Bone [JOURNAL]
Sun
200 papers
LncRNA FGF13-AS1 predicts delayed fracture healing and promotes osteoporotic fracture healing by regulating miR-128-3p/CBFB-mediated osteogenesis and osteoclast activity.
Yao S, Meng J, Qin Z … +1 more , Zhang Y
Bone · 2026 Aug · PMID 42025821 · Publisher ↗
OBJECTIVE: Osteoporotic fracture (OPF) disrupts bone homeostasis via resorption-formation imbalance. This study investigates the expression and role of the long non-coding RNA FGF13 antisense RNA 1 (FGF13-AS1) in OPF bon...
OBJECTIVE: Osteoporotic fracture (OPF) disrupts bone homeostasis via resorption-formation imbalance. This study investigates the expression and role of the long non-coding RNA FGF13 antisense RNA 1 (FGF13-AS1) in OPF bone healing. METHODS: Recruited 110 patients with osteoporosis (OP) and 138 patients with OPF and 90 healthy people, then divided OPF patients into normal healing (NFH) and delayed healing groups (DFH) after a 4-month follow-up. In vitro, MC3T3-E1 cells undergo osteogenic differentiation while RAW264.7 cells undergo osteoclastogenic differentiation. Serum FGF13-AS1 and miR-128-3p levels were determined by real-time quantitative reverse transcription PCR (RT-qPCR). The receiver operating characteristic (ROC) curve assessed FGF13-AS1's diagnostic value for OP. Logistic regression pinpointed potential risk factors for DFH. Cell counting kit-8 (CCK-8) and flow cytometry assays were used to determine cell proliferation and apoptosis. Alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activity were measured via commercial kits. RT-qPCR evaluated expression of osteogenic and osteoclast differentiation markers. RESULTS: Serum FGF13-AS1 levels decline significantly in OP patients, particularly in OPF cases. DFH patients have lower levels than NFH patients. Low FGF13-AS1 expression predicts DFH and is a potential risk factor for its onset. MC3T3-E1 cells in osteoblastic differentiation showed marked upregulation of FGF13-AS1 and core-binding factor subunit β (CBFB) and downregulation of miR-128-3p. FGF13-AS1 overexpression enhanced ALP activity, osteogenic marker expression, and cell proliferation, and suppressed apoptosis; miR-128-3p effectively reversed these effects. During osteoclast differentiation, FGF13-AS1 and CBFB decreased, and miR-128-3p increased. Inhibition of FGF13-AS1 elevated TRAP activity and osteoclast differentiation markers. This effect was markedly mitigated by reducing miR-128-3p levels. CONCLUSION: Low FGF13-AS1 serves as a marker for delayed fracture healing in osteoporosis. It likely acts via the miR-128-3p/CBFB axis to balance osteogenic differentiation and promote bone formation. Deficiency of FGF13-AS1 may contribute to delayed healing and represents a potential clinical molecular target.
Myostatin inhibition from preconception through lactation improves maternal muscle and skeletal health in the osteogenesis imperfecta murine mouse model.
Crawford TK, Lafaver BN, Davis BR … +6 more , Chapman IM, Mastaitis J, Ohler AM, Oestreich AK, Schulz LC, Phillips CL
Bone · 2026 Aug · PMID 42019805 · Publisher ↗
Osteogenesis imperfecta (OI) is a rare type I collagenopathy characterized primarily by skeletal fragility. Despite extensive genetic and clinical understanding of OI, there is no cure and current treatment strategies ar...
Osteogenesis imperfecta (OI) is a rare type I collagenopathy characterized primarily by skeletal fragility. Despite extensive genetic and clinical understanding of OI, there is no cure and current treatment strategies are not compatible with pregnancy or lactation. Pregnancy and lactation are natural periods of maternal bone loss, as calcium is extracted from maternal bone to support offspring skeletal development, further challenging maternal musculoskeletal health in OI. We hypothesize targeting muscle-bone crosstalk through pharmacological myostatin inhibition in utero can improve maternal musculoskeletal health and reduce maternal bone loss during pregnancy and lactation. Previous attempts to increase muscle and bone mass in the osteogenesis imperfecta model mouse (oim) demonstrated prenatal administration of anti-myostatin antibody (Mstn-Ab) was safe for gestation and fetal development. The current study examines the impact of Mstn-Ab treatment on maternal musculoskeletal health in wildtype (WT) and +/oim dams during preconception, pregnancy, and lactation. Mstn-Ab treatment improved maternal WT and +/oim muscle mass and cortical bone outcomes compared to control antibody (Ctrl-Ab) treatment following lactation. As maternal OI is a risk factor for uterine rupture, a secondary aim was to evaluate the uterine biomechanics of WT and +/oim dams following Mstn-Ab treatment. Uterine biomechanical integrity was reduced in both virgin oim/oim and postpartum +/oim mice relative to WT littermates but was unchanged by maternal myostatin status. These findings suggest myostatin inhibition from preconception through postpartum provides a promising therapeutic strategy to increase maternal musculoskeletal health in OI.
A scoping review of animal models of growth plate injury organized by Salter-Harris classification.
Sun H, Kuhn L
Bone · 2026 Aug · PMID 41997338 · Full text
The severity of growth arrest and angular deformities experienced by adolescent patients who have fractured their bone growth plates depends on the Salter-Harris (SH) classification of the injury. The SH classification d...
The severity of growth arrest and angular deformities experienced by adolescent patients who have fractured their bone growth plates depends on the Salter-Harris (SH) classification of the injury. The SH classification depends on which anatomical elements of the zonal structure of the growth plate and the adjacent bone structures are injured. Animal models can provide indispensable insights into these injuries, elucidating cellular and molecular repair mechanisms inaccessible in clinical studies. This scoping review maps twelve different animal models of growth plate injury to SH-like classifications based on which anatomical elements of the growth plate and adjacent bone structures were disrupted when creating the injury. Seventy-nine studies were included across mice, rats, rabbits, pigs, and sheep. The more severe SH IV-like injuries predominated (69/79 studies). Gaps include under-representation of the clinically most common SH type II, and types III and V. Pros and cons of the various models are discussed, including the technical challenges of surgically creating well-defined injuries in the soft growth plate zonal structure in small animals, most suited for mechanistic studies. This scoping review provides a resource for investigators interested in selecting an animal model for testing new therapeutic strategies aiming to improve healing outcomes for children with growth plate injuries.
3D polyurethane scaffolds for exploring osteogenic differentiation and mechanical stimulation of mesenchymal stromal cells.
Boehm TM, Müller-Deubert S, Krug M … +8 more , Mussoni C, Stahlhut P, Stepanenko V, Rudert M, Kusan B, Docheva D, Ahmad T, Ebert R
Bone · 2026 Jul · PMID 41997337 · Publisher ↗
Bone marrow-derived mesenchymal stromal cells (MSC) support bone regeneration by differentiating into osteogenic lineages in response to biochemical and mechanical cues such as fluid-flow and compression, processes repli...
Bone marrow-derived mesenchymal stromal cells (MSC) support bone regeneration by differentiating into osteogenic lineages in response to biochemical and mechanical cues such as fluid-flow and compression, processes replicable in vitro using bioreactors and 3D scaffolds. Human MSC were cultured on medium-stiffness and hard 3D polyurethane (PU) scaffolds, characterized by atomic force microscopy, scanning electron microscopy (SEM), and stiffness measurements, and subjected to fluid-flow and compression. Two-dimensional PU and polystyrene (PS) substrates served as controls. Cultures were maintained in expansion or osteogenic medium. Cell attachment and morphology were analyzed by SEM and F-actin staining; osteogenic differentiation was evaluated by qPCR. Alkaline phosphatase activity was quantified, and extracellular matrix (ECM) formation and mineralization were assessed using Picrosirius Red, Alizarin Red, and inductively coupled plasma mass spectrometry (ICP-MS). Mechanosensitivity was analyzed via FOS and PTGS2 expression, YAP/TAZ nuclear localization, and Wnt, Notch, and cAMP signaling. Cells adhered and spread throughout the scaffolds, exhibiting pore-spanning morphologies. Gene expression showed material- and time-dependent upregulation of osteoblastic and osteocytic markers, with PU scaffolds eliciting stronger responses than PS, even without osteogenic supplements. The scaffolds also supported ECM formation and mineralization. Mechanical stimulation via fluid-flow and compression induced time- and stimulus-dependent regulation of mechanoresponsive genes and activation of key mechanotransduction pathways, with distinct expression patterns for each loading mode. In this study, we developed a standardized, cost-effective, and easy-to-handle 3D PU scaffold that effectively supports hMSC adhesion and promotes osteogenic differentiation. The cells' mechanoresponse further highlights the scaffold's suitability as a versatile platform for in vitro studies under physiologically relevant conditions.
Proteomic profiling links increased mast cell activity in regenerating callus to impaired scaffold-guided bone regeneration in diabetic rats.
Wiltzsch V, Dias DB, Schmidt JR … +4 more , Kirwan JA, Lehmann J, Poh PSP, Kalkhof S
Bone · 2026 Aug · PMID 41990899 · Publisher ↗
Type 2 diabetes mellitus significantly impairs bone healing, with delayed regeneration observed in over 60% of patients with diabetes. Using time-resolved proteome profiling of critical-sized femoral defects in diabetic...
Type 2 diabetes mellitus significantly impairs bone healing, with delayed regeneration observed in over 60% of patients with diabetes. Using time-resolved proteome profiling of critical-sized femoral defects in diabetic and non-diabetic rats treated with polycaprolactone scaffolds, we investigated the molecular mechanisms underlying diabetes-associated compromised regeneration. Explanted regenerated callus and contralateral bone tissue were analyzed at 21 and 42 days post-surgery using mass spectrometry-based quantitative proteomics and functional enrichment analysis, complemented by histological analysis and histamine quantification. Diabetic defects were characterized by disorganized fibrous and adipose tissue without mineralized bone after 42 days, whereas non-diabetic defects exhibited new bone formation. Deep proteome coverage identified 4384 proteins. At 42 days post-surgery, diabetic defects showed significantly reduced extracellular matrix proteins, while inflammatory proteins were higher abundant. Neutrophil degranulation signatures persisted at 42 days, suggesting sustained neutrophil extracellular trap (NET) formation. Notably, a distinct mast cell protease cluster (tryptase, chymase, carboxypeptidase A3, mast cell protease-1) was enriched in diabetic tissue at both timepoints, linking molecular to cellular dysregulation. Immunofluorescence staining revealed 2.5-fold more mast cells with peripheral, halo-like histamine structures typical for degranulation. Additionally, tissue histamine was elevated in diabetic defects. Conclusively, this comprehensive proteomic study points to a previously uncharacterized mast cell-neutrophil crosstalk in diabetic bone regeneration, converting physiologically transient inflammatory processes into pathologically sustained networks. This creates a self-reinforcing catabolic niche that prevents inflammatory resolution and matrix maturation. These findings identify mast cell stabilization and NET modulation as promising therapeutic targets for improving scaffold-guided bone regeneration in diabetic rats.
Anabolic effect of parathyroid hormone (1-34) to prevent ovariectomy induced bone loss is attenuated in Col1A1-cre floxed monocyte chemotactic protein 1 (MCP1, CCL2) mice.
Morrison N, Jones M, Delumani D … +5 more , Massa H, Partridge N, Pettit A, Millard S, Forwood M
Bone · 2026 Aug · PMID 41985703 · Publisher ↗
The anabolic effect of Parathyroid Hormone (PTH 1-34) is a potent anti-osteoporosis treatment. In rat bone, the chemokine MCP1 (also known as CCL2) is induced about 250-fold occurring within 1 h of PTH injection and is t...
The anabolic effect of Parathyroid Hormone (PTH 1-34) is a potent anti-osteoporosis treatment. In rat bone, the chemokine MCP1 (also known as CCL2) is induced about 250-fold occurring within 1 h of PTH injection and is the highest induced gene. In mice, we showed previously that global knockout (KO) of MCP1 blocked the anabolic effect of PTH. In the present work, we used cre-lox genetic models to generate cell lineage specific MCP1 KO in the osteoblast/osteocyte lineage by using the type 1 collagen promoter (Col1A1) to drive cre recombinase in mice carrying loxP sites flanking the MCP1 gene (MCP1). In contrast to a 2.6 standard deviation (SD) increase in total bone in the proximal tibial metaphysis (p = 4 × 10) in control mice, there was no response to anabolic PTH in mice in which the MCP1 gene was deleted (MCP1 Col-cre+, p = 0.6). We then tested whether ovariectomy (OVX) induced bone loss could be suppressed by simultaneous anabolic PTH treatment (OVX-PTH) in such animals. In control animals, OVX resulted in a 2.0 SD decrease in bone density. OVX-PTH treated animals had bone density 1.6 SD higher than baseline untreated and 3.6 SD increased from the low OVX level. In contrast, the anabolic PTH effect was significantly blunted (p = 0.01) in OVX MCP1 Col-cre + animals with a 1.4 SD change. These data suggest a role for osteoblast/osteocyte expressed MCP1 in the anabolic effect of PTH.
Prevalent vertebral fracture (PVFx) and abdominal aortic calcification (AAC) independently predict incident atherosclerotic cardiovascular disease (ASCVD) events in older men.
Schousboe JT, Lewis JR, Langsetmo L … +6 more , Saleem A, Gilani SZ, Ilyas Z, Szulc P, Leslie WD, Ensrud KE
Bone · 2026 Aug · PMID 41985702 · Publisher ↗
PURPOSE: To estimate the associations of prevalent vertebral fracture (PVFx) and abdominal aortic calcification (AAC) with incident ASCVD (myocardial infarction, fatal or non-fatal cerebrovascular accident, or coronary h...
PURPOSE: To estimate the associations of prevalent vertebral fracture (PVFx) and abdominal aortic calcification (AAC) with incident ASCVD (myocardial infarction, fatal or non-fatal cerebrovascular accident, or coronary heart disease death). METHODS: 2799 older men (mean [SD] age 76.3 [5.5] years) enrolled in the MrOS sleep ancillary study had PVFx (SQ grade 2 or 3) assessed by human reader and AAC by automated convolutional neural networks on baseline lateral spine radiographs. Auto-AAC was categorized as low, moderate, or high (24-point scale score < 2, 2 to <6, or ≥ 6). Men were contacted every 4 months for ascertainment of possible ASCVD events over a mean (SD) follow-up of 8.4 (3.1) years. Associations of PVFx and auto-AAC category with incident ASCVD were estimated with modified proportional hazards models accounting for non-CVD mortality. RESULTS: PVFx was present in 7.3% of the cohort; 34.5% had moderate auto-AAC, 28.8% had high auto-AAC, and 396 (14.1%) had an incident ASCVD event. Compared to men with low auto-AAC, those with moderate (HR 1.34, 95% CI 1.01, 1.77) and high (HR 1.55, 95% CI 1.16, 2.06) auto-AAC had increased risk of ASCVD events adjusted for PVFx and other risk factors. Compared to men with no PVFx, those with PVFx had a higher risk of ASCVD events (HR 1.51, 95% CI 1.07, 2.14) adjusted for auto-AAC level and other risk factors. CONCLUSION: AAC assessed by automated methods and PVFx are independently associated with incident ASCVD events and may aid in ASCVD risk stratification in older men, but confirmatory studies are needed.
Age-specific loss of life expectancy after hip fracture in Asian adults: A nationwide population-based cohort study.
Kim KJ, Kwon SJ, Lee S … +5 more , Ahn SH, Park SY, Kim HY, Kim KM, KSBMR Epidemiology Study Group
Bone · 2026 Jul · PMID 41974401 · Publisher ↗
BACKGROUND: Hip fracture is associated with excess mortality beyond the acute post-fracture period but is often regarded as a transient event after clinical recovery. The magnitude of residual life expectancy loss and it...
BACKGROUND: Hip fracture is associated with excess mortality beyond the acute post-fracture period but is often regarded as a transient event after clinical recovery. The magnitude of residual life expectancy loss and its variation across age groups remain inconclusive. METHODS: We conducted a nationwide cohort study using the National Health Insurance Service database of South Korea. Adults aged ≥50 years with incident hip fractures between 2010 and 2018 were identified and matched 1:2 by age and sex to individuals without fracture. To assess long-term mortality, follow-up began one year after the index date using a landmark approach. Mortality risk was evaluated using Cox proportional hazards models with sequential adjustment for age, comorbidities, and anti-osteoporotic medication use. Loss of life expectancy was estimated using restricted mean survival time analysis. The RMST time horizon (τ) was defined as the maximum common follow-up time across the compared groups within each age stratum, which corresponded to approximately 13.5 years in this dataset. RESULTS: The study included 39,670 individuals with hip fracture and 73,428 matched controls from the South Korean population. Both men and women with hip fracture experienced persistently higher mortality than controls beyond the initial fracture event. Relative mortality risks were highest in younger adults and declined with advancing age. In contrast, the greatest absolute residual loss of life expectancy occurred among individuals aged 70-79 years, amounting to 2.94 years in men and 2.03 years in women. Residual life expectancy loss was more pronounced among individuals with diabetes mellitus and lower socioeconomic status. CONCLUSIONS: Hip fracture was associated with sustained reductions in life expectancy beyond the acute post-fracture period in this nationwide cohort of South Koreans. Quantifying age-specific life expectancy loss clarifies long-term mortality risk after hip fracture and provides clinically interpretable estimates across age groups.
Association of intradialytic hypotension and physical performance with fall and fracture incidence in hemodialysis patients: The REPnet-HD study.
Usui N, Shirai N, Abe Y … +16 more , Okamura D, Kasai T, Kojima S, Sakuyama A, Sato Y, Shinozaki N, Shimano Y, Takahashi H, Nishiyama Y, Noji T, Noda I, Hamada T, Mikami K, Monoe S, Yamada Y, Saitoh M
Bone · 2026 Jul · PMID 41966444 · Publisher ↗
Although hypotension has been linked to fall-related injuries in older adults, evidence in hemodialysis (HD) patients remains limited. This study examined the effects of intradialytic hypotension (IDH) and physical perfo...
Although hypotension has been linked to fall-related injuries in older adults, evidence in hemodialysis (HD) patients remains limited. This study examined the effects of intradialytic hypotension (IDH) and physical performance on the risk of subsequent falls and fractures. In this prospective cohort study, 518 ambulatory HD patients were observed over 1 year to track the occurrence of accidental falls, severe falls (those requiring medical intervention), and fractures. Baseline assessments included IDH (defined as nadir systolic blood pressure [BP] during dialysis <90 mmHg or intervention for hypotensive events [Nadir SBP90 + intervention]), nadir diastolic BP <50 mmHg (Nadir DBP50), and physical dysfunction. While IDH was not associated with overall falls, physical dysfunction was (odds ratio 2.10 [1.27, 3.45], P = 0.004). However, physical dysfunction was not independently linked to severe falls or fractures. Both Nadir SBP90 + intervention and Nadir DBP50 were associated with increased risks of severe falls (hazard ratio [HR] 3.84 [1.90, 7.75], P < 0.001; 2.56 [1.23, 5.35], P = 0.01, respectively) and fractures (HR 3.57 [1.52, 8.42], P = 0.003; 2.70 [1.15, 6.35], P = 0.02, respectively). Additionally, falls occurring after HD were more frequently associated with severe falls and fractures (post-HD 39.1%, pre-HD 15.4%, non-HD day 13.3%, night 8.3%; P = 0.02). The inclusion of Nadir SBP90 + intervention in prediction models improved severe fall risk discrimination (Δ area under the curve 0.05, P = 0.04). These findings emphasize the need to address cardiovascular mechanisms regulating BP during dialysis to mitigate fall-related injuries.
Incidence, risk factors, characteristics and shoulder joint function status of heterotopic ossification following surgical treatment of clavicle fracture or acromioclavicular joint dislocation.
Jiang Y, Yang S, Zhang J … +2 more , Zhang Y, Feng D
Bone · 2026 Jul · PMID 41962790 · Publisher ↗
BACKGROUND: Heterotopic ossification (HO) around the shoulder is common in patients with clavicle fracture or acromioclavicular joint (ACJ) dislocation. Periarticular HO sometimes leads to poor joint function. HO of the...
BACKGROUND: Heterotopic ossification (HO) around the shoulder is common in patients with clavicle fracture or acromioclavicular joint (ACJ) dislocation. Periarticular HO sometimes leads to poor joint function. HO of the elbow and hip requires active prevention. However, studies on the incidence, risk factors, characteristics, and shoulder joint function of HO around the shoulder after surgical treatment of clavicle fracture or ACJ dislocation are still lacking. STUDY HYPOTHESIS: ACJ dislocation, clavicular hook plate fixation and excessive screw length are independent high-risk factors for postoperative shoulder HO; shoulder HO may impair joint function, with its anatomical location potentially being the key influencing factor. MATERIALS AND METHODS: This retrospective study enrolled patients with clavicle fracture or ACJ dislocation who underwent surgical treatment from January 2016 to October 2021. Patient radiographs were collected to observe the characteristics of HO, which was classified by location, diameter, and shape. Shoulder function was evaluated using the Visual Analog Scale (VAS), Constant-Murley score, and Disabilities of the Arm, Shoulder and Hand (DASH) score at the final follow-up. RESULTS: A total of 1181 patients were included, with a mean follow-up of 15 months (range, 3 to 122 months). The overall incidence of shoulder HO was 9.05% (n = 98), with 4.46% in clavicle fracture patients and 23.43% in ACJ dislocation patients; the incidence was 17.95% in hook plate fixation and 1.71% in clavicular anatomical plate fixation. Multivariate logistic regression confirmed that increasing age, male gender, smoking index ≥200, ACJ dislocation, clavicular hook plate fixation, and excessive screw length were independent risk factors for HO. The diameter and shape of HO were not associated with shoulder function scores, while the location of HO might affect Constant-Murley and DASH scores. The mean VAS was 0.26 ± 0.58, mean Constant-Murley score was 98.34 ± 2.80, and mean DASH score was 1.15 ± 1.57. No patient had significant shoulder function impairment or vascular nerve entrapment. CONCLUSION: The overall incidence of shoulder HO after surgical treatment of clavicle fracture or ACJ dislocation is 9.05%. Independent risk factors include increasing age, male gender, smoking index ≥200, ACJ dislocation, clavicular hook plate fixation, and excessive screw length. Most shoulder HO patients have favorable shoulder function without obvious impairment. Routine prophylaxis or targeted treatment is generally not necessary for unselected patients, although individualized evaluation may be warranted in high-risk subgroups.
Association between age-related AGE accumulation and deterioration of canalicular physical properties in a mouse model of senile osteoporosis: Potential implications for osteocyte mechanotransduction.
Liu CJ, Zheng MY, Wang CL … +6 more , Zhou RL, Li S, Ren Z, Wu XT, Yang X, Sun LW
Bone · 2026 Aug · PMID 41962789 · Publisher ↗
BACKGROUND: Senile osteoporosis (SOP) is characterized by diminished bone mass and deteriorated bone microstructure. A key pathogenic factor of it is the impaired mechanosensing function of osteocytes, whose mechanism re...
BACKGROUND: Senile osteoporosis (SOP) is characterized by diminished bone mass and deteriorated bone microstructure. A key pathogenic factor of it is the impaired mechanosensing function of osteocytes, whose mechanism remains unclear. The mechano-response of osteocytes depends on the physical microenvironment of the lacunar-canalicular system (LCS). While advanced glycation end products (AGEs) accumulation impairs bone quality at meso-level, its correlation with the micro-level LCS physical microenvironment and osteocyte function remains unclear. This study investigated the association between AGE accumulation and the LCS physical microenvironment during aging, specifically focusing on its morphology and micromechanical properties. Furthermore, the expression of mechanosensing elements in osteocyte processes were evaluated within the context of these microenvironmental changes to explore their potential functional impact. METHODS: Sixteen female C57BL6J mice were divided into young (2-month-old, 2 M) and aged (18-month-old, 18 M) groups. Bone microstructure was evaluated by Micro-computed tomography (micro-CT); LCS/osteocyte morphology and pericanalicular elastic modulus were determined by Transmission electron microscopy (TEM) and Atomic force microscopy (AFM); bone pentosidine (PEN) and fluorescent AGEs were detected by High-performance liquid chromatography (HPLC) and fluorescence microscopy. Pericanalicular PEN and carboxymethyl-lysine (CML) was quantified by confocal Raman spectroscopy (CRS), and their correlation with indicators of LCS physical microenvironment was analyzed; osteocyte mechanosensing elements (integrin αVβ3, tethering elements (TEs)/Perlecan(PLN)) were assessed by immunofluorescence staining. RESULTS: The results showed that compared to the 2 M group, the 18 M group exhibited significantly higher AGEs at both meso- and micro-levels. This accumulation correlated with adverse physical changes in LCS including a smaller canalicular cross-sectional area and higher pericanalicular elastic modulus. Furthermore, the aged mice displayed a reduction in mechanosensing elements, indicated by significantly fewer TEs and lower PLN expression in osteocytes. CONCLUSIONS: Our findings indicate that AGEs accumulate in the pericanalicular matrix with aging, which is accompanied with the alterations in canalicular physical properties, including the canalicular narrowing and pericanalicular matrix stiffening. This physical deterioration potentially contributes to the significant downregulation of key mechanosensing elements in osteocyte processes, via theoretically attenuating interstitial fluid flow and matrix strain. This study highlights a critical association between age-related AGE accumulation and the compromised mechanosensing environment for osteocytes, offering a novel perspective for understanding SOP mechanisms and exploring potential therapeutic interventions.
The effect of prior osteoporosis treatment on bone mineral density response to romosozumab.
Ta B, Ho FCW, Bliuc D … +3 more , Chen W, Center JR, Sheu A
Bone · 2026 Aug · PMID 41962788 · Publisher ↗
BACKGROUND: Romosozumab is an osteoanabolic agent with dual anabolic and antiresorptive effects, with substantial benefits on bone mineral density (BMD) and fracture risk reduction. BMD gains are attenuated by prior anti...
BACKGROUND: Romosozumab is an osteoanabolic agent with dual anabolic and antiresorptive effects, with substantial benefits on bone mineral density (BMD) and fracture risk reduction. BMD gains are attenuated by prior antiresorptive treatment. This study aimed to compare real-world effects of romosozumab on BMD and bone turnover markers (BTM) according to prior antiresorptive treatment. METHODS: We conducted a retrospective audit of patients who completed 12 months of romosozumab treatment between April 2021 and October 2024 at a tertiary hospital and affiliated clinics. Patients were analysed according to treatment history: treatment-naïve, prior bisphosphonate, or prior denosumab. Primary outcome was percentage change in BMD at the lumbar spine (LS) over 12 months. Secondary outcomes were percentage changes in femoral neck (FN), total hip (TH) BMD and bone turnover markers (procollagen type 1 n-propeptide and c-telopeptide) over 12 months. Between-group differences were assessed using ANCOVA and linear mixed models. Subgroup analyses examined the effect of duration of prior treatment and timing of transition from denosumab on BMD. RESULTS: Seventy-two patients were included (mean age 72.4 ± 11.9 years; 83% female). 20 patients were treatment naïve, 32 transitioned from bisphosphonates and 20 transitioned from denosumab. Patients in the treatment naïve group were younger, had lower baseline BMD and fracture risk compared to the bisphosphonate or denosumab group. The median duration of bisphosphonate use in the bisphosphonate group was 48 months and the median duration of denosumab use in the denosumab group was 50 months. LS BMD gains were significantly greater in treatment-naïve patients compared to those with prior bisphosphonate or denosumab exposure (13.1% vs 8.5% vs 4.4%, p = 0.04). There were no significant differences in percentage change for FN or TH BMD across groups. A longer duration of prior antiresorptive therapy and later romosozumab initiation following denosumab were associated with smaller BMD gains. C-terminal teloptide (CTx) levels decreased in both treatment naïve and prior bisphosphonate groups but transiently increased in the prior denosumab group before stabilising by 6-12 months. CONCLUSION: In our real-world cohort, romosozumab effectively increased BMD, particularly in treatment-naïve patients. Duration of prior antiresorptive therapy and timing of transition from denosumab significantly influenced BMD gains. Prospective studies are needed to optimise transition strategies from antiresorptive agents.
Increased osteoblast Gα level compromises bone healing quality by suppressing high-density bone formation.
Lee KK, Changoor A, Grynpas MD … +1 more , Mitchell J
Bone · 2026 Jul · PMID 41962787 · Publisher ↗
Gα proteins that couple G protein-coupled receptors to stimulate phospholipase C play important roles in the skeletal system as previously demonstrated by bone abnormalities when activating mutations or when overexpressi...
Gα proteins that couple G protein-coupled receptors to stimulate phospholipase C play important roles in the skeletal system as previously demonstrated by bone abnormalities when activating mutations or when overexpression of these G proteins occur in mice or humans. Here we investigated the effect of increased Gα in osteoblastic cells on bone fracture repair in transgenic (G-Tg) mice in comparison to wild type (WT). Following stabilized tibial osteotomies in male mice, fracture healing was examined weekly over 4 weeks by micro-CT, histomorphometry, and gene expression analysis and bone biomechanics after 4 weeks. Histomorphometry showed diminished cartilage in G-Tg mice at peak soft callus formation. Histology showed diminished osteoblasts on the healing bone of G-Tg mice throughout the 4 weeks ending with lower bone volume and bone mineral content as seen by micro-CT. Consistent with the lower amounts of cartilage and bone, mRNAs encoding chondrocyte proteins, Sox 9, Col 2a1 and Col 10a1 were significantly lower in G-Tg compared to WT at week 1. From 2 to 4 weeks Runx2, the master regulator of osteoblasts, and osteocalcin, a mature osteoblast marker, were significantly lower in G-Tg than in WT. Osteoclasts were not significantly different between G-Tg and WT. After 4 weeks, torsion testing showed significantly lower yield torque and torsional stiffness in G-Tg compared to WT. Together our results show that increased Gα inhibits endochondral bone development following fracture by suppressing both chondrocyte and osteoblast formation resulting in mechanically weaker bone.
Diagnostic agreement of bone histomorphometry for renal bone disease.
Jørgensen HS, Ystrøm IK, Maes C … +14 more , Nefyodova E, Kröger H, Tong X, Ferreira A, Ferreira AC, Poole K, Skingle L, Tabegna FGA, Gerbaix MC, Trombetti A, Lafage-Proust MH, Evenepoel P, Bravenboer N, European Renal Osteodystrophy initiative of the CKD-MBD working group of the European Renal Association
Bone · 2026 Jul · PMID 41962786 · Publisher ↗
INTRODUCTION: An iliac bone biopsy with semi-quantitative histomorphometry is the gold standard for evaluating renal osteodystrophy (ROD). However, lack of standardization of the bone biopsy procedure, sample handling, r...
INTRODUCTION: An iliac bone biopsy with semi-quantitative histomorphometry is the gold standard for evaluating renal osteodystrophy (ROD). However, lack of standardization of the bone biopsy procedure, sample handling, reading and reporting represent barriers to research synthesis and clinical collaboration. This study assessed diagnostic agreement across European laboratories performing histomorphometry for evaluation of ROD. METHODS: Five-millimeter transiliac biopsy slides from 5 cases were converted to digital images for analysis by experts from 7 laboratories. Parameters included quantitative histomorphometry, bone turnover, mineralization and volume (TMV) classification, and a concluding diagnosis. Agreement was analysed using Kappa statistics for categorical and intraclass correlation coefficients (ICC) for continuous variables. RESULTS: Agreement on histomorphometric variables ranged from poor to excellent. High agreement was observed for the static parameters bone area (ICC 0.91), osteoid area (ICC 0.95) and osteoid perimeter (ICC 0.84). For dynamic parameters, agreement was high for mineralizing surface (ICC 0.87) and bone formation rate (ICC 0.74), but poor for mineral apposition rate (ICC -0.13) and mineralization lag time (ICC 0.07). Agreement on the TMV classification was substantial for bone turnover (Kappa 0.77), slight for bone mineralization (Kappa 0.14), and substantial for bone volume (Kappa 0.73). The concluding diagnoses showed a high degree of consistency. CONCLUSIONS: Despite considerable inter-reader variability in bone histomorphometric measures, the clinical diagnoses of ROD were consistent across laboratories. Key sources of variability included analytical methods, disagreement on reference values, and differences in the definition of mineralization disorder. Further work should be undertaken to reach consensus on these points.
Bisphosphonate use and pregnancy complications: Insights from the FDA adverse event reporting system (FAERS) database.
Yazdalı Köylü N, Esen BH, Mutlu Ü … +3 more , Hacişahinoğulları H, Yenidünya Yalın G, Kubat Üzüm A
Bone · 2026 Jul · PMID 41951118 · Publisher ↗
PURPOSE: The sustained incorporation of bisphosphonates (BPs) into bone matrix, together with their documented transplacental transfer, raises concerns regarding their use in women of childbearing potential. We conducted...
PURPOSE: The sustained incorporation of bisphosphonates (BPs) into bone matrix, together with their documented transplacental transfer, raises concerns regarding their use in women of childbearing potential. We conducted a comprehensive evaluation of pregnancy-related adverse events (AEs) associated with BP exposure, utilizing data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: AEs associated with BP exposure during pregnancy reported to the FAERS between 2004 and 2025 were analyzed. Disproportionality analyses were performed using four standard signal-detection methods: reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). RESULTS: A total of 871 pregnancy-related AEs were identified. Alendronate accounted for the majority of exposures (n = 745). Pregnancy-related complications constituted the largest category of AEs (n = 751; 86%), followed by congenital, familial, and genetic disorders (n = 121; 14%), termination of pregnancy and risk of abortion (n = 40; 4.5%), and neonatal disorders (n = 39; 4.5%). AE reporting was higher with intravenous BPs than with oral agents, particularly for neonatal disorders (ROR = 3.35), fetal disorders (ROR = 2.50), and pregnancy termination or abortion-related events (ROR = 2.37). CONCLUSION: BP exposure during pregnancy appears to be associated with an increased risk of pregnancy- and fetal-related complications. Intravenous agents showed higher reporting of pregnancy complications.
Jagged ligand expression by alpha-SMA progenitors is required for normal fracture healing.
Kabadas FB, Wessels E, Buckles M … +13 more , Capobianco C, Schroeder L, Ford AJ, Cragg K, Noorily J, Deshmukh T, Hart M, Shaw S, Donneys A, Novak S, Wagley Y, Kalajzic I, Hankenson KD
Bone · 2026 Jul · PMID 41951117 · Publisher ↗
Fracture healing is a tightly regulated process dependent on coordinated activation and differentiation of mesenchymal progenitor cells and their progeny through spatiotemporally regulated signaling pathways. Canonical N...
Fracture healing is a tightly regulated process dependent on coordinated activation and differentiation of mesenchymal progenitor cells and their progeny through spatiotemporally regulated signaling pathways. Canonical Notch signaling has been implicated in governing mesenchymal progenitor fate in both calvarial and long bone healing. Endogenous Notch ligands, particularly Jagged-1 (Jag1), are highly expressed during the bone healing process, yet the role of Jag1 and its homolog, Jagged-2 (Jag2), during fracture healing have not been fully examined. Herein, we utilized temporally controlled, inducible transgenic mouse models to disrupt Jag1 and Jag2 in all cells of the callus (Rosa-CreERT2) and more specifically in early osteochondral progenitor cells (alpha-SMA-CreERT2) during traumatic tibial fracture healing. Absence of Jag1 and Jag2 in all cells or only in the progenitors impaired bone regeneration with distinct phenotypic differences in callus composition, mineral deposition, and cartilage resolution. Rosa-CreERT2-Jag1/Jag2-double knock out mice showed diminished callus bone volume and prolonged chondrogenesis without altering overall callus size, whereas lineage-specific deletion in alpha-SMA+ osteochondral progenitors resulted in disproportionate callus expansion, delayed cartilage clearance and altered mineral deposition. These findings identify Jag1 and Jag2 ligands as regulators of chondrogenesis and cartilage remodeling in alpha-SMA+ progenitors and underscore the spatiotemporal specificity of Notch signaling in coordinating endochondral ossification. Targeted activation of Jagged-mediated Notch signaling in osteochondral progenitors may represent a promising therapeutic strategy to enhance skeletal regeneration and accelerate endochondral repair in cases of nonunion or delayed fracture healing.
Efficacy and safety of Burosumab in tumor-induced osteomalacia: A systematic review and meta-analysis.
Rodrigues CG, de Oliveira CT, de Lima IF … +3 more , Antonello BB, Giovacchini G, Ribeiro PVZ
Bone · 2026 Jul · PMID 41951116 · Publisher ↗
INTRODUCTION: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by defective bone mineralization due to excessive fibroblast growth factor 23 production, leading to hypophosphatemia, phosphaturia...
INTRODUCTION: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by defective bone mineralization due to excessive fibroblast growth factor 23 production, leading to hypophosphatemia, phosphaturia, and osteomalacia. Burosumab, a monoclonal antibody that targets fibroblast growth factor 23, has emerged as a promising therapeutic option for patients with tumor-induced osteomalacia. This systematic review and meta-analysis assesses the efficacy and safety profile of Burosumab in managing tumor-induced osteomalacia, particularly in cases refractory to conventional treatments or when surgical resection of the tumor is not feasible. METHODS: This systematic review and meta-analysis adhered to the PRISMA guidelines and the Cochrane Handbook. Eligible studies included clinical trials evaluating Burosumab against placebo or standard care in patients with tumor-induced osteomalacia. Key outcomes encompassed serum phosphate levels, histomorphometric osteoid parameters, worst pain scale scores, and safety endpoints. Data extraction and quality appraisal were undertaken independently by two reviewers. Pooled means and events per 100 observations were derived using an inverse-variance random-effects model. RESULTS: Four studies met the eligibility criteria, encompassing 44 patients treated with Burosumab. Burosumab effectively stabilized serum phosphate levels (MD = 0.99; IC 95% 0.77-1.21; I = 0%). Histomorphometric parameters of osteoid tissue demonstrated marked improvements following Burosumab treatment, including reductions in thickness (MD = -4.56; IC 95% -6.72 to -2.40; I = 29.6%), volume (MD = -5.45; IC 95% -6.91 to -3.99; I = 0%), however, no significant change was observed in surface area (MD = -0.56; IC95% -3.63 - 2.50; I = 0%). Burosumab also significantly reduced pain score (MD = -1.11; IC95% -2.27 - 0.04; I = 0%). Safety analyses revealed that 79.33% (IC 95% 15, 84-98,74; I = 80.7%) of patients experienced adverse events, which were predominantly mild and seldom necessitated treatment discontinuation. CONCLUSION: Burosumab was associated with improvements in serum phosphate and bone histomorphometric parameters. A trend toward pain reduction was observed. The safety profile appeared acceptable, although adverse events were frequent. Findings should be interpreted considering the limited evidence base.
Plant-based dietary patterns and peak bone mass in healthy young adult women.
Zagarins S, Azarmanesh D, Bertone-Johnson ER
Bone · 2026 Jul · PMID 41942016 · Publisher ↗
Fifty percent of women over the age of 50 experience osteoporotic fractures. However, peak bone mass is achieved in young adulthood. Recent research suggests that plant-based dietary patterns may be associated with lower...
Fifty percent of women over the age of 50 experience osteoporotic fractures. However, peak bone mass is achieved in young adulthood. Recent research suggests that plant-based dietary patterns may be associated with lower bone mineral density and greater fracture risk in older adults. Limited evidence exists among younger populations, particularly studies assessing overall diet quality using index-based dietary measures. We examined associations between plant-based dietary patterns and bone density in a cross-sectional sample of 260 healthy women aged 18-30 participating in the UMass Vitamin D Status Study. Dietary intake was assessed using a modified Harvard Food Frequency Questionnaire, also used to determine vegetarian status and to calculate multiple versions of the Plant-Based Diet Index (PDI). Bone mineral density was measured using dual-energy X-ray absorptiometry. We examined associations between dietary patterns and continuous BMAD using multivariable linear regression models. In unadjusted models, higher unhealthy PDI scores were weakly and inversely associated with body bone mineral apparent density (BMAD) (β = -0.088; P = 0.16), while higher healthy PDI scores were weakly and positively associated with BMAD (β =0.077; P = 0.21). These associations were further attenuated following adjustment for overall diet quality, body fat percentage, and physical activity. Our findings indicate that plant-based dietary patterns are not independently associated with bone density in young adult women. These results provide reassurance that well-planned, plant-based diets in young adulthood are unlikely to compromise peak bone mass development. Longitudinal studies are needed to confirm these findings and evaluate potential long-term implications for bone health.
Glucocorticoid receptor represses the LGR4 gene by binding to the nGRE sequence and recruiting HDAC4 in mice monocytes.
Fang Q, Chen B, Lu S … +8 more , Li G, Chen D, Song W, Zhu Q, Ding P, Zhu D, Gao Y, Liu P
Bone · 2026 Jul · PMID 41933640 · Publisher ↗
The glucocorticoid receptor (GR) is a ligand-activated transcriptional regulator that translocates from the cytoplasm to the nucleus and modulates gene expression by binding DNA elements and recruiting coregulators. Synt...
The glucocorticoid receptor (GR) is a ligand-activated transcriptional regulator that translocates from the cytoplasm to the nucleus and modulates gene expression by binding DNA elements and recruiting coregulators. Synthetic glucocorticoids promote osteoclast overactivation, but the transcriptional mechanisms in osteoclast precursors remain incompletely defined. In glucocorticoid-stimulated monocytes, the leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a gene inhibiting osteoclastogenesis, is significantly repressed and osteoclast differentiation genes are upregulated. In our previous work, we found that classical monocytes contribute to osteoclastogenesis and display low expression of LGR4. However, the underlying mechanism has not been fully elucidated. In this study, we show that the glucocorticoid receptor occupies a negative glucocorticoid response element (nGRE) within the LGR4 promoter and recruits histone deacetylase 4 (HDAC4), thereby repressing LGR4 transcription and enhancing osteoclast differentiation programs. These findings suggest that disrupting GR-HDAC4-mediated repression of LGR4 may provide a strategy to mitigate glucocorticoid-enhanced osteoclastogenesis.
Denosumab-induced hypocalcemia: detection of drug-drug interactions using disproportionality analysis in VigiBase®.
Batteux B, Gras-Champel V, Cohen-Solal M … +2 more , Al Balkhi MH, Bennis Y
Bone · 2026 Jul · PMID 41933639 · Publisher ↗
BACKGROUND: Denosumab-induced hypocalcemia has been reported more frequently in real-world studies than in pivotal clinical trials; this is probably due to a closer monitoring of medication regimens in trials. Here, we s...
BACKGROUND: Denosumab-induced hypocalcemia has been reported more frequently in real-world studies than in pivotal clinical trials; this is probably due to a closer monitoring of medication regimens in trials. Here, we sought to detect signals for drug-drug interactions (DDIs) between denosumab and other hypocalcemia-inducing drugs. METHODS: We performed a disproportionality analysis of data in VigiBase® between January 1st, 2011, and February 7th, 2024. The frequency of hypocalcemia reports for all drugs known to induce hypocalcemia was compared with that for all other drugs and was quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. Generalized linear models were used to test for additive and multiplicative DDIs with denosumab. RESULTS: Of 3,076,045 reports recorded in Vigibase®, 2638 concerned hypocalcemia. The ROR [95%CI] values for co-exposures of denosumab with calcimimetics (850.5 [397.6-1819.6]), loop diuretics (251.6 [204.5-309.4]), proton pump inhibitors (164.5 [142.2-190.3]), calcitonin (462.5 [171.5-1247.1]), H2 receptor antagonists (157.2 [114.6-215.7]), aminoglycosides (134.7 [41.5-437.4]), cisplatin (464.1 [256.8-839.0]), sodium bicarbonate (510.4 [296-879.9]), and calcium channel blockers (175.3 [143.7-213.7]) were higher than the sum of the RORs for each drug taken individually. The δ coefficient of additive models of these co-exposures was significant, while that of multiplicative models was not. CONCLUSION: We found significant signals for hypocalcemia associated with DDIs between denosumab and a range of other hypocalcemia-inducing drugs, suggesting an increased risk of hypocalcemia. With a view to providing guidance on safe prescribing, the hypotheses generated in our disproportionality analysis need to be confirmed by further studies.
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