Bone [JOURNAL]
Sun
200 papers
Increased prevalence of morphometric vertebral fractures in patients with hypercalcitoninemia due to medullary thyroid carcinoma.
di Filippo L, Franzese V, Incampo G … +9 more , Formenti AM, Albanese L, Doga M, Onorati D, Maggiore R, Rosati R, Perticone F, Giubbini R, Giustina A
Bone · 2026 Jul · PMID 41933638 · Publisher ↗
CONTEXT: Calcitonin is a well-established biomarker of medullary thyroid cancer (MTC) but it is also known to exert distinct effects on bone metabolism. Previous studies evaluating calcitonin actions on skeletal health h...
CONTEXT: Calcitonin is a well-established biomarker of medullary thyroid cancer (MTC) but it is also known to exert distinct effects on bone metabolism. Previous studies evaluating calcitonin actions on skeletal health have yielded inconsistent results regarding its protective or deleterious role. To date, the impact of chronic hypercalcitoninemia, typically observed in patients with MTC, on skeletal fragility complications, particularly vertebral fractures (VFs), has not been investigated. DESIGN: We included patients with MTC and baseline calcitonin levels >50 pg/mL, matched 1:2 for demographics and comorbidities with patients affected by papillary thyroid carcinoma (PTC). VFs were assessed through morphometric analysis of preoperative lateral chest X-rays. RESULTS: 99 patients were included (33 MTC, 66 PTC; median age 57 years; 27% male). No differences were observed in sex, age, or comorbidities between groups. VF prevalence was significantly higher in MTC patients than in PTC patients (24% vs. 7.6%, p = 0.029). Median calcitonin levels were higher in patients with VFs compared to those without (1267 vs. 501 pg/mL, p = 0.005). In multivariate analysis, MTC diagnosis was the only independent predictor of VFs (OR 4.3, p = 0.028). ROC curve analysis confirmed a significant predictive value of calcitonin levels for the presence of VFs (p = 0.006). CONCLUSIONS: This is the first study to demonstrate an increased prevalence of thoracic VFs in patients with MTC and hypercalcitoninemia compared with a matched population affected by another form of thyroid cancer. These findings expand the clinical spectrum of calcitonin-related effects, suggesting a potential role of excessive calcitonin levels in skeletal fragility risk.
Estimating motion artifacts of HR-pQCT scans using automatically derived standard parameters of bone structure- and density-quantification.
Albrecht E, Bartosik M, Simon A … +6 more , Baumbach J, Barvencik F, Amling M, Oheim R, Tsoy O, von Brackel FN
Bone · 2026 Jul · PMID 41932417 · Publisher ↗
Motion grading in high-resolution peripheral quantitative computed tomography (HR-pQCT) is a critical task for data validity, dependent on the operator. In routine clinical practice, validating the grading performed by t...
Motion grading in high-resolution peripheral quantitative computed tomography (HR-pQCT) is a critical task for data validity, dependent on the operator. In routine clinical practice, validating the grading performed by technical staff is challenging. This is of critical importance since motion also affects the derived results of HR-pQCT. To address these issues, we focused on using established clinical HR-pQCT-derived structure-density parameters to predict whether imaging samples are motion corrupted. Using a dataset of 1000 scans from the tibia and radius, we employed a logistic regression model to classify whether scans are corrupted or not, condensing the task into a binary problem. Additionally, we evaluated the performance specifically for patients with altered bone microstructure. We achieved a high sensitivity with an average of 0.7. Our results suggest that motion-corrupted scans affect derived parameters differently than disease-related changes in bone microstructure. Thresholds for model trust were established to estimate the reliability of our predictions. Furthermore, feature importance was assessed, aligning with previous work on motion artifacts. Thus, we provide a low (computational) cost, efficient, and robust internal quality-control approach for grading derived data validity in clinical routine. Additionally, we enable cleaning large cohort datasets, enabling a retrospective evaluation without the need of image data retrieval or handling. By adding conformity thresholds, users can optimize their workflow to allow for high data quality.
Altered bone structure in Niemann-Pick Type C1 mice, especially in females.
Mattern N, Brandt N, Bräuer AU … +9 more , Steinhoff LM, Wree A, Scherberich J, Windfelder AG, Kampschulte M, Krombach GA, Heiss C, Windhorst A, Lips KS
Bone · 2026 Jul · PMID 41932416 · Publisher ↗
Niemann-Pick type C disease (NPC) is a rare lysosomal storage disorder belonging to the group of sphingolipidoses and is caused by a genetic defect affecting cholesterol trafficking. Since other sphingolipidoses with lip...
Niemann-Pick type C disease (NPC) is a rare lysosomal storage disorder belonging to the group of sphingolipidoses and is caused by a genetic defect affecting cholesterol trafficking. Since other sphingolipidoses with lipid accumulations show disrupt bone, this study investigated bone structure in an Npc1 mouse model and assessed whether pharmacological treatments (miglustat, 2-hydroxypropyl-β-cyclodextrin [HPßCD], and combination therapy including allopregnanolone) affected it. Femora from Npc1/ mice of postnatal day (P) 65 were analysed using histology, histomorphometry and micro-CT. Additionally, femur and vertebral bodies of mice from P30, P40 and P65 were examined by real-time RT-PCR. Histomorphometric findings revealed a significantly reduced relative bone area in female Npc1/ mice compared to wild-type mice. Micro-CT analysis confirmed this by demonstrating deteriorated trabecular bone structures in female Npc1/ mice. Following treatment, particularly with combination therapy, an improvement in the bone microarchitecture was observed. Differences relative to wild-type mice were often no longer detectable. Furthermore, there was some evidence that combi therapy also increased the relative numbers of osteoblasts and osteoclasts. Since real-time RT-PCR indicated low expression of osteoclast and osteocyte targets cathepsin K and connexin-43, respectively, a stimulation of bone cells might decelerate postnatal disease progression. While at P30, sphingosine-kinase-1 (SphK1) expression was increased in female Npc1/ mice, it decreased in femur at P40 and in vertebral bodies at P65. This decline was not measured in male Npc1/ mice revealing a sex-dependent decline of bone structures in female Npc1/ mice. Overall, disease-modifying treatment regimens targeting lipid storage improved bone microarchitecture in a sex-dependent manner.
Effects of spermine on osteoblasts during iron deficiency in vitro and in vivo during chronic kidney disease.
Miller C, Segvich DM, Wanner J … +6 more , Mahmood H, Kirschner KM, Matz JA, Santangelo S, Wallace JM, Clinkenbeard EL
Bone · 2026 Jul · PMID 41931864 · Publisher ↗
Chronic kidney disease (CKD), affecting millions worldwide, displays alterations in mineral metabolism ultimately adversely affecting bone integrity, yet the mechanisms remain unclear. Iron deficiency, which can often oc...
Chronic kidney disease (CKD), affecting millions worldwide, displays alterations in mineral metabolism ultimately adversely affecting bone integrity, yet the mechanisms remain unclear. Iron deficiency, which can often occur with aging and CKD, is independently associated with bone loss and increased mortality. Indeed, iron is a necessary component for osteoblast differentiation and mineralization. A recent study found that iron deficiency can intrinsically change polyamine concentrations through its impact on synthesis and catabolic pathways. Another study associated a decrease in specific polyamines with increased CKD severity. Furthermore, marrow stromal cells lacking the capacity to synthesize the polyamine spermine having reduced osteogenic mineralization. The purpose of this study was to assess the effects of polyamine supplementations during iron deficiency both in vitro and in vivo. We used mouse progenitor cells differentiated under standard osteogenic protocols in the presence of the iron chelator deferoxamine (DFO) with or without spermine supplementation. Iron deficiency negatively impacted mineralization which was reversed with spermine supplementation. In vivo, CKD was induced with 0.2% adenine-containing diet, with adenine-fed subgroups receiving spermine in the drinking water for four to eight weeks. Oral spermine supplementation exhibited a negative effect with no improvements in bone RNA expression, additional bone loss, and a dose dependent decrease in circulating intact fibroblast growth factor 23 (iFGF23). Ultimately, adenine-fed mice supplemented with the highest concentrations of spermine exhibited incidence of heart calcifications which were absent from the vehicle control adenine-fed mice. These data suggest polyamines are potential modulators of mineral metabolism especially in the setting of chronic kidney disease.
The effects of anti-Parkinsonian medications on bone mineral density: A systematic review.
Ó Breasail M, El-Leissy MB, Singh KP … +10 more , Smith M, Mesinovic J, Sim M, Evans A, Blacker D, Heshmat S, Mahant N, Girgis C, Ebeling PR, Zengin A
Bone · 2026 Jul · PMID 41921715 · Publisher ↗
INTRODUCTION: Parkinson's disease (PD) is associated with elevated fracture risk, particularly at the hip. Antiparkinsonian medications have also been associated with increased fracture risk; although their direct effect...
INTRODUCTION: Parkinson's disease (PD) is associated with elevated fracture risk, particularly at the hip. Antiparkinsonian medications have also been associated with increased fracture risk; although their direct effects on bone mineral density (BMD) remains unclear. OBJECTIVE: Investigate whether antiparkinsonian medications influence BMD. METHODS: A systematic search of four databases (Embase, MEDLINE, APA PsycINFO, Web of Science) was conducted up to 24/11/2025 using terms related to PD, antiparkinsonian medications and bone. RESULTS: A total of 748 records were identified, with 543 screened following deduplication. Fourteen studies underwent full-text review, of which seven met inclusion criteria. Three studies assessed bone mineral content or surrogate measures at non-standard sites (hand radiographs or skull Hounsfield Units) and reported no associations with L-Dopa therapy. Four studies reported areal BMD (aBMD) from dual energy x-ray absorptiometry (DXA). One study showed negative correlations between L-Dopa dosage with aBMD at the hip and spine. Two studies (RCT and cross-sectional) implicated elevated serum homocysteine (Hcy) levels induced by L-Dopa as a potential mechanism for osteoporosis risk in PD. In the cross-sectional study, although L-Dopa therapy was associated with higher Hcy and lower aBMD, there were no causal associations between L-Dopa and hip aBMD. In the RCT, lower Hcy was associated with reduced annual aBMD loss with L-Dopa therapy. One further study found no associations between L-Dopa therapy and aBMD at any site. CONCLUSIONS: The contribution of antiparkinsonian medication to low BMD in PD remains unclear. Despite plausible mechanisms of action, evidence of causal associations is lacking.
Piezo1 Mediates Mechanical Strain-Induced Bone Remodeling in TMJ Condylar Cartilage via PI3K/Akt Signaling.
Zhang Y, Feng X, Yan Y … +3 more , He J, Zheng B, Liu Y
Bone · 2026 Jun · PMID 41912060 · Publisher ↗
INTRODUCTION: This study aims to investigate the role of Piezo1 in temporomandibular joint (TMJ) condylar bone remodeling under mechanical stimulation in orthodontic treatment. METHODS: Piezo1; Col2α1-Cre(Piezo1KO) and P...
INTRODUCTION: This study aims to investigate the role of Piezo1 in temporomandibular joint (TMJ) condylar bone remodeling under mechanical stimulation in orthodontic treatment. METHODS: Piezo1; Col2α1-Cre(Piezo1KO) and Piezo1; Col2α1-Cre(Control) mice were generated for in vivo study. A mandibular advancement (MA) model was established to induce bone remodeling in TMJ condyle. Subchondral bone quality was assessed using micro-CT, while changes in the distribution and expression levels of Piezo1, Osx, and Ocn were evaluated via immunofluorescence staining. In vitro, ATDC5 cells were subjected to 6% cyclic tensile strain (CTS) using Flexcell 5000 T. ShPiezo1 ATDC5 model was constructed by lentiviral transfection. The influence of Piezo1 on osteogenic markers and PI3K/Akt pathway under CTS was evaluated through a real-time polymerase chain reaction analysis and Western blot. An Akt agonist (SC79) was used to observe the rescue effect of Akt activation on experiments carried out on ShPiezo1 cells under CTS, and the protein expression of Akt, pAkt, Osx, and Ocn was detected by Western blot. RESULTS: Piezo1, Osx and Ocn were overexpressed in the MA-induced condylar cartilage and ATDC5 under CTS. Conditional knockout of Piezo1 inhibited the bone remodeling of TMJ condylar cartilage in mice. Piezo1 silencing suppressed osteogenic marker expression and PI3K/Akt signaling in CTS-stimulated ATDC5 cells, which was partially rescued by treatment with SC79. CONCLUSIONS: Piezo1 is essential for mechanical stimulation-induced bone remodeling in TMJ condylar cartilage. Under CTS, Piezo1 mediates the upregulation of osteogenic markers in chondrocytes via activation of PI3K/Akt pathway, highlighting its potential as a mechanotherapeutic target in craniofacial bone regeneration.
METTL3-mediated m6A modification of circWDR85 drives breast cancer bone metastasis via the CKB/c-Jun axis.
Li N, Fan X
Bone · 2026 Jul · PMID 41912059 · Publisher ↗
BACKGROUND: Bone metastasis is a common and life-threatening complication in advanced breast cancer (BC), yet its underlying molecular mechanisms remain incompletely understood. Circular RNAs (circRNAs) have emerged as c...
BACKGROUND: Bone metastasis is a common and life-threatening complication in advanced breast cancer (BC), yet its underlying molecular mechanisms remain incompletely understood. Circular RNAs (circRNAs) have emerged as critical regulators of tumor progression, including metastasis. Here, we investigated biological role and regulatory mechanism of circWDR85 (hsa_circ_0089696) in BC bone metastasis. METHODS: circWDR85 expression and its m6A modification by METTL3 were assessed using RT-qPCR, RIP, MeRIP, and mutational analysis. Functional role of circWDR85 was evaluated via in vitro assays and in vivo intracardiac injection metastasis models. Mechanistic studies were conducted to explore the interaction of circWDR85 with CKB and its effect on c-Jun phosphorylation, ubiquitination, and stability. RESULTS: circWDR85 was significantly overexpressed in highly metastatic BC cell lines and bone metastatic tissues. METTL3 directly bound and methylated pre-circWDR85 at a defined m6A site, enhancing its biogenesis. Functionally, circWDR85 promoted bone metastasis in vivo, as its knockdown reduced skeletal lesions and improved survival. Mechanistically, circWDR85 recruited CKB, which directly interacted with c-Jun and facilitated its phosphorylation at T91, thereby stabilizing c-Jun protein by inhibiting ubiquitination. Rescue experiments confirmed that circWDR85 functionally depends on c-Jun activity to drive osteolytic metastasis. CONCLUSION: circWDR85 acts as a novel m6A-modified circRNA that promotes BC bone metastasis by stabilizing c-Jun through CKB-mediated phosphorylation.
Interval rehabilitation with intermittent rest modulates systemic immune response and improves healing following bone injury.
Williams KE, Hajarizadeh A, Link K … +2 more , Gill D, Guldberg RE
Bone · 2026 Jul · PMID 41905480 · Publisher ↗
Rehabilitative exercise has shown potential to enhance bone healing, but the optimal design of exercise protocols following injury remains unclear. This study investigated how two rehabilitation parameters-progressive lo...
Rehabilitative exercise has shown potential to enhance bone healing, but the optimal design of exercise protocols following injury remains unclear. This study investigated how two rehabilitation parameters-progressive loading and intermittent rest between running bouts-influence bone regeneration and the systemic immune response following traumatic femoral defects in rodents. Rehabilitation protocols with varying treadmill inclines were applied after 3 mm segmental bone defects. Despite incorporating gradual or delayed increases in treadmill incline, all groups exhibited minimal bone formation and high nonunion rates, suggesting that these treadmill protocols may be insufficient to promote healing in 3 mm defects. Next, we tested whether incorporating one minute of intermittent rest in between every minute of treadmill running could enhance regeneration in bilateral femoral defects (2 mm and 3 mm). Interval running with intermittent rest significantly increased bone volume in 3 mm defects and resulted in a near-significant improvement in 2 mm defects compared to continuous running and sedentary controls. Flow cytometry of longitudinal blood samples revealed that interval running also resulted in a more accelerated reduction of circulating MDSCs toward baseline levels than continuous treadmill running without intermittent rest and sedentary controls. Treadmill interval running also significantly reduced monocyte levels one week after post-injury rehabilitation began. These findings suggest that interval running with intermittent rest can attenuate injury-induced inflammation while improving bone outcomes, highlighting the therapeutic potential of interval exercise regimens to promote mechanical and immunological environments favorable for bone repair. This work advances our understanding of how exercise design can be optimized to improve post-injury healing outcomes.
Deletion of the glucocorticoid receptor in osteoblasts and osteocytes drives trabecular bone loss in Col2.3-Cre and OG2-Cre knockout mice.
Macfarlane E, Cavanagh L, Massarotti C … +6 more , Fong-Yee C, Imlay E, Tannous J, Tuckermann J, Seibel MJ, Zhou H
Bone · 2026 Jun · PMID 41903788 · Publisher ↗
Studies using the 11β-HSD2 transgenic mouse model have established that endogenous glucocorticoids in bone forming cells are important for normal trabecular and cortical bone mass and structure. However, the role of the...
Studies using the 11β-HSD2 transgenic mouse model have established that endogenous glucocorticoids in bone forming cells are important for normal trabecular and cortical bone mass and structure. However, the role of the glucocorticoid receptor in mature osteoblasts and osteocytes for maintaining the skeleton remains unknown. We generated two glucocorticoid receptor knockout models targeting mature osteoblasts and osteocytes (by utilizing the Col2.3-Cre or OG2-Cre). We found that deletion of the glucocorticoid receptor using either knockout model profoundly reduced vertebral bone volume fraction across various ages from 7 to 26 weeks in male and female mice compared to wild-type animals. At the tibia we found sex-specific differences in trabecular bone volume fraction, which was reduced in male but not female Col2.3-Cre and OG2-Cre glucocorticoid receptor knockout mice. Compared to trabecular bone, changes in cortical bone mass and structure in glucocorticoid receptor knockout mice were age and model dependent. Young male and female Col2.3-Cre glucocorticoid receptor knockout mice exhibited a reduction in cortical area and thickness. However, in male but not female OG2-Cre glucocorticoid receptor knockout mice, cortical area fraction and cortical thickness were increased compared to control animals. By 26 weeks of age, cortical bone structure was comparable in Col2.3-Cre and OG2-Cre glucocorticoid receptor knockout mice compared to wild-type animals. Our results provide evidence that glucocorticoid receptor signalling in mature osteoblasts and osteocytes is critical for the maintenance of trabecular and cortical bone mass and structure.
Systemic administration of osteoblast-derived collagenase released extracellular vesicles restores trabecular bone loss in ovariectomized mice.
Mizukami Y, Takahashi Y, Otera H … +6 more , Kawao N, Yamao H, Sano E, Mine Y, Kishigami R, Kaji H
Bone · 2026 Jun · PMID 41903787 · Publisher ↗
Matrix vesicles (MtVs), a type of extracellular vesicles (EVs), are secreted by osteoblasts and initiate bone mineralization. Recent evidence suggests that MtVs are also involved in intercellular communication, inhibitin...
Matrix vesicles (MtVs), a type of extracellular vesicles (EVs), are secreted by osteoblasts and initiate bone mineralization. Recent evidence suggests that MtVs are also involved in intercellular communication, inhibiting osteoclast formation, and promoting bone repair. These findings suggest that MtVs might hold therapeutic potential for osteoporosis; however, their effects on osteoporosis have incompletely remained understood. In this study, we investigated the effects of mineralized mouse osteoblastic MC3T3-E1 cell-derived collagenase-released EVs (MC-CREVs) on bone loss in ovariectomized mice, using C2C12 myotube-derived EVs (MT-EVs) as a control. MC-CREVs approximately 100 nm in size were isolated from collagenase-digested mineralized MC3T3-E1 cultures by density gradient ultracentrifugation. Systemic administration of MC-CREVs restored trabecular bone mineral density, bone volume, and trabecular thickness in ovariectomized mice, while the number of osteoclasts on the trabecular bone surface was decreased. In vitro experiments, MC-CREVs suppressed osteoclast formation and osteoclast marker gene expression induced by RANKL more effectively than MT-EVs in RAW264.7 cells. The miRNA array analyses showed that miR-1224-5p was abundantly expressed in MC-CREVs. In conclusion, we demonstrated that systemic administration of MC-CREVs is effective for trabecular bone loss presumably through suppression of bone resorption in ovariectomized mice.
Sagittal abdominal diameter and abdominal aortic calcification are associated with incident major adverse cardiovascular events: The Manitoba Bone Density Registry.
Abraha HN, Gebre AK, Sim M … +12 more , Smith C, Gilani SZ, Ilyas Z, Zarzour F, Schousboe JT, Lix LM, Binkley N, Reid S, Monchka BA, Kimelman D, Lewis JR, Leslie WD
Bone · 2026 Jul · PMID 41903786 · Publisher ↗
BACKGROUND: Sagittal abdominal diameter (SAD), a measure of visceral adiposity, has been linked to major adverse cardiovascular events (MACE). However, the relationship between SAD and abdominal aortic calcification (AAC...
BACKGROUND: Sagittal abdominal diameter (SAD), a measure of visceral adiposity, has been linked to major adverse cardiovascular events (MACE). However, the relationship between SAD and abdominal aortic calcification (AAC), a marker of subclinical vascular disease, and whether they independently and jointly predict MACE remains unclear. OBJECTIVE: To investigate whether weight-normalized SAD and AAC scored using a validated machine learning algorithm (ML-AAC24) are independently and jointly associated with incident MACE. METHODS: SAD and ML-AAC24 were measured from dual-energy X-ray absorptiometry (DXA) posteroanterior and lateral spine images, respectively, from the Manitoba Bone Density registry. RESULTS: Among 8806 individuals (mean age 75.1 ± 6.6 years, 93.9% women), 11.3% experienced MACE during a mean follow-up of 3.8 years. SAD/weight and ML-AAC24 were positively correlated (Spearman r = 0.11, P < 0.001). Individuals with moderate and high ML-AAC24 had 1.1% and 3.0% higher mean SAD/weight, respectively, than those with low ML-AAC24. Both ML-AAC24 and SAD/weight were independently associated with higher risk of MACE. Adjusted hazard ratios [HRs] for MACE were 1.45, 95%CI 1.24-1.71 and 1.99, 95%CI 1.67-2.35 for moderate and high ML-AAC24, respectively, vs. low. The HR for the highest vs. lowest tertile of SAD/weight was 1.37, 95%CI 1.16-1.61. Individuals who had both high ML-AAC24 and were in the highest SAD/weight tertile had the highest MACE risk (HR 2.63, 95% CI 2.02-3.44). CONCLUSION: Higher baseline SAD/weight was associated with higher ML-AAC24 scores. Both measures independently and jointly associated with MACE. Their combined use may potentially help identify individuals at high risk for cardiovascular disease during routine bone density testing.
Denervation induces rapid bone degeneration concurrent to neurovascular and mechanical changes.
Pan K, Cheng X, Wu Y … +9 more , Orozco E, Shin SH, Du J, Ma Y, Jerban S, Hughes-Austin JM, Bukata S, Chang EY, Shah SB
Bone · 2026 Jun · PMID 41871705 · Publisher ↗
Denervation results in reduced bone quality, largely attributed to reduced loading due to concurrent muscle atrophy. However, sensory and sympathetic nerves also directly innervate bone, suggesting additional potential i...
Denervation results in reduced bone quality, largely attributed to reduced loading due to concurrent muscle atrophy. However, sensory and sympathetic nerves also directly innervate bone, suggesting additional potential inputs into bone remodeling. A quantitative baseline of bone morphological and functional changes after nerve injury is lacking. We investigated structural, biomechanical, and histological outcomes for time points up to three months following peripheral nerve injury. Our primary objective was to establish timelines over which bone and muscle structure and biomechanical function degraded after denervation. Additionally, we evaluated remodeling of bone innervation and vascularity and alterations in bone homeostatic markers after injury. Using a Lewis rat nerve injury model (n = 60 total rats), our findings showed rapid bone deterioration following transection of sciatic nerves of both male and female rats. Biomechanical properties of bone, including three-point bending yield force (P < 0.001), ultimate force (P < 0.001), and stiffness (P < 0.001), were significantly reduced as early as two weeks post-injury. At a slight delay compared to biomechanical changes, micro-CT and MRI revealed that bone mineral density (P < 0.0001) and cortical thickness (P < 0.001) also declined and porosity increased (P < 0.05) within three months. Immunohistochemical analysis revealed marked decreases in sensory (calcitonin gene-related protein; CGRP) and sympathetic (Neuropeptide-Y; NPY) neuropeptides, reduced osteoblast density in periosteal regions, and increased vascular (CD-31) area fraction, accompanied by increased vascular fragmentation. These findings support the possibility that both muscle and neuronal influences underlie denervation-related bone atrophy, setting the stage for evaluation of bone health after nerve repair and targeted rehabilitative or therapeutic interventions.
Association of outdoor light exposure with bone mineral density and osteoporosis risk: A gene-environment interaction analysis.
Wang YX, Zhou HL, Cui ZB … +8 more , Chen ZW, Ling DY, Zhang Y, Ke P, Li DK, Zhang C, Wang Q, Di DS
Bone · 2026 Jun · PMID 41871704 · Publisher ↗
OBJECTIVE: The association between time spent in outdoor light (TOL), genetic predisposition, and the risk of osteoporosis (OP) remains unclear. This study aimed to quantify the association between TOL and OP risk, and t...
OBJECTIVE: The association between time spent in outdoor light (TOL), genetic predisposition, and the risk of osteoporosis (OP) remains unclear. This study aimed to quantify the association between TOL and OP risk, and to evaluate whether genetic predisposition modifies this relationship. METHODS: Data from the UK Biobank on 326,216 participants based on self-reported TOL, estimated bone mineral density (eBMD), and hospital inpatient records for OP diagnosis. A polygenic risk score (PRS) for OP was calculated and categorized into tertiles. We used generalized linear models, Cox proportional hazards models, and Laplace regression to evaluate the cross-sectional and longitudinal associations between TOL, PRS, and OP risk. RESULTS: Higher average TOL was associated with increased eBMD (β = 0.0021 g/cm, 95% CI: 0.0018-0.0024) and lower OP risk (OR = 0.9739, 95% CI: 0.8839-0.9952) in cross-sectional analysis. Participants who spent more than 3 h/day in outdoor light during summer had a reduced risk of incident OP (HR = 0.9505, 95% CI: 0.9088-0.9942) and experienced a delayed by 0.36 years (50th percentile difference = 0.3634, 95% CI: 0.0794-0.6473), compared with those exposed ≤3 h/day. Subgroup analysis indicated an additive effect of limited TOL and high genetic risk on OP susceptibility. CONCLUSION: Prolonged exposure to outdoor light is associated with higher eBMD and a lower risk of developing OP, even among individuals with high genetic susceptibility. These findings suggest that increasing TOL may be a modifiable lifestyle factor to reduce OP risk, especially in genetically predisposed populations.
Modeling and investigating the interactive role of fluid velocity and pore pressure within the lacunar-canalicular system in load-induced osteogenesis.
Shekhar H, Prasad J
Bone · 2026 Jun · PMID 41864527 · Publisher ↗
Current models propose that osteogenesis occurs in regions of high mechanical stimuli such as strain, fluid velocity, or pore pressure. However, in vivo experiments on mouse tibiae subjected to cantilever loading reveale...
Current models propose that osteogenesis occurs in regions of high mechanical stimuli such as strain, fluid velocity, or pore pressure. However, in vivo experiments on mouse tibiae subjected to cantilever loading revealed new bone formation exclusively on the anterolateral side, although the opposite posteromedial surface experienced comparable magnitudes of these stimuli. This indicates that individual stimulus magnitude is insufficient and indicate an interactive mechanism. To investigate this, a poroelastic finite element model was developed to quantify the combined effects of load-induced fluid velocity and pore pressure. Tensile loading generated negative pore pressure that stretched osteocyte processes, whereas compressive loading produced positive pore pressure that compressed them. Because fluid flow exerts drag forces that also stretch osteocytes, the combined effect of flow and negative pressure on the tensile side was hypothesized to enhance mechanotransduction and trigger osteogenesis. Four candidate stimuli were evaluated: dissipation energy density arising from (i) pore pressure, (ii) fluid velocity, (iii) their non-interactive sum, and (iv) their interaction. Comparison with in vivo data showed that only the interactive dissipation energy density accurately predicted both the spatial pattern and the average rate of new bone formation per unit bone surface under high, low, and rest-inserted cantilever loading. The model also predicted osteogenesis under axial loading, demonstrating robustness. These findings advance mechanistic understanding by establishing that the interaction between fluid velocity and pore pressure, rather than their independent effects, governs load-induced osteogenesis, and provide a predictive basis for optimizing mechanical and clinical interventions to promote bone formation and mitigate bone loss.
Bone phenotype of patients with telomere biology disorders.
Zervou Z, Aalbers AM, van Velsen EFS … +3 more , Valk PJM, Raaijmakers MHGP, Zillikens MC
Bone · 2026 Jun · PMID 41861895 · Publisher ↗
Telomere biology disorders (TBD) are a group of diseases that interfere with normal maintenance of telomeres, the ends of chromosomes that protect them from DNA damage. The most common manifestations are bone marrow fail...
Telomere biology disorders (TBD) are a group of diseases that interfere with normal maintenance of telomeres, the ends of chromosomes that protect them from DNA damage. The most common manifestations are bone marrow failure, pulmonary and liver fibrosis. Systematic data on bone health in patients with TBD are scarce. Our aim was to elucidate the bone phenotype of these patients. The cohort comprises 36 adult patients (20 women and 16 men), with genetically confirmed TBD. Demographic, clinical and genetic characteristics, dual-energy X-ray absorptiometry (DXA) scans, spine X-rays and treatment details were reviewed. Median age of patients was 53.5 (43.0, 64.2) years. (Likely) pathogenic variants of the TERT gene were present in most patients. Osteopenia was diagnosed in 38.9% and osteoporosis in 25.0% of patients, 25.0% had a clinical fracture within the past 5 years, and 40.0% had at least one prevalent vertebral fracture (grade 1-3). T-score at the lumbar spine (-0.98 ± 1.48SD) was lower than at the femoral neck (-0.60 ± 1.09SD). Mean trabecular bone score (TBS) T-score was -1.32 ± 1.29SD. Bone-active therapy was used by 44.4% of the population, mostly oral bisphosphonates (85.7%). To conclude, we reported a high prevalence of osteopenia, osteoporosis, recent fractures and prevalent vertebral fractures, in patients with TBD. These results highlight the necessity of addressing the risk of osteoporosis and fractures in these patients during medical assessments. Most importantly, additionally to a DXA scan, a vertebral fracture assessment (VFA) or spine X-ray, is recommended to evaluate vertebral fractures.
Diabetic neuropathy and fracture risk - a nation-wide case/control study.
Graversen JL, Kvist AV, Rasmussen NH … +2 more , Vestergaard P, Røikjer J
Bone · 2026 Jun · PMID 41833833 · Publisher ↗
INTRODUCTION/AIM: Fracture risk is increased in type 1 (T1D) and type 2 diabetes (T2D). Diabetic neuropathy may contribute to this risk. We examined the association between diabetes and fracture risk, and whether diabeti...
INTRODUCTION/AIM: Fracture risk is increased in type 1 (T1D) and type 2 diabetes (T2D). Diabetic neuropathy may contribute to this risk. We examined the association between diabetes and fracture risk, and whether diabetic neuropathy, including possible painless and possible painful neuropathy, was associated with increased risk of fracture. METHODS: In this population-based case-control study, adults (≥18 years) with and without diabetes were identified using Danish health registries. All incident fractures (excluding skull/facial) from 2019 to 2021 were included, and up to three age- and sex-matched controls were selected per case. Diabetes and diabetic neuropathy were defined by ICD and ATC codes; neuropathy was classified as possible painful or painless based on prescriptions for neuropathic pain medications. Associations between diabetes, neuropathy, and fracture risk at different sites were estimated using conditional logistic regression adjusted for confounders. RESULTS: We included 265,405 individuals with incident fractures and 778,466 matched controls. After multivariable adjustment, fracture risk was increased in T1D (OR 1.68, 95% CI 1.61-1.76) but not in T2D (OR 0.93, 95% CI 0.91-0.94). Diabetic neuropathy was independently associated with higher fracture risk (OR 1.47, 95% CI 1.40-1.55), with the highest risk in possible painful neuropathy (OR 1.62, 95% CI 1.50-1.74). The association between diabetic neuropathy and fracture risk appeared stronger in men and younger individuals. Site-specific analyses suggested larger point estimates for lower leg fractures and comparatively smaller estimates for vertebral, hip and lower arm fractures. The effect of neuropathy did not differ between diabetes type. CONCLUSION: Diabetic neuropathy is an independent risk factor for fracture, with particularly high risk in individuals with possible painful neuropathy, potentially due to increased fall risk and impaired bone quality.
Sympathetic overactivity-induced type H endothelial cell senescence contributes to the impairment of vascularized osteogenesis by PKM2-mediated glycolysis in preclinical stages of Alzheimer's mice.
Zhang W, Liu T, Rong X … +2 more , Liu H, Li M
Bone · 2026 Jun · PMID 41833832 · Publisher ↗
Alzheimer's disease (AD) is characterized by early-onset bone loss, yet the underlying mechanisms remain elusive. Here, we demonstrated that sympathetic hyperactivity drives vascularized osteogenesis impairment in precli...
Alzheimer's disease (AD) is characterized by early-onset bone loss, yet the underlying mechanisms remain elusive. Here, we demonstrated that sympathetic hyperactivity drives vascularized osteogenesis impairment in preclinical AD through a novel PKM2-glycolysis-mediated bone vascular endothelial cell (EC) senescence pathway. Utilizing systematic transcriptome profiling complemented by in vitro functional assays and in vivo validation studies, we found that norepinephrine (NE)-induced PKM2 downregulation disrupts glycolytic flux, triggering mitochondrial dysfunction-induced senescence (MiDAS) in vascular ECs. This metabolic reprogramming of vascular ECs inhibits the differentiation of osteoprogenitors by reducing the secretion of pro-osteogenic factors. Pharmacological inhibition of β-adrenergic signaling or PKM2 activation rescues EC senescence and bone loss. Mechanistically, NE released by the sympathetic nerve suppresses c-Maf, a transcription factor critical for PKM2 expression, linking sympathetic activation to metabolic dysfunction. Furthermore, our results also showed that combination therapy with oryzanol (sympathetic modulator) and eldecalcitol (senolytic) synergistically restores vascularized osteogenesis by targeting both neurovascular and metabolic axes. These findings establish a pathogenic role for sympathetic hyperactivity in AD-related skeletal dysfunction and highlight a therapeutic strategy targeting EC senescence and glycolytic metabolism.
Bone strain index improves 10-year fracture risk prediction beyond bone mineral density and FRAX® in community-dwelling older women: A study of the FRISBEE cohort.
de Filette J, Bellanger A, Rinaudo L … +11 more , Ulivieri FM, Calderone I, Cuttone S, Sanchez-Rodriguez D, Baleanu F, Hambye AS, Benoit F, Surquin M, Iconaru L, Body JJ, Bergmann P
Bone · 2026 Jun · PMID 41831746 · Publisher ↗
OBJECTIVES: The Bone Strain Index (BSI), derived from finite element analysis of DXA, quantifies mechanical strain within bone. Its predictive value for fragility fractures in older women remains to be established in lar...
OBJECTIVES: The Bone Strain Index (BSI), derived from finite element analysis of DXA, quantifies mechanical strain within bone. Its predictive value for fragility fractures in older women remains to be established in large prospective studies. METHODS: This prospective cohort study assessed the association between BSI, incident fragility and major osteoporotic fractures (MOF) in 3338 community-dwelling older women (age 64-77 years) during a 5-year and 10-year follow-up. BSI was calculated at the lumbar spine, total hip, and femoral neck using baseline DXA scans. Incident fragility and MOF were radiographically validated. Discriminative performance was assessed using ROC curves, optimal cut-offs (Youden index), and Cox proportional-hazards models adjusted for age, areal bone mineral density (aBMD), or FRAX® score. RESULTS: During the 10-year follow-up, 803 women (24.1%) sustained at least one fragility fracture, including 525 MOF. Higher BSI values were significantly associated with increased fracture risk at 5 and 10 years, independently of age, aBMD, or FRAX®. Total hip BSI showed the strongest performance among all sites (AUC 0.63 at 5 and 10 years), outperforming lumbar spine BSI (AUC 0.58). Each 1-SD increase in total hip BSI was associated with higher fracture risk (HR 1.42 [1.32-1.53] at 5 years; 1.41 [1.34-1.49] at 10 years), which remained significant after FRAX® adjustment (HR 1.24 [1.14-1.35]). CONCLUSIONS: BSI independently predicted incident fragility fractures and MOF during a 5-year and 10-year follow-up in a large cohort of community-dwelling older women. Total hip BSI showed stronger predictive performance than lumbar spine BSI, and both provided discriminative value beyond aBMD and FRAX®.
Porphyromonas gingivalis lipids enhance RANKL-mediated osteoclast formation.
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 Jun · PMID 41825583 · Full text
Periodontitis is associated with microbial lipid accumulation in gingival tissues at sites where bone destruction occurs. The primary lipid analytes identified in diseased periodontal tissues are known to be produced by...
Periodontitis is associated with microbial lipid accumulation in gingival tissues at sites where bone destruction occurs. The primary lipid analytes identified in diseased periodontal tissues are known to be produced by Porphyromonas gingivalis (Pg), a pathogen strongly associated with periodontitis. These compounds accumulate in tissues despite clearance by gingival fibroblasts and macrophages in specific contexts. This investigation quantified lipid-dependent modulation of RANKL-mediated osteoclast formation in bone marrow macrophages and RAW 264.7 cells. The effects of Pg lipids were tested in both repeat-exposure studies, i.e. lipid priming prior to RANKL administration, and concomitant treatment with RANKL. For these studies, we used RANKL concentrations that mirror concentrations measured at disease sites. Osteoclast formation was evaluated by quantifying TRAP-positive cells. Our findings show that RANKL-induced osteoclast formation from bone marrow macrophages and RAW cells is enhanced, particularly in cells primed with lipids prior to RANKL administration. These results show a 2- to 10-fold increased in numbers of osteoclasts formed in cultures pre-exposed to Pg lipids with significance levels often at p < 0.0001. Enhanced osteoclast formation occurs despite loss of TNF-α secretory responses after repeated lipid exposure. These results indicate that RANKL at levels observed in periodontitis gingival tissues will promote osteoclast formation when bacterial lipids are also present. This suggests that lipid deposition could be used to identify at-risk sites for bone destruction in periodontitis. Collectively, our data support the notion that osteoclast formation is enhanced by the site-specific deposition of Pg lipids which contribute to localized bone loss around teeth in human periodontitis.
Paget's disease of bone: Clinical and epidemiological characterisation of the population of a Portuguese tertiary centre.
Lopes AR, Ochôa Matos C, Pereira da Costa R … +8 more , Travessa A, Dias P, Martins P, Tenazinha C, Fernandes S, Barros R, Cruz-Machado AR, Romeu JC
Bone · 2026 Jul · PMID 41819196 · Publisher ↗
PURPOSE: Paget's disease of bone (PDB) is the second most common metabolic bone disorder. We aimed to characterize the clinical and demographic profile of a Portuguese PDB cohort, identify factors associated with polyost...
PURPOSE: Paget's disease of bone (PDB) is the second most common metabolic bone disorder. We aimed to characterize the clinical and demographic profile of a Portuguese PDB cohort, identify factors associated with polyostotic disease, and compare retreatment needs between patients treated with zoledronate or alternative first-line therapies. METHODS: Retrospective, longitudinal, single-centre cohort study. Demographic and clinical data were collected. Associations with polyostotic disease were assessed using parametric and non-parametric tests and multivariable logistic regression. Drug survival was analysed with Kaplan-Meier analysis, and retreatment rates compared using log-rank test and Cox regression. RESULTS: Eighty patients diagnosed between 1974 and 2021 were included; 58.8% were female and age at diagnosis was 63.0 ± 12.2 years. Most patients (72.5%) were born in rural areas, with clustering in Alentejo. Forty-one patients (51.2%) had polyostotic PDB. Vertebrae, femur, pelvis, sacrum and skull involvement were associated with polyostotic disease. Seventeen patients (22.1%) required retreatment. Mean first-line drug survival with zoledronate was 16.0 years (95% CI 14.3-17.6) compared to 11.7 years (95% CI 4.9-18.4) with other drugs. Drug survival was significantly lower with non-zoledronate therapy, with higher retreatment rates (crude HR 9.49 [95% CI 3.28-27.44]; log-rank p < 0.001), even after adjustment (adjusted HR 10.10 [95% CI 2.12-48.0]; p = 0.004). CONCLUSION: This study, the largest Portuguese PDB cohort, highlights a predominance in rural areas, identifies skeletal sites linked to polyostotic disease, and shows zoledronate is associated with significantly lower retreatment rates.
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