Journal of Bone and Mineral Research最新文献

{"title":"Treat to Target in Osteoporosis - the Time is Right.","authors":"Peter R Ebeling","doi":"10.1093/jbmr/zjaf151","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf151","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal Involvement in Tumor-Induced Osteomalacia†.","authors":"Salvatore Minisola, Luciano Colangelo, Jessica Pepe, Cristiana Cipriani, Alessandro Corsi","doi":"10.1093/jbmr/zjaf148","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf148","url":null,"abstract":"<p><p>Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism secondary to the overproduction of fibroblast growth factor 23 by small-sized mesenchymal tumors typically located in soft tissues and bone. The tumor has adverse effects on bone and patients complain of skeletal symptoms and in severe cases they suffer multiple devastating fractures. Specific features may characterize the histology of tumors located in bone with respect to those found in extra-skeletal sites. Indeed, the matrix may contain foci resembling primitive cartilage and osteoid. Light microscopy of bone biopsy samples reveal accumulation of osteoid due to thickening of osteoid seams and, if tetracyclines were sequentially administrated, fluorescence microscopy reveals prolongation of the mineralization lag time. Areal bone mineral density assessed by DXA is significantly lower at both the lumbar and femoral sites in patients with TIO and values of trabecular bone score are significantly reduced with respect to healthy individuals. Patients with TIO are also characterized by significant impairment in bone quality at both the trabecular and cortical compartment when evaluated by high-resolution peripheral quantitative computed tomography. Successful surgical removal of the causative tumor completely reverts biochemical abnormalities. Bone mineral density accrual is impressive in the short term at the central (spine and hip) level but may take longer to improve, together with microstructural parameters, at peripheral sites (radius and tibia). Future studies should address effects of long-term treatment on quality-of-life outcomes related to irreversible events, such as vertebral fractures. This is particularly important in patients with a heavy burden due to a long-standing disease.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive activation of ALK3 in chondrocytes exacerbates skeletal dysplasia in mice with Achondroplasia.","authors":"Min Jin, Hangang Chen, Huabing Qi, Shuo Huang, Xiaoqing Luo, Junmei Qi, Peng Yang, Junlan Huang, Qiaoyan Tan, Fengtao Luo, Jing Yang, Liang Kuang, Can Li, Hua Chen, Xiaolan Du, Yangli Xie, Nan Su, Lin Chen","doi":"10.1093/jbmr/zjaf142","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf142","url":null,"abstract":"<p><p>Achondroplasia (ACH), the most common skeletal dysplasia in humans, is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Activation of FGFR3 and its downstream signaling pathways lead to disturbed chondrogenesis in achondroplasia. Nevertheless, the pathogenic mechanism of achondroplasia has yet not been fully elucidated. Previous studies have indicated that Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) signaling may have opposing actions on the growth plate development. To clarify the crosstalk between FGFR3 and Activin Receptor-Like Kinase 3 (ALK3) signaling in achondroplasia, we generated caALK3col2-ACH mice expressing a constitutively active mutant of ALK3 in the chondrocytes of mice with ACH resulting from a Gly369Cys mutation in FGFR3. Unexpectedly, these mice exhibited a more severe chondrodysplasia phenotype than ACH mice, as evidenced by a greater decrease in chondrocyte proliferation and impaired hypertrophy of chondrocytes in the growth plates. These changes were correlated with an increased expression of p21 and activation of Extracellular Regulated protein Kinase (ERK)/ Mitogen-Activated Protein Kinase (MAPK) pathway. This study provides an in vivo genetic demonstration of the imbalanced interaction between the FGFR3 and ALK3 signaling pathways in the growth plate of caALK3col2-ACH mice, suggesting that the ERK/MAPK pathway play an essential role in growth plate chondrogenesis.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The gSOS Polygenic Score is Associated with Bone Density and Fracture Risk in Childhood.","authors":"Jonathan A Mitchell, Jonathan Bradfield, Shana E McCormack, Alessandra Chesi, Heidi J Kalkwarf, Joan M Lappe, Sharon E Oberfield, Dana L Duren, John A Shepherd, Kurt D Hankenson, Andrea Kelly, Hakon Hakonarson, Struan F A Grant, Babette S Zemel","doi":"10.1093/jbmr/zjaf149","DOIUrl":"10.1093/jbmr/zjaf149","url":null,"abstract":"<p><p>The polygenic risk score genetic quantitative ultrasound speed of sound (gSOS) was developed using machine learning algorithms in adults of European ancestry and associates with reduced odds of fracture in adults. We aimed to determine if gSOS was associated with bone health in children. Two observational studies of children were evaluated: (1) children enrolled in the Bone Mineral Density in Childhood Study (BMDCS) with genetic data (N = 1727); and (2) children with genetic data for research at the Children's Hospital of Philadelphia (CHOP; N = 10 301). Genetic variants were used to calculate gSOS and genetic ancestry. For the BMDCS, puberty stage, dietary calcium, physical activity and fracture accumulation (none or ≥ 1 fracture) were self-reported, height and weight were measured and BMI calculated. Areal bone mineral density (aBMD) of the lumbar spine, hip, radius, and whole body were assessed by dual energy X-ray absorptiometry and expressed as Z-scores. The CHOP study paired genetic data with documentation of fracture in the electronic health record (EHR). gSOS associated with higher aBMD Z-scores across 7 skeletal sites [eg, a 1 SD increase in gSOS associated with 0.17 (95% CI: 0.10-0.24) higher lumbar spine aBMD Z-score]. These associations were consistent for males and females, age, puberty stage, and lifestyle factors, and most consistent among children of European genetic ancestry. A 1 SD increase in gSOS associated with 24% reduced likelihood of self-reported fracture in the BMDCS (OR = 0.76, 95% CI: 0.66, 0.88) and a 12% reduced likelihood of a recorded fracture in the CHOP EHR (OR = 0.88; 95% CI: 0.82, 0.95). No sex or genetic ancestry differences were found. A higher gSOS score associated with higher aBMD at multiple skeletal sites and reduced odds of fracture in two independent pediatric samples. This genetic tool may have clinical utility to help enhance bone health in early life and protect against fracture across the lifespan.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Bone Fragility in Diabetes Mellitus.","authors":"Peter R Ebeling","doi":"10.1093/jbmr/zjaf147","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf147","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanosensitive Ion Channels as Novel Targets in Osteoporosis.","authors":"Christoph Beyersdorf, Uwe Maus, Felix Wiedmann, J Juliana Franziska Bousch, Maximilian Waibel, Constanze Schmidt, Merten Prüser","doi":"10.1093/jbmr/zjaf145","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf145","url":null,"abstract":"<p><p>Osteoporosis is the most prevalent metabolic bone disease globally, characterized by decreased bone mass and microarchitectural deterioration, leading to an increased risk of fractures. While its pathogenesis is multifactorial, including hormonal changes, aging and inflammatory processes, and thus far incompletely understood, recent advances in ion channel research have shed light on the importance of mechanosensitive ion channels as novel players in these pathophysiological processes. This perspective discusses the involvement of the mechanosensitive ion channels TREK-1, Piezo, and VRACs as potential novel pharmacological targets for the treatment of osteoporosis. TREK-1, a mechanosensitive K2P channel is important for maintaining the resting membrane potential in many cells, including osteoblasts and osteoclasts. K2P channels regulate osteoblast proliferation and differentiation, as well as osteoclast activity, potentially modulating bone remodeling in osteoporosis. Piezo channels influence osteoblast differentiation and osteoclast activity by modulating calcium influx, which is crucial for osteogenic signaling pathways such as Wnt/β-catenin and ERK1/2. Piezo1 activation promotes bone formation, while its deficiency leads to impaired osteogenesis and increased bone resorption. VRACs have been shown to be involved in osteoblast adaptation to mechanical stress and macrophage polarization, which indicates their importance for bone homeostasis. Chronic inflammation is a major contributor to osteoporosis progression. Evidence of ion channel involvement in this process has emerged in recent years. Specifically, macrophage function in osteoporosis seems to be linked to ion channel activity. Inflammatory polarization of macrophages is a key player in inflammation-induced bone loss and can be driven by mechanosensitive ion channels. Modulating these ion channels may provide therapeutic opportunities, as evidenced by studies showing that targeting TREK-1 and Piezo1 can alter macrophage polarization and reduce osteoclast-mediated bone resorption. Given the complexity of ion channel interactions in bone cells and their regulatory role in bone remodeling, understanding their precise function in osteoporosis is essential. Targeted modulation of mechanosensitive ion channels holds promise as a novel therapeutic approach to mitigate inflammation-driven bone loss and improve bone density. Further research into their role in osteoclasts and macrophage-driven bone degradation will aid in developing innovative osteoporosis treatments.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a Polygenic Score for Bone Health-Related Outcomes in Childhood.","authors":"Melissa Fiscaletti, Despoina Manousaki","doi":"10.1093/jbmr/zjaf146","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf146","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated abdominal aortic calcification and trabecular bone score independently predict incident fracture during routine osteoporosis screening.","authors":"Abadi K Gebre, Marc Sim, Syed Zulqarnain Gilani, Afsah Saleem, Cassandra Smith, Didier Hans, Siobhan Reid, Barret A Monchka, Douglas Kimelman, Mohammad Jafari Jozani, John T Schousboe, Joshua R Lewis, William D Leslie","doi":"10.1093/jbmr/zjaf144","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf144","url":null,"abstract":"<p><p>Abdominal aortic calcification (AAC), a marker of subclinical cardiovascular disease, has previously shown to be associated with low bone mineral density (BMD) and fracture. However, it remains unclear whether AAC is associated with trabecular bone score (TBS), a gray-level textural measure, or whether it predicts fracture risk independent of this measure. Here, we examined the cross-sectional association of AAC scored using a validated machine learning algorithm (ML-AAC24) with TBS, and their simultaneous associations with incident fractures in 7,691 individuals (93.4% women) through the Manitoba BMD Registry (mean age 75.3 years). The association between ML-AAC24 and TBS was tested using generalised linear regression. Cox proportional hazards models tested the simultaneous relationships of ML-AAC24 and TBS with incident fractures. At baseline, 41.3% of the study cohort had low (<2), 32.4% had moderate (2 to <6) and 26.3% had high (≥6) ML-AAC24. Compared to low ML-AAC24, high ML-AAC24 was associated with a 0.81% lower TBS in the multivariable-adjusted model. Independent of each other and multiple established fracture risk factors, ML-AAC24 and TBS were each associated with an increased risk of incident fractures. Specifically, high ML-AAC24 (HR 1.41 95%CI 1.15-1.73, compared to low ML-AAC24) and lower TBS (HR 1.13 95%CI 1.05-1.22, per SD decrease) were associated with increased relative hazards for any incident fracture. High ML-AAC24 and lower TBS were also associated with incident major osteoporotic fracture (HR 1.48 95%CI 1.18-1.87 and HR 1.15 95%CI 1.06-1.25, respectively) and hip fracture (HR 1.56 95%CI 1.05-2.31 and HR 1.25 95%CI 1.08-1.44, respectively). In conclusion, high ML-AAC24 is associated with lower TBS in older adults attending routine osteoporosis screening. Both measures were associated with incident fractures. The findings of this study highlight high ML-AAC24, seen in more than 1 in 4 of the study cohort, and lower TBS provide complementary prognostic information for fracture risk.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypophosphatasia - Pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments.","authors":"Jose Luis Millán","doi":"10.1093/jbmr/zjaf141","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf141","url":null,"abstract":"<p><p>Hypophosphatasia (HPP) is the genetic disorder caused by loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme essential for physiological skeletal/dental mineralization. In HPP, TNAP deficiency leads to the accumulation of extracellular pyrophosphate (PPi), a potent inhibitor of calcification, resulting in skeletal and dental hypomineralization, with disease severity varying from the life-threatening perinatal and infantile forms to the milder later-onset forms that manifest in adulthood or only affect dentition. Enzyme replacement therapy based on recombinant mineral-targeted alkaline phosphatase (asfotase alfa) has been approved multinationally since 2015 for the treatment of pediatric-onset HPP, remarkably increasing the lifespan, their skeletal condition and the quality of life of patients affected by the severe forms of HPP. However, non-skeletal symptoms remain as important clinical concerns. As its moniker implies, TNAP is expressed in a large variety of tissues and cell types, and TNAP may be engaged in distinct metabolic pathways in each tissue. A better understanding of the cells expressing TNAP physiologically, the metabolic pathways involved and the natural substrates of TNAP in each tissue will help design improved and/or alternative therapies to prevent/correct known or yet to be discovered non-skeletal manifestations of HPP. Figure 1 graphically lays out the topics discussed in this invited perspective article that follows the contents of the Louis V Avioli Memorial lecture delivered during the ASBMR 2025 annual meeting.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Loss, Botulinum Toxin, and Cardiovascular Function.","authors":"Rhonda D Prisby","doi":"10.1093/jbmr/zjaf137","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf137","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}