Pub Date : 2026-01-22DOI: 10.1016/j.bone.2026.117804
Fernanda Perin Maia Starck , Barbara C. Silva , Victória Zeghbi Cochenski Borba
Purpose
To evaluate the impact of soft-tissue thickness correction on trabecular bone score (TBS) in obese women across different BMI categories, comparing software versions 3.0 and 4.0, and to examine their associations with bone mineral density (BMD), fracture occurrence, and clinical variables.
Methods
This cross-sectional study included 247 obese women (BMI ≥30 kg/m2) who underwent lumbar spine densitometry with TBS assessment using versions 3.0 and 4.0 of the TBS iNsight® software. Demographic, anthropometric, and BMD data were analyzed. Correlations and multivariate linear regression models were used to assess associations between TBS 4.0, BMD, fractures, and clinical parameters.
Results
TBS 4.0 were lower than TBS 3.0 across all BMI categories (p < 0.001), with the largest reductions observed in women with BMI ≥ 37 kg/m2. Classification of TBS changed in 34% of cases when using version 4.0, with a greater proportion reclassified to degraded categories. TBS 4.0 showed a positive correlation with lumbar spine BMD (r = 0.51, p < 0.001) and BMI (r = 0.17, p = 0.007), but showed no significant correlation with abdominal wall thickness (r = −0.08, p = 0.229). The correlation between TBS and BMI was stronger for version 3.0 than for version 4.0 (r = 0.32 vs. r = 0.17, respectively). In multivariate analysis, abdominal wall thickness emerged as an independent predictor of TBS 4.0. A multivariate regression model including TBS 3.0, age, L1–L4 BMD, and abdominal wall thickness explained 86% of the variability in TBS 4.0, enabling estimation of TBS 4.0 from clinical variables and the earlier software version. Women with fractures showed lower TBS values, though not significant.
Conclusions
The TBS 4.0, by incorporating automatic correction for soft-tissue thickness, provides lower values that possibly better characterize trabecular microarchitecture in individuals with obesity, especially in those with higher BMIs, and mitigates the bias attributable to differences in body composition observed with previous versions of the TBS software.
{"title":"Impact of abdominal adiposity correction on trabecular bone score (TBS) in obese women: A comparative study of software versions 3.0 and 4.0 with a predictive model","authors":"Fernanda Perin Maia Starck , Barbara C. Silva , Victória Zeghbi Cochenski Borba","doi":"10.1016/j.bone.2026.117804","DOIUrl":"10.1016/j.bone.2026.117804","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the impact of soft-tissue thickness correction on trabecular bone score (TBS) in obese women across different BMI categories, comparing software versions 3.0 and 4.0, and to examine their associations with bone mineral density (BMD), fracture occurrence, and clinical variables.</div></div><div><h3>Methods</h3><div>This cross-sectional study included 247 obese women (BMI ≥30 kg/m<sup>2</sup>) who underwent lumbar spine densitometry with TBS assessment using versions 3.0 and 4.0 of the TBS iNsight® software. Demographic, anthropometric, and BMD data were analyzed. Correlations and multivariate linear regression models were used to assess associations between TBS 4.0, BMD, fractures, and clinical parameters.</div></div><div><h3>Results</h3><div>TBS 4.0 were lower than TBS 3.0 across all BMI categories (<em>p</em> < 0.001), with the largest reductions observed in women with BMI ≥ 37 kg/m<sup>2</sup>. Classification of TBS changed in 34% of cases when using version 4.0, with a greater proportion reclassified to degraded categories. TBS 4.0 showed a positive correlation with lumbar spine BMD (<em>r</em> = 0.51, <em>p</em> < 0.001) and BMI (<em>r</em> = 0.17, <em>p</em> = 0.007), but showed no significant correlation with abdominal wall thickness (<em>r</em> = −0.08, <em>p</em> = 0.229). The correlation between TBS and BMI was stronger for version 3.0 than for version 4.0 (<em>r</em> = 0.32 vs. <em>r</em> = 0.17, respectively). In multivariate analysis, abdominal wall thickness emerged as an independent predictor of TBS 4.0. A multivariate regression model including TBS 3.0, age, L1–L4 BMD, and abdominal wall thickness explained 86% of the variability in TBS 4.0, enabling estimation of TBS 4.0 from clinical variables and the earlier software version. Women with fractures showed lower TBS values, though not significant.</div></div><div><h3>Conclusions</h3><div>The TBS 4.0, by incorporating automatic correction for soft-tissue thickness, provides lower values that possibly better characterize trabecular microarchitecture in individuals with obesity, especially in those with higher BMIs, and mitigates the bias attributable to differences in body composition observed with previous versions of the TBS software.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117804"},"PeriodicalIF":3.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.bone.2026.117803
Jingrui Hu , Junning Chen , Steve Wells , Karen Knapp
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-BaSO4), 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.
{"title":"Development of a novel anthropomorphic bone phantoms for mimicking osteoporosis in medical imaging development","authors":"Jingrui Hu , Junning Chen , Steve Wells , Karen Knapp","doi":"10.1016/j.bone.2026.117803","DOIUrl":"10.1016/j.bone.2026.117803","url":null,"abstract":"<div><div>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<sub>4</sub>), 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.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117803"},"PeriodicalIF":3.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.bone.2026.117802
Yuanpeng Zhu , Di Liu , Xiangjie Yin , Terry Jianguo Zhang , Nan Wu
Purpose
Redox signaling governs bone remodeling, but whether systemic redox balance is associated with incident osteoporosis, genetic susceptibility, and proteomic/inflammatory pathways at population scale remains unclear.
Methods
We analyzed UK Biobank participants free of osteoporosis at baseline. Serum redox balance score (SRBS) combined albumin, total bilirubin, and γ-glutamyl transferase. Cox proportional hazards models adjusted for prespecified covariates. Effect modification by an osteoporosis polygenic risk score (PRS) was tested on multiplicative and additive scales. Mediation was evaluated in a proteomics subset and an inflammatory-panel subset using counterfactual mediation with multiple-testing control.
Results
Over a median follow-up of 12.8 years (IQR, 11.7–13.7), 12,893 incident osteoporosis cases were observed. SRBS demonstrated a nonlinear inverse association with osteoporosis, displaying a J-shaped pattern: relative to Q1, multivariable hazard ratios (95% CIs) were 0.82 (0.78–0.86) for Q2, 0.75 (0.71–0.78) for Q3, and 0.72 (0.68–0.75) for Q4; the per–standard-deviation increase corresponded to an HR of 0.85 (0.83–0.87). Cumulative-incidence curves diverged early and showed a stepwise gradient across quartiles. Associations were stronger among men and physically inactive participants. SRBS interacted with the osteoporosis PRS on the multiplicative scale (interaction HR, 1.03; 95% CI, 1.02–1.04), whereas evidence for additive interaction was limited. Proteomic mediation implicated EGFR, TNFRSF10A, CBLN4, CD27, and IGDCC4 (≈8–11% each); inflammatory mediation implicated C-reactive protein (≈8%), platelets (≈4%), and neutrophils (≈4%).
Conclusion
Systemic redox balance values were linked to osteoporosis risk, with partial mediation through plasma-protein and inflammatory pathways and only modest modification by polygenic risk.
{"title":"Association between systemic redox balance and osteoporosis: prospective evidence, polygenic modification, and proteomic and inflammatory mediation in the UK Biobank","authors":"Yuanpeng Zhu , Di Liu , Xiangjie Yin , Terry Jianguo Zhang , Nan Wu","doi":"10.1016/j.bone.2026.117802","DOIUrl":"10.1016/j.bone.2026.117802","url":null,"abstract":"<div><h3>Purpose</h3><div>Redox signaling governs bone remodeling, but whether systemic redox balance is associated with incident osteoporosis, genetic susceptibility, and proteomic/inflammatory pathways at population scale remains unclear.</div></div><div><h3>Methods</h3><div>We analyzed UK Biobank participants free of osteoporosis at baseline. Serum redox balance score (SRBS) combined albumin, total bilirubin, and γ-glutamyl transferase. Cox proportional hazards models adjusted for prespecified covariates. Effect modification by an osteoporosis polygenic risk score (PRS) was tested on multiplicative and additive scales. Mediation was evaluated in a proteomics subset and an inflammatory-panel subset using counterfactual mediation with multiple-testing control.</div></div><div><h3>Results</h3><div>Over a median follow-up of 12.8 years (IQR, 11.7–13.7), 12,893 incident osteoporosis cases were observed. SRBS demonstrated a nonlinear inverse association with osteoporosis, displaying a J-shaped pattern: relative to Q1, multivariable hazard ratios (95% CIs) were 0.82 (0.78–0.86) for Q2, 0.75 (0.71–0.78) for Q3, and 0.72 (0.68–0.75) for Q4; the per–standard-deviation increase corresponded to an HR of 0.85 (0.83–0.87). Cumulative-incidence curves diverged early and showed a stepwise gradient across quartiles. Associations were stronger among men and physically inactive participants. SRBS interacted with the osteoporosis PRS on the multiplicative scale (interaction HR, 1.03; 95% CI, 1.02–1.04), whereas evidence for additive interaction was limited. Proteomic mediation implicated EGFR, TNFRSF10A, CBLN4, CD27, and IGDCC4 (≈8–11% each); inflammatory mediation implicated C-reactive protein (≈8%), platelets (≈4%), and neutrophils (≈4%).</div></div><div><h3>Conclusion</h3><div>Systemic redox balance values were linked to osteoporosis risk, with partial mediation through plasma-protein and inflammatory pathways and only modest modification by polygenic risk.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117802"},"PeriodicalIF":3.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.bone.2026.117801
Gabriele Ricciardi , Domenico Donadio , Giovanni Ficarra , Chiara Nasso , Pietro Foglia , Alessandra Bitto , Rosa Scarfì , Guido Fadda , Flavio Corpina , Erica Cutè , Maurizio Martini , Marco Ferlazzo
Total joint replacement is one of the most successful interventions in modern orthopedics, but long-term outcomes depend on effective osseointegration. Pharmacological strategies such as bisphosphonates, estrogens, and monoclonal antibodies can enhance bone–implant integration, but their clinical use is limited by adverse effects. Nutraceuticals, including polyphenols, carotenoids, and polyunsaturated fatty acids, have emerged as promising adjuncts to support bone health and osseointegration, thanks to their safety profile and biological activity. This review summarizes the molecular mechanisms involved in osseointegration, analyzes preclinical and clinical evidence on nutraceuticals, and critically assesses their translational potential. These compounds promote osteoblastogenesis, inhibit osteoclast differentiation, and mitigate oxidative stress, thereby improving peri-implant bone stability. Despite encouraging results, the clinical translation of nutraceuticals remains limited. Most available data are preclinical or based on surrogate endpoints such as bone mineral density, whereas true clinical success is determined by bone-to-implant contact and implant survival, which are rarely investigated in randomized controlled trials (RCTs). Advances in bioavailability strategies (liposomes, nanoemulsions, nanostructured lipid carriers) may improve systemic exposure, but future research must standardize dosages and provide high-quality RCTs to clarify the role of nutraceuticals as complementary tools in orthopedic implant surgery.
{"title":"Nutraceuticals in orthopedic implant osseointegration: Mechanisms, evidence, and clinical perspectives","authors":"Gabriele Ricciardi , Domenico Donadio , Giovanni Ficarra , Chiara Nasso , Pietro Foglia , Alessandra Bitto , Rosa Scarfì , Guido Fadda , Flavio Corpina , Erica Cutè , Maurizio Martini , Marco Ferlazzo","doi":"10.1016/j.bone.2026.117801","DOIUrl":"10.1016/j.bone.2026.117801","url":null,"abstract":"<div><div>Total joint replacement is one of the most successful interventions in modern orthopedics, but long-term outcomes depend on effective osseointegration. Pharmacological strategies such as bisphosphonates, estrogens, and monoclonal antibodies can enhance bone–implant integration, but their clinical use is limited by adverse effects. Nutraceuticals, including polyphenols, carotenoids, and polyunsaturated fatty acids, have emerged as promising adjuncts to support bone health and osseointegration, thanks to their safety profile and biological activity. This review summarizes the molecular mechanisms involved in osseointegration, analyzes preclinical and clinical evidence on nutraceuticals, and critically assesses their translational potential. These compounds promote osteoblastogenesis, inhibit osteoclast differentiation, and mitigate oxidative stress, thereby improving peri-implant bone stability. Despite encouraging results, the clinical translation of nutraceuticals remains limited. Most available data are preclinical or based on surrogate endpoints such as bone mineral density, whereas true clinical success is determined by bone-to-implant contact and implant survival, which are rarely investigated in randomized controlled trials (RCTs). Advances in bioavailability strategies (liposomes, nanoemulsions, nanostructured lipid carriers) may improve systemic exposure, but future research must standardize dosages and provide high-quality RCTs to clarify the role of nutraceuticals as complementary tools in orthopedic implant surgery.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117801"},"PeriodicalIF":3.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bone.2026.117800
Runkang Chen , Bowen Wang , Samuel J. Stephen , Joseph P. Bidwell , Deepak Vashishth
<div><div>Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH <span><span>[1]</span></span>, <span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>, <span><span>[5]</span></span>, <span><span>[6]</span></span>, <span><span>[7]</span></span>, <span><span>[8]</span></span>, <span><span>[9]</span></span>, <span><span>[10]</span></span>, <span><span>[11]</span></span>, <span><span>[12]</span></span>, <span><span>[13]</span></span>, <span><span>[14]</span></span>, <span><span>[15]</span></span>, <span><span>[16]</span></span>, <span><span>[17]</span></span>, <span><span>[18]</span></span>, <span><span>[19]</span></span>, <span><span>[20]</span></span>, <span><span>[21]</span></span>, <span><span>[22]</span></span>, <span><span>[23]</span></span>, <span><span>[24]</span></span>, <span><span>[25]</span></span>, <span><span>[26]</span></span>, <span><span>[27]</span></span>, <span><span>[28]</span></span>, <span><span>[29]</span></span>, <span><span>[30]</span></span>, <span><span>[31]</span></span>, <span><span>[32]</span></span>, <span><span>[33]</span></span>, <span><span>[34]</span></span>, 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 (<em>Nmp4</em>), in which PTH treatment of mice globally lacking <em>Nmp4</em> (<em>Nmp4</em><sup><em>−/−</em></sup>) enhanced bone formation. Yet, the changes in the compositional quality of PTH-stimulated bone in <em>Nmp4</em><sup><em>−/−</em></sup> mice are unknown, which in turn could impact the efficiency of this approach. To this end, we characterized cortical bone quality in <em>Nmp4</em><sup><em>−/−</em></sup> 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 <em>Nmp4</em> 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 <em>Nmp4</em><sup><em>−/−</em></sup> 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 <em>Nmp4,</em> in concert with PTH treatment, improved bone function by modulating bone structure and matrix composition. Our findings demonstrate the potential utility of targeting <em>Nmp4</em> to improve PTH potency and bone qual
{"title":"Improvements in bone quality by parathyroid hormone treatment are enhanced in the Nmp4 knockout mouse model","authors":"Runkang Chen , Bowen Wang , Samuel J. Stephen , Joseph P. Bidwell , Deepak Vashishth","doi":"10.1016/j.bone.2026.117800","DOIUrl":"10.1016/j.bone.2026.117800","url":null,"abstract":"<div><div>Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH <span><span>[1]</span></span>, <span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>, <span><span>[5]</span></span>, <span><span>[6]</span></span>, <span><span>[7]</span></span>, <span><span>[8]</span></span>, <span><span>[9]</span></span>, <span><span>[10]</span></span>, <span><span>[11]</span></span>, <span><span>[12]</span></span>, <span><span>[13]</span></span>, <span><span>[14]</span></span>, <span><span>[15]</span></span>, <span><span>[16]</span></span>, <span><span>[17]</span></span>, <span><span>[18]</span></span>, <span><span>[19]</span></span>, <span><span>[20]</span></span>, <span><span>[21]</span></span>, <span><span>[22]</span></span>, <span><span>[23]</span></span>, <span><span>[24]</span></span>, <span><span>[25]</span></span>, <span><span>[26]</span></span>, <span><span>[27]</span></span>, <span><span>[28]</span></span>, <span><span>[29]</span></span>, <span><span>[30]</span></span>, <span><span>[31]</span></span>, <span><span>[32]</span></span>, <span><span>[33]</span></span>, <span><span>[34]</span></span>, 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 (<em>Nmp4</em>), in which PTH treatment of mice globally lacking <em>Nmp4</em> (<em>Nmp4</em><sup><em>−/−</em></sup>) enhanced bone formation. Yet, the changes in the compositional quality of PTH-stimulated bone in <em>Nmp4</em><sup><em>−/−</em></sup> mice are unknown, which in turn could impact the efficiency of this approach. To this end, we characterized cortical bone quality in <em>Nmp4</em><sup><em>−/−</em></sup> 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 <em>Nmp4</em> 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 <em>Nmp4</em><sup><em>−/−</em></sup> 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 <em>Nmp4,</em> in concert with PTH treatment, improved bone function by modulating bone structure and matrix composition. Our findings demonstrate the potential utility of targeting <em>Nmp4</em> to improve PTH potency and bone qual","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117800"},"PeriodicalIF":3.6,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-18DOI: 10.1016/j.bone.2026.117799
Dimitra Micha , Sandra Escalante Quirós , Elisabeth Marelise W. Eekhoff , Vivi M. Heine , Jae-Hyuck Shim , Lidiia Zhytnik
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.
{"title":"Modeling rare genetic skeletal disorders with bone organoids: a narrative review","authors":"Dimitra Micha , Sandra Escalante Quirós , Elisabeth Marelise W. Eekhoff , Vivi M. Heine , Jae-Hyuck Shim , Lidiia Zhytnik","doi":"10.1016/j.bone.2026.117799","DOIUrl":"10.1016/j.bone.2026.117799","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117799"},"PeriodicalIF":3.6,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Clec4a2 deficiency promotes post-fission osteoclast cell death and suppresses acute inflammation-induced bone loss in the mouse","authors":"Hirofumi Fujita , Yuma Tai , Kenji Takahashi , Yuto Ueda , Wakana Kitagawa , Mitsuaki Ono , Toshitaka Oohashi , Hideyo Ohuchi","doi":"10.1016/j.bone.2026.117797","DOIUrl":"10.1016/j.bone.2026.117797","url":null,"abstract":"<div><div>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 <em>Clec4a2</em> and <em>Clec4d</em> using a multi-targeted CRISPR-Cas9 system. <em>Clec4a2</em> KO <em>and</em> DKO enhanced osteoclast differentiation in vitro, and <em>Clec4a2</em> KO also stimulated enlargement of osteoclasts. <em>Clec4d</em> KO slightly reduced trabecular bone thickness in the femur, while <em>Clec4a2</em> 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 <em>Clec4a2</em> KO paradoxically increased osteoclast formation while reducing resorption efficiency due to cell death of osteoclasts and its daughter cells after fission. <em>Clec4a2</em> 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.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117797"},"PeriodicalIF":3.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.bone.2026.117798
Xinluan Jiang , Bilan Li , Yunfei Ma , Jiaxin Huang , Chengwei Gu , Yucui Jin , Huimin Ding , Changyan Ma
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.
{"title":"Prmt1-mediated methylation of Ddx17 promotes osteoblast differentiation via regulating the alternative splicing of Sh2b1","authors":"Xinluan Jiang , Bilan Li , Yunfei Ma , Jiaxin Huang , Chengwei Gu , Yucui Jin , Huimin Ding , Changyan Ma","doi":"10.1016/j.bone.2026.117798","DOIUrl":"10.1016/j.bone.2026.117798","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117798"},"PeriodicalIF":3.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.bone.2026.117796
Maria Florez-Martin, Adriana-Monica Radu, Kaveh Shakib, Gavin Jell
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 M, significantly higher () than concentrations associated with no effect (1 M) or beneficial responses (0.75 M). 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 (). 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.
背景：唑来膦酸盐（ZOL）是一种有效的含氮双膦酸盐（BP），被广泛用于骨质疏松症和转移性骨病。虽然破骨细胞抑制对ZOL的治疗作用和药物相关性颌骨骨坏死（MRONJ）的病理生理至关重要，但对其对成骨细胞的直接影响知之甚少。了解剂量和时间依赖性成骨细胞反应对于改善体外建模和告知再生策略至关重要。方法：我们根据PRISMA指南（方案注册，DOI:10.17605/OSF.IO/GWDP5），对报告ZOL成骨细胞反应的体外研究进行了系统综述。Web of Science和Scopus检索确定了606条记录，其中77条符合纳入标准。提取细胞增殖、代谢活性、细胞凋亡、碱性磷酸酶（ALP）、生物矿化、胶原形成和血管生成的数据。统计比较评估了剂量依赖性和时间依赖性效应。结果：在2057个数据点中，中位[ZOL]为10 μM时出现不良结果（代谢活性或增殖降低，细胞凋亡增加），显著高于无效果（1 μM）或有益反应（0.75 μM）的浓度（p≤0.0001）。理想的纳摩尔剂量结果在研究中并不常见且不一致。ALP和生物矿化受到剂量依赖性损害，而胶原合成不受影响。在48-71 h时，成骨细胞对ZOL浓度的耐受高于其他时间点（p≤0.05）。培养基成分影响反应，高钙（≥1.8 mM）培养基保护负面效应，可能是由于ZOL-Ca复合物的形成。结论：ZOL对成骨细胞具有直接的、剂量依赖性的体外抑制作用，其效果受暴露时间和培养基组成的影响。这篇综述强调了标准化方案的必要性，并为MRONJ建模和再生干预测试提供了定量指导。
{"title":"Osteoblastic cell responses to zoledronate treatment in-vitro: A systematic review","authors":"Maria Florez-Martin, Adriana-Monica Radu, Kaveh Shakib, Gavin Jell","doi":"10.1016/j.bone.2026.117796","DOIUrl":"10.1016/j.bone.2026.117796","url":null,"abstract":"<div><h3>Background:</h3><div>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 <em>in-vitro</em> modelling and informing regenerative strategies.</div></div><div><h3>Methods:</h3><div>We performed a systematic review of <em>in-vitro</em> 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.</div></div><div><h3>Results:</h3><div>Across 2057 datapoints, undesirable outcomes (reduced metabolic activity or proliferation, increased apoptosis) occurred at median [ZOL] of 10 <span><math><mi>μ</mi></math></span>M, significantly higher (<span><math><mrow><mi>p</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>0001</mn></mrow></math></span>) than concentrations associated with no effect (1 <span><math><mi>μ</mi></math></span>M) or beneficial responses (0.75 <span><math><mi>μ</mi></math></span>M). 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 (<span><math><mrow><mi>p</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>05</mn></mrow></math></span>). Media composition influenced responses, with higher calcium (<span><math><mo>≥</mo></math></span>1.8 mM) media protective of negative effects, likely due to ZOL–Ca complex formation.</div></div><div><h3>Conclusion:</h3><div>ZOL exerts direct, dose-dependent inhibitory effects on osteoblasts <em>in-vitro</em>, 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.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117796"},"PeriodicalIF":3.6,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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