Bone [JOURNAL]
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200 papers
Inhibition of sphingomyelinase blocks the recruitment of alkaline phosphatase to mineralization-competent matrix vesicles.
Hayann L, Cominal JG, Lima IS … +8 more , Patricio MR, Mello MT, Andrilli LHS, de Sousa JRS, Sorgi CA, Millán JL, Ramos AP, Ciancaglini P
Bone · 2026 Sep · PMID 42107620 · Publisher ↗
Mineralizing cells release extracellular vehicles (EVs), including mineralization-competent matrix vesicles (MVs), that bind to collagen and initiate mineralization. MVs budding from lipid-raft-rich domains contain enzym...
Mineralizing cells release extracellular vehicles (EVs), including mineralization-competent matrix vesicles (MVs), that bind to collagen and initiate mineralization. MVs budding from lipid-raft-rich domains contain enzymes such as tissue-nonspecific alkaline phosphatase (TNAP), which is crucial for mineral formation. This study examined the effect of inhibiting neutral sphingomyelinase (SMase) on extracellular vesicle (EV) and MV release, and TNAP recruitment to MVs. Our results suggest that SMase inhibition significantly reduced TNAP recruitment and phosphomonohydrase activity in MVs as well as altered MV topography and morphology due to changes in the lipid profile.
Characterization of the osteochondral phenotype in human classical osteogenesis imperfecta and in Col1a2 mice.
Matzke S, Ocokoljic A, Yorgan TA … +4 more , Oheim R, Beil FT, Alimy AR, Rolvien T
Bone · 2026 Sep · PMID 42106052 · Publisher ↗
Osteogenesis imperfecta (OI) is associated with an increased risk of early-onset osteoarthritis (OA); however, it remains unclear whether this risk is driven by underlying osteochondral alterations. Here, we aimed to cha...
Osteogenesis imperfecta (OI) is associated with an increased risk of early-onset osteoarthritis (OA); however, it remains unclear whether this risk is driven by underlying osteochondral alterations. Here, we aimed to characterize the osteochondral phenotype in OI to identify osteochondral features that may be relevant to increased OA susceptibility. We collected bilateral tibial plateaus from one adult with classical OI (COL1A2) who underwent bilateral total knee arthroplasty, and a femoral head from a second adult (COL1A1) who underwent total hip arthroplasty. The specimens were analyzed using histology and quantitative backscattered electron imaging (qBEI), and the results were compared with those from ten patients with primary knee OA and ten patients with primary hip OA. In addition, we examined hip and knee joints of six-week-old Col1a2 mice and wild-type (WT) controls by μCT, histology, and qBEI. In human samples, overall osteochondral morphology was comparable between OI and primary OA, but osteoarthritic subchondral bone in OI showed higher matrix mineralization. Col1a2 mice exhibited a pronounced low bone mass phenotype in hip and knee joints, while growth plate architecture and articular cartilage thickness were preserved. However, articular cartilage contained larger chondrocyte clusters, and subchondral trabecular bone showed a hypermineralized and compositionally heterogeneous matrix with increased osteocyte lacunar density. Moreover, the osteocyte lacunocanalicular network was severely disrupted, with shorter canaliculi and fewer canaliculi per osteocyte. Together, these exploratory human case-based observations and juvenile murine data suggest that type I collagen defects are associated with prominent subchondral bone matrix and osteocyte abnormalities alongside altered chondrocyte organization, which together may contribute to joint vulnerability in OI.
Opportunistic screening for osteoporosis using chest X-rays and deep learning: A systematic review and meta-analysis.
Skaik K, Abdallah JP, Koucheki R … +6 more , Lex JR, Ahn H, Toor J, Ravi B, Larouche J, Abbas A
Bone · 2026 Sep · PMID 42106051 · Publisher ↗
PURPOSE: To evaluate the diagnostic performance of deep learning (DL) algorithms applied to chest radiographs (CXR) for detecting osteoporosis and assess their potential for clinical implementation. METHODS: A systematic...
PURPOSE: To evaluate the diagnostic performance of deep learning (DL) algorithms applied to chest radiographs (CXR) for detecting osteoporosis and assess their potential for clinical implementation. METHODS: A systematic review and meta-analysis was conducted including studies that validated convolutional neural network (CNN)-based DL models to detect osteoporosis from CXRs. Exclusion criteria included studies using imaging other than CXR and non-DL models. Quantitative synthesis included pooled sensitivity, specificity, and construction of a summary receiver operating characteristic (SROC) curve. Model quality was evaluated using the APPRAISE-AI framework. RESULTS: Out of 1401 records screened, 12 studies met inclusion criteria, comprising a total of 200,796 patients and 20 unique DL models. For internal validation of 13 DL models, the pooled sensitivity was 0.85 [95% CI: 0.82-0.87] and specificity of 0.83 [95% CI: 0.81-0.85]. The SROC analysis of all 20 DL models yielded a summary AUC of 0.69 [95% CI: 0.68-0.71]. A total of six studies performed external validation, with AUCs ranging from 73.4% to 94.6%, and specificity ranging from 74.2% to 90.9%, aside from one outlier. Heterogeneity was high (I > 98%) and driven primarily by country of origin. The APPRAISE-AI assessment indicated nine studies were high quality, supporting their use as a clinical decision support tool, while the others were of moderate quality. CONCLUSION: DL models applied to CXR show promising diagnostic performance for opportunistic osteoporosis screening. However, substantial heterogeneity in internal validation and the limited number of externally validated studies underscore the need for further research to improve generalizability and support real-world clinical implementation.
Cranial neural crest cells in zebrafish: Insights into craniofacial skeletal development and malformation.
Zhu Y, Wagener FADTG, Metz JR … +1 more , Von den Hoff JW
Bone · 2026 Sep · PMID 42103044 · Publisher ↗
Many craniofacial malformations are linked to cranial neural crest cell (CNCC) dysfunction. This multipotent cell population is essential for craniofacial skeletal development in vertebrates. Their differentiation to car...
Many craniofacial malformations are linked to cranial neural crest cell (CNCC) dysfunction. This multipotent cell population is essential for craniofacial skeletal development in vertebrates. Their differentiation to cartilage or bone is regulated by key signaling pathways, including Wnt, BMP, FGF, Notch and Hedgehog. These pathways act in concert with broader transcriptional, epigenetic, and tissue-interactions to coordinate craniofacial development. Owing to their external development, genetic tractability and the conservation of fundamental craniofacial developmental mechanisms with humans, the zebrafish are uniquely suited for live imaging, genetic manipulation and investigating the etiology of craniofacial malformations. This review explains how CNCCs give rise to craniofacial skeletal structures during their specification, migration and differentiation. In addition, we discuss how disruption of these processes leads to craniofacial malformations. We emphasize that defects arising at distinct developmental stages are associated with different phenotypic outcomes. In general, early defects in CNCC specification and migration are more often associated with multisystem disorders, including neurocristopathies, hearing loss and cardiac anomalies. Defects in frontonasal CNCC migration more commonly lead to midline and upper facial malformations. By contrast, cartilage and bone malformations can result from defects across multiple stages of CNCC development. We also summarize current zebrafish models and experimental tools, including transgenic reporters, mutant lines, live imaging and single-cell technologies that have advanced our understanding of CNCC biology. Finally, we discuss current limitations and highlight future directions for zebrafish research in the field of craniofacial malformations.
Age-dependent musculoskeletal changes during mechanical unloading with bisphosphonate treatment.
Orr SV, Gilmore NK, Pathak S … +4 more , Edan HA, Langer H, Baar K, Christiansen BA
Bone · 2026 Sep · PMID 42103043 · Publisher ↗
Mechanical unloading (disuse) leads to reductions in bone and muscle mass. Bone and muscle adaptation are often studied together in terms of mechanical stimulus, but non-mechanical (biological) crosstalk during periods o...
Mechanical unloading (disuse) leads to reductions in bone and muscle mass. Bone and muscle adaptation are often studied together in terms of mechanical stimulus, but non-mechanical (biological) crosstalk during periods of disuse and how this is affected by age and bone-preserving pharmaceuticals has not been assessed. This study aimed to determine how mechanical unloading and concurrent bisphosphonate treatment affect bone and muscle structure and function in young, middle-aged, and old mice. We hypothesized that unloading would cause bone loss in untreated mice, but bisphosphonate treatment would prevent this loss. Additionally, we expected that unloading would result in muscle atrophy and reduced contraction force, but we hypothesized that these reductions would be partially mitigated by bisphosphonate treatment due to decreased release of osteokines, and that this mitigation would decrease with age. To investigate these hypotheses, young (3-mo, n = 40), middle-aged (12-mo, n = 40), and old (20-m, n = 40) male C57BL/6 J mice received biweekly subcutaneous bisphosphonate injections (0.03 mg alendronate/mouse) or vehicle injections starting one week before unloading. Mice underwent hindlimb unloading (HLU) via tail suspension for 14 days. Maximum force production of the hind limb was measured after 14 days of unloading. Femurs were imaged with micro-computed tomography (μCT 35, SCANCO Medical AG); cortical bone was analyzed at the mid-diaphysis, and trabecular bone was analyzed at the distal femur to determine bone microstructural outcomes. Muscle fiber cross-sectional area (CSA) and fiber type were analyzed via IHC. Muscle myostatin and serum TGF-β1 levels were measured via ELISA. Achilles tendon mechanical properties were also assessed using tensile testing. We found that HLU decreased the mass of the triceps surae muscles, and this loss was not recovered during bisphosphonate treatment. Muscle mass in old mice decreased during HLU with bisphosphate treatment. Maximum hindlimb force production and respective force to muscle mass ratio differed between all age groups and did not correlate with bone or muscle changes. Muscle myostatin concentrations increased with age (p = 0.040), bisphosphonate treatment (p = 0.003), and unloading (p = 0.002), as well as due to the interaction of treatment and unloading (p = 0.0239). Serum levels of TGF-β1 increased with age (p < 0.0001) and unloading (p = 0.012), as well as with interactions between both age and treatment (p = 0.006) and age and unloading (p = 0.013). Age impacted muscle, tendon, and bone responses to unloading and/or bisphosphonate treatment. Bone and muscle adaptation to unloading are different across the lifespan, as are the effects of bisphosphonate treatment. Characterizing these changes is essential for understanding clinical outcomes related to periods of disuse and clinical bone and muscle preserving treatments during bedrest, immobilization, or even spaceflight across different age groups.
Conformity to stochastic invariance of microstructure influences mechanical competence of trabecular bone.
Zhang H, Xiao P, Ye K … +1 more , Wang X
Bone · 2026 Aug · PMID 42097349 · Publisher ↗
Bone fragility fractures are not solely determined by bone mineral density (BMD), as patients with similar BMD often exhibit markedly different fracture risks due to factors beyond bone mass. One such factor may be disru...
Bone fragility fractures are not solely determined by bone mineral density (BMD), as patients with similar BMD often exhibit markedly different fracture risks due to factors beyond bone mass. One such factor may be disruption of stochastic stability in trabecular bone microarchitecture, characterized by previously observed invariant probability distributions of trabecular size and spatial organization. This within-donor paired study tested the hypothesis that disruption of such stochastic stability (i.e., invariance) impairs mechanical competence, independent of bone volume fraction (BV/TV) and structural anisotropy. Trabecular bone cubes were digitally extracted from micro-CT models of human cadaveric proximal femurs. From the elderly donor group, thirteen BV/TV-matched cube pairs (N = 13 pairs) were identified from four donors, with each pair originating from the same anatomical location within the same femur. Within each pair, one cube exhibited invariant distributions, whereas the other showed significant deviations from at least one of these distributions. Micro-CT-based finite element simulations were performed to evaluate the elastic properties of the paired cubes. The results indicated that cubes not conforming to stochastic invariance exhibited consistent mechanical deficits, ranging from 6% to 35% across all stiffness tensor components relative to their paired counterparts. Analysis of covariance (ANCOVA) further confirmed that these mechanical deficits were independent of BV/TV and structural anisotropy within the current sample. Moreover, variances in the averaged measures of trabecular size and spatial arrangement were most likely associated with changes in stochastic stability status. These findings demonstrate that the stochastic organization of trabecular microstructure plays a distinct role in determining mechanical competence beyond conventional bone mass, morphometric, and fabric-based measures, providing mechanistic insight into bone fragility.
Sex- and site-specific associations between hemoglobin levels and cortical bone structure and microarchitecture in older adults.
Sekel NM, Lovalekar M, Mroz KH … +11 more , Roe LS, Heilmann NZ, Freeland KS, Koltun KJ, Aaron KG, Lane NE, Newman AB, Hughes JM, Strotmeyer ES, Nindl BC, Cauley JA
Bone · 2026 Aug · PMID 42081927 · Publisher ↗
UNLABELLED: Anemia is prevalent among older adults and is associated with increased fracture risk, yet its relationship with bone microarchitecture remains poorly understood. We examined associations between hemoglobin (...
UNLABELLED: Anemia is prevalent among older adults and is associated with increased fracture risk, yet its relationship with bone microarchitecture remains poorly understood. We examined associations between hemoglobin (Hgb) concentrations and compartment-specific bone density, microarchitecture, structure and strength in older males and females. METHODS: This cross-sectional analysis included 126 males and 185 females aged ≥70 years. Hgb quartiles and anemia status (Males: <13 g/dL; Females: <12 g/dL) were measured at baseline. High-resolution peripheral quantitative computed tomography (HR-pQCT) assessed bone parameters at the tibial (T) and radial (R) metaphysis (M) and diaphysis (D). Multiple linear regression models evaluated associations between Hgb quartile and anemia with sex-standardized bone parameters. RESULTS: At the RM, females in higher quartiles of Hgb tended to have the lowest total area (p trend = 0.034) and the highest cortical porosity (p trend = 0.006). In males, higher Hgb was associated with greater TD total volumetric bone mineral density (Tt.vBMD; Q4 vs. Q2: β = 0.67, p = 0.005), but anemia status showed no significant associations. In females, lower Hgb was linked to greater cortical perimeter (Q1 vs. Q2: β = 0.66, p = 0.003) at the TM and greater total area (Q1 vs. Q2: β = 0.71, p = 0.002) at the TM and RD (Q1 vs. Q2: β = 0.59, p = 0.018). Anemic females exhibited greater total area (β = 0.80, p = 0.018) and cortical perimeter (β = 0.75, p = 0.014) but lower Tt.vBMD (β = -0.56, p = 0.022, vs. non-anemic) at the RD. CONCLUSIONS: Hgb levels and anemia status exhibited sex- and site-specific associations with cortical bone structure with more pronounced effects in females. Higher Hgb in males correlated with increased bone density, while in females, it was related to smaller bone areas and more pronounced porosity. These findings suggest cortical bone is more sensitive to Hgb variations than trabecular bone, potentially due to differences in vascularization and oxygen supply.
Renal osteodystrophy in pediatric patients. A systematic review and meta-analysis.
Bedram LG, Canziani MEF, Bittencourt ALML … +4 more , Messias M, Figueiredo ACMG, Andrade MC, Carvalho AB
Bone · 2026 Sep · PMID 42081926 · Publisher ↗
Chronic kidney disease (CKD) in children is associated with significant comorbidities, including mineral and bone disorder (CKD-MBD). A key manifestation of CKD-MBD is renal osteodystrophy (ROD), diagnosed by bone biopsy...
Chronic kidney disease (CKD) in children is associated with significant comorbidities, including mineral and bone disorder (CKD-MBD). A key manifestation of CKD-MBD is renal osteodystrophy (ROD), diagnosed by bone biopsy followed by histomorphometric analysis. In pediatric patients, ROD can lead to bone deformities and impaired growth. However, the limited use of bone biopsy in this population hampers the understanding of ROD patterns and severity. This systematic review and meta-analysis aimed to evaluate histomorphometric findings in children with CKD. We screened 5082 abstracts published up to 2024 and included 28 eligible studies, encompassing 980 bone biopsies from children in different stages of CKD. Significant heterogeneity in nomenclature, abbreviations, and reference units of histomorphometric parameters was observed, despite the ASBMR recommendations. Osteitis fibrosa was the most prevalent type of ROD. Notably, 36% of the studies did not report dynamic parameters. Meta-analyses revealed substantial variability in both histomorphometric and biochemical measures. Meta-regression identified study design, age, sex, and CKD treatment modality as key contributors to heterogeneity in bone structure, formation, and resorption parameters. In conclusion, most children with CKD exhibit some form of ROD. Standardized biopsy protocols and normative histomorphometric references stratified by age and sex are needed to enhance result interpretation and comparability across future studies.
Progenitors from distinct perichondrium layers initiate tumor formation in hereditary multiple osteochondromas as revealed in a mouse model.
Mundy C, Ramesh S, Catheline SE … +3 more , Saunders C, Koyama E, Pacifici M
Bone · 2026 Aug · PMID 42070715 · Full text
Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric disease characterized by osteochondromas that form next to the growth plates, accumulate over time and cause major health problems. Most HMO cases are linked...
Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric disease characterized by osteochondromas that form next to the growth plates, accumulate over time and cause major health problems. Most HMO cases are linked to loss-of-function mutations in Golgi-resident proteins EXT1 or EXT2, but tumor development remains unclear. In particular, the source of tumor-forming progenitors has long been debated, with recent studies pointing to a perichondrial origin. Perichondrium normally flanks the growth plates, has essential roles in skeletal growth, and is composed of an inner cuboidal cell layer and an outer fibroblastic cell layer. Here, we set out to determine by genetic approaches whether the tumors do in fact derive from perichondrium and if one or both layers provide progenitors. We employed Pdgfrα-CreER and Fgf18-CreER transgenic mice that respectively, target inner and outer layers or the outer layer only. Mice were mated with floxed Ext1 mice to conditionally ablate the causative gene, mimicking tumor induction in patients. Compound juvenile Pdgfrα-CreER;Ext1 and Fgf18-CreER;Ext1 mice were injected with tamoxifen and monitored for tumor development over time. By 4-8 weeks post-tamoxifen, osteochondromas had formed in Pdgfrα;Ext1 mutants targeting both layers, but none were appreciable in Fgf18;Ext1 mutants targeting the outer layer, based on μCT scans, histochemistry and td-Tomato cell lineage tracing. In situ analyses verified that Ext1 had been ablated in the outer layer of Fgf18;Ext1 mutants. Analyses also showed that the developing osteochondromas in the Pdgfrα;Ext1 mutants displayed strong expression of cartilage proteins and abundant pSMAD1 and pSMAD2 proteins that mediate pro-chondrogenic BMP/TGFβ signals. The data provide new evidence that perichondrium progenitors, and more specifically inner layer cells delineated by Pdgfrα expression, initiate osteochondroma formation, being redirected into an ectopic chondrogenic program by Ext1 loss and deficiency of its vital function.
PPy-coated wire actuators for micromechanostimulation of cells - identification of immediate-early responsive mechanoregulatory genes in osteoblasts.
Chen J, Ortega-Santos AB, Hayano S … +5 more , Wang Z, Martinez JG, Hara ES, Jager EWH, Kamioka H
Bone · 2026 Aug · PMID 42069275 · Publisher ↗
Mechanotransduction, i.e., the conversion of mechanical cues into biochemical signals, is essential for bone development, remodeling, and adaptation. Although mechanical loading is known to regulate osteoblast function a...
Mechanotransduction, i.e., the conversion of mechanical cues into biochemical signals, is essential for bone development, remodeling, and adaptation. Although mechanical loading is known to regulate osteoblast function and bone homeostasis, dissecting the early and sustained mechanotransductive responses at the microscale remains challenging due to limitations of existing in vitro models. Here, we report the development and application of a mechanostimulation system comprising a polypyrrole (PPy)-based wire actuator that expands and contracts (4 μm in radius) upon electrical actuation and enables precise, localized micromechanical stimulation of a small number of cells within standard culture formats. Using this system, we applied short-term (30 min) cyclic (Cyc30) or static (Stat30), as well as prolonged (120 min) cyclic (Cyc120) stimulations to two osteoblast-like cells (MC3T3-E1 or KUSA-A1). Subsequent transcriptomic profiling and computational network analyses revealed that Cyc30 was not capable of inducing significant changes in mRNA expression, suggesting cellular adaptation to short-term cyclic loading. In contrast, Stat30 induced the upregulation of Fos, Btg2, Egr1, and Fosl1, all known genes associated with mechanotransduction, supporting the validity and reproducibility of our experimental mechanostimulation system. Notably, two long non-coding RNAs (B930036N10Rik and 5430431A17Rik) were identified for the first time as being upregulated in response to Stat30 stimuli. Among the differentially expressed genes (DEGs) upregulated by Cyc120 stimuli, Hmox1, a stress-inducible enzyme known for its roles in maintaining cellular homeostasis and promoting survival, was the only DEG repeatedly observed across the Cyc30/Cyc120 and Stat30/Cyc120 comparisons in both cell types, potentially emerging as a key stress-response gene under prolonged mechanical loading. Collectively, these results establish the PPy-based microactuator as a powerful tool for microscale mechanobiology, and provide molecular insight into immediate-early responsive transcriptional programs underlying osteoblastic mechanoadaptation conserved across different cell types.
Anatomy data driven mechanical adaptation of bone tunnel-screw interface in ACL reconstruction.
Jiang WB, Shi XZ, Gu JQ … +11 more , Jin XX, Wang JW, Luo WW, Shah MAA, Wang HK, Li C, Gilmore C, Fang X, Chen W, Yu SB, Sui HJ
Bone · 2026 Aug · PMID 42061491 · Publisher ↗
PURPOSE: Anatomical information about bone microstructure at the anterior cruciate ligament attachment sites could guide biomimetic strategies in anterior cruciate ligament reconstruction. This study intends to apply P45...
PURPOSE: Anatomical information about bone microstructure at the anterior cruciate ligament attachment sites could guide biomimetic strategies in anterior cruciate ligament reconstruction. This study intends to apply P45 plastination technology to overcome the limitations of conventional imaging techniques and quantitatively characterize the trabecular bone structure at ACL insertion sites. The research objective is to establish a biomimetic strategy for guiding the orientation and depth of bony tunnels and design functionally graded interference screw, thereby optimizing surgical outcomes. MATERIALS AND METHODS: Sixty human knee joint specimens were analyzed using P45 plastination technique, U-Net convolutional neural networks for image segmentation, and MATLAB digital processing to extract morphometric parameters (porosity, trabecular number, degree of anisotropy, and orientation) of trabecular bone at Anterior cruciate ligament femoral and tibial attachments. Based on the extracted trabecular parameters, four uniform and four functionally graded screw models (Double Gyroid, Diamond, Fischer-Koch S, and Octet) were designed in nTopology and use finite element simulation to evaluate the differences in mechanical performance between this method and traditional methods within the bone tunnel. RESULTS: The trabecular bone at the Anterior cruciate ligament-attachment sites exhibited distinct, site-specific architectural patterns. The femoral attachment site formed a rectangular area (1.47 ± 0.18 cm length, 0.68 ± 0.07 cm width) with trabeculae oriented perpendicular to the insertion plane. Porosity showed a gradual transition (0.52 ± 0.05 to 0.47 ± 0.04), trabecular number averaged 2.45 ± 0.25 /mm, and anisotropy averaged 0.73 ± 0.07. The tibial attachment site formed a larger rectangular area (1.76 ± 0.21 cm length, 0.76 ± 0.21 cm width) with trabeculae aligned parallel to the ligament axis. Porosity transitioned from 0.53 ± 0.03 to 0.58 ± 0.05, trabecular number averaged 3.6 ± 0.63/mm, and anisotropy averaged 0.64 ± 0.09. Finite element analysis revealed that the gradient Double Gyroid screw exhibited superior mechanical compatibility (lowest average stress: 8.86 MPa) at the femoral site, while the gradient Octet screw performed best (lowest average stress: 12.26 MPa) at the tibial site. CONCLUSION: An integrated mesoscopic approach for quantitatively analyzing Anterior cruciate ligament attachment site trabecular bone and applying these parameters to biomimetic screw design and bone tunnel positioning was presented. The findings provide a strategic framework for enhancing the anatomic and biomechanical compatibility of Anterior cruciate ligament reconstruction, potentially leading to improved surgical success rates.
Resistance and interval running exercise exert differential short-term post-exercise bone metabolic marker responses in postmenopausal.
Guisado-Cuadrado I, Romero-Parra N, Bell M … +4 more , Elliott-Sale KJ, Sale C, Klentrou P, Peinado AB
Bone · 2026 Aug · PMID 42055105 · Publisher ↗
PURPOSE: This study examined the effects of resistance exercise versus interval running on post-exercise concentrations of bone metabolic markers in postmenopausal females. METHODS: Thirteen physically active postmenopau...
PURPOSE: This study examined the effects of resistance exercise versus interval running on post-exercise concentrations of bone metabolic markers in postmenopausal females. METHODS: Thirteen physically active postmenopausal women (51 ± 3 years) completed this crossover trial consisting of two exercise modalities: an interval running protocol (8 × 3 min at 85% maximal aerobic speed) and an eccentric-based resistance protocol (10 × 10 parallel back squats at 60% 1RM). Blood samples were obtained at baseline and 24 h post-exercise. Dickkopf-related protein 1 (DKK-1), fibroblast growth factor 23 (FGF-23), osteocalcin, osteoprotegerin (OPG), parathyroid hormone (PTH), and sclerostin were analysed in serum. A mixed linear model was used to examine the main effects of exercise and time, and the Exercise × Time interaction. RESULTS: Significant Exercise × Time interactions were shown for osteocalcin (p = 0.015), OPG (p = 0.021), and sclerostin (p = 0.002), with higher concentrations 24 h after resistance exercise than following endurance exercise. A main effect of Exercise was detected for FGF-23 (p = 0.048), showing higher values in resistance exercise. CONCLUSION: Resistance and interval running exercise elicited distinct short-term bone metabolic responses in postmenopausal women. Twenty-four hours after exercise, resistance loading resulted in higher concentrations of total osteocalcin, sclerostin, and OPG, but not DKK-1, FGF-23 or PTH, compared with interval running. These findings show some upregulation of bone metabolic signalling after resistance exercise compared to interval running, although interpretation must remain cautious given that total osteocalcin and OPG do not directly reflect net bone formation or resorption.
PDK4 knockdown suppresses osteoclast differentiation in osteoporosis through glycolytic flux suppression and AMPK activation.
Huang Y, Zhou R, Liang R … +1 more , Shen J
Bone · 2026 Aug · PMID 42055104 · Publisher ↗
BACKGROUND: Osteoporosis (OP) is a metabolic bone disorder primarily driven by excessive osteoclast-mediated bone resorption. Metabolic reprogramming, particularly a shift toward glycolysis, is crucial for osteoclast dif...
BACKGROUND: Osteoporosis (OP) is a metabolic bone disorder primarily driven by excessive osteoclast-mediated bone resorption. Metabolic reprogramming, particularly a shift toward glycolysis, is crucial for osteoclast differentiation. However, the key regulators linking metabolism to bone resorption remain incompletely defined. METHODS: Bioinformatic analysis identified pyruvate dehydrogenase kinase 4 (PDK4) as a key glycolysis-associated gene in OP. Its role was validated using PDK4-knockdown RAW264.7 cells stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and ovariectomized (OVX) rat models treated with PDK4-knockdown lentivirus, with or without the AMP-activated protein kinase (AMPK) inhibitor Dorsomorphin in each setting. Western blot was conducted to assess the expression of osteoclast differentiation markers and glycolysis-associated proteins. Glycolytic flux was determined by measuring glucose uptake, intracellular ATP, and lactate levels. Bone microstructure was evaluated by micro-computed tomography, while osteoclast activity was examined by tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: PDK4 was significantly upregulated in RANKL-induced osteoclasts. PDK4 knockdown suppressed the expression of osteoclast differentiation markers and glycolytic flux in vitro. Mechanistically, PDK4 silencing activated the AMPK pathway. The anti-osteoclastic effects of PDK4 knockdown were reversed by the AMPK inhibitor Dorsomorphin. In OVX rats, PDK4 knockdown ameliorated bone loss, reduced osteoclast activity and markers, and suppressed glycolysis-associated protein expression in femur tissues. These therapeutic benefits were again negated by co-administration of Dorsomorphin. CONCLUSION: PDK4 knockdown suppresses osteoclastogenesis and OP progression by suppressing glycolysis via activating the AMPK pathway. Targeting the PDK4-AMPK-glycolysis axis presents a novel metabolic strategy for OP treatment.
Gut microbiota depletion alters functional recovery and bone healing following fracture in mice.
Kooima P, Oesterle DA, Hematti Y … +3 more , Kay DM, McFarlane K, Roberts JL
Bone · 2026 Aug · PMID 42044685 · Full text
Bone fracture pain evolves dynamically with tissue repair, yet current analgesic strategies are limited by adverse effects and concerns regarding impaired healing. The gut microbiome is an established regulator of pain a...
Bone fracture pain evolves dynamically with tissue repair, yet current analgesic strategies are limited by adverse effects and concerns regarding impaired healing. The gut microbiome is an established regulator of pain and inflammation; however, its contribution to post-fracture recovery remains unclear. We tested whether antibiotic-induced microbiota depletion alters functional recovery and behavior after femoral fractures. Young female C57BL/6J mice received a broad-spectrum oral antibiotic cocktail or control water for two weeks prior to femoral fracture and were assessed longitudinally over 28 days after fracture. Microbiota depletion was associated with prolonged deficits in hindlimb loading and zone clearance performance, and continuous home-cage monitoring revealed decreased vertical rearing activity and voluntary wheel-running, collectively indicating sustained functional and motivational impairment. Despite a hypoinflammatory systemic and intestinal phenotype, microbiota-depleted mice exhibited elevated ipsilateral lumbar DRG expression of Ngf and Cxcl1 at Day 7 post-fracture alongside suppressed DRG Il10. NGF immunoreactivity was also elevated in the ipsilateral lumbar DRG of microbiota-depleted mice at the same timepoint. Microarchitectural analysis of fracture callus were suggestive of delayed secondary fracture healing. Together, these findings indicate that antibiotic-induced microbiota depletion was associated with altered inflammatory, behavioral, and skeletal responses after fracture. These results identify the gut microbiome as a potential contributor to the integrated pain-healing response to skeletal injury.
Factors of mineralization dynamics - A mathematical model for microstructural bone remodeling.
Modiz C, Castoldi NM, Calvo-Gallego JL … +5 more , Scheiner S, Sansalone V, Martelli S, Martínez-Reina J, Pivonka P
Bone · 2026 Aug · PMID 42035905 · Publisher ↗
Bone mineralization critically influences bone strength and fracture risk, yet the dependency on bone porosity across the range from cortical to trabecular bone remains incompletely understood. We present a novel mathema...
Bone mineralization critically influences bone strength and fracture risk, yet the dependency on bone porosity across the range from cortical to trabecular bone remains incompletely understood. We present a novel mathematical framework that explicitly models bone mineralization dynamics as a function of bone turnover, which can be linked to porosity. Unlike existing fixed-porosity models, our approach incorporates porosity-dependent cellular activity based on remodeling surface availability, enabling analysis across the entire porosity range. We tested three biologically motivated hypotheses to explain mineral content variations with porosity, involving variations in turnover rate, targeted resorption and mineral apposition rate. Through systematic hypothesis testing validated against experimental data, we successfully reproduced the characteristic relationship between material and apparent density observed across varying bone porosities. Results indicate that porosity-dependent turnover and mineral apposition rate primarily drive mineralization. Global sensitivity analysis confirmed the mineral apposition rate as the most influential parameter. Additionally, our analysis supports that dispersion in mid-porosity experimental data can be explained by trabecular microarchitectural variations, specifically the proportion of rod-like versus plate-like structures affecting specific surface area. This framework provides a mechanistic explanation for bone mineralization variations across the porosity range.
Sites of non-enzymatic crosslinks pentosidine and glucosepane in collagen I of human cortical bone.
Voziyan P, Brown KL, Uppuganti S … +4 more , Berestesky ED, Leser M, Rose KL, Nyman JS
Bone · 2026 Aug · PMID 42035904 · Publisher ↗
Structural alterations of bone extracellular matrix (ECM) may affect bone quality, which, along with bone mass, affects the ability of bone to resist fracture. In particular, an increase in advanced glycation end-product...
Structural alterations of bone extracellular matrix (ECM) may affect bone quality, which, along with bone mass, affects the ability of bone to resist fracture. In particular, an increase in advanced glycation end-product (AGE) crosslinking of type I collagen has been implicated in contributing to increased bone fragility in diabetes and ageing. However, the location of these crosslinks and their relative abundance is unknown, thus hindering our understanding of how AGE crosslinks impact bone quality. We analyzed physiological crosslinks, glucosepane (GN) and pentosidine (PE), in collagen I from cortical bone of 12 male and 12 female cadaveric femurs using liquid chromatography-tandem mass spectrometry. The analysis identified 11 distinct crosslinks at 8 different sites within the collagen I triple helix. Crosslinks at two sites formed only within the same collagen chain, while the remaining crosslinks formed within the same triple helical molecule and/or between different molecules of the neighboring microfibrils. Most of the GN and PE crosslinks were located to the D-periodic overlap zone of the microfibril. The relative crosslink levels varied significantly at different sites: 0.005% to 2.1% for PE and 0.06% to 24.9% for GN. Female donors had fewer crosslink sites compared to male donors. While total PE and total fAGE levels did not correlate with bone mechanical properties in the present sample size, the level of GN at one site positively correlated with ultimate stress, while the level of PE at another site negatively correlated with post-yield toughness. However, these correlations were weak, and several other correlations between site-specific GN and PE levels and these mechanical properties were not consistent between the sexes. ln conclusion, this study identified the native locations of GN and PE within collagen I of bone, an innovation essential for addressing the question of how the specific structural features of bone ECM affect bone quality.
A NOTCH2 pathogenic variant alters the osteoblast and vascular cell transcriptome of mouse femurs.
Canalis E, Schilling L, Denker E
Bone · 2026 Aug · PMID 42035903 · Full text
Pathogenic variants of NOTCH2 that lead to a gain or loss of function are associated with serious clinical consequences. A recently reported novel NOTCH2 4006G > C variant was associated with decreased Notch signaling an...
Pathogenic variants of NOTCH2 that lead to a gain or loss of function are associated with serious clinical consequences. A recently reported novel NOTCH2 4006G > C variant was associated with decreased Notch signaling and skeletal fragility in humans and mouse (Notch2) lines. In the present study, we analyze the transcriptome of femoral bones from mature control and Notch2 mice following the exclusion of hematological cells. Single cells were analyzed following microfluidic partitioning on a Chromium X instrument using a 3' gene expression library. Uniform manifold approximation and projection (UMAP) for non-linear dimensional reduction defined 15 different cell clusters comprised of macrophages, red blood cells, endothelial, vascular and smooth and striated muscle cells and cells of the osteoblast lineage. Notch2 and Hes1 were the prevalent Notch receptor and target gene in most clusters. Independent clustering analysis of transcriptomes from control and Notch2 femurs revealed a 35-45% decrease in cells forming the osteogenic and a 50-55% decrease in cells comprising the vascular cluster in Notch2 femurs. Expression of Hes1 was decreased in Notch2 cells. Analysis of nascent transcripts (intron/exon sequences) using the scVelo pipeline revealed suppressed velocity in vascular and osteogenic clusters from Notch2 cells implying decreased transcription of genes constituting these clusters. In conclusion, a novel NOTCH2 deleterious variant associated with skeletal fragility alters the osteogenic and vascular transcriptome in femurs from adult mice.
Multiparametric assessment of bone health in metastatic hormone-sensitive prostate cancer patients receiving androgen deprivation + enzalutamide ± zoledronic acid (BonEnza study).
Caramella I, Dalla Volta A, Valcamonico F … +20 more , Bergamini M, Buffoni M, Zivi A, Procopio G, Sepe P, Di Meo N, Foti S, Zamboni S, Messina C, Rizzi A, Lucchini E, Ravanelli M, Zamparini M, Zacchi F, Laganà M, Cosentini D, Bresciani R, Suardi N, Farina D, Berruti A
Bone · 2026 Aug · PMID 42035902 · Publisher ↗
Androgen deprivation therapy has a negative effect on bone mineral density and trabecular bone score in prostate cancer patients. The addition of androgen receptor pathway inhibitors can result in worsened skeletal fragi...
Androgen deprivation therapy has a negative effect on bone mineral density and trabecular bone score in prostate cancer patients. The addition of androgen receptor pathway inhibitors can result in worsened skeletal fragility. BonEnza is a prospective phase II trial in which metastatic hormone sensitive prostate cancer patients were randomized to receive androgen deprivation therapy plus enzalutamide with (EZ arm) or without (E arm) the addition of zoledronic acid. Bone quantity and quality parameters were evaluated by dual-energy x-ray absorptiometry (DXA) scan at baseline and after 18 months of therapy. Alkaline phosphatase (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline and after 18 months of treatment. Eighty-nine patients had paired DXA evaluation at both timepoints. After 18 months of treatment femoral neck and lumbar spine bone mineral density significantly decreased in E arm (-8.6% and - 9.26% respectively; p < 0.001), while improved in EZ arm (+1.83%, p 0.019; and + 5.47%, p < 0.001). Trabecular bone score significantly worsened in E arm (-3.35%, p < 0.001) and improved in EZ arm (+3.01%, p 0.004). Both ALP and CTX showed marked reduction overtime among patients receiving zoledronic acid (-35.6%, p < 0.0001, and - 58.9%, p < 0.0001, respectively), while remaining stable (-0.6%, p 0.934) or significantly increasing (39.5%, p 0.011) respectively among patients from E arm. The addition of zoledronic acid to enzalutamide and androgen deprivation improved bone mineral density, trabecular bone score, and reduced bone turnover markers. Future studies in mHSPC should consider the use of lower doses of bone protecting agents and regard the reduction in morphometric fractures by DXA as a primary endpoint.
How bending causes distal radius fracture: Evidence from 6dof load measurement and digital image correlation.
Robinson DL, Lee PVS
Bone · 2026 Aug · PMID 42034150 · Publisher ↗
Distal radius fractures, specifically Colles-type injuries, are highly prevalent in older females and typically result from falls on an outstretched hand. Clinically, these fractures appear to originate on the volar side...
Distal radius fractures, specifically Colles-type injuries, are highly prevalent in older females and typically result from falls on an outstretched hand. Clinically, these fractures appear to originate on the volar side of the distal radius due to a substantial dorsiflexion bending moment, yet most biomechanical and finite element (FE) studies rely on simplified axial loading assumptions that fail to reproduce the tensile strain gradients responsible for these fractures. This study quantified the full six-degree-of-freedom (6DOF) force and moment components acting on the distal radius during loading in a dorsiflexed posture, while simultaneously measuring volar cortical strain using full-field digital image correlation (DIC). Twenty cadaveric forearms from ten female donors underwent quantitative CT imaging to obtain specimen-specific geometry and density distributions. Each radius was then loaded against a 30° inclined plate at 0.1 mm/s until failure. Two distinct fracture patterns emerged: distal volar fractures consistent with Colles injuries (n = 10) and proximal diaphyseal fractures (n = 10). Colles-type fractures were associated with lower metaphyseal bone density and exhibited elevated distal tensile strains that exceeded the cortical ultimate tensile strain threshold (∼19,000 με). In contrast, diaphyseal fractures were characterised by higher bone density, larger displacements, and higher proximal tensile strains. Across all specimens, peak dorsiflexion moments averaged 20.0 ± 5.5 Nm, confirming that bending-rather than pure compression-is the primary driver of failure. These findings provide a comprehensive multicomponent experimental characterisation of distal radius loading under realistic fall conditions, highlighting the central role of bending in fracture initiation and offering high-fidelity data for validating FE models to improve clinical fracture risk prediction.
Evaluating the dose-response relationship between drop-jump height and bone adaptation: A randomized controlled trial.
Scott R, Sale C, James R … +2 more , Barnett CT, Varley I
Bone · 2026 Aug · PMID 42033922 · Publisher ↗
Exercise interventions frequently prescribe impact activities assuming that identical tasks produce similar mechanical loads, yet few studies quantify the external loads experienced during such interventions. This study...
Exercise interventions frequently prescribe impact activities assuming that identical tasks produce similar mechanical loads, yet few studies quantify the external loads experienced during such interventions. This study examined drop-jump height and skeletal adaptation and whether quantified external load is associated with changes in bone in low-active, healthy young adults. Forty-eight participants (22 ± 2 years) were randomized to perform diagonal drop jumps (DDJ) from 0 cm, 40 cm, or 60 cm, or to a non-exercise group for 16 weeks (40 jumps, 4 days·week). Force plates, inertial measurement units (IMU) and motion capture were taken at baseline, 6-, 12- and 16 weeks. Whole-body dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative computed tomography (pQCT) were performed at baseline and week 16, with additional pQCT at week 12. Cortical density (Ct.D) increased at the dominant distal tibia from the 40 cm jumps (0.4%, p = 0.006) and control group (0.7%, p = 0.027), whereas the 60 cm jumps decreased (-1.7%) at week 12. Similarly, Ct.D at the tibial diaphysis increased in the 40 cm group (1.6%) but decreased in the control group (-1.6%, p = 0.033). No significant effects were detected for DXA-derived outcomes. Negative associations were found between the change in cortical and trabecular outcomes and loading variables, such as impact peak, load rate and ankle moment. Findings demonstrate that increased prescribed jump height does not necessarily reflect loading dose, highlighting the importance of quantifying mechanical load when designing exercise interventions. Furthermore, as the changes in cortical density did not exceed the pQCT least significant change, the results should be interpreted cautiously.
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