Bone [JOURNAL]
Sun
200 papers
Association between glucagon-like peptide-1 receptor agonists and femur fracture risk in type 2 diabetes: A large-scale target trial emulation.
Chang YJ, Fuh CS, Chang JF … +2 more , Chen MT, Tsai MH
Bone · 2026 Jun · PMID 41819195 · Publisher ↗
INTRODUCTION: Type 2 diabetes mellitus (T2DM) paradoxically increases fracture risk despite normal or elevated bone mineral density. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in bone health...
INTRODUCTION: Type 2 diabetes mellitus (T2DM) paradoxically increases fracture risk despite normal or elevated bone mineral density. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in bone health, evidence remains controversial. This large-scale real-world study evaluated the primary outcome of femur fracture risk associated with GLP-1 RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in T2DM patients using a rigorous target trial emulation approach. METHODS: This retrospective cohort study adopted a large-scale target trial emulation framework with a new-user, active-comparator design using data from the TriNetX US Collaborative Network. Adults (≥18 years) with T2DM identified between 2018 and 2022 (n = 3,620,983) were classified as GLP-1 RA (n = 491,936) or DPP-4i (n = 345,484) users at treatment initiation. Propensity score matching (PSM) was performed to emulate random assignment and balance baseline characteristics. Cox proportional-hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for bone fractures during a maximum 5-year follow-up. RESULTS: After 1:1 PSM, each cohort included 172,381 patients (mean age 59 years; 51% male) with a mean follow-up of 40 months. GLP-1 RA users demonstrated significantly lower femoral fracture risk compared to DPP-4i users (HR 0.91, 95% CI 0.85-0.98), with consistent protective effects across all sensitivity analyses. Similar associations were observed when comparing GLP-1 RAs with most other antidiabetic medications. CONCLUSIONS: GLP-1 RA use was associated with a modest reduction in femur fracture risk. However, given the observational design, possible residual confounding, and multiple testing, these findings are exploratory and require prospective confirmation before clinical application.
Ketogenic diet causes bone loss in growing and adult mice and reduces the skeletal response to exercise.
Osipov B, Robison L, Hanel J … +12 more , Orr SV, Lin YY, Buxton A, Rahmati M, Tseng MC, Renato MR, Shenoy R, Bhat AS, Saiz A, Ferguson VL, Loots GG, Christiansen BA
Bone · 2026 Jun · PMID 41812964 · Publisher ↗
The ketogenic diet (KD) is an established treatment for intractable epilepsy in children. KD has also become increasingly popular for weight loss, and it has shown therapeutic potential for treating neurodegenerative dis...
The ketogenic diet (KD) is an established treatment for intractable epilepsy in children. KD has also become increasingly popular for weight loss, and it has shown therapeutic potential for treating neurodegenerative diseases. However, KD causes bone loss in epileptic children, and its effects on the adult skeleton are unknown. In the current study, we investigated the effect of KD on bone at different ages using growing (4-week-old) and adult (14-week-old) male C57BL/6 J mice. We also examined if KD-induced bone loss could be recovered via exercise. We hypothesized that KD would cause bone loss at all ages, the rate of bone loss would depend on age, and that KD alters osteoblast, osteoclast, and osteocyte activity. We also predicted KD would reduce the anabolic effects of exercise. We quantified bone density in-vivo and conducted ex-vivo analysis of bone microstructure and strength, osteoblast and osteoclast activity, and osteocyte lacunar size. KD induced bone loss was evident after 4 weeks in growing animals and after 8 weeks in adult mice. Analysis of serum showed that KD caused declines in bone formation markers, and measurement of osteocyte lacunar dimensions via x-ray microscopy showed increases in lacunar volume, but osteoclasts were unaffected. KD also reduced the magnitude of exercise induced changes in cortical bone mechanical properties. These findings suggest that KD-initiated bone loss is not a clinical problem limited to children, and it may be a significant risk factor for osteoporotic fracture in adults.
Shape-based profiling of cortical bone mineral density in growing children: a proof-of-concept pQCT study.
Markarian AM, Taaffe DR, Galvão DA … +4 more , Wilkie JC, Peddle-McIntyre CJ, Schiferl DJ, Newton RU
Bone · 2026 Jun · PMID 41806653 · Publisher ↗
BACKGROUND: Understanding how bones adapt during growth is essential for promoting lifelong skeletal health. Peripheral quantitative computed tomography (pQCT) is a widely used imaging technique for assessing volumetric...
BACKGROUND: Understanding how bones adapt during growth is essential for promoting lifelong skeletal health. Peripheral quantitative computed tomography (pQCT) is a widely used imaging technique for assessing volumetric bone mineral density (vBMD) in pediatric populations; however, conventional methods may obscure subtle cortical adaptations. The primary aim of this study was to evaluate the feasibility of shape-based cortical vBMD profiling, with an exploratory objective of assessing its sensitivity to inter-individual variation in lean mass index (LMI). METHODS: Eighteen children (6-12 years) underwent pQCT scanning at the 38% and 66% tibial sites (distal and proximal diaphysis). Cortical vBMD was quantified across three concentric compartments (endocortical, mid-cortical, and pericortical). Differences in vBMD across compartments were assessed using one-way repeated-measures ANOVA. Quadratic models were fit, and participant-specific linear (slope) and quadratic (curvature) coefficients were extracted to characterize cortical vBMD profiles. Exploratory regression analyses examined associations between these coefficients and dual-energy X-ray absorptiometry-derived LMI. RESULTS: Linear and quadratic coefficients were successfully extracted for all participants at both tibial sites, supporting the feasibility of shape-based cortical profiling. Significant differences in vBMD were observed across cortical compartments (p < 0.001). Quadratic models explained 65-72% of the variance in normalized vBMD, and the extracted shape coefficients captured inter-individual and site-specific variation associated with LMI, suggesting sensitivity to biologically meaningful differences in cortical mineral distribution. CONCLUSION: Shape-based cortical vBMD profiling using pQCT is feasible in children. With further refinement and validation in larger, diverse pediatric cohorts, this approach may offer a sensitive tool for investigating skeletal adaptations during growth.
Vitamin D supplementation during pregnancy and offspring bone microarchitecture: A post hoc analysis of the MAVIDOS randomised controlled trial.
Maden C, D'Angelo S, Westbury LD … +8 more , Curtis EM, Crozier SR, Godfrey KM, Ward KA, Cooper C, Harvey NC, Moon RJ, MAVIDOS Study Group
Bone · 2026 Jun · PMID 41802552 · Publisher ↗
BACKGROUND: Randomised trials have shown that pregnancy vitamin D supplementation results in greater offspring bone mineral density (BMD) in childhood. The effect of this intervention on bone microarchitecture, a further...
BACKGROUND: Randomised trials have shown that pregnancy vitamin D supplementation results in greater offspring bone mineral density (BMD) in childhood. The effect of this intervention on bone microarchitecture, a further determinant of bone strength, and possible interactions with genetic variation in vitamin D metabolism, have not previously been investigated. We investigated these in a post hoc analysis of a randomised controlled trial. METHODS: MAVIDOS was a randomised placebo-controlled trial of 1000 IU/day cholecalciferol from 14 to 17 weeks' gestation until delivery. Offspring tibial bone microarchitecture was assessed at age 6-7 years using high resolution peripheral quantitative computed tomography (HR-pQCT; Stratec Xtreme CTII). Maternal and child genotype at four single nucleotide polymorphisms (SNPs) [rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), rs2282679 (GC)] was determined using serum samples. Differences in bone microarchitecture by randomisation were assessed using linear regression, and additionally across clusters of bone microarchitecture phenotypes generated using cluster analysis approaches. RESULTS: 222 children (placebo n = 110, cholecalciferol n = 112) were included. No significant differences in cross-sectional area, cortical thickness or porosity, trabecular thickness or number, or volumetric BMD (total, cortical or trabecular) were found using linear regression, and there was no interaction with either maternal or offspring SNP genetic variants. Three phenotypic bone clusters were generated. Differences in child anthropometry were evident across clusters, but the proportion of mothers randomised to cholecalciferol was similar across the clusters (p = 1.0). CONCLUSION: In this subset of children born to mothers participating in a trial of vitamin D supplementation in pregnancy, no effect of the supplementation on tibial microarchitecture was observed.
Cannabichromene attenuates fracture pain but impairs bone repair in a murine tibial fracture model.
Khajuria DK, Wee H, Koroneos ZA … +6 more , Tantawy MA, Lewis GS, Raup-Konsavage WM, Vrana KE, Kamal F, Elbarbary RA
Bone · 2026 Jun · PMID 41794091 · Publisher ↗
Fractures are common musculoskeletal injuries associated with severe pain, and effective analgesia is essential for fracture management. Current therapies such as NSAIDs and opioids have significant limitations, driving...
Fractures are common musculoskeletal injuries associated with severe pain, and effective analgesia is essential for fracture management. Current therapies such as NSAIDs and opioids have significant limitations, driving interest in alternative analgesics, an avenue where cannabinoids hold great promise. While cannabinoids are increasingly promoted for various indications, robust scientific evidence supporting their use remains limited. We previously demonstrated that cannabidiol (CBD) and cannabigerol (CBG), two non-psychoactive cannabinoids, alleviate fracture pain and promote bone repair. Cannabichromene (CBC), another non-psychoactive cannabinoid, has shown analgesic effects in different disease models, but its impact on fracture pain and healing is unknown. Using a murine tibial fracture model, we investigated CBC's effects on pain and bone healing. CBC significantly reduced fracture pain, improving mechanical and cold allodynia, thermal hyperalgesia, and gait function. However, bone healing was impaired, with delayed soft-callus resorption, increased bone cell apoptosis, elevated osteoclast activity, and reduced bone formation and mineralization. In vitro, CBC promoted osteoclastogenesis, supporting its resorptive effect. These findings contrast with the reported benefits of CBD and CBG on fracture repair, highlighting that not all cannabinoids are suitable for fracture management. Individual compounds must be carefully evaluated to balance analgesia with bone healing. Caution is warranted when using medical cannabis or cannabinoid oils with variable compositions, as their effects on healing are unpredictable. The divergent effects of CBD and CBG versus CBC may also guide future structure-activity relationship studies for designing synthetic cannabinoids to promote fracture healing.
HOXD12 a candidate gene for a novel form of synpolydactyly.
Khan H, Bilal M, Bharadwaj T … +4 more , Acharya A, Schrauwen I, Ahmad W, Leal SM
Bone · 2026 Jun · PMID 41786235 · Publisher ↗
Synpolydactyly is a rare limb deformity characterized by a unique combination of syndactyly and polydactyly. Synpolydactyly has an autosomal dominant mode of inheritance often with reduced penetrance. Variants in HOXD13,...
Synpolydactyly is a rare limb deformity characterized by a unique combination of syndactyly and polydactyly. Synpolydactyly has an autosomal dominant mode of inheritance often with reduced penetrance. Variants in HOXD13, FBLN1, GLI3, and TTC30B have been reported to underlie the etiology of synpolydactyly. Here, we describe a three-generational Pakistani family segregating a form of synpolydactyly which has not previously been reported that includes, severe hand involvement characterized by bilateral syndactyly of the third, fourth, and fifth fingers, accompanied by preaxial polydactyly in all affected family members. Synpolydactyly of the feet was absent and only one family member presented with unilateral syndactyly of the third, fourth, and fifth toes. Exome sequencing of DNA samples obtained from members of the family led to the identification of a missense variant in HOXD12 [NM_021193.4:c.512A>G, p.(Asn171Ser)] that segregates with the synpolydactyly. HOXD12 is expressed in the posterior half of developing limb and is involved in bone development by regulating digit formation and patterning. It has also been implicated in limb deformities in mice and humans. Although HOXD12 has been reported to be involved in the etiology of clubfoot, this is the first report of its involvement in etiology of synpolydactyly.
Craniofacial CBCT: Addressing volume-resolution dilemma using generative artificial intelligence.
Hosseinitabatabaei S, Nelson AJ, Piché N … +2 more , Dagdeviren D, Reznikov N
Bone · 2026 Jun · PMID 41763378 · Publisher ↗
In large field-of-view tomographic images, fine structures such as bone texture, porosity or root canals are poorly resolved. We developed a Generative-Adversarial-Network (GAN)-based super-resolution method for craniofa...
In large field-of-view tomographic images, fine structures such as bone texture, porosity or root canals are poorly resolved. We developed a Generative-Adversarial-Network (GAN)-based super-resolution method for craniofacial cone-beam CT (CBCT) that recovers sharp edges while avoiding hallucinations. CBCT scans of 1 human skull, 4 cadaveric human heads, and 6 sheep heads were acquired at 270 μm and 135 μm voxel, and a GAN (Unet-Structure-Preserving Super-Resolution [UNetSPSR]) was designed to recover fine image details in the low-resolution images. Performance was benchmarked against state-of-the-art methods using peak-signal-to-noise-ratio (PSNR) and learned-perceptual-image-patch-similarity (LPIPS), and evaluated in segmentation of trabecular bone and root canals. Independent archival clinical CBCT scans from five patients and an external public dataset (n = 50) were used for generalization testing. UNetSPSR achieved the highest PSNR (+0.66 on seen and +0.11 on unseen data relative to the runner-up) and the lowest LPIPS (-0.01), indicating superior recovery of fine image details. The comparable performance between seen and unseen internal test sets, demonstrates strong generalization within the target data distribution. On independent clinical and external datasets, the network enhanced fine structures without introducing visible artifacts, despite heterogeneous acquisition parameters, although the absence of high-resolution reference standards precluded definitive validation. UNetSPSR substantially reduced overestimation of trabecular morphology, decreasing trabecular thickness bias from 61% to 11%, and significantly improved microarchitectural measures on external data (p < 0.05). Root canal segmentations more closely resembled high-resolution references, with improved quantitative metrics. UNetSPSR enables structure-preserving super-resolution of craniofacial CBCT, improving visualization of fine anatomical features. While results demonstrate internal generalization, further external validation is warranted.
Methodological considerations and clinical implications of pain assessment in rare bone diseases.
Morri M, Pedrini E, Moroni A … +1 more , Sangiorgi L
Bone · 2026 May · PMID 41759874 · Publisher ↗
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Nomogram prediction of short-term collapse progression in osteonecrosis of the femoral head: A combination of clinical data and radiomics features from hip magnetic resonance imaging.
Lin X, Fang K, Dai Z … +1 more , Wu W
Bone · 2026 May · PMID 41748054 · Publisher ↗
PURPOSE: This study investigates the development of a nomogram for predicting the short-term collapse progression of osteonecrosis of the femoral head by integrating clinical data with radiomics features obtained from hi...
PURPOSE: This study investigates the development of a nomogram for predicting the short-term collapse progression of osteonecrosis of the femoral head by integrating clinical data with radiomics features obtained from hip joint MRI. METHODS: The study involved 364 patients with osteonecrosis of the femoral head who had not yet severe collapsed(Collapse < 2 mm or no collapse) from two medical centers, selected from a major medical center. MRI images of their hip joints were analyzed to extract radiomics features. A clinical model was developed using criteria such as ARCO classification, CJFH classification, JIC classification, and the modified Kerboul angle. The outcome variable was the occurrence of collapse progression within one year post-examination. Features most significantly associated with collapse progression were identified from both radiomics and clinical data, which were then integrated into separate models. A combined Nomogram model was constructed by merging the clinical and radiomics models. The performance of these models was compared to assess their effectiveness in predicting collapse progression. RESULTS: The Nomogram model demonstrated superior predictive performance compared to both the clinical and radiomics models across all cohorts. In the external validation set, the Nomogram achieved an AUC of 0.919 and an accuracy of 0.879, outperforming the clinical (AUC = 0.809) and radiomics (AUC = 0.875) models. Statistical significance was confirmed between the Nomogram and clinical model in all cohorts. CONCLUSION: In summary, our study demonstrates that a nomogram combining hip MRI-based radiomics with clinical data shows superior predictive performance compared to clinical-only models for assessing short-term collapse risk in osteonecrosis of the femoral head.
SOCS2 deficiency drives sex-specific remodeling of mineralized tissues.
Toyama RV, Colares JP, Refaxo NA … +14 more , de Arruda JAA, André CB, Rocha AL, Duffles LF, Campideli-Santana AC, Galvão I, Lima VTM, Szawka RE, Grattan DR, Machado FS, Amaral FA, Silva TA, Moreira AN, Macari S
Bone · 2026 Jun · PMID 41730408 · Publisher ↗
Sex-specific differences in bone development and remodeling are increasingly recognized as critical determinants in skeletal biology. We investigated the impact of SOCS2 deficiency on craniofacial and long bone structure...
Sex-specific differences in bone development and remodeling are increasingly recognized as critical determinants in skeletal biology. We investigated the impact of SOCS2 deficiency on craniofacial and long bone structures in female and male mice. C57BL/6 wild-type (WT) and SOCS2 knockout (SOCS2/) mice underwent orthodontic tooth movement (OTM) on the right side, while the contralateral side served as control. Maxillae, dental roots, femur, adipose tissue, and serum were collected for histomorphometry, micro-computed tomography (microCT), biomechanical testing, adiposity index assessment, qPCR, Western blot, and ELISA. SOCS2/ males exhibited greater alveolar bone loss and increased OTM than SOCS2/ females. Whereas SOCS2/ females showed reduced OTM compared with WT females. MicroCT revealed higher maxillary bone mineral density (BMD) in SOCS2/ females, but lower BMD, bone volume/total volume, and trabecular thickness, with increased trabecular separation, in SOCS2/ males. These phenotypes were associated with increased Howship's lacunae and c-Jun N-terminal kinase activity in SOCS2/ males, sex-divergent Pparγ, Il6, and Runx2 expression, and unchanged Rankl/Opg ratio in maxillary bone. Femoral evaluations showed sex-specific changes in growth, bone structure, and mechanical strength. Root analyses revealed compromised architecture in SOCS2/ males and increased odontoclast activity in both sexes. SOCS2/ males displayed increased serum testosterone and adiposity, despite reduced adipocyte area, whereas SOCS2/ females exhibited higher prolactin levels and enlarged adipocytes. SOCS2 influences skeletal remodeling in a sex-dependent manner, with underlying mechanisms involving metabolic and hormonal alterations, as well as local imbalances in the regulation of osteoblast and osteoclast activity.
Mapping the evidence: Effects of malnutrition and sarcopenia on fracture healing.
Velasquez-Hammerle MV, Garcia M, Misra P … +7 more , Simonian M, Nafisi N, Hedayatzadeh Razavi A, Rackauskas O, Rodriguez EK, Vaziri A, Nazarian A
Bone · 2026 May · PMID 41720230 · Publisher ↗
OBJECTIVE: To determine how sarcopenia and malnutrition affect fracture-healing outcomes and to identify clinical implications for screening and peri-fracture care. METHODS: A PRISMA-guided search (PubMed/MEDLINE, Cochra...
OBJECTIVE: To determine how sarcopenia and malnutrition affect fracture-healing outcomes and to identify clinical implications for screening and peri-fracture care. METHODS: A PRISMA-guided search (PubMed/MEDLINE, Cochrane Central, Cochrane Library; last search June 25, 2024; English language) identified in vivo human and animal studies evaluating fracture healing in the presence of sarcopenia or malnutrition. Two reviewers independently screened records, extracted data, and assessed the risk of bias using the MINORS tool. PRIMARY OUTCOME: nonunion (as defined in each study). SECONDARY OUTCOMES: time-to-union, surgical complications, mortality, and biomechanical properties. Owing to heterogeneity, a structured narrative synthesis was performed. RESULTS: Twelve studies met criteria: seven human (four malnutrition; three sarcopenia) and five animal (malnutrition). Large database studies linked malnutrition to higher nonunion risk (e.g., OR ≈2.0) and to post-operative complications and mortality. Definitions of malnutrition and sarcopenia varied widely across studies and included biochemical markers, anthropometric measures, imaging-based muscle assessments, and clinical screening tools. Due to this heterogeneity, associations with fracture healing outcomes were evaluated using study-level definitions rather than standardized diagnostic thresholds. Small clinical cohorts have associated sarcopenia with higher nonunion rates, and in one randomized pilot study, dietary protein/energy, combined with exercise, improved function and reduced pain while modestly shortening the time-to-union. Animal models consistently demonstrated lower BMD/BMC, altered callus composition, and reduced early mechanical strength under protein restriction, with partial reversal after re-feeding. Study heterogeneity and moderate-to-poor quality limited generalizability. CONCLUSIONS: Across human and animal data, malnutrition and sarcopenia adversely affect fracture healing, increasing the risk of nonunion and complications, and impairing early callus quality. These findings highlight the importance of early identification of sarcopenia and nutritional risk in fracture patients. While emerging data suggest potential benefit from targeted interventions, the current evidence remains limited, underscoring the need for adequately powered randomized trials before routine clinical implementation. LEVEL OF EVIDENCE: Systematic Review, I.
TNAP-positive matrix vesicles are enriched in Annexin II and tetraspanins.
Anghileri G, de Voogt WS, Hyden-Shepherd T … +5 more , Murdoch TJ, Mebarek S, Vader P, Martín-Fabiani I, Davies OG
Bone · 2026 May · PMID 41720229 · Publisher ↗
Matrix vesicles (MVs) provide a specialised niche for the nucleation of biological apatite. While the mineralisation enabling enzyme tissue non-specific alkaline phosphatase (TNAP) is commonly applied as a marker, its or...
Matrix vesicles (MVs) provide a specialised niche for the nucleation of biological apatite. While the mineralisation enabling enzyme tissue non-specific alkaline phosphatase (TNAP) is commonly applied as a marker, its organisation and relative abundance on MVs remains incompletely defined. The relationship between MVs and unbound exosomes/microvesicles recovered from culture media (mEVs) also remains a point of contention. We show that MVs expressed markers of ESCRT (endosomal sorting complexes required for transport) biogenesis common to exosomes/microvesicles, including Alix, TSG101 and CD63. TEM and AFM analysis revealed heterogeneity in the MV population, with pro-mineralising electron-dense and non-mineralising MVs observed. Few MVs (< 7%) expressed TNAP independently of CD63. Applying a bespoke immuno-isolation protocol, we showed that TNAP was only expressed in 36% (MV) and 10% (mEV) of the total vesicle population. Super-resolution microscopy revealed the majority of TNAP MVs (mean of 82.3%) and mEVs (mean of 72.7%) localised with the calcium channelling protein annexin II. Annexin V (alternative calcium channel) was not upregulated in the TNAP fraction. Both MVs and mEVs were capable of mineral nucleation, though only MVs isolated at earlier time points (days 7 and 9) appeared capable of generating hydroxyapatite-like material. In conclusion, we identify for the first time that mineralisation-competent TNAP MVs are enriched in annexin II and express common markers of endosomal biogenesis. We show that a TNAP/annexin II population is also present in mEV fractions but only quantifiable using high-resolution techniques. These results provide new insights into the composition of pro-mineralising vesicles and give further credence to the hypothesis that MVs may represent anchored exosomes.
Bone mineral density and bone turnover changes with advanced menstrual recovery: The REFUEL study.
Salamunes ACC, Williams NI, Ricker EA … +3 more , Mallinson RJ, Koltun KJ, De Souza MJ
Bone · 2026 May · PMID 41707966 · Publisher ↗
PURPOSE: To investigate whether experiencing ≥2 consecutive menstrual cycles of <36 days improved bone mineral density (BMD) and bone turnover markers in response to increased energy intake in young exercising women with...
PURPOSE: To investigate whether experiencing ≥2 consecutive menstrual cycles of <36 days improved bone mineral density (BMD) and bone turnover markers in response to increased energy intake in young exercising women with oligo-amenorrhea. METHODS: The REFUEL study was a 12-month RCT designed to increase energy intake to improve menstrual function and bone health in exercising women with oligo-amenorrhea. Participants from the intervention group were considered recovered (REC; n = 14) if they experienced ≥2 consecutive menstrual cycles of <36 days, and non-recovered otherwise (non-REC; n = 11). DXA scans assessed body composition and BMD at baseline and at the last measurement time point (month 6, 9, or 12). Urinary estrone-1-glucuronide (E1G) and pregnanediol glucuronide were measured daily. Serum insulin-like growth factor-1 (IGF-1), carboxy-terminal telopeptide of type I collagen (CTx), procollagen type 1 N-terminal propeptide (P1NP), and osteocalcin were assessed at baseline and at the last measurement time point (month 3, 6, 9, or 12). Bone balance (BB) was calculated from P1NP, CTx, and osteocalcin ratios relative to a healthy reference population. Linear mixed models assessed changes over time. RESULTS: Significant group*time effects were observed for lumbar spine BMD (F(1,20.1) = 4.65, p = 0.043), BB calculated from P1NP and CTx (F(1,23) = 5.60, p = 0.027), E1G AUC (F(1,20.7) = 9.86, p = 0.005), and E1G mean (F(1,20.6) =11.84, p = 0.002), indicative of improvements in the REC group compared with non-REC. Significant group effects demonstrated higher IGF-1 in REC than non-REC (F(1,22.9) = 8.43, p = 0.009). CONCLUSION: These results indicate that a nutrition intervention can improve bone health when ≥2 consecutive menstrual cycles of <36 days are achieved.
Genetic profile of Lepr skeletal stem/progenitor cells in the periodontal ligament and functional compensation during aging and bone repair.
Shidara S, Ito S, Desai K … +8 more , Tokuyama A, Leng R, Kawakami M, Matsunaga S, Komori T, Hosoya A, Nishii Y, Mizoguchi T
Bone · 2026 May · PMID 41692367 · Publisher ↗
Skeletal stem/progenitor cells (SSPCs) play a fundamental role in maintaining skeletal homeostasis throughout life. Leptin receptor (Lepr)-positive cells were initially identified as SSPCs in the long bone marrow and lat...
Skeletal stem/progenitor cells (SSPCs) play a fundamental role in maintaining skeletal homeostasis throughout life. Leptin receptor (Lepr)-positive cells were initially identified as SSPCs in the long bone marrow and later in the craniofacial skeleton, where they localize within the periodontal ligament (PDL), particularly among fibroblastic cells (PDLCs). However, their hierarchical organization, maintenance of stemness, and relationships with other SSPC populations remain poorly understood. Through lineage tracing and single-cell RNA sequencing facilitated by Runx2-GFP expression, we identified a Lepr subpopulation characterized by Thy1 expression but lacking Runx2, which is hierarchically positioned at the apex of the Lepr PDLC lineage and gives rise to downstream osteogenic progeny. However, their SSPC capacity to contribute to osteocytes and cementocytes is quantitatively limited and declines with age, and this contribution may exhibit sexual dimorphism. At the single-cell transcriptome level, Lepr PDLCs shared an expression profile with long bone-derived Lepr SSPCs; however, the expression of Kit ligand (Kitl) was uniquely restricted to Lepr cells within the PDLCs. In contrast, they were not enriched for other PDLC-associated SSPC markers, such as Axin2, Gli1, and Acta2. Although Lepr PDLCs contributed to bone regeneration by differentiating into osteocytes after tooth extraction, their contribution was limited. Moreover, genetic ablation of Lepr PDLCs did not reduce the regenerated bone volume, suggesting compensatory contributions from other SSPC populations. Collectively, these findings reveal a previously unrecognized hierarchical and functional organization of Lepr PDLCs and demonstrate that their contribution to skeletal homeostasis progressively declines with age, with potential compensation by other SSPC populations.
Under-prescribed and underutilized: National trends in osteoporosis medication use after fragility fracture.
Wadhwa H, Isakoff KJ, Pham NS … +3 more , Goodnough LH, Bishop JA, Gardner MJ
Bone · 2026 May · PMID 41690441 · Publisher ↗
BACKGROUND: Fragility fractures are common among older adults with osteoporosis, yet most patients do not receive recommended treatment. Prescribing trends in the US after fragility fractures and patient-level predictors...
BACKGROUND: Fragility fractures are common among older adults with osteoporosis, yet most patients do not receive recommended treatment. Prescribing trends in the US after fragility fractures and patient-level predictors of medication prescription remain unclear. This study evaluates prescribing patterns and predictive factors of osteoporosis medication prescription after fragility fracture to identify gaps in secondary prevention and guide future interventions. METHODS: Using a commercial claims database (Merative™ MarketScan®), adult patients over 50 with a new fragility fracture from 2015 to 2022 were retrospectively reviewed. Fragility fractures were defined as hip, vertebral compression (VCF), or distal radius fractures (DRF) without concomitant injuries that would be present in a higher energy mechanism. Patients with prior osteoporosis diagnosis or treatment were excluded. The primary outcome was osteoporosis medication prescription within 90 days post-fracture, categorized as bisphosphonate, non-bisphosphonate antiresorptive, or anabolic agent. Multivariable logistic regression identified factors associated with overall prescription and medication class. RESULTS: Among 53,679 patients with a fragility fracture (mean age 75.1; 62.3% female), only 7.7% were prescribed osteoporosis medication within 90 days of a fragility fracture. Of those treated, 68.8% received bisphosphonates, 26.4% non-bisphosphonate antiresorptives, and 11.1% anabolic agents. The only anabolic agent prescribed was teriparatide. Osteoporosis medication prescription declined over the study period. CONCLUSIONS: Only 8% of patients with fragility fractures receive osteoporosis medication, with bisphosphonates most commonly prescribed. Anabolic therapies are rarely used, despite evidence supporting their efficacy. Additional resources should be dedicated to improving secondary fracture prevention with pharmacological therapy, particularly among older adults and those with comorbidities.
NSUN6-mediated m5C RNA methylation aggravate osteosarcoma progression through promoting PKP2 mRNA stability and expression.
Zhao C, Tang Y, He Y … +5 more , Zhang F, Li W, Chen X, Yu Z, Fu K
Bone · 2026 Jun · PMID 41687845 · Publisher ↗
BACKGROUND: Osteosarcoma (OS) is a highly aggressive malignant bone tumor with poor prognosis. Both Plakophilin 2 (PKP2) and NOP2/Sun RNA methyltransferase 6 (NSUN6) were reported to be upregulated in OS, and NSUN6 is on...
BACKGROUND: Osteosarcoma (OS) is a highly aggressive malignant bone tumor with poor prognosis. Both Plakophilin 2 (PKP2) and NOP2/Sun RNA methyltransferase 6 (NSUN6) were reported to be upregulated in OS, and NSUN6 is one of the important RNA methyltransferases catalyzing 5-methylcytosine (m5C) formation and participates in many critical bioprocesses in various tumors. However, the roles and underlying molecular mechanisms of NSUN6-mediated m5C modification in OS remain unclear. METHODS: Differentially expressed genes in OS and the expression of PKP2 were analyzed using the GSE126209 dataset of the GEO database. The mRNA and protein levels of PKP2 as well as NSUN6 in OS tissues and cells were then measured by RT-qPCR and western blot. Then, the relationship between the expression of PKP2 and the survival rate of OS patients was presented by the Kaplan-Meier (KM) survival curve. Subsequently, OS cell proliferation, migration, and apoptosis were assessed by colony formation, Transwell, and flow cytometry. Meanwhile, the mitochondrial membrane potential, the levels of MDA, ROS, and Fe was determined by the corresponding kits. Besides, the binding of PKP2 and NSUN6 was verified by RIP assay. Dot blot and Me-RIP assay were used to evaluate the 5-methylcytosine (m5C) modification level of PKP2. Finally, a xenograft model was constructed to investigate the role of NSUN6/PKP2 axis in vivo. RESULTS: PKP2 was highly expressed in OS tissues and cells. PKP2 knockdown could effectively inhibit the proliferation and migration of OS cells, and promote their apoptosis, oxidative stress and ferroptosis. NSUN6 stabilized PKP2 expression through m5C methylation modification. Moreover, overexpression of PKP2 effectively reversed the effects of NSUN6 knockdown on OS cells and xenograft tumors in mice. CONCLUSION: NSUN6 regulated the m5C methylation modification of PKP2 to stabilize its expression, thereby driving the malignant progression of OS cells, providing a promising targeted therapeutic strategy for OS.
Effect of increased soft tissue thickness on bone density and microstructure measurements using the 2nd generation HR-pQCT scanner.
Cooke LM, Garrahan MA, Gehman S … +4 more , Tedtsen TA, Smith NI, Coulombe J, Bouxsein ML
Bone · 2026 May · PMID 41672265 · Full text
Bone density and microarchitecture measurements from high-resolution peripheral computed tomography (HR-pQCT) are increasingly being used to predict fracture risk and to gain insight into the pathophysiology of skeletal...
Bone density and microarchitecture measurements from high-resolution peripheral computed tomography (HR-pQCT) are increasingly being used to predict fracture risk and to gain insight into the pathophysiology of skeletal fragility. Using the first-generation HR-pQCT scanner, we previously showed that extraosseous soft tissue can impact HR-pQCT measurements. Yet similar data is not available for the second-generation scanner. Thus, we aimed to determine the impact of increased soft tissue on bone density, microarchitecture and strength measurements acquired using the second-generation HR-pQCT scanner. We performed HR-pQCT scans on a hydroxyapatite phantom and in human volunteers (n = 12) with no soft tissue covering, and with a thin (0.5 cm) and thick (1 cm) layer of soft tissue surrounding the phantom or limb. We found that density values of the phantom were minimally affected by the thin layer of soft tissue. In contrast, with the thick (1 cm) layer of soft-tissue, bone density was significantly lower than baseline (no bolus), with greater deficits as the density of the rod increased (-1% to -3.6%, p < 0.01 for all). In human volunteers, soft tissue layering influenced measures of both cortical and trabecular microarchitecture at the distal tibia and radius, with larger differences observed in trabecular versus cortical measures and at the tibia compared to the radius. For example, at the tibia, Tt.BMD was lower than the baseline scan under both soft tissue layering conditions (thin: -1.3%, p < 0.001; thick: -2.4%, p = 0.003), while at the radius Tt.BMD was only significantly lower for the thick layer (-1.2%, p = 0.004). Ct.BMD followed a similar pattern, with slightly greater magnitude of BMD decline with increased soft tissue (thin: -1.5%, p < 0.001, thick -2.8%, p < 0.001 at the tibia) compared to Tt.BMD. Altogether our results indicate that HR-pQCT measurements at both the metaphyseal and diaphyseal sites must be interpreted carefully when comparing subjects with varying body composition, or when assessing longitudinal changes in individuals who experience marked changes in weight and/or body composition as true differences to these measures may be more or less extreme than they appear.
DXA-derived three-dimensional finite element models of the femur: validation against CT-based models.
Aldieri A, Bhattacharya P, Paggiosi M … +2 more , Eastell R, Grassi L
Bone · 2026 May · PMID 41672264 · Publisher ↗
Three-dimensional finite element (FE) models derived from Computed Tomography (CT) images predict hip fractures better than areal bone mineral density measurements from Dual-energy X-ray Absorptiometry (DXA). Yet, these...
Three-dimensional finite element (FE) models derived from Computed Tomography (CT) images predict hip fractures better than areal bone mineral density measurements from Dual-energy X-ray Absorptiometry (DXA). Yet, these results have not justified the adoption of CT in clinical practice, and only 2D DXA images are clinically available. Statistical shape and appearance models can be used to reconstruct three-dimensional FE models from 2D DXA images. While ex vivo validations have been performed on 3D reconstructed DXA-based FE models, it is not clear how well 3D reconstructed DXA-based FE models can predict fractures compared to CT-based models. The aim of this study was thus to evaluate the ability of one such methodology, namely DXA2FEM, to predict fractures in a clinical cohort of pair-matched fractured and control subjects, for whom both DXA and CT images were available. 3D FE models of the femur were built from both DXA and CT, and FE simulations were run reproducing a sideways fall in 28 different femoral configurations. An absolute risk of fracture (ARF0) was then computed based on the FE-predicted femoral strength values. DXA- and CT-derived models were compared with respect to geometry, density distribution, and FE-predicted proximal femoral strength. DXA-derived 3D FE models had an average point-to-surface distance of -2 mm from CT-based models, whereas the Young's moduli were 29% higher. ARF0 by CT reported statistically significantly better diagnostic accuracy (0.83, 95% CI 0.75 to 0.91) than standard hip DXA (0.69, 95% CI 0.6 to 0.8) or FRAX (0.69, 95% CI 0.57 to 0.81). The diagnostic accuracy of ARF0 by DXA was between ARF0 by CT and standard hip DXA/FRAX (0.74, 95% CI 0.62 to 0.86), albeit neither difference was statistically significant in the analysed cohort.
The role of muscle fascia in heterotopic ossification and maintenance of skeletal muscle integrity in fibrodysplasia ossificans progressiva.
Hanson LR, Scalise KL, Esch RM … +2 more , Nevo L, Goldhamer DJ
Bone · 2026 Jun · PMID 41672263 · Full text
The rare genetic disorder fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification (HO) of skeletal muscles and associated soft tissues. FOP is caused by a gain-of-function mut...
The rare genetic disorder fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification (HO) of skeletal muscles and associated soft tissues. FOP is caused by a gain-of-function mutation in the type l BMP receptor ACVR1 (also known as ALK2) that renders the receptor inappropriately responsive to activin ligands. HO is associated with muscle destruction and compromised muscle regeneration, although little is known of the mechanistic relationship between these pathophysiological disease manifestations. In mouse FOP models, HO is experimentally induced by direct injury to muscle using chemical or mechanical means, thereby obscuring the relationship between HO formation and muscle destruction. We show that direct muscle injury is not required for induction of a robust HO response. Rather, a small incision in the fascia superior to the tibialis anterior muscle was sufficient to induce HO when fibro-adipogenic progenitors (FAPs) were targeted for Acvr1 expression. Intermuscular fascial layers were the primary sites of lesional growth when HO was exacerbated by genetic, pharmacological, or physical means. In contrast to control mice, fascial injury in FOP mice caused pronounced destruction of the muscle subjacent to the injured fascia. Further, areas of muscle degeneration did not undergo a productive regenerative response. Unlike most models of impaired regeneration, adipocyte accumulations were not observed in areas of muscle degeneration, which were destined for pathological bone formation. These data point to the primary role of fascia in HO initiation and growth, and indicate that Acvr1-expressing FAPs directly or indirectly create an abnormal tissue environment that destabilizes muscle tissue and is incompatible with muscle regeneration. The advantages of this new model of injury-induced HO for understanding early events in FOP pathogenesis are discussed.
Atypical femoral fracture with early PET/CT changes from denosumab for metastatic breast cancer and transition from denosumab to zoledronic acid.
Tan C, Day D, White M … +4 more , Man G, Nguyen HH, Ebeling PR, Milat F
Bone · 2026 May · PMID 41654156 · Publisher ↗
Atypical femoral fractures (AFFs) are potential complications arising from long-term use of bone modifying agents such as denosumab. We describe a case of bilateral AFFs that was treated surgically in a middle-aged woman...
Atypical femoral fractures (AFFs) are potential complications arising from long-term use of bone modifying agents such as denosumab. We describe a case of bilateral AFFs that was treated surgically in a middle-aged woman receiving oncologic doses of denosumab for treatment of metastatic breast cancer for seven years. In retrospect, early cortical change was present on scout computer tomography (CT) and positron emission tomography-computer tomography (PET-CT) prior to her left AFF. This case highlights the potential for earlier opportunistic AFF radiologic screening during cancer surveillance. It also describes our experience with preserving spinal bone density following the cessation of oncologic doses of denosumab through sequential zoledronic acid therapy.
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