Bone [JOURNAL]
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200 papers
Erratum to "Porphyromonas gingivalis lipids enhance RANKL-mediated osteoclast formation" [Bone 207 (2026) 117852].
Zambrello MA, Sanjay A, Rahmlow A … +8 more , Chen L, Etoh N, Lamm E, Sobue T, Uddaraju K, Clark RB, Rowe DW, Nichols FC
Bone · 2026 Sep · PMID 42225463 · Publisher ↗
Abstract loading — click title to view on PubMed.
A longitudinal imaging study of the effects of type 2 diabetes and microvascular disease on diabetic bone disease.
Zhou M, Wu PH, Joseph GB … +7 more , Kolluri P, Yu I, Fan B, Schafer AL, Schwartz AV, Link TM, Kazakia GJ
Bone · 2026 Sep · PMID 42214803 · Publisher ↗
Skeletal fragility is a major complication of type 2 diabetes (T2D), occurring despite normal or elevated bone mineral density. However, pathophysiological mechanisms underlying diabetic bone disease remain poorly unders...
Skeletal fragility is a major complication of type 2 diabetes (T2D), occurring despite normal or elevated bone mineral density. However, pathophysiological mechanisms underlying diabetic bone disease remain poorly understood, partly due to the lack of longitudinal studies evaluating bone microarchitecture and function in T2D. Therefore, the current study employed an imaging-centered approach, applying high-resolution peripheral quantitative computed tomography and dynamic contrast-enhanced magnetic resonance imaging to assess changes in bone microarchitecture, biomechanics, and intracortical vessel microstructure and perfusion in 55 participants with or without T2D over 2 years. Both longitudinal and cross-sectional comparisons were conducted within and between groups. Interactions between T2D and microvascular disease (MVD), a common T2D comorbidity increasingly implicated in diabetic bone deterioration, were also examined for key cortical microarchitecture and intracortical vessel metrics. The findings suggested a trend toward greater longitudinal cortical deterioration in participants with T2D compared with controls, including a 3-fold greater loss in cortical bone mineral density and 6-fold greater increase in cortical porosity at the tibia. Significant longitudinal declines in intracortical vessel volume and perfusion were also observed in participants with T2D. No (T2D × MVD) interaction was observed for cortical microarchitecture or intracortical vessel metrics. Interestingly, significant decline in intracortical perfusion was associated with peripheral neuropathy, a common T2D sequela. In conclusion, this is the first longitudinal study capturing bone quality alterations with T2D in both men and women, highlighting adverse changes in cortical microarchitecture and intracortical vasculature. Peripheral neuropathy may represent a clinically relevant factor for managing diabetic skeletal fragility.
Callus geometry as a reflection of fracture healing biology and a candidate imaging biomarker: A systematic review of biological, mechanical, and clinical evidence.
Razavi AH, Mirahmadi A, Jelalian A … +3 more , Vician M, Rodriguez EK, Nazarian A
Bone · 2026 May · PMID 42208753 · Publisher ↗
Fracture healing is a complex, multiscale process governed by the interaction between biological activity and mechanical environment, and fracture callus geometry represents an integrated manifestation of these processes...
Fracture healing is a complex, multiscale process governed by the interaction between biological activity and mechanical environment, and fracture callus geometry represents an integrated manifestation of these processes. Although callus morphology is routinely assessed during healing, its value as an objective and predictive marker of mechanical competence and clinical outcome has not been systematically established. This review synthesizes current experimental and clinical evidence to clarify the determinants of callus geometry and to evaluate its potential as an early indicator of fracture healing. A systematic review was conducted in accordance with the PRISMA guidelines, using major databases to identify preclinical and clinical studies reporting qualitative or quantitative measures of fracture callus geometry. Eligible studies examined biological, mechanical, systemic, or pharmacologic influences on callus formation, or assessed associations between callus morphology and biomechanical strength or clinical healing outcomes. Extracted data included study design, fracture model, imaging modality, geometric parameters, and functional endpoints. Given substantial heterogeneity in models, measurement techniques, and assessment timing, findings were synthesized narratively. Forty-eight studies met the inclusion criteria. Across species and fracture models, callus geometry consistently reflected the underlying healing environment. Angiogenic and osteoanabolic interventions, including deferoxamine, platelet-rich plasma, and sclerostin inhibition, were associated with larger, more mineralized, or better-organized calluses, highlighting the importance of vascular and osteoblastic signaling. In contrast, chronic PTH or PTHrP stimulation often produced smaller yet structurally organized calluses, underscoring the need to interpret geometric measures within a biological context. Advanced imaging studies demonstrated strong associations between microarchitectural features and mechanical strength, while automated and CT-based methods improved reproducibility and translational feasibility. Non-modifiable factors such as metabolic disease, systemic inflammation, and traumatic brain injury also produced characteristic alterations in callus morphology. Overall, callus geometry emerges as a biologically meaningful and mechanically informative marker of fracture repair. Standardized, quantitative assessment of callus geometry shows promise as a candidate imaging biomarker of healing trajectory and warrants prospective clinical validation before a prognostic role can be established.
DPP3 deficiency impacts bone quality and sensitizes to metabolic alterations.
Bevacqua E, Granata V, Panetta D … +14 more , Longo E, Prašek M, Sanchez PJ, Violi F, Giacchi L, Bertola L, Tromba G, Santillo M, Rucci N, Recordati C, Mazziotti G, Morenghi E, Menale C, Sobacchi C
Bone · 2026 Sep · PMID 42208752 · Publisher ↗
The goal of this study was to evaluate whether the dipeptidyl peptidase 3 (DPP3), recently recognized as a key molecule in bone pathophysiology and proposed as a biomarker of bone health status, plays a role in skeletal...
The goal of this study was to evaluate whether the dipeptidyl peptidase 3 (DPP3), recently recognized as a key molecule in bone pathophysiology and proposed as a biomarker of bone health status, plays a role in skeletal and systemic alterations induced by common unbalanced nutritional conditions. We focused on nutrient excess, and in particular on excessive intake of calories from fat, which is known to predispose to osteoporosis, among other complications. Based on the known sex differences in metabolic processes, we considered the impact of this variable, too, in our experimental setting. In detail, we fed young adult male and female C57BL/6J wild-type (WT) and Dpp3 knock-out (Dpp3 ko) mice with 45% kcal fat Western diet for 14 weeks. We assessed DPP3 concentration and enzymatic activity in the serum of WT mice, and performed microstructural (trabecular and cortical), biomechanical (damage resistance and elastic deformation), and histological analysis of bone, and serological analysis of glucose metabolism and inflammatory markers. We found that DPP3 concentration/activity ratio strongly depended on sex and diet (both alone and in combination), and that metabolic response to high fat diet, bone microstructural changes particularly affecting the trabecular compartment and resulting in different biomechanical properties, and changes in bone turnover markers in the peripheral blood were moderately different as a function of the genotype. Of note, DPP3 protein levels in the serum correlated with clinically relevant parameters, including insulin, bone volume/total volume ratio, and serum tartrate-resistant acid phosphatase. This work agrees with a possible role for DPP3 as a biomarker of bone health in relation to diet and justifies studies in the context of other preclinical models of malnutrition, as well as in cohorts of patients.
Association of blood pressure variability with bone mineral density and incident hip fracture: the Cardiovascular Health Study.
Rodriguez AJ, Buzkova P, Mukamal KJ … +2 more , Chen Z, Fink HA
Bone · 2026 Sep · PMID 42208751 · Publisher ↗
BACKGROUND: Blood pressure (BP), autonomic function and atherosclerosis are associated with adverse bone-related outcomes. These entities may affect blood pressure variability (BPV). The few studies that have directly in...
BACKGROUND: Blood pressure (BP), autonomic function and atherosclerosis are associated with adverse bone-related outcomes. These entities may affect blood pressure variability (BPV). The few studies that have directly investigated the association of BPV with hip fracture or bone mineral density (BMD) were limited to Asian populations and reported few BPV measures. METHODS: Individuals with BP measurements at ≥4 of the 6 Cardiovascular Health Study (CHS), a large, prospective, observational cohort, visits between 1989 and 90 and 1994-95 and who attended the 1994-95 visit were included. Systolic (SBP), diastolic (DBP) and pulse pressure (PP) variability were estimated as: between-visit mean, between-visit slope (linear trajectory over time) and between-visit standard deviation (SD) of the observed residuals (departure from linear trajectory). Incident hip fractures between 1994 and 95 and 2015 were recorded. The association of BPV with hip fracture was estimated with Cox models (95% confidence intervals, CI). Primary analyses were conducted in individuals not using BP-lowering medications at baseline. Secondary analyses were conducted in those with stable use of BP-lowering medications during look back. Total hip BMD was measured at the 1994-95 study visit in a subset of individuals and analysed for cross-sectional associations with BPV. RESULTS: Among 1820 individuals not using BP-lowering medications at baseline (60% women; age 76 ± 5 years), 292 incident hip fractures (222 women, 70 men) occurred. After multivariable adjustment, a one SD increase (3.12 mmHg) in DBP residual was associated with an 8.9% increased relative risk (95%CI, 0.4% to 18.2%) in men only. No other BPV measures were associated with hip fractures in men or women. No BPV measure was associated with BMD. Among 1958 individuals with stable BP medication use, 297 incident hip fractures (229 women, 68 men) occurred. In this group, no BPV measure was associated with incident hip fracture or BMD. CONCLUSION: We found no consistent association of BPV with BMD or hip fracture, which did not validate results from prior studies. Low BPV in this cohort may have limited our ability to identify associations with adverse skeletal outcomes but also may reflect limited clinical importance of BPV for bone.
Osteoporotic fractures prevalence in Latin American countries: A systematic review of literature and meta-analysis.
Parra-Gómez LA, Lora-Mantilla AJ, Ayala MC … +4 more , Amaya MC, Rodríguez JM, Hernández-Quiñonez D, Camacho López PA
Bone · 2026 Sep · PMID 42173420 · Publisher ↗
BACKGROUND: Osteoporotic fractures (OF), or fragility fractures, are a major cause of morbidity, mortality, and healthcare utilization worldwide. While their burden is well described in high-income countries, data in Lat...
BACKGROUND: Osteoporotic fractures (OF), or fragility fractures, are a major cause of morbidity, mortality, and healthcare utilization worldwide. While their burden is well described in high-income countries, data in Latin America remain fragmented and poorly synthesized. OBJECTIVE: To systematically review and synthesize available evidence on the prevalence of OF among adults in Latin America. METHODS: We conducted a systematic review and meta-analysis of observational studies, following JBI methodology and PRISMA 2020 guidelines. MEDLINE, Scopus, Virtual Health Library, and Google Scholar were searched up to January 8, 2025. Random-effects meta-analysis with restricted maximum likelihood estimation and Hartung-Knapp adjustment was used. Subgroup and sensitivity analyses were conducted according to population type, fracture ascertainment method, age group, sex, country, setting, and fracture type. Univariable meta-regression was used to explore sources of heterogeneity. Risk of bias was assessed using the JBI checklist. RESULTS: Twenty-two studies were included in the systematic review, and 16 contributed to the meta-analysis, comprising 1,182,219 participants and 47,954 osteoporotic fractures. The pooled prevalence of OF was 10.2% (95% CI 5.0-16.9%), with substantial heterogeneity (I = 100%). Prevalence varied significantly according to population type (p < 0.001), with higher estimates in clinical samples than in population-based studies, and by fracture type (p = 0.002), with vertebral fractures being the most frequent (19.1%). No overall sex differences were identified, although women had higher prevalence of vertebral and non-vertebral fractures after stratification. Meta-regression identified country and fracture type as significant contributors to heterogeneity. CONCLUSIONS: OF represent a substantial but highly heterogeneous health burden, and pooled prevalence estimates should be interpreted as indicative rather than precise estimates. Strengthening epidemiological surveillance and implementing early diagnosis and prevention strategies should be prioritized to address the growing impact of OF in the region.
Clinical and femoral radiological characteristics of South-East Asian osteoporosis patients with atypical femoral fractures: Case control study with matching of bisphosphonate exposure.
Gani LU, King TFJ, Choo KS … +2 more , Koh J, Chong LR
Bone · 2026 Sep · PMID 42173419 · Publisher ↗
BACKGROUND: Atypical femoral fractures (AFF) are stress fractures in the femur that may occur with prolonged exposure to anti-resorptive treatments. Asians have a disproportionately higher risk factor for AFF at 5-6 time...
BACKGROUND: Atypical femoral fractures (AFF) are stress fractures in the femur that may occur with prolonged exposure to anti-resorptive treatments. Asians have a disproportionately higher risk factor for AFF at 5-6 times that of Caucasian and Hispanic patients. It has been hypothesized that the Asian femora geometry may be a contributing factor in the pathogenesis of AFF. We conducted a case-control study with matching of bisphosphonate exposure to assess the role of femoral geometry and imaging in association with clinical risk factors in South-East Asian patients with AFF. METHODS: This is a single-site case-control study of clinical risk factors and femoral radiological characteristics in AFF patients, matched on bisphosphonate (BP) exposure. Subjects were recruited from Changi General Hospital fracture database as well as orthopaedic wards and endocrine clinics. They were matched by age, gender, and BP exposure duration. We analysed demographic, clinical, and biochemical variables. RESULTS: The 46 AFF cases and 46 controls recruited were well matched in clinical and demographic characteristics, as well as in the duration of exposure to BP (78.7 months in AFF cases and 70.7 months in controls). There were larger femoral offsets in AFF patients compared to controls (41.9 mm vs 36.3 mm, p = 0.0409). A subgroup analysis showed that lateral femoral bowing angles were more varus in shaft AFFs vs subtrochanteric AFFs (-6.53° vs -2.81°, p = 0.013), while the site of maximal femoral cortical thickness was situated more distally in shaft compared to subtrochanteric AFFs (0.432 vs 0.385, p = 0.023). Baseline and follow-up hip BMD for AFF cases were significantly higher in the total hip and femoral neck region compared to controls, there were similar rates of BMD improvements in both groups. CONCLUSION: In this study of clinical and femoral radiological characteristics of South-East Asian AFF cases and matched controls, there were significantly larger femoral offsets and higher BMD scores in the hip of AFF cases versus controls. Further studies are needed to better understand the role of femoral radiological and BMD characteristics in the development of AFF in individuals exposed to bisphosphonates.
Effects of transcutaneous CO application on fracture healing in a rat fracture model of disuse osteoporosis.
Kondo H, Fukui T, Sawauchi K … +6 more , Kumabe Y, Nishida R, Jonathan, Fukumoto G, Kuroda R, Oe K
Bone · 2026 Sep · PMID 42167504 · Publisher ↗
Transcutaneous carbon dioxide (CO) therapy has been shown to accelerate fracture healing and osteogenesis by enhancing endochondral ossification and angiogenesis. We aimed to investigate the effects of this therapy on fr...
Transcutaneous carbon dioxide (CO) therapy has been shown to accelerate fracture healing and osteogenesis by enhancing endochondral ossification and angiogenesis. We aimed to investigate the effects of this therapy on fracture healing in a rat hindlimb suspension model of disuse osteoporosis. Eleven-week-old male Sprague-Dawley rats were randomly assigned to three groups: 1) Control group (normal ambulation for 3 weeks, followed by femoral fracture with Kirschner-wire fixation); 2) Hindlimb suspension (HS) group (HS; 3 weeks of HS before fracture); 3) HS + CO group (same as HS, followed by transcutaneous CO therapy after fracture). HS was induced by tail suspension at a 30° head-down tilt to prevent hindlimb weight-bearing. Transcutaneous CO therapy involved applying a CO-permeable hydrogel and enclosing both hindlimbs in polyethylene bags filled with 100% CO for 20 min/day, 5 days/week. The HS + CO group showed significantly higher modified Radiographic Union Score for Tibial fractures than did the HS group at weeks 3 and 4, as well as a significantly higher radiographic union rate at week 4. They also showed significantly higher Allen's histological grading scores at week 3. Compared with the HS group, the CO-treated animals showed significantly higher expression levels of runt-related transcription factor 2 and Osterix at weeks 1 and 2, respectively. These findings suggested that transcutaneous CO therapy promoted osteogenic activation and accelerated radiological and histological fracture healing of disuse osteoporosis, supporting its potential as an adjunctive strategy for fragility fractures.
Parametric sensitivity of MRI-based vertebral bone quality scores: Impact of repetition time and echo time on diagnostic effect for osteoporosis.
Wang L, Zhang WX, Gao JY … +1 more , Huang AB
Bone · 2026 Sep · PMID 42167503 · Publisher ↗
PURPOSE: To evaluate the impact of repetition time (TR) and echo time (TE) on vertebral bone quality (VBQ) scores and their diagnostic performance for osteoporosis. METHODS: Patients aged ≥45 with lumbar degenerative dis...
PURPOSE: To evaluate the impact of repetition time (TR) and echo time (TE) on vertebral bone quality (VBQ) scores and their diagnostic performance for osteoporosis. METHODS: Patients aged ≥45 with lumbar degenerative diseases were enrolled. Relationships between VBQ scores, TR, TE, and T-scores were analyzed using linear regression and Pearson's correlation. Inter-group comparisons across varied MRI scanners and bone quality categories were performed. Diagnostic performance across 1.5 T scanners with distinct TR/TE parameters was evaluated via Receiver operating characteristic curves. RESULTS: This study included 168 eligible patients (50 osteoporosis; mean age: 63.74 ± 9.08; 113 females). Significant inter-scanner differences existed for TR, TE and VBQ scores (all p < 0.001). Notably, Philips utilized significantly shorter TR and TE than Siemens. VBQ scores correlated inversely with TR and TE (both p < 0.01). At 1.5 T, VBQ scores correlated more strongly with T-scores in Philips (r = -0.54) than in Siemens (r = -0.38) (both p < 0.001). For assessing osteoporosis, 1.5 T Philips outperformed Siemens (Area Under the Curves: 0.79 vs. 0.70). At their respective optimal cut-offs (3.87 vs. 3.17), 1.5 T Philips yielded 87% specificity and 60% sensitivity; 1.5 T Siemens showed 61% specificity and 81% sensitivity. CONCLUSION: This study confirmed that VBQ measurement is highly sensitive to acquisition parameters. Utilizing shorter TR and TE significantly optimizes VBQ measurements and enhance their diagnostic accuracy. Therefore, standardizing MRI parameters is vital to ensure consistent VBQ measurements across research and clinical settings.
A three-level model of diffuse idiopathic skeletal hyperostosis (DISH): Integrating susceptibility, activation, and clinical trajectories.
Pariente E, Martínez-Taboada VM, Hernández JL
Bone · 2026 Sep · PMID 42162602 · Publisher ↗
OBJECTIVE: Diffuse idiopathic skeletal hyperostosis (DISH) exhibits marked phenotypic heterogeneity. Despite similar cardiometabolic backgrounds, individuals may develop rapid axial ossification, limited progression, or...
OBJECTIVE: Diffuse idiopathic skeletal hyperostosis (DISH) exhibits marked phenotypic heterogeneity. Despite similar cardiometabolic backgrounds, individuals may develop rapid axial ossification, limited progression, or no structural disease. We aimed to identify longitudinal trajectories and to propose a hierarchical, three-level model integrating upstream-susceptibility, downstream-activation, and structural outcomes. METHODS: Longitudinal analysis within the Camargo Cohort (10-year follow-up), including clinical, metabolic, laboratory, and radiographic parameters (Schlapbach graded scale; AAC-24). Four trajectory definitions were established a priori. Analyses included Shapley-R decomposition, mixed-effects models, and Spearman correlations, stratified by sex. RESULTS: Of 502 participants, 302 (60.2%) were classified into trajectories: Fast Ossifier (FO, n = 61), Low-Load DISH (LLD, n = 148), Vascular-Dominant DISH (VDD, n = 48), and Persistent Non-DISH (PND, n = 45). Downstream activation index (DAI-5) increased across susceptibility tertiles (median [IQR]: 94.5 [86-103], 98.6 [90-106], 102.2 [93-113]; p = 0.0001). VDD showed the highest activation (median DAI-5 = 103). FO and VDD exhibited preserved associations between susceptibility and activation, whereas PND showed a flat or negative relationship, indicating upstream-downstream uncoupling despite maximal susceptibility. FO displayed efficient skeletal resolution with the greatest axial progression, while VDD combined high activation with predominant vascular involvement (AAC-24 = 12.07) and severe trabecular deterioration (TBS = 1.220). LLD showed fragmented coupling and minimal structural progression. Waist circumference was the most consistent determinant of structural outcomes across domains in mixed-effects models. CONCLUSIONS: DISH can be understood as a system-level process in which susceptibility, activation, and trajectory-specific coupling determine tissue-level resolution of a calcific impulse. This exploratory framework could explain phenotypic divergence and may support improved skeletal and cardiovascular risk stratification.
Corrigendum to "The C-type lectin receptor mincle is functionally expressed by murine bone cells and can mediate inflammatory osteoblast responses to Staphylococcus aureus" [Bone volume 203 February 2026, 117689].
Mills EL, Krueger QA, Noyal A … +2 more , Johnson MB, Marriott I
Bone · 2026 Sep · PMID 42151021 · Publisher ↗
Abstract loading — click title to view on PubMed.
The C-type lectin receptor mincle is functionally expressed by murine bone cells and can mediate inflammatory osteoblast responses to Staphylococcus aureus.
Mills EL, Krueger QA, Noyal A … +2 more , Johnson MB, Marriott I
Bone · 2026 Feb · PMID 42149719 · Full text
It is now apparent that osteoblasts and osteoclasts have immune functions that play a critical role in shaping host responses and the abnormal bone remodeling associated with staphylococcal infections. Both cell types ex...
It is now apparent that osteoblasts and osteoclasts have immune functions that play a critical role in shaping host responses and the abnormal bone remodeling associated with staphylococcal infections. Both cell types express various pattern recognition receptors (PRRs) that enable them to perceive pathogens and initiate the production of mediators that can exacerbate infection-induced inflammatory bone loss. Macrophage-inducible C-type lectin (Mincle) is a tyrosine activation motif-coupled PRR that can recognize glycolipids from diverse pathogens to initiate inflammatory mediator production. In the lung, an important role for Mincle has been suggested in host defense against Gram positive bacteria. In the present study, we report that RNA Tag-Seq analysis of S. aureus infected murine osteoclasts and osteoblasts revealed enrichment of genes associated with C-type lectin receptor-mediated responses and elevated expression of mRNA encoding Mincle and its key downstream signaling components. We have found robust levels of Mincle protein in murine osteoclasts and osteoblasts, and demonstrated the inducible expression of this molecule in primary human osteoblasts. The functional nature of Mincle expression by osteoclasts and osteoblasts was confirmed by the ability of Mincle-specific agonists to elicit inflammatory cytokine production by these cells. Importantly, we have shown that the cytokine responses of S. aureus challenged murine and human osteoblasts are attenuated following Mincle blockade. Together, these studies support the assertion that bone cells functionally express Mincle and that this C-type lectin can mediate, at least in part, the inflammatory immune responses of osteoblasts to S. aureus challenge.
Macrophage reprogramming nodes for bone repair identified by single-cell and spatial omics.
Chen H, Lei C, Yeo GC … +2 more , Lim KS, Xu C
Bone · 2026 Sep · PMID 42142794 · Publisher ↗
Early fracture repairs are characterized by dynamic immune-skeletal interactions. While immune cells are known to be critical, how macrophage polarization (M1 to M2) and metabolism jointly shape the microenvironment repa...
Early fracture repairs are characterized by dynamic immune-skeletal interactions. While immune cells are known to be critical, how macrophage polarization (M1 to M2) and metabolism jointly shape the microenvironment repairs remains unclear. Here, we integrated three mouse long bone fracture sc/snRNA-seq datasets with multi-algorithm consensus annotation. Fracture expanded and rewired intercellular communication, with redistribution of incoming signaling toward immune populations, especially macrophage subsets, and increased relative flow through TGF-β, BMP, and FN1 pathways. From days 1 to 7 post-injury, macrophages followed a graded M1-to-M2 continuum, while M1-like cells remained prevalent across this interval. Distinct transcriptional programs were associated with M1-like and M2-like macrophages, with Creb3l2/Fos enriched in M1-like cells and Maf/Mafb enriched in M2-like cells alongside differential metabolic features. Data-driven prioritization across integrated public mouse omics datasets nominated Pbx3, Creb3l2, Nfix, Maf, and Mafb as candidate regulators associated with macrophage polarization, with spatial enrichment in macrophage-associated niches. A fracture-associated repair module comprised skeletal stem/progenitor cells (SSPCs), fibroblasts, macrophages, and osteoclasts, and was accompanied by predicted metabolite-mediated communication, with communication involving glutamine, sterol/cholesterol, and GABA prioritized as relatively increased and communication involving heme and 27-hydroxycholesterol as relatively reduced. SSPC lineage tracing revealed Taco1 as an early dynamic marker and branch-specific drivers, Runx2/Egfr (osteogenesis), Ebf1 (chondrogenesis), and Stat5a (adipogenesis). Collectively, these findings provide a computational atlas of early fracture healing, suggest that macrophages may play an important coordinating role during this stage, and prioritize transcriptional and metabolic candidates for future experimental validation.
5,7-Dihydroxycoumarin counteracts osteoporosis by inhibition of PI3K/Akt signaling to suppress osteoclastogenesis: A study-based network pharmacology and experimental validation.
Yang M, Yu Z, Wang H … +4 more , Geng Y, Li R, Qiao J, Li Y
Bone · 2026 Sep · PMID 42142793 · Publisher ↗
BACKGROUND: Osteoporosis is characterized by excessive osteoclast mediated bone resorption, resulting in trabecular deterioration and increased fracture risk. Natural small molecules with multi-target regulatory properti...
BACKGROUND: Osteoporosis is characterized by excessive osteoclast mediated bone resorption, resulting in trabecular deterioration and increased fracture risk. Natural small molecules with multi-target regulatory properties have attracted increasing attention as potential candidates for anti-osteoporotic therapy. 5,7-Dihydroxycoumarin (5,7-DHC), a coumarin derivative with reported anti-inflammatory potential, has not yet been fully investigated for its therapeutic effects on osteoporosis. METHODS: Network pharmacology and molecular docking were applied to identify potential 5,7-DHC targets and signaling pathways associated with osteoporosis. The binding stability of the 5,7-DHC-Akt1 complex was further evaluated using molecular docking and 100-ns molecular dynamics simulations. In vitro, bone marrow derived macrophages were used to assess osteoclast differentiation, F-actin ring formation, acidified vesicle secretion, bone resorption, and expression of osteoclast related genes and proteins using TRAP staining, phalloidin/AO staining, bone resorption assays, RT-PCR, and western blotting). In vivo, the bone protective effects of 5,7-DHC were evaluated in ovariectomized (OVX) mice using micro-CT and histological analyses. RESULTS: Network pharmacology identified 47 overlapping genes between 5,7-DHC targets and osteoporosis-related genes, enriched mainly in the PI3K/Akt, MAPK, and EGFR pathways. Molecular docking showed strong affinity between 5,7-DHC and Akt1, with a binding energy of -7.4 kcal/mol. This predicted interaction was further supported by molecular dynamics simulations, which yielded a favorable binding free energy of -63.38 ± 3.38 kJ/mol. In vitro, 5,7-DHC (75-200 μM) significantly inhibited RANKL induced osteoclast differentiation, disrupted F-actin ring formation, reduced acidified vesicle secretion, bone resorption, and downregulated osteoclast-related markers including NFATc1, c-Fos, DC-STAMP, OC-STAMP, CTSK, and MMP9. Mechanistically, 5,7-DHC suppressed phosphorylation of PI3K, Akt, and GSK3β during early osteoclastogenesis. In OVX mice, 5,7-DHC markedly attenuated estrogen deficiency-induced bone loss and improved trabecular microarchitecture, as reflected by increased BV/TV, BMD, BS/TV, reduced Tb.Sp, and improved histological morphology. CONCLUSION: These findings suggest that 5,7-DHC exerts bone-protective effects by suppressing osteoclast differentiation and function, at least partly through inhibition of the PI3K/Akt/GSK3β signaling axis. This study provides preliminary experimental evidence supporting 5,7-DHC as a potential natural compound for the prevention or treatment of osteoclast mediated bone loss.
Exogenous vitamin C regulates osteoclast differentiation kinetics, cytoskeletal maturation, and bone resorption through ERK1/2-DAPK1-caspase-3 signaling.
Chiang CH, Huang CC, Ma YS … +5 more , Wu YT, Kuo CH, Wei YH, Chen CM, Liou YM
Bone · 2026 Sep · PMID 42134613 · Publisher ↗
BACKGROUND: Vitamin C (VC) plays essential but incompletely defined roles in osteoclast (OC) development. We examined how exogenous VC and AKR1A-dependent endogenous VC regulate OC differentiation, cytoskeletal organizat...
BACKGROUND: Vitamin C (VC) plays essential but incompletely defined roles in osteoclast (OC) development. We examined how exogenous VC and AKR1A-dependent endogenous VC regulate OC differentiation, cytoskeletal organization, resorptive activity, and apoptosis. METHODS: Murine bone marrow-derived macrophages (BMDMs) from wild-type and AKR1A-deficient mice, together with RAW264.7 cells, were used to assess the effects of exogenous and endogenous VC on OC differentiation, actin ring formation, resorption, apoptotic signaling, and ERK1/2 activation. RESULTS: AKR1A1 deficiency altered osteoclastogenic kinetics, delaying early differentiation, impairing actin ring formation and early resorption, yet promoting late accumulation of large multinucleated OCs. VC exhibited stage-dependent effects: it was required to initiate osteoclastogenesis but, when supplemented at later stages, suppressed OC maturation and enhanced apoptosis. In both primary cells and RAW264.7 cultures, VC dose-dependently promoted peripheral F-actin ring assembly and increased matrix resorption. Mechanistically, VC enhanced ERK1/2 phosphorylation in mature OCs, selectively increased reactive oxygen species, and activated the DAPK1-caspase-3 axis, including nuclear localization of phospho-DAPK1 and cleaved caspase-3. Pharmacologic ERK inhibition suppressed OC formation and resorptive function. CONCLUSION: VC acts as a stage-dependent modulator of OC fate, linking ERK1/2-associated cytoskeletal maturation and resorptive activity to DAPK1-caspase-3-mediated apoptotic termination during bone remodeling.
Semaglutide, at a dose that produces modest weight loss, induces mild suppression of bone remodeling in healthy control rats and those with chronic kidney disease.
Allen MR, Metzger CE, Chen NX … +5 more , Tinsley IC, DiMarchi RD, O'Neill K, Matter EK, Moe SM
Bone · 2026 Sep · PMID 42128321 · Publisher ↗
The effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment on bone are unclear. The goal of this study was to investigate the effects of semaglutide, a GLP-1RA, on bone structure, remodeling, and mechani...
The effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment on bone are unclear. The goal of this study was to investigate the effects of semaglutide, a GLP-1RA, on bone structure, remodeling, and mechanical properties in healthy control animals and those with chronic kidney disease (CKD). Male Cy/+ rats with progressive CKD and littermate controls were treated with escalating doses of semaglutide for 28 days. Endpoint measures included bone structure, assessed by micro-CT, bone remodeling, assessed by histomorphometry, and bone mechanical properties, assessed by 3-point bending tests. Semaglutide treatment led to reduced food intake and weight loss, with CKD rats receiving semaglutide having 15% lower body weight at the end of the study compared to untreated CKD rats, while control rats did not have a statistical difference in weight (-5%) at the end of the study. Muscle mass was also lower in semaglutide-treated animals compared to untreated groups. CKD led to higher blood urea nitrogen with no effect of semaglutide. Serum PTH was lower in control rats treated with semaglutide, but this effect was not seen in the CKD cohorts. There were also main effects of semaglutide on serum calcium and phosphorus levels. CKD resulted in lower trabecular bone volume and higher cortical porosity with no effect of semaglutide. Mineralizing surfaces from dynamic histomorphometry were lower in control rats treated with semaglutide compared to untreated control and bone formation rate also trended lower in semaglutide-treated animals (∼20%). CKD animals had lower mechanical properties; semaglutide effects were only noted in toughness. At doses causing mild weight loss, semaglutide modestly lowered trabecular bone remodeling with little interaction with CKD disease status.
Age-related differences in the skeletal phenotype of Brown Norway rats induced to develop chronic kidney disease.
Metzger CE, Tak LY, Scorziello JM … +9 more , Back LA, Matter EK, Connerly TJ, O'Neill KD, Srinivasan S, Needham BD, Chen NX, Moe SM, Allen MR
Bone · 2026 Sep · PMID 42128320 · Publisher ↗
A large proportion of the chronic kidney disease (CKD) population is over the age of 65 with age being a significant factor increasing fracture incidence in CKD. However, the interactions of aging and CKD on the skeleton...
A large proportion of the chronic kidney disease (CKD) population is over the age of 65 with age being a significant factor increasing fracture incidence in CKD. However, the interactions of aging and CKD on the skeleton remain unclear in part due to limited pre-clinical models to study the intersection of aging and CKD. In the current study, we aimed to define age-related differences in the skeletal manifestations of CKD using an adenine-induction model in young (3-month-old) and aging (17-month-old) Brown Norway rats. We hypothesized that there would be a greater CKD-Mineral Bone Disorder phenotype in aging rats compared to young rats. Serum blood urea nitrogen, creatinine, and parathyroid hormone were higher in aging CKD rats compared to young. Bone turnover was high in all CKD rats, but osteoclast-covered trabecular surfaces were highest in aging CKD. Additionally, osteoid surfaces and osteoid width were only elevated in aging adenine rats. Cortical porosity was only present in the aging cohort and elevated due to CKD. A marker of cellular senescence was elevated in cortical osteocytes due to both CKD and aging. Parathyroid hormone receptor 1 (PTHR1) was elevated due to CKD only in young CKD rats. In conclusion, this study demonstrates that aging rodents develop a more severe CKD-MBD phenotype than young rodents with higher osteoclasts, elevated osteoid, and greater cortical porosity. These data highlight both a pre-clinical model suitable to study age-related CKD and that CKD-induced skeletal changes have age-specific effects.
Polycystic bone disease: A new family.
Verdun C, Ltaief-Boudrigua A, Gensburger D … +7 more , Sekri A, Gazeu A, Mokhtar H, Chotel F, Rongieras F, Chapurlat R, Rossi M
Bone · 2026 Sep · PMID 42119630 · Publisher ↗
Bone cysts are benign fluid-filled lytic lesions, which can be unicameral (UBC) or partially separated. Usually, they are solitary and resolve spontaneously. Even if they are often asymptomatic, pathological fractures ca...
Bone cysts are benign fluid-filled lytic lesions, which can be unicameral (UBC) or partially separated. Usually, they are solitary and resolve spontaneously. Even if they are often asymptomatic, pathological fractures can occur. Multiple UBC are very rare and, to the best of our knowledge, only one familial case of multiple bone cysts has been reported to date; this condition was named Polycystic Bone Disease (PCBD). Here, we report three further related patients affected by PCBD, thus providing new insights into the clinical and radiological characterization of this ultra-rare disease. Furthermore, we describe for the first time the pathological phenotype of this condition. Our study confirms that PCBD represents a specific autosomal dominant condition, which should be included in the nosology of skeletal disorders. We hope that the report of further cases will allow the characterization of the molecular basis of this condition.
Radiofrequency echographic multispectrometry assessment of osteoporosis in severe motor and intellectual disabilities: A cross-sectional study.
Sakai T, Hirao M, Mizushima Y … +3 more , Takashina Y, Matsuoka N, Oishi T
Bone · 2026 Sep · PMID 42119629 · Publisher ↗
Conventional bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry is challenging in individuals with severe motor and intellectual disability (SMID) because of scoliosis, hip dislocation, joint co...
Conventional bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry is challenging in individuals with severe motor and intellectual disability (SMID) because of scoliosis, hip dislocation, joint contractures, and involuntary movements. Radiofrequency echographic multispectrometry (REMS) is a feasible, radiation-free alternative to bedside BMD assessment. In this cross-sectional study, we aimed to characterize REMS-based BMD profiles of lumbar spine (L1-L4) and femoral neck in individuals with SMID residing at a care facility and identify clinical factors associated with reduced BMD. Demographic variables, feeding status, and physical activity levels were obtained, and subgroup and multivariate regression analyses were performed. REMS measurements were successfully obtained at both sites in 84.3% of 121 participants. Femoral neck demonstrated significantly lower BMD, compared with lumbar spine (p = 0.038). T-scores at both sites were strongly correlated (r = 0.65, p < 0.001). Subgroup comparisons revealed no significant differences based on feeding route or physical activity. Multivariable analyses identified age and body weight as independent determinants of femoral neck T-scores. Physical activity was not independently associated with BMD after adjustment. These findings indicate that REMS enables bedside assessment, with body weight and age as primary determinants of BMD. Although physical activity may contribute to bone health, its independent effect appears limited. These results highlight the potential role of REMS in clinical evaluation, longitudinal monitoring, and osteoporosis prevention strategies in individuals with SMID. Given the high osteoporosis risk in this population, REMS-derived BMD should be interpreted cautiously to avoid underestimation of disease severity.
Height-for-age adjusted bone mineral density and associated factors in youth with type 1 diabetes.
Tantivit N, Volkening LK, Renthal NE … +2 more , Jacobsen CM, Laffel LM
Bone · 2026 Sep · PMID 42114588 · Full text
INTRODUCTION: Bone fragility is a known complication of type 1 diabetes (T1D) and because DXA provides areal rather than volumetric bone mineral density (BMD), height-for-age adjustment offers a more accurate assessment...
INTRODUCTION: Bone fragility is a known complication of type 1 diabetes (T1D) and because DXA provides areal rather than volumetric bone mineral density (BMD), height-for-age adjustment offers a more accurate assessment of bone density. AIMS: To evaluate HAZ-adjusted BMD z-scores (BMD z-scores adjusted for height-for-age [HAZ]) in youth with T1D and identify factors associated with height-adjusted bone density. METHODS: This cross-sectional study included youth aged 8-17 years with T1D ≥1 year underwent DXA; T1D-related history, anthropometrics, dietary intake, and 25-hydroxyvitamin D [25(OH)D] were analyzed in association with HAZ-adjusted BMD z-scores. RESULTS: A total of 124 youth participated (mean age 12.9 ± 2.5 years; BMI z-score 0.67 ± 0.81; HAZ 0.25 ± 0.96; diabetes duration 6.0 ± 3.2 years; HbA1c 8.1 ± 1.1%). Mean daily intake was 8.7 ± 9.0 μg vitamin D, 1011.1 ± 464.7 mg calcium, and 1.5 ± 0.6 g/kg/day protein; recommended dietary allowance targets were met by 17%, 23%, and 85%, respectively. Vitamin D status was 9% deficient, 48% insufficient, and 43% sufficient. Mean HAZ-adjusted BMD z-score was -0.36 ± 1.01, significantly lower than the reference data (p = 0.0001). BMD z-scores correlated with BMI z-scores (r = 0.27, p = 0.002) and 25(OH)D (r = 0.25, p = 0.005). The vitamin D-deficient group had significantly lower HAZ-adjusted BMD z-scores than both the insufficient and sufficient groups (Δ = 1.06, p = 0.004; Δ = 1.02, p = 0.004). No associations were observed with diabetes duration, HbA1c, or dietary intake of vitamin D, calcium, or protein. CONCLUSIONS: Youth with T1D had lower HAZ-adjusted BMD compared with the reference population, and HAZ-adjusted BMD was associated with BMI z-scores and 25(OH)D levels. Maintaining healthy weight and adequate vitamin D levels remains important for bone health in this population.
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