Bone [JOURNAL]
Sun
200 papers
Development of a novel anthropomorphic bone phantoms for mimicking osteoporosis in medical imaging development.
Hu J, Chen J, Wells S … +1 more , Knapp K
Bone · 2026 Apr · PMID 41570963 · Publisher ↗
Osteoporosis (OP) is characterised by loss of bone mineral density (BMD) and deterioration of trabecular microarchitecture, yet routine clinical imaging techniques remain limited in their ability to fully characterise bo...
Osteoporosis (OP) is characterised by loss of bone mineral density (BMD) and deterioration of trabecular microarchitecture, yet routine clinical imaging techniques remain limited in their ability to fully characterise bone microarchitecture. As new imaging technologies are developed, the potential for point of care bone assessment with both density and microarchitectural parameters of bone becomes a reality. Although advanced imaging modalities such as high-resolution peripheral quantitative computed tomography (HR-pQCT) offers improved sensitivity to bone structure, this is primarily focused on research settings. The development of higher resolution digital tomosynthesis (DT), required rethinking of phantoms, otherwise development and pre-clinical validation are constrained by the lack of reproducible, structure-controlled reference standards. In this study, we present a novel anthropomorphic bone phantom designed as a preclinical platform for calibration, benchmarking, and validation of bone imaging systems and quantitative analysis methods. The phantom integrates digital-twin trabecular models derived from micro-computed tomography (μ-CT), enabling parametric control of trabecular thickness and bone volume fraction to represent healthy and osteoporotic conditions. BMD is independently controlled using calibrated contrast agent (PVP-BaSO), while moulded lean and adipose soft-tissue equivalents are incorporated to provide realistic X-ray attenuation for projection-based imaging. The phantoms were evaluated using multiple imaging modalities, including X-ray, DXA, pQCT, DT, and μCT, to verify their fidelity in reproducing both BMD and trabecular microstructural features. Imaging-derived parameters showed strong correlations with controlled variations in trabecular architecture and BMD, demonstrating the utility of the phantom as a source of controlled ground truth for cross-modality comparison. This reproducible platform enables systematic evaluation of imaging systems and facilitates early osteoporosis detection by bridging structure-density relationships. Our phantom serves as a valuable tool for preclinical diagnostic validation, imaging quality assurance, and the development of bone health biomarkers, thereby reducing reliance on animal or cadaveric studies.
Improvements in bone quality by parathyroid hormone treatment are enhanced in the Nmp4 knockout mouse model.
Chen R, Wang B, Stephen SJ … +2 more , Bidwell JP, Vashishth D
Bone · 2026 Apr · PMID 41565170 · Full text
Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH 1-34, is an FDA-approved therapeutic for osteoporosis that enhances bone formation. However,...
Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH 1-34, is an FDA-approved therapeutic for osteoporosis that enhances bone formation. However, as PTH treatment potency declines over time, it is necessary to investigate the mechanisms involved in this attenuation to reinforce its long-term efficacy. This need has led to investigations into the transcription factor nuclear matrix protein 4 (Nmp4), in which PTH treatment of mice globally lacking Nmp4 (Nmp4) enhanced bone formation. Yet, the changes in the compositional quality of PTH-stimulated bone in Nmp4 mice are unknown, which in turn could impact the efficiency of this approach. To this end, we characterized cortical bone quality in Nmp4 mice and wild-type littermates treated with PTH for 8 weeks, starting at 16 weeks of age, using micro-computed tomography, Raman spectroscopy, X-ray diffraction, biochemical assays, and biomechanical characterization (whole-bone strength, fracture toughness). PTH treatment and Nmp4 ablation increased tissue and marrow area and maximum moment of inertia. Femora from PTH-treated mice exhibited increased stiffness, maximum load, and fracture resistance. Bone in Nmp4 mice with PTH treatment demonstrated lower mineral crystallinity, decreased mineral-to-matrix ratio, lattice spacing, altered levels of advanced glycation end-products, increased levels of osteocalcin, and increased matrix phosphorylation levels. These results suggest that ablation of Nmp4, in concert with PTH treatment, improved bone function by modulating bone structure and matrix composition. Our findings demonstrate the potential utility of targeting Nmp4 to improve PTH potency and bone quality.
Modeling rare genetic skeletal disorders with bone organoids: a narrative review.
Micha D, Escalante Quirós S, Eekhoff EMW … +3 more , Heine VM, Shim JH, Zhytnik L
Bone · 2026 Apr · PMID 41558554 · Publisher ↗
Rare genetic skeletal disorders (RGSDs) encompass a heterogeneous group of hundreds rare conditions affecting the skeletal system. The rarity of these disorders, phenotypic and genetic diversity, combined with the limita...
Rare genetic skeletal disorders (RGSDs) encompass a heterogeneous group of hundreds rare conditions affecting the skeletal system. The rarity of these disorders, phenotypic and genetic diversity, combined with the limitations of conventional cellular and animal RGSD models, have hindered progress in understanding their pathophysiology and developing effective therapies. However, the latest advances in stem cell and bone tissue engineering techniques offer transformative opportunities in investigation of RGSD, particularly through bone organoids that enable disease modeling within a precision medicine framework. This review outlines the progress in RGSD organoid research, starting with the pivotal concepts of RGSDs bone biology, and extending to the disease-specific molecular signatures essential for selecting cell sources, biomaterials, and biofabrication strategies to improve the translational relevance of the models. We critically evaluate existing bone organoid models for osteogenesis imperfecta, hypophosphatasia, fibrous dysplasia, Gaucher disease, and other representative RGSDs. Finally, we consider ethical implications of animal-free and patient-centric organoid research. By integrating the latest advancements in RGSD biology and organoid research, this review outlines how molecular pathophysiology can guide organoid design and highlights key methodological advances that could accelerate therapeutic discovery and progress in precision skeletal medicine.
Clec4a2 deficiency promotes post-fission osteoclast cell death and suppresses acute inflammation-induced bone loss in the mouse.
Fujita H, Tai Y, Takahashi K … +5 more , Ueda Y, Kitagawa W, Ono M, Oohashi T, Ohuchi H
Bone · 2026 Apr · PMID 41548678 · Publisher ↗
To achieve efficient bone resorption by osteoclasts, the specialized innate immune cells, it is important not only to promote osteoclast differentiation and activation but also to maintain their survival. C-type lectin (...
To achieve efficient bone resorption by osteoclasts, the specialized innate immune cells, it is important not only to promote osteoclast differentiation and activation but also to maintain their survival. C-type lectin (CLEC) receptors recognize pathogen ligands and altered self-tissues, comprising activating and inhibitory types whose balance eliminates pathogens while preventing excessive immune responses. However, roles of CLEC receptors in osteoclast differentiation, function, and survival remain unclear. We established knockout (KO) mice of CLEC receptor genes highly expressed by osteoclast and analyzed osteoclast features and bone morphology. We conducted comprehensive in silico screening of osteoclast lineage-specific CLEC receptors utilizing a mouse gene expression dataset and generated single and double KO (DKO) mice of Clec4a2 and Clec4d using a multi-targeted CRISPR-Cas9 system. Clec4a2 KO and DKO enhanced osteoclast differentiation in vitro, and Clec4a2 KO also stimulated enlargement of osteoclasts. Clec4d KO slightly reduced trabecular bone thickness in the femur, while Clec4a2 KO and DKO did not affect bone morphology under physiological conditions. Contrary to conventional understanding that enhanced osteoclast differentiation leads to increased bone resorption, our time-lapse analysis revealed that Clec4a2 KO paradoxically increased osteoclast formation while reducing resorption efficiency due to cell death of osteoclasts and its daughter cells after fission. Clec4a2 KO provided protection against inflammatory bone loss induced by lipopolysaccharide, demonstrating the first evidence that Clec4a2 could serve as therapeutic targets for inflammatory osteolytic diseases. This study introduces a novel paradigm that osteoclast survival regulation by Clec4a2 is fundamental for efficient bone resorption.
Prmt1-mediated methylation of Ddx17 promotes osteoblast differentiation via regulating the alternative splicing of Sh2b1.
Jiang X, Li B, Ma Y … +5 more , Huang J, Gu C, Jin Y, Ding H, Ma C
Bone · 2026 Apr · PMID 41548677 · Publisher ↗
Osteoporosis (OP) is characterized by impaired osteoblast-mediated bone formation and reduced mineralization, which increases fracture risk and challenges global skeletal health. Ddx17 (DEAD-box helicase 17) is implicate...
Osteoporosis (OP) is characterized by impaired osteoblast-mediated bone formation and reduced mineralization, which increases fracture risk and challenges global skeletal health. Ddx17 (DEAD-box helicase 17) is implicated in multiple cancers, but its role and mechanism in bone biology, especially in osteoblast differentiation and osteoporosis pathogenesis remain unclear. In this study, we demonstrated that Ddx17 expression was significantly reduced in trabecular bones of patients with osteoporosis. During osteoblastic differentiation of MC3T3-E1 and C3H10T1/2 cells, Ddx17 expression levels increased gradually in a time-dependent manner. Loss-of-function and gain-of-function experiments revealed that Ddx17 promoted osteoblast proliferation and differentiation. Mechanistically, Ddx17 was a direct substrate of Prmt1 (protein arginine methyltransferase 1), which specifically catalyzed ADMA modification of Ddx17 at R426, thereby enhancing Ddx17 protein stability. Stabilized Ddx17 modulated the alternative splicing of Sh2b1 mRNA, thereby promoting the expression of Sh2b1-T1 while suppressing that of Sh2b1-T2. Rescue experiments demonstrated that re-expression of Sh2b1-T1, but not Sh2b1-T2, reversed the impairment of osteoblast differentiation triggered by Ddx17 knockdown. Taken together, these findings underscore the critical role of the Prmt1-Ddx17-Sh2b1 axis in regulating osteoblast differentiation and suggest this axis as a promising therapeutic target for osteoporosis.
Considerations on the interpretation of pain-related analyses in genetic metabolic bone diseases.
Qu X, Huang T, Yang D … +1 more , Chen B
Bone · 2026 May · PMID 41547492 · Publisher ↗
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Osteoblastic cell responses to zoledronate treatment in-vitro: A systematic review.
Florez-Martin M, Radu AM, Shakib K … +1 more , Jell G
Bone · 2026 Apr · PMID 41547491 · Publisher ↗
BACKGROUND: Zoledronate (ZOL), a potent nitrogen-containing bisphosphonate (BP), is widely prescribed for osteoporosis and metastatic bone disease. While osteoclast inhibition is central to ZOL's therapeutic action and t...
BACKGROUND: Zoledronate (ZOL), a potent nitrogen-containing bisphosphonate (BP), is widely prescribed for osteoporosis and metastatic bone disease. While osteoclast inhibition is central to ZOL's therapeutic action and to the pathophysiology of medication-related osteonecrosis of the jaw (MRONJ), less is known about its direct effects on osteoblasts. Understanding dose- and time-dependent osteoblastic responses is essential for improving in-vitro modelling and informing regenerative strategies. METHODS: We performed a systematic review of in-vitro studies reporting osteoblastic responses to ZOL, adhering to PRISMA guidelines (protocol registered, DOI:10.17605/OSF.IO/GWDP5). Web of Science and Scopus searches identified 606 records, of which 77 met inclusion criteria. Data were extracted for proliferation, metabolic activity, apoptosis, alkaline phosphatase (ALP), biomineralisation, collagen formation, and angiogenesis. Statistical comparisons assessed dose- and time-dependent effects. RESULTS: Across 2057 datapoints, undesirable outcomes (reduced metabolic activity or proliferation, increased apoptosis) occurred at median [ZOL] of 10 μM, significantly higher (p≤0.0001) than concentrations associated with no effect (1 μM) or beneficial responses (0.75 μM). Desirable nanomolar-dose outcomes were infrequent and inconsistent across studies. ALP and biomineralisation were dose-dependently impaired, whereas collagen synthesis was unaffected. At 48-71 h, osteoblasts tolerated higher ZOL concentrations compared to later timepoints (p≤0.05). Media composition influenced responses, with higher calcium (≥1.8 mM) media protective of negative effects, likely due to ZOL-Ca complex formation. CONCLUSION: ZOL exerts direct, dose-dependent inhibitory effects on osteoblasts in-vitro, with outcomes influenced by exposure time and media composition. This review highlights the need for standardised protocols and provides quantitative guidance for modelling MRONJ and testing regenerative interventions.
Combined antiresorptive and antiangiogenic therapy versus antiresorptive monotherapy: Impact on the surgical prognosis of MRONJ patients with advanced malignancies.
Zou Y, Zhao N, Huang H … +7 more , Zhou Y, Yang Y, Qiao Q, Li Q, Zhu J, Wang Y, Guo Y
Bone · 2026 Apr · PMID 41544880 · Publisher ↗
For patients with advanced cancer and bone metastasis, antiresorptive medications (ARMs) and antiangiogenic medications (AGMs) are commonly employed to manage tumor progression and skeletal complications. This study eval...
For patients with advanced cancer and bone metastasis, antiresorptive medications (ARMs) and antiangiogenic medications (AGMs) are commonly employed to manage tumor progression and skeletal complications. This study evaluates the effects of distinct pharmacotherapeutic strategies-ARM monotherapy versus ARM+AGM combined therapy on surgical outcomes of medication-related osteonecrosis of the jaw (MRONJ) in this population. A retrospective cohort analysis was conducted on 157 patients: 106 received ARM monotherapy, and 51 underwent combined ARM+AGM treatment. Demographic data, MRONJ clinical characteristics, and quality of life (QoL) metrics were systematically collected and analyzed using univariate and multivariate statistical methods. Univariate analysis revealed that the ARM group had a higher proportion of females, longer antiresorptive therapy duration, and more favorable outcomes, including reduced postoperative pain and improved QoL compared to the ARM+AGM group. Multivariate analysis demonstrated that the ARM+AGM group exhibited a 2.8-fold recurrence risk relative to the ARM group, with prognosis significantly influenced by medication strategy, disease stage, and surgical approach. These findings indicate that combined ARM+AGM therapy is associated with a poorer prognosis and heightened recurrence risk in MRONJ patients compared to ARM monotherapy.
Electroacupuncture remodels brain functional connectivity and improves bone metabolism in ovariectomized rats.
Zhang L, Rong Y, Wang X … +6 more , Chen Y, Xu M, Tang C, Yang Y, Chen G, Li S
Bone · 2026 Apr · PMID 41539419 · Publisher ↗
Electroacupuncture has demonstrated established efficacy in treating postmenopausal osteoporosis, yet the central mechanisms underlying its action via the brain-bone axis remain incompletely understood. This study employ...
Electroacupuncture has demonstrated established efficacy in treating postmenopausal osteoporosis, yet the central mechanisms underlying its action via the brain-bone axis remain incompletely understood. This study employed multimodal resting-state functional magnetic resonance imaging to investigate neurofunctional changes induced by electroacupuncture in a rat model of postmenopausal osteoporosis. Twenty-four female Sprague-Dawley rats were randomly allocated to electroacupuncture, sham, and model (ovariectomized) groups. The electroacupuncture group received an 8-week intervention at acupoints GB30, GB34, and GB39. We assessed brain function through amplitude of low-frequency fluctuation, regional homogeneity, and region-of-interest functional connectivity, while simultaneously measuring serum bone turnover markers via enzyme-linked immunosorbent assay. Our results demonstrated that electroacupuncture significantly improved bone microstructure and reduced bone resorption marker levels. Neuroimaging revealed enhanced cerebellar neural activity which correlated negatively with bone resorption, alongside decreased neural synchronization in the entorhinal cortex. Furthermore, strengthened functional connectivity between entorhinal and visual cortices positively correlated with bone formation markers, while weakened somatosensory-cerebellar connectivity correlated with reduced bone resorption. Bayesian mediation analysis provided strong statistical evidence for the role of the entorhinal-visual pathway involvement in bone formation regulation and cerebellar mediation of bone resorption suppression. These findings systematically reveal the association between electroacupuncture-induced brain functional reorganization and bone metabolic improvements, offering new insights into the role of the brain-bone axis in osteoporosis management.
Integrated methylome and hydroxymethylome analysis identifies CAMK2G, NFATC4, and SFRP2 as TET1-regulated drivers of odontoblastic differentiation in human dental pulp cells.
Li Q, Li J, Zhang D … +1 more , Xu Q
Bone · 2026 Apr · PMID 41534676 · Publisher ↗
AIM: DNA 5-methylcytosine (5mC) dynamics are pivotal for tooth differentiation. However, the 5mC landscape during human dental pulp cell (hDPCs) odontoblastic differentiation and the role of Ten-eleven translocation 1 (T...
AIM: DNA 5-methylcytosine (5mC) dynamics are pivotal for tooth differentiation. However, the 5mC landscape during human dental pulp cell (hDPCs) odontoblastic differentiation and the role of Ten-eleven translocation 1 (TET1)-mediated 5mC regulation remain unclear. This study aimed to characterize methylation dynamics and identify TET1-regulated drivers of odontoblastic differentiation. METHODOLOGY: Genome-wide DNA methylation was profiled by microarray, and hydroxymethylation changes after TET1 knockdown were assessed by hMeDIP-seq. RESULTS: Methylation and demethylation maintained a dynamic equilibrium during odontoblastic differentiation. A total of 9752 differentially methylated genes were identified and were enriched in pathways related to mesenchymal stem cell and ameloblast differentiation and neurotrophin signaling. hMeDIP-seq demonstrated that TET1 knockdown in hDPCs resulted in 2237 peaks with decreased 5-hydroxymethylcytosine (5hmC) levels and 3285 peaks with increased 5hmC levels compared to controls, corresponding to 1477 hypo-hydroxymethylated genes and 1905 hyper-hydroxymethylated genes. Integrated analysis of hypo-methylated genes and hypo-hydroxymethylated genes identified 88 overlapping candidates. Functional enrichment analyses highlighted tooth mineralization, osteoblast differentiation, TGF-β, and Wnt pathways. Among these, CAMK2G, NFATC4, and SFRP2 were specifically enriched in Wnt signaling and exhibited reduced 5hmC levels after TET1 knockdown. scRNA-seq data further confirmed increased expression of these three genes during odontoblast differentiation. CONCLUSIONS: This study delineated the genome-wide DNA methylation landscape during odontoblastic differentiation and identifies CAMK2G, NFATC4, and SFRP2 as novel TET1-regulated epigenetic drivers via 5hmC modification. These findings highlight potential therapeutic targets for epigenetic intervention in dentin regeneration and dental tissue engineering.
Gα variant detection discerns skeletal cell types involved in fibrous dysplasia pathogenesis.
Michel Z, MacDonald V, Arif A … +10 more , Elbashir II, Freeman J, Gun ZH, Osamor C, Taylor J, Collins MT, Roszko KL, de Castro LF, Kram V, Boyce AM
Bone · 2026 Apr · PMID 41534675 · Publisher ↗
Fibrous dysplasia (FD) is a mosaic disorder caused by activating Gα variants. Skeletal stem cells give rise to abnormal osteoprogenitors, resulting in fibro-osseous lesions with prominent osteoclastogenesis. Gα variants...
Fibrous dysplasia (FD) is a mosaic disorder caused by activating Gα variants. Skeletal stem cells give rise to abnormal osteoprogenitors, resulting in fibro-osseous lesions with prominent osteoclastogenesis. Gα variants are reliably demonstrated in osteoprogenitors, however involvement in other skeletal cell types is not well-characterized. We evaluated human specimens to investigate Gα variant expression in chondrocytes and osteoclasts, two prominent cell types in FD lesions. Seven of 20 bone specimens had cartilage present in addition to typical fibrous tissue. Droplet digital polymerase chain reaction detected variant Gα DNA in all cartilaginous samples and most fibrous tissue, in similar proportions. Variant-specific staining of Gα mRNA using BaseScope demonstrated variant expression in approximately 14% of chondrocytes. Approximately 3.4% of osteoclasts expressed variants, below the 5% assay false positivity rate. To further investigate this surprising finding, primary murine osteoclast cultures were treated with dibutyryl-cAMP to mimic Gα activation. Treatment attenuated osteoclastogenesis, diminished resorption, and toxic at high doses. To further investigate the lack of osteoclast variant expression, we isolated pre-osteoclastic monocytes from patient whole blood samples. Monocytes demonstrated an average variant allele frequency of ∼20%, with strong correlations to overall FD burden. We demonstrate that chondrogenesis is common in FD and arises directly from Gα variants. While osteoclasts play a pivotal role in FD pathogenesis, our results surprisingly indicate that direct expression of Gα variants may impair osteoclastogenesis. This study provides key insights into FD as a complex disorder driven by interplay of multiple cellular lineages and will inform development of targeted therapies.
Development of a deep learning-based histological evaluation model for critical-size bone defect healing in rats - an objective tool.
Neijhoft J, Virefléau W, Zhao Y … +5 more , Bianconi S, Verboket R, Antink CH, Marzi I, Henrich D
Bone · 2026 Apr · PMID 41525839 · Publisher ↗
INTRODUCTION: Critical-size femoral defects in rats are a well-established model for preclinical bone regeneration research. Histological evaluation is essential for assessing healing but remains time-consuming and subje...
INTRODUCTION: Critical-size femoral defects in rats are a well-established model for preclinical bone regeneration research. Histological evaluation is essential for assessing healing but remains time-consuming and subject to observer variability. Machine learning, particularly convolutional neural networks (CNNs), offers potential for objective and scalable analysis of histological sections. MATERIALS AND METHODS: We developed a modified U-Net model to perform semantic segmentation and classification of bone healing stages based on Movat pentachrome-stained histological sections (n = 669). Five tissue classes (bone, cartilage, bone marrow, granulation tissue, background) were manually annotated to train the model. Data were split into training (64%), validation (16%), and test (20%) sets. The model then was used to segment and rank histological images. In addition, a subset of 20 independent test images was scored by four orthopedic experts, seven medical students, and the AI using a refined bone healing score ranging from -10 to +10. RESULTS: The model achieved high segmentation performance, particularly for bone and background. AI-generated healing scores showed strong correlation with expert ratings (Spearman r = 0.819, p < 0.0001) and similar accuracy to student ratings (mean absolute deviation: AI = 0.468 vs. students = 0.469; p = 0.5753). ICC analysis confirmed excellent agreement between AI and experts (ICC = 0.820) and revealed a significant difference favoring AI over students (bootstrap p = 0.0466). CONCLUSION: This study introduces a CNN-based model capable of expert-level performance in the histological assessment of bone healing. It offers a reproducible and time-efficient tool for future preclinical applications.
Quantitative analysis of osseointegration of glass fiber-reinforced composite-bioactive glass cranial implants.
Klieverik VM, Muradin MSM, Nicolai N … +3 more , Kortes J, Robe PA, Woerdeman PA
Bone · 2026 Apr · PMID 41525838 · Publisher ↗
BACKGROUND: Glass fiber-reinforced composite-bioactive glass (FRC-BG) implants are emerging as an alternative to autologous bone grafts with the potential for new bone formation and ingrowth from the surrounding skull. H...
BACKGROUND: Glass fiber-reinforced composite-bioactive glass (FRC-BG) implants are emerging as an alternative to autologous bone grafts with the potential for new bone formation and ingrowth from the surrounding skull. However, clinical evidence of osseointegration remains to be demonstrated. OBJECTIVE: To evaluate radiological measures of osseointegration of FRC-BG implants used for cranioplasty. METHODS: A retrospective cohort study was conducted including adult patients who underwent cranioplasty with FRC-BG implants between 2016 and 2021. Sequential non-contrast head CT-scans were obtained within 24 h postoperatively and after one year of follow-up. Using three-dimensional (3D) segmentation and analysis software, changes in bone volume (in cm) and bone density (in Hounsfield units [HU]) of a standardized one cm-wide region of skull bone surrounding the margins of the FRC-BG implants were quantified. Paired samples t-tests assessed differences between baseline and after one year of follow-up. RESULTS: A total of 38 patients were included (mean age 50.2 ± 18.4 years). After one year of follow-up, significant increases were observed in both skull bone volume (mean difference 6.04 cm, 95% confidence interval [CI] 4.65-7.43, p < 0.001) and skull bone density (mean difference 45.84 HU, 95% CI 1.15-90.52, p = 0.045) surrounding the FRC-BG implants. CONCLUSION: The present study shows radiological signs of osseointegration of FRC-BG implants used for cranioplasty.
Models of myeloma bone disease: In vivo and in vitro approaches.
Wang J, Zweegman S, Groen RWJ
Bone · 2026 Apr · PMID 41525837 · Publisher ↗
This review focuses on experimental models developed to study myeloma bone disease (MBD), a major cause of morbidity in multiple myeloma (MM). Under physiological conditions, bone remodeling is regulated by osteoclasts (...
This review focuses on experimental models developed to study myeloma bone disease (MBD), a major cause of morbidity in multiple myeloma (MM). Under physiological conditions, bone remodeling is regulated by osteoclasts (OCs) and osteoblasts (OBs); in MM, this balance is disrupted, resulting in enhanced bone resorption and suppressed bone formation. Myeloma cells alter the bone marrow (BM) microenvironment by increasing the RANKL/OPG ratio and secreting Wnt pathway inhibitors such as DKK-1 and sclerostin, thereby promoting osteoclastogenesis and inhibiting osteoblast differentiation. To dissect these mechanisms and evaluate therapeutic strategies, diverse preclinical systems have been developed. Syngeneic murine models, notably the 5T series, remain the most established for reproducing both osteolysis and impaired bone formation, though interspecies differences limit translational relevance. Humanized mouse systems and three-dimensional (3D) in vitro models increasingly address these constraints by incorporating human stromal and hematopoietic elements. Emerging induced pluripotent stem cell-derived bone marrow organoids (iBMOs) offer a fully human platform capable of modeling both osteoclast and osteoblast dynamics. While current iBMOs lack mineralized bone and mature vascular or immune components, advances in differentiation control and matrix engineering are expected to bridge these gaps, providing physiologically relevant and ethically sustainable models for studying MBD and testing therapeutic interventions.
Sex chromosome and gonadal contributions to body composition and skeletal mass and strength in aged four core genotypes (FCG) mice.
Ortiz Gonzalez P, Teal A, Chellaganapathy L … +6 more , Ramirez G, Pianeta R, Segvich DM, Liu Z, Wallace JM, Plotkin LI
Bone · 2026 Apr · PMID 41520751 · Full text
Sex differences in musculoskeletal aging are often attributed to gonadal hormones, but the independent role of sex chromosomes remains unclear. Using the Four Core Genotype mouse model, which dissociates sex chromosomes...
Sex differences in musculoskeletal aging are often attributed to gonadal hormones, but the independent role of sex chromosomes remains unclear. Using the Four Core Genotype mouse model, which dissociates sex chromosomes (XX vs. XY) from gonadal sex (ovaries vs. testes), our goal was to examine sex chromosomes and gonads independent and interactive effects on bone, muscle and organ phenotypes from 8 to 20 months of age in XXO, XYO, XXT, and XYT mice. XYO mice showed high mortality (38.7%-survival by 20 months) when compared with other genotypes (67-86.7%). Between 8 and 20 months, XYO mice showed increases in lean mass and femoral BMD and improved bone structural parameters, yet lower cortical tissue mineral density. XXO mice displayed pronounced late-life gains in body weight, lean and fat mass not observed in other genotypes, although lean mass differed only versus XXT mice at 20 months. Total and spine BMD declined in XXO mice, accompanied with lower structural parameters and higher tissue mineral density than XYO mice. XXT mice displayed bone loss at all skeletal sites, whereas XYT mice showed a selective decline in spine BMD. Overall, chromosome sex adversely affected bone and muscle mass in XX versus XY mice, while gonadal sex influenced bone structure and absolute muscle mass, with mice bearing ovaries generally exhibiting lower muscle mass. Organ weight effects were modest and limited to spleen (XYO > XXO/XYT) and brain (XYT > XXT). Collectively, these findings reveal a previously unrecognized, tissue-specific contribution of sex chromosomes to musculoskeletal aging, independent of gonadal sex.
Alterations in osteocyte mechanostimulation within trabecular-lacunar cavities of human bone from intact to implanted cases: a multiscale model elucidating the role of osteocyte mechanosensors.
Gupta A, Rana M, Das A … +2 more , Chowdhury AR, Verdonschot N
Bone · 2026 Apr · PMID 41519278 · Publisher ↗
Osteocytes, being embedded within the bone, sense mechanical stimuli through their various mechanosensors under physiological loading. However, the insertion of metallic implants alters the local mechanical environment,...
Osteocytes, being embedded within the bone, sense mechanical stimuli through their various mechanosensors under physiological loading. However, the insertion of metallic implants alters the local mechanical environment, potentially disrupting osteocyte stimulation and affecting bone remodelling, particularly in the peri-implant cancellous bone. To quantify the changes in osteocyte mechanostimulation from the intact to the implanted state and to explore the potential of optimized implants in restoring these stimulations, a three-level multiscale modelling approach was developed. This approach transferred boundary conditions from the global femur (intact or implanted) to a trabecular-level model and subsequently to a cellular-level model. At the cellular level, the osteocyte was modelled within its interstitial fluid and surrounding bone matrix, with a specific focus on its various mechanosensors, aiming to examine quantitative changes in their mechanostimulation before and after implantation. The results showed that osteocyte stimulation in the peri-implant cancellous bone decreased by nearly 60-75% after inserting a solid implant, depending on whether the region corresponded to low or high marrow cell stimulation as defined by fluid shear stress on the trabecular surface. The simulation appeared to be sensitive to a change of implant design showing a recovery of this stimulation of approximately 5% when an optimized porous implant was employed, particularly enhancing osteocyte response near high shear stress regions on the trabecular surface. This study provides a mechanobiological explanation for altered bone remodelling around implants and demonstrates how an optimized implant design can enhance osteocyte stimulation and improve remodelling outcomes.
ITAM-Syk signaling mediates the rebound phenomenon after anti-RANKL antibody discontinuation.
Ishizu H, Hasegawa T, Shimizu T … +4 more , Yamamoto T, Asano T, Iwasaki N, Amizuka N
Bone · 2026 Apr · PMID 41490759 · Publisher ↗
Rebound bone loss following discontinuation of antiresorptive therapy, especially denosumab, represents a major clinical issue due to rapid osteoclast activation and increased fracture risk. However, the molecular basis...
Rebound bone loss following discontinuation of antiresorptive therapy, especially denosumab, represents a major clinical issue due to rapid osteoclast activation and increased fracture risk. However, the molecular basis of this phenomenon remains poorly understood. In this study, we investigated the role of the DAP12/TREM2-Syk signaling pathway in rebound-associated bone resorption using a murine model treated with and withdrawn from a RANKL-neutralizing antibody. Wild-type (WT) mice exhibited marked rebound bone loss, with elevated expression of DAP12/TREM2-related genes (Tyrobp and Trem2), increased infiltration of CD206 M2 macrophages, and enhanced osteoclast formation. In contrast, DAP12/DAP10 double-knockout (DKO) mice showed diminished osteoclast activity, reduced M2 macrophage presence, and preserved bone mass, indicating the essential role of this signaling axis. Furthermore, pharmacological inhibition of Syk in WT mice effectively prevented rebound bone loss without disturbing normal bone turnover. Histological and ultrastructural analyses revealed hyperactive osteoclasts with enlarged ruffled borders in WT but not in DKO mice. These results identify the DAP12/TREM2-Syk pathway as a key regulator of pathological osteoclast activation after anti-RANKL therapy withdrawal, suggesting that its inhibition may provide a novel therapeutic approach to prevent rebound bone loss while maintaining physiological bone remodeling.
Hyperbaric oxygen therapy for osteoporosis: A systematic review of preclinical evidence and mechanisms.
Wang H, Ma X, Sun Y … +3 more , Guo Z, Wang J, Sun M
Bone · 2026 Apr · PMID 41483655 · Publisher ↗
Hyperbaric oxygen therapy (HBOT) has been proposed as a direct anti-osteoporotic intervention rather than solely an adjunctive therapy. We systematically synthesized preclinical in vivo evidence and underlying mechanisms...
Hyperbaric oxygen therapy (HBOT) has been proposed as a direct anti-osteoporotic intervention rather than solely an adjunctive therapy. We systematically synthesized preclinical in vivo evidence and underlying mechanisms following PRISMA, with prospective registration (PROSPERO CRD42024525038), by searching PubMed, Embase, Cochrane Library, and Web of Science to November 2025. Of 3281 records, six studies (2016-2025) met inclusion across ovariectomy, hindlimb unloading, spinal cord transection, and D-galactose-induced aging models in Wistar and Sprague-Dawley rats. HBOT protocols most used 2.0-2.2 atm absolute with 85-100 % oxygen for 40-60 min per session. Across studies, HBOT improved bone mineral density and trabecular microarchitecture (e.g., BV/TV, Tb.Th, Tb.N), enhanced biomechanical strength, increased formation markers (e.g., procollagen type I N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin), and reduced resorption markers (e.g., C-terminal telopeptide of type I collagen, tartrate-resistant acid phosphatase-5b). Mechanistic signals converged on remodeling and vascular-metabolic pathways: modulation of the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis; restoration of Wnt/β-catenin signaling with reduced sclerostin; attenuation of oxidative and inflammatory stress (e.g., tumor necrosis factor-α); pro-angiogenic support (vascular endothelial growth factor, basic fibroblast growth factor); and neuropeptide-related effects (calcitonin gene-related peptide). Risk-of-bias profiles were mixed and heterogeneity precluded meta-analysis. Collectively, preclinical data indicate that HBOT mitigates osteoporotic bone loss primarily through coordinated, mechanisms of action that rebalance bone remodeling and improve the osteovascular milieu, while underscoring the need for standardized dosing parameters and rigorously designed human studies powered for clinically meaningful endpoints.
Temporal transcriptomic profiling of bone autograft healing reveals dynamic immune, vascular, and osteogenic programs.
Mereness JA, Basu S, Benoodt L … +1 more , Benoit DSW
Bone · 2026 Apr · PMID 41478392 · Full text
Bone autograft healing is a highly orchestrated process that integrates immune activation, vascular ingrowth, and osteogenic remodeling. To define the molecular and cellular programs driving early autograft integration,...
Bone autograft healing is a highly orchestrated process that integrates immune activation, vascular ingrowth, and osteogenic remodeling. To define the molecular and cellular programs driving early autograft integration, bulk and single-cell RNA sequencing was used to analyze graft-associated tissues over 14 days in a murine periosteal-mediated autograft model. Global transcriptomic analysis revealed rapid and dynamic remodeling, with maximal gene expression changes occurring within the first week. The first 48 h were dominated by pro-inflammatory signaling, including TNF, IL-1, TLR, and MAPK pathways, accompanied by transcriptional signatures of phagocytosis and cellular clearance. These early inflammatory programs gave way to pro-regenerative signals, including activation of HIF-1, PI3K-AKT, Wnt, and BMP pathways, coincident with angiogenesis, osteogenesis, and matrix deposition. By day 14, extracellular matrix production and remodeling predominated, marked by metalloproteinase activity and structural matrix gene enrichment. Single-cell RNA sequencing revealed that donor-derived (eGFP) graft cells were rare and transient, whereas host-derived immune cells were progressively replaced by myofibroblasts, endothelial cells, and neurogenic cell types, including GABAergic neurons and IGSF21 dendritic cells, suggesting active neurovascular crosstalk during healing. Together, these data define a temporal immune-to-regenerative cascade in bone autograft repair and highlight candidate cellular and molecular targets to enhance graft performance.
o-Vanillin enhances bone health and fracture healing by inhibiting cellular senescence in aging mice.
Ouyang X, Geng S, Abdullah M … +24 more , Geng Y, Heng K, Sha L, Geng Y, Nie P, Liu F, Zhai J, Song X, Zhai H, Huang J, Wang G, Geng R, Xue K, Wang Q, Huang W, Zhang H, Geng Y, Lan J, Hu H, Liu Y, Suo S, Guo Y, Li J, Geng Q
Bone · 2026 Apr · PMID 41478391 · Publisher ↗
Aging is associated with skeletal fragility driven by impaired bone remodeling, increased oxidative stress, and the accumulation of senescent cells. To determine whether ortho-vanillin (o-Vanillin) can alleviate age-rela...
Aging is associated with skeletal fragility driven by impaired bone remodeling, increased oxidative stress, and the accumulation of senescent cells. To determine whether ortho-vanillin (o-Vanillin) can alleviate age-related deficits in bone, we examined femoral bone microarchitecture, biomechanical properties, bone turnover, bone marrow adiposity, oxidative stress, DNA damage, osteocyte senescence, and femoral fracture healing in C57BL/6 J mice. DEXA was additionally used to assess bone mineral density and content at the femur, tibia, spine, and whole body. Aged mice displayed substantial deterioration in femoral trabecular and cortical structure, reduced mechanical strength, diminished osteogenic activity, enhanced osteoclastogenesis, and increased marrow adiposity. Aging also elevated oxidative stress, lipid peroxidation, and DNA damage, and induced significant osteocyte senescence with upregulation of SASP factors. o-Vanillin administration attenuated these changes, improving femoral bone microarchitecture and strength, restoring osteoblast function, suppressing osteoclast activity and adipogenesis, reducing oxidative stress and γH2AX accumulation, and decreasing osteocyte senescence and SASP expression. In a mid-diaphyseal femoral fracture model, aged mice exhibited impaired callus formation and delayed healing, whereas o-Vanillin partially improved early cartilage formation, osteoblast activity, and mechanical strength of the healing callus. These findings demonstrate that o-Vanillin mitigates multiple age-related impairments in the femur and partially restores fracture healing capacity, supporting its potential as a senescence-targeting approach to improve skeletal health during aging.
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