capability, particularly within the indeterminate range where most clinical uncertainty lies. This study aimed to develop and evaluate quantitative computed tomography (qCT)-based subject-specific finite element (SSFE) models to predict vertebral strength in presence of different metastatic lesion types. Twelve ex vivo human spine segments, each containing one metastatic (n = 12) and one adjacent control vertebra (n = 12), were scanned using qCT and calibrated using a calibration phantom. Homogenised nonlinear finite element models were developed with spatially heterogeneous, isotropic, density-dependent material properties and loaded under uniaxial compression corresponding to 1.9% apparent strain. Ultimate failure load, stiffness, and strain distributions were compared between metastatic and control vertebrae. Predicted failure load ranged from 0.2 kN to 6.2 kN (median (IQR): 1.10 (0.64-2.68) kN metastatic; 1.21 (0.69-2.84) kN control), with no statistically significant difference between groups (p > 0.05). Normalised failure load varied widely, reflecting lesion-specific mechanical heterogeneity. Lytic lesions generally weakened vertebrae, whereas mixed and blastic lesions occasionally enhanced strength, likely due to localised sclerosis or reactive bone formation. High compressive axial strains (greater than 0.019) were frequently concentrated near the endplates, particularly in lytic vertebrae. qCT-derived bone mineral density strongly correlated with failure load (R = 0.74-0.77). These findings highlight the complexity of metastatic vertebral mechanics and demonstrate that qCT-based SSFE modelling provides a quantitative framework for assessing fracture risk, complementing conventional imaging-based tools.
Implementation of a primary care-based fracture liaison service with information technology support to improve osteoporosis management in general practice - a pilot study.
Lyubomirsky G, Hogan C, Del Fante P … +8 more , Chen W, Lyons D, Cotter E, Niddrie F, Marine F, Ebeling PR, Jurd KL, Wong P
Bone · 2026 Jun · PMID 42250898 · Publisher ↗
PURPOSE: This study evaluated the effectiveness and acceptability of implementing a Fracture Liaison Service (FLS) and Information Technology (IT) platform into Australian general practices to improve osteoporosis manage...
PURPOSE: This study evaluated the effectiveness and acceptability of implementing a Fracture Liaison Service (FLS) and Information Technology (IT) platform into Australian general practices to improve osteoporosis management. METHODS: Fracture Liaison Coordinators (FLCs) supported participating general practices in case-finding, and bone health education and assessment in at-risk individuals over 18 months from June 2022 to December 2023. Using the Compass IT platform, FLCs generated individualised patient management plans aligned with clinical guidelines for discussion between the general practitioner (GP) and patient. Initiation of bone protective medication occurred, as appropriate. Post-intervention surveys evaluated the effectiveness and acceptability of the intervention by participating GPs and patients. RESULTS: Overall, 1299 individuals and 66 GPs across 51 general practice sites participated in the study, an enrolment rate of 3.1% for invited GPs (n = 66/2118) and 4.7% for invited clinic sites (n = 51/1083). Three hundred and sixteen patients were newly identified with osteoporosis based on bone mineral density (BMD) assessment by dual energy x-ray absorptiometry (DXA) scan, spinal x-ray, or prior history of fragility fracture, who were not on treatment. Of these, 141 patients commenced osteoporosis treatment, a treatment rate of 45% (n = 141/316). In post-intervention evaluation surveys, 89% of participating GPs and 92% of patient respondents found the FLS service valuable and acceptable. CONCLUSION: This real-world study of a general practice-based FLS supported by a disease-specific IT platform improved osteoporosis diagnosis and management and was acceptable to both GPs and patients. SUMMARY: Osteoporosis is under-diagnosed and under-treated in primary care. Our study found that implementing an integrated Fracture Liaison Service (FLS) and Information Technology (IT) platform into Australian general practices improved osteoporosis diagnosis and management and was acceptable to both general practitioners and patients. Wider implementation could complement and enhance hospital-based FLSs to improve bone health management in the community.
Fracture risk thresholds for majority incident fracture identification: A registry-based cohort analysis.
Leslie WD, Glüer CC
Bone · 2026 Jun · PMID 42242481 · Publisher ↗
PURPOSE: The World Health Organization (WHO) is reviewing its positions on osteoporosis. The current analysis was performed to inform whether FRAX-based risk thresholds can identify the majority of individuals who will s...
PURPOSE: The World Health Organization (WHO) is reviewing its positions on osteoporosis. The current analysis was performed to inform whether FRAX-based risk thresholds can identify the majority of individuals who will sustain fractures during follow-up and thereby help to address limitations inherent in the use of BMD T-scores. METHODS: The study population consisted of 38,525 women aged 50 years and older (mean age 66.0 years) with baseline fracture risk prediction (FRAX major osteoporotic fracture probability estimated with BMD). Incident fractures identified through linked administrative healthcare data were categorized as any fracture, major osteoporotic fracture, and hip/vertebral fracture. We considered three time horizons: incident fracture within 10 years, within 5 years and within 2 years. RESULTS: During 10 years of follow-up there were 5353 women (13.7%) sustaining any incident fracture; hip/vertebral fractures within 2 years were registered in 1475 (3.8%). It was possible to define age-dependent and overall (age-independent) risk thresholds that identified the majority of incident fractures regardless of the fracture outcome assessed. As a rule, a lower risk threshold was required in younger versus older individuals. In contrast, a BMD T-score of -2.5 or lower failed to identify the majority of incident fractures under most scenarios. Diagnostic odds ratios from osteoporotic T-scores were consistently lower than from corresponding FRAX-based age-independent risk thresholds. CONCLUSIONS: FRAX-based risk thresholds can identify the majority of older women who will sustain incident fractures during the next 2-10 years.
Effect of combination versus sequential teriparatide initiation on vertebral bone marrow microenvironment in postmenopausal women with prior denosumab treatment: A propensity score-matched study.
Hao J, Yan F, Yao Y … +5 more , Zhang T, Zhang Y, Li Z, Xu H, Jiang X
Bone · 2026 Jun · PMID 42235813 · Publisher ↗
BACKGROUND: The optimal strategy for transitioning from long-term denosumab (DMAb) to teriparatide (TPTD) in postmenopausal osteoporosis remains a clinical dilemma, as DMAb withdrawal can trigger a deleterious rebound in...
BACKGROUND: The optimal strategy for transitioning from long-term denosumab (DMAb) to teriparatide (TPTD) in postmenopausal osteoporosis remains a clinical dilemma, as DMAb withdrawal can trigger a deleterious rebound in bone resorption. While bone mineral density (BMD) is the traditional benchmark, it fails to capture critical aspects of bone quality, such as the bone marrow microenvironment. This study investigated whether the method of TPTD initiation-adding it to ongoing DMAb (combination) versus switching after DMAb withdrawal (sequential)-differentially affects the vertebral bone marrow microenvironment, assessed by the MRI-derived vertebral bone quality (VBQ) score, a novel marker of marrow adiposity. METHODS: In this retrospective cohort study, postmenopausal women with osteoporosis who received TPTD for ≥12 months after at least 24 months of DMAb were included. Propensity score matching (1:1) yielded 60 patients in the combination group and 60 in the sequential group. The primary outcome was the percentage change in VBQ (ΔVBQ%) from baseline to 12 months. RESULTS: Combination therapy resulted in a significant improvement in the bone marrow microenvironment (ΔVBQ%: -7.1% ± 3.0%), whereas sequential therapy did not (-0.5% ± 5.4%), with an adjusted between-group difference of -6.5% (95%CI: -8.1 to -4.9, P < 0.001). This was accompanied by superior gains in lumbar spine BMD (+9.4% vs. +5.6%, P < 0.001) and trabecular bone score (+4.8% vs. +1.5%, P < 0.001). Notably, the combination group maintained complete suppression of bone resorption (CTX), while the sequential group experienced a marked and sustained CTX rebound. Furthermore, in the combination group, the improvement in VBQ was significantly correlated with early bone formation activation (ΔPINP at M + 3, r = -0.50) and with gains in lumbar spine BMD (r = -0.40) and TBS (r = -0.77), suggesting a mechanistic link between modeling-based bone formation and microenvironmental restoration. CONCLUSIONS: In postmenopausal women with long-term prior denosumab treatment, initiating teriparatide while continuing denosumab was associated with significantly greater improvement in the vertebral bone marrow microenvironment (greater VBQ reduction), more consistent gains in lumbar spine BMD and TBS, and better control of bone resorption markers over 12 months compared with a sequential switch after denosumab withdrawal. These findings suggest that the combination strategy may be more favorable than a sequential switch for improving vertebral bone quality. While our data provide mechanistic support for current guideline recommendations, confirmation in prospective randomized studies is required before clinical translation.
Novel female murine alveolar osteoblasts responsive to hormones and mechanical forces.
Sinyakova G, Diagne M, Banville M … +8 more , Guo L, Wu Q, Enabulele I, Zhang X, Curtin K, Luban M, Hollos P, Divieti Pajevic P
Bone · 2026 Jun · PMID 42235812 · Publisher ↗
There is a need for a comprehensive understanding of alveolar bone biology, given its unique characteristics compared to other skeletal sites. To this end, we established novel female murine alveolar osteoblastic cell li...
There is a need for a comprehensive understanding of alveolar bone biology, given its unique characteristics compared to other skeletal sites. To this end, we established novel female murine alveolar osteoblastic cell lines and analyzed their responses to hormones and mechanical cues. Cell lines were obtained by conditionally immortalizing primary alveolar osteoblasts isolated from the jaws of wild-type female mice and screened for high expression of alkaline phosphatase. Three clones were selected for further characterization. All clones differentiate into mature osteoblasts and mineralize the matrix. Two clones, ObB5-2 and ObC4-2, were further analyzed for their responsiveness to hormones and mechanical forces. Both responded to parathyroid hormone (PTH), 1,25OHD, and mechanical stimulations. Continuous treatment with PTH or 1,25OHD, inhibited mineralization and significantly suppressed Dmp1 expression. Intermittent PTH (iPTH) also inhibited mineralization in both clones. In ObB5-2, iPTH suppressed Dmp1, Sost, and Opg expression at doses as low as 1 nM PTH. Next, we assessed whether these cells support osteoclastogenesis. Both clones promoted the formation of TRAP-positive osteoclasts when cultured with bone marrow macrophages. Lastly, cells were subjected to fluid flow shear stress and simulated microgravity prior to gene expression analysis. ObC4-2 was highly sensitive to mechanical loads whereas ObB5-2 responded more to simulated microgravity. In summary, these findings describe novel female murine alveolar osteoblastic cell lines that provide a valuable model for studying the cellular and molecular mechanisms of alveolar bone remodeling. Unlike long bone derived cells and primary osteoblasts, these cells did not increase mineralization upon intermittent PTH, highlighting site specific differences in osteoblast function.
Osteogenic promotion by naringin through the PI3K/AKT/mTOR pathway-mediated activation of autophagy and inhibition of apoptosis.
Cui Y, Yu G, Li D … +4 more , Fu X, Yang Z, Yang W, Yang F
Bone · 2026 Jun · PMID 42235811 · Publisher ↗
Osteoporosis is a common age-related metabolic bone disease closely associated with osteoblast dysfunction, abnormal apoptosis, and dysregulated autophagy. Naringin, a dihydroflavonoid compound mainly found in citrus fru...
Osteoporosis is a common age-related metabolic bone disease closely associated with osteoblast dysfunction, abnormal apoptosis, and dysregulated autophagy. Naringin, a dihydroflavonoid compound mainly found in citrus fruits and various traditional Chinese medicinal herbs (e.g., Aurantii Fructus Immaturus and Rhizoma Drynariae), exhibits potential anti-aging and osteoprotective effects; however, its specific mechanism requires systematic elucidation. Network pharmacology analysis revealed that the core targets of naringin are significantly enriched in the PI3K/AKT signaling pathway, as well as pathways related to apoptosis and autophagy. Subsequent in vitro experiments demonstrated that naringin promotes osteoblast proliferation, differentiation, and mineralization; upregulates the expression of osteogenic markers; activates protective autophagy; and inhibits apoptosis. By employing the autophagy inhibitor 3-MA and the PI3K/AKT agonist 740Y-P to modulate PI3K/AKT/mTOR-mediated autophagy, we confirmed that the anti-apoptotic effect of naringin is dependent on the activation of autophagy. In vivo, naringin administration inhibited the excessive activation of the PI3K/AKT/mTOR pathway, enhanced autophagy, suppressed excessive apoptosis, ameliorated bone microarchitecture, and increased bone mineral density in ovariectomized mice. Our findings elucidate the mechanism by which naringin exerts its anti-osteoporotic effects through regulating the balance between autophagy and apoptosis, thereby providing a theoretical basis for developing naringin-based anti-aging strategies for bone protection.
Osteocyte and vascular network in hip osteoarthritis: A multimodal imaging and histological analysis.
Quinn MJ, Findlay DM, Quarrington RD … +2 more , Solomon LB, Muratovic D
Bone · 2026 Jun · PMID 42235810 · Publisher ↗
OBJECTIVE: Hip osteoarthritis (OA) is characterised by increased remodelling of the subchondral bone, for which the underlying cellular and microvascular mechanisms are unclear. This study investigated alterations in the...
OBJECTIVE: Hip osteoarthritis (OA) is characterised by increased remodelling of the subchondral bone, for which the underlying cellular and microvascular mechanisms are unclear. This study investigated alterations in the osteocyte lacunocanalicular network and vascular canal architecture in the femoral head in human hip OA, using a multimodal imaging and histological approach. DESIGN: Femoral head samples from OA patients (n = 8; 4 female, 4 male; age 69 ± 14) undergoing hip replacement, and healthy controls (n = 8; 5 female, 3 male; age 64 ± 12), were imaged by MRI to assess cartilage volume and subchondral bone pathology. Four trabecular bone cores per femoral head, representing four distinct anatomical sites, were analysed with synchrotron radiation micro-CT to examine osteocyte lacunar morphometry and vascular canal characteristics. Histology was used to evaluate osteocyte viability, senescence, connectivity, and osteoclast activity. RESULTS: Compared to controls, OA bone showed a significant increase in lacunar volume (p = 0.002) and reduced lacunar sphericity (p = 0.04). OA was also characterised by increased osteocyte loss, reflected by a higher proportion of empty lacunae (p = 0.002), and shorter canaliculi (p = 0.01). Additionally, there was increased vascular canal volume (p = 0.004) and higher vascular canal density (p = 0.002) in OA compared to controls. While some parameters varied across different anatomical regions, most OA-related changes were not region-specific. CONCLUSIONS: Hip OA is characterised by widespread disruption of the osteocyte lacunocanalicular network, associated with reduced bone cell viability, connectivity, and remodelling. Concurrent microvascular alterations further support the hypothesis that osteocyte-vascular network dysfunction contributes to subchondral bone pathology.
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