Pub Date : 2025-10-02DOI: 10.1016/j.bone.2025.117663
Ling Yu , Mingquan Yan , Sarah M. Wolff , Joseph D. Knue , Hannah M. Smith , Connor P. Dolan , Ken Muneoka , Selim Romero , James J. Cai , Carissa Yun , Devon J. Boland , Regina Brunauer , Lindsay A. Dawson
Due to increases in vascular diseases, the incidence of limb loss is predicted to more than double in the next quarter century. Therefore, developing a greater understanding of the latent regenerative capacity in mammals is a significant and growing goal. Mammals, including humans and mice, have limited regenerative capacity following limb amputation, with regenerative responses restricted to amputations transecting the distal digit tip (P3). Unlike P3, amputations of the adjacent skeletal segment, the middle phalanx, P2, are non-regenerative and result in bone truncation and soft tissue scar formation. As such, P2 amputation is a simple yet powerful model to test strategies for inducing mammalian musculoskeletal regeneration from an otherwise non-regenerative amputation plane. Here, we report that Fibroblast Growth Factor 8 (FGF8) drives synovial joint regeneration at P2 amputation wounds in neonate mice. This response is characterized by the regeneration of a synovial cavity, a skeletal nodule lined with articular cartilage, and tendon and ligament regeneration. FGF8 also induces cartilage formation on the P2 stump that serves as a template for partial P2 bone regeneration, thus FGF8 drives the composite regeneration of stump and joint tissues. FGF8-induced joint regeneration is associated with the upregulation of several, but not all, genes that characterize joint development, and is morphologically distinct from digit joint development. Lineage tracing studies demonstrate that cells at the amputation wound contribute to the regenerated joint structures. These studies provide evidence that the otherwise non-regenerative P2 amputation wound possesses tremendous regenerative capacity that is dormant under normal circumstances.
{"title":"FGF8 induces bone and joint regeneration at digit amputation wounds in neonate mice","authors":"Ling Yu , Mingquan Yan , Sarah M. Wolff , Joseph D. Knue , Hannah M. Smith , Connor P. Dolan , Ken Muneoka , Selim Romero , James J. Cai , Carissa Yun , Devon J. Boland , Regina Brunauer , Lindsay A. Dawson","doi":"10.1016/j.bone.2025.117663","DOIUrl":"10.1016/j.bone.2025.117663","url":null,"abstract":"<div><div>Due to increases in vascular diseases, the incidence of limb loss is predicted to more than double in the next quarter century. Therefore, developing a greater understanding of the latent regenerative capacity in mammals is a significant and growing goal. Mammals, including humans and mice, have limited regenerative capacity following limb amputation, with regenerative responses restricted to amputations transecting the distal digit tip (P3). Unlike P3, amputations of the adjacent skeletal segment, the middle phalanx, P2, are non-regenerative and result in bone truncation and soft tissue scar formation. As such, P2 amputation is a simple yet powerful model to test strategies for inducing mammalian musculoskeletal regeneration from an otherwise non-regenerative amputation plane. Here, we report that Fibroblast Growth Factor 8 (FGF8) drives synovial joint regeneration at P2 amputation wounds in neonate mice. This response is characterized by the regeneration of a synovial cavity, a skeletal nodule lined with articular cartilage, and tendon and ligament regeneration. FGF8 also induces cartilage formation on the P2 stump that serves as a template for partial P2 bone regeneration, thus FGF8 drives the composite regeneration of stump and joint tissues. FGF8-induced joint regeneration is associated with the upregulation of several, but not all, genes that characterize joint development, and is morphologically distinct from digit joint development. Lineage tracing studies demonstrate that cells at the amputation wound contribute to the regenerated joint structures. These studies provide evidence that the otherwise non-regenerative P2 amputation wound possesses tremendous regenerative capacity that is dormant under normal circumstances.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117663"},"PeriodicalIF":3.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hereditary hypophosphatemia (HH) are rare diseases, characterized by excessive renal phosphate wasting, rickets and osteomalacia in growing children, and osteomalacia in adults. There are several types of HH caused by pathogenic variants in a number of different genes. We present a large Danish family consisting of 19 family members with clinically and biochemically hypophosphatamia caused by a previously unreported deep intronic splice variant in PHEX: c.1080-687 A > G (p.?). The affected family members displayed a milder HH phenotype compared with a larger group of individuals with other disease causing PHEX variants. We were able to genetically confirm a diagnosis of X-linked hypophosphatemia (XLH) by genome sequencing intron analysis and in vitro analysis consisting of an exon trapping assay. Our findings emphasize the phenotypic variability of XLH, where this family in general displays a milder phenotype. Furthermore, our findings demonstrate that XLH can be caused by intron variants in PHEX.
遗传性低磷血症（HH）是一种罕见的疾病，其特征是过度的肾磷酸盐消耗、佝偻病和成长期儿童骨软化症以及成人骨软化症。有几种类型的HH是由许多不同基因的致病变异引起的。我们提出了一个由19个家庭成员组成的丹麦大家庭，其临床和生化低磷血症是由先前未报道的PHEX深内含子剪接变异引起的：c.1080-687 a > G （p.?）。与其他疾病引起的PHEX变异个体相比，受影响的家庭成员表现出较轻的HH表型。通过基因组测序内含子分析和体外外显子捕获分析，我们能够从遗传学上确认x连锁低磷血症（XLH）的诊断。我们的研究结果强调了XLH的表型变异性，这个家族通常表现出较温和的表型。此外，我们的研究结果表明XLH可能是由PHEX的内含子变异引起的。
{"title":"A deep intronic PHEX variant in a large Danish family with hereditary hypophosphatemia and a milder skeletal, but more severe dental phenotype","authors":"Jenny Blechingberg , Kristian Alsbjerg Skipper , Signe Sparre Beck-Nielsen , Pernille Axél Gregersen","doi":"10.1016/j.bone.2025.117666","DOIUrl":"10.1016/j.bone.2025.117666","url":null,"abstract":"<div><div>Hereditary hypophosphatemia (HH) are rare diseases, characterized by excessive renal phosphate wasting, rickets and osteomalacia in growing children, and osteomalacia in adults. There are several types of HH caused by pathogenic variants in a number of different genes. We present a large Danish family consisting of 19 family members with clinically and biochemically hypophosphatamia caused by a previously unreported deep intronic splice variant in <em>PHEX</em>: c.1080-687 A > G (p.?). The affected family members displayed a milder HH phenotype compared with a larger group of individuals with other disease causing <em>PHEX</em> variants. We were able to genetically confirm a diagnosis of X-linked hypophosphatemia (XLH) by genome sequencing intron analysis and in vitro analysis consisting of an exon trapping assay. Our findings emphasize the phenotypic variability of XLH, where this family in general displays a milder phenotype. Furthermore, our findings demonstrate that XLH can be caused by intron variants in <em>PHEX</em>.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117666"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-28DOI: 10.1016/j.bone.2025.117662
Yi Zhang , Kai Zhang , Weizheng Kong , Xiaolin Hu , Lirong Chai , Weijing Wang , Dongfeng Zhang , Junning Fan
Background
Limited evidence exists regarding the association of frailty with fractures of different types and the potential mediating factors. This study investigated the prospective associations of frailty status with incident fracture risk and potential mediating role of inflammatory biomarkers.
Methods
This prospective cohort study utilized the UK Biobank data (median follow-up: 13.6 years). Frailty status was assessed using the frailty index (FI) and Fried's phenotype (FP). The outcomes of interest were any, vertebral, hip, and non-hip non-vertebral (NHNV) fractures. Cox regression models were employed to estimate association between frailty and fracture outcomes. Subgroup analyses by age, sex, and body mass index were conducted. Additionally, mediation analyses were performed to explore whether and quantify the extent to which inflammation may mediate the frailty-fracture association.
Results
Among 418,700 participants aged 38–72 years, frailty significantly increased risk of incident fracture, taking the frailty index as an example, with hazard ratios (HRs) and 95 % confidence intervals (CIs) of 1.53 (1.45–1.60) for any fractures, 2.33 (2.04–2.66) for vertebral fractures, 1.74 (1.55–1.95) for hip fractures, and 1.43 (1.35–1.52) for NHNV fractures. The FI-any fracture association was stronger in participants aged ≥60 years compared to younger participants (Pinteraction = 0.0414); FP exhibited more pronounced associations with any fractures in men than women (Pinteraction = 0.0001). Moreover, three inflammatory biomarkers - C-reactive protein, neutrophils, and platelets - significantly mediated 0.86–2.20 % of the frailty-fracture relationships.
Conclusion
Frailty was independently linked to increased risks of incident fracture, partially mediated through inflammatory biomarkers. These findings underscore the clinical importance of frailty screening in fracture prevention settings.
{"title":"Association of frailty with incident fractures and the mediating effect of inflammatory biomarkers: a prospective cohort study from the UK Biobank","authors":"Yi Zhang , Kai Zhang , Weizheng Kong , Xiaolin Hu , Lirong Chai , Weijing Wang , Dongfeng Zhang , Junning Fan","doi":"10.1016/j.bone.2025.117662","DOIUrl":"10.1016/j.bone.2025.117662","url":null,"abstract":"<div><h3>Background</h3><div>Limited evidence exists regarding the association of frailty with fractures of different types and the potential mediating factors. This study investigated the prospective associations of frailty status with incident fracture risk and potential mediating role of inflammatory biomarkers.</div></div><div><h3>Methods</h3><div>This prospective cohort study utilized the UK Biobank data (median follow-up: 13.6 years). Frailty status was assessed using the frailty index (FI) and Fried's phenotype (FP). The outcomes of interest were any, vertebral, hip, and non-hip non-vertebral (NHNV) fractures. Cox regression models were employed to estimate association between frailty and fracture outcomes. Subgroup analyses by age, sex, and body mass index were conducted. Additionally, mediation analyses were performed to explore whether and quantify the extent to which inflammation may mediate the frailty-fracture association.</div></div><div><h3>Results</h3><div>Among 418,700 participants aged 38–72 years, frailty significantly increased risk of incident fracture, taking the frailty index as an example, with hazard ratios (HRs) and 95 % confidence intervals (CIs) of 1.53 (1.45–1.60) for any fractures, 2.33 (2.04–2.66) for vertebral fractures, 1.74 (1.55–1.95) for hip fractures, and 1.43 (1.35–1.52) for NHNV fractures. The FI-any fracture association was stronger in participants aged ≥60 years compared to younger participants (<em>P</em> <sub>interaction</sub> = 0.0414); FP exhibited more pronounced associations with any fractures in men than women (<em>P</em> <sub>interaction</sub> = 0.0001). Moreover, three inflammatory biomarkers - C-reactive protein, neutrophils, and platelets - significantly mediated 0.86–2.20 % of the frailty-fracture relationships.</div></div><div><h3>Conclusion</h3><div>Frailty was independently linked to increased risks of incident fracture, partially mediated through inflammatory biomarkers. These findings underscore the clinical importance of frailty screening in fracture prevention settings.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117662"},"PeriodicalIF":3.6,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1016/j.bone.2025.117646
Lyan Abdul Wadood , Victoria McHugh , Kristin K. Clemens , Mary E. Jenkins , Jeffrey D. Holmes , Jamie L. Fleet
Background
Parkinson's Disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic neurons in the basal ganglia. It leads to a range of motor symptoms such as tremors, bradykinesia, rigidity, and gait instability. A significant, but often overlooked, sequela of PD is osteoporosis, which contributes to a higher incidence of fractures. This risk is exacerbated by both PD itself as well as the medications used to manage PD. Despite the heightened risk of fragility fractures, osteoporosis in PD is frequently under-recognized and inadequately managed.
Objective
This review aimed to explore the current literature on osteoporosis management strategies specifically for individuals with PD.
Methods
MEDLINE, Scopus, and EMBASE were searched from database inception to August 10, 2025.
Results
Following a two-stage review process conducted by two independent reviewers, 18 relevant articles were identified. Of these, 17 were review articles and one was an interventional study. The literature most commonly identified lifestyle modifications, pharmacological treatments, and surgical interventions as management strategies for osteoporosis in PD. However, most of the recommendations were based on research conducted in the general population, raising concerns about their effectiveness for individuals with PD, who may have unique clinical needs.
Conclusions
We note a significant gap in research focused on osteoporosis management in PD patients. Research efforts should prioritize developing tailored strategies to manage osteoporosis in individuals with PD.
{"title":"Management of osteoporosis in Parkinson's disease: A scoping review","authors":"Lyan Abdul Wadood , Victoria McHugh , Kristin K. Clemens , Mary E. Jenkins , Jeffrey D. Holmes , Jamie L. Fleet","doi":"10.1016/j.bone.2025.117646","DOIUrl":"10.1016/j.bone.2025.117646","url":null,"abstract":"<div><h3>Background</h3><div>Parkinson's Disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic neurons in the basal ganglia. It leads to a range of motor symptoms such as tremors, bradykinesia, rigidity, and gait instability. A significant, but often overlooked, sequela of PD is osteoporosis, which contributes to a higher incidence of fractures. This risk is exacerbated by both PD itself as well as the medications used to manage PD. Despite the heightened risk of fragility fractures, osteoporosis in PD is frequently under-recognized and inadequately managed.</div></div><div><h3>Objective</h3><div>This review aimed to explore the current literature on osteoporosis management strategies specifically for individuals with PD.</div></div><div><h3>Methods</h3><div>MEDLINE, Scopus, and EMBASE were searched from database inception to August 10, 2025.</div></div><div><h3>Results</h3><div>Following a two-stage review process conducted by two independent reviewers, 18 relevant articles were identified. Of these, 17 were review articles and one was an interventional study. The literature most commonly identified lifestyle modifications, pharmacological treatments, and surgical interventions as management strategies for osteoporosis in PD. However, most of the recommendations were based on research conducted in the general population, raising concerns about their effectiveness for individuals with PD, who may have unique clinical needs.</div></div><div><h3>Conclusions</h3><div>We note a significant gap in research focused on osteoporosis management in PD patients. Research efforts should prioritize developing tailored strategies to manage osteoporosis in individuals with PD.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117646"},"PeriodicalIF":3.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1016/j.bone.2025.117655
Nataira Regina Momesso , Ana Carolina Zucon Bacelar-Marcolino , Claudia Cristina Biguetti , Rafael Carneiro Ortiz , Edilson Ervolino , Mariza Akemi Matsumoto
Alveolar socket is a highly dynamic site of bone remodeling and a clinically relevant model for studying healing disturbances associated with antiresorptive therapy. The present study aimed to investigate how different models of premature ovarian failure - ovariectomy (OVX) and chemically induced follicular depletion using 4-vinylcyclohexene diepoxide (VCD) - influence post-extraction alveolar bone repair in female mice, particularly when combined with zoledronic acid (ZL). Fifty C57Bl/6J female mice (4–6 months old) were assigned to six experimental groups: control (CT), OVX, chemically induced estropause using VCD, and their respective groups treated with ZL (CT + ZL, OVX + ZL, VCD + ZL). ZL (500 μg/kg/week, intraperitoneally) was administered for four weeks before maxillary incisor extraction and continued until euthanasia. Bone healing was evaluated at 7 and 21 days post-extraction using microCT, histology, birefringence, and immunohistochemistry for OPG and TRAP. At 21 days, ZL-treated groups exhibited reduced BV/TV compared to their untreated counterparts. The VCD + ZL group showed delayed healing, with disorganized trabeculae, persistent inflammatory infiltrates, and immature collagen matrix. In contrast, the OVX + ZL and CT + ZL groups showed improved bone quality and increased collagen maturation. No significant differences were observed in TRAP or OPG immunostaining across groups. The effects of ovarian failure were evident in the microarchitectural analysis of the 5L vertebrae. These findings suggest that while estrogen deprivation alone (via OVX or VCD) does not impair alveolar bone healing, the combination of VCD-induced premature ovarian failure and ZL treatment negatively impacts the healing process. This highlights a potential vulnerability in patients undergoing bisphosphonate therapy during premature menopause.
{"title":"Comparative effects of ovariectomy and chemically induced menopause on alveolar bone healing in zoledronate-treated female mice","authors":"Nataira Regina Momesso , Ana Carolina Zucon Bacelar-Marcolino , Claudia Cristina Biguetti , Rafael Carneiro Ortiz , Edilson Ervolino , Mariza Akemi Matsumoto","doi":"10.1016/j.bone.2025.117655","DOIUrl":"10.1016/j.bone.2025.117655","url":null,"abstract":"<div><div>Alveolar socket is a highly dynamic site of bone remodeling and a clinically relevant model for studying healing disturbances associated with antiresorptive therapy. The present study aimed to investigate how different models of premature ovarian failure - ovariectomy (OVX) and chemically induced follicular depletion using 4-vinylcyclohexene diepoxide (VCD) - influence post-extraction alveolar bone repair in female mice, particularly when combined with zoledronic acid (ZL). Fifty C57Bl/6J female mice (4–6 months old) were assigned to six experimental groups: control (CT), OVX, chemically induced estropause using VCD, and their respective groups treated with ZL (CT + ZL, OVX + ZL, VCD + ZL). ZL (500 μg/kg/week, intraperitoneally) was administered for four weeks before maxillary incisor extraction and continued until euthanasia. Bone healing was evaluated at 7 and 21 days post-extraction using microCT, histology, birefringence, and immunohistochemistry for OPG and TRAP. At 21 days, ZL-treated groups exhibited reduced BV/TV compared to their untreated counterparts. The VCD + ZL group showed delayed healing, with disorganized trabeculae, persistent inflammatory infiltrates, and immature collagen matrix. In contrast, the OVX + ZL and CT + ZL groups showed improved bone quality and increased collagen maturation. No significant differences were observed in TRAP or OPG immunostaining across groups. The effects of ovarian failure were evident in the microarchitectural analysis of the 5L vertebrae. These findings suggest that while estrogen deprivation alone (via OVX or VCD) does not impair alveolar bone healing, the combination of VCD-induced premature ovarian failure and ZL treatment negatively impacts the healing process. This highlights a potential vulnerability in patients undergoing bisphosphonate therapy during premature menopause.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117655"},"PeriodicalIF":3.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1016/j.bone.2025.117661
Hiroshi Kawaguchi
{"title":"Structural challenges in using Japanese claims databases for real-world evidence in osteoporosis research","authors":"Hiroshi Kawaguchi","doi":"10.1016/j.bone.2025.117661","DOIUrl":"10.1016/j.bone.2025.117661","url":null,"abstract":"","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117661"},"PeriodicalIF":3.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.bone.2025.117660
Mette Bøegh Levring , Marta Diaz-delCastillo , Michael Tveden Gundesen , Oriane Cédile , Christian Walther Andersen , Anne Lerberg Nielsen , Hanne Elisabeth Højsgaard Møller , Pernille Just Vinholt , Jon Thor Asmussen , Ida Bruun Kristensen , Charlotte Guldborg Nyvold , Moustapha Kassem , Niels Abildgaard , Thomas Levin Andersen , Thomas Lund
Myeloma bone disease (MBD), a common complication in multiple myeloma (MM), causes increased risk of fractures leading to morbidity and impaired quality of life for patients. Proteasome inhibitors, a cancer-targeting therapy for MM, have been shown to have a beneficial off-target bone anabolic effect. However, side effects and toxicities of proteasome inhibitors limits their long-term use, especially in patients in disease remission. Ixazomib is an oral proteasome inhibitor with anti-myeloma effect, but a less severe toxicity profile compared to other approved proteasome inhibitors. To investigate the effect of ixazomib on MBD, we conducted a single-center clinical study where 30 patients with MM in remission received ixazomib, and evaluated bone-specific changes through serum markers, imaging, cell cultures, and bone histomorphometry. We have previously shown that short-term ixazomib treatment (3 months) induces increased trabecular bone volume and formation of enlarged bone structural units (BSU) without changing osteoblast number or activity. Here, we present evidence that long-term (24 months) ixazomib treatment inhibits the activation of new bone remodeling events through attenuation of both bone resorption and formation. The initial gains in percentage of superficial trabecular BSU bone volume remained stable and the proportion of large BSUs containing woven bone decreased, suggesting improved bone mineralization over time. Overall, our results indicate that long-term ixazomib treatment led to prolonged bone formation events during the initial treatment phase, followed by inhibition of new bone resorption and its coupled bone formation, preserving the gained bone and possibly preventing advancement of MBD in patients with MM in remission.
{"title":"Ixazomib treatment has a dual effect on bone remodeling in patients with multiple myeloma: follow-up results from a phase 2 clinical study","authors":"Mette Bøegh Levring , Marta Diaz-delCastillo , Michael Tveden Gundesen , Oriane Cédile , Christian Walther Andersen , Anne Lerberg Nielsen , Hanne Elisabeth Højsgaard Møller , Pernille Just Vinholt , Jon Thor Asmussen , Ida Bruun Kristensen , Charlotte Guldborg Nyvold , Moustapha Kassem , Niels Abildgaard , Thomas Levin Andersen , Thomas Lund","doi":"10.1016/j.bone.2025.117660","DOIUrl":"10.1016/j.bone.2025.117660","url":null,"abstract":"<div><div>Myeloma bone disease (MBD), a common complication in multiple myeloma (MM), causes increased risk of fractures leading to morbidity and impaired quality of life for patients. Proteasome inhibitors, a cancer-targeting therapy for MM, have been shown to have a beneficial off-target bone anabolic effect. However, side effects and toxicities of proteasome inhibitors limits their long-term use, especially in patients in disease remission. Ixazomib is an oral proteasome inhibitor with anti-myeloma effect, but a less severe toxicity profile compared to other approved proteasome inhibitors. To investigate the effect of ixazomib on MBD, we conducted a single-center clinical study where 30 patients with MM in remission received ixazomib, and evaluated bone-specific changes through serum markers, imaging, cell cultures<strong>,</strong> and bone histomorphometry. We have previously shown that short-term ixazomib treatment (3 months) induces increased trabecular bone volume and formation of enlarged bone structural units (BSU) without changing osteoblast number or activity. Here, we present evidence that long<strong>-</strong>term (24 months) ixazomib treatment inhibits the activation of new bone remodeling events through attenuation of both bone resorption and formation. The initial gains in percentage of superficial trabecular BSU bone volume remained stable and the proportion of large BSUs containing woven bone decreased, suggesting improved bone mineralization over time. Overall, our results indicate that long-term ixazomib treatment led to prolonged bone formation events during the initial treatment phase, followed by inhibition of new bone resorption and its coupled bone formation, preserving the gained bone and possibly preventing advancement of MBD in patients with MM in remission.</div></div><div><h3>Clinical trial registration</h3><div><span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> ID <span><span>NCT04028115</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117660"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.bone.2025.117658
Yun Zhao , Xingyao Yang , Jialun Wang , Fangdong Chen , Guojia Shi , Jun Cheng , Shuxing Xing , Xiao Liu
Purpose
Osteoporosis (OP) is influenced by dysregulated miRNAs, particularly during osteoblast differentiation. The precise mechanisms are still under debate. This study aimed to explore the impact of bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-133b-3p on the TGF-β1/Treg-mediated immune pathway, offering insights into OP's pathogenesis and potential therapeutic targets.
Materials and methods
Bioinformatics analysis of GEO dataset (GSE64433) identified differentially expressed miRNAs in osteoporosis. Target genes were predicted using TargetScan, miRDB, miRTarBase, and miRWalk databases, followed by GO and KEGG pathway enrichment analyses. An OP rat model was constructed by ovariectomy (n = 36, randomly allocated into three groups: control, OP, and OP+exosomal miR-133b-3p, n = 12 per group). BMSCs were isolated at 12 weeks post-OVX.Flow cytometry was used to identify the surface markers of BMSCs, CD29, CD44, CD106, CD34, and CD45. Exosomes were isolated from passages 3–5 BMSCs using ExoQuick kit. Transmission electron microscopy and nanoparticle tracking analysis were used to observe the morphology and size distribution of exosomes, and the expression of exosomal protein markers CD9, CD63, and TSG101 was detected by Western blot. qRT-PCR was performed to detect miR-133b-3p and TGF-β1 expression in exosomes. Dual-luciferase reporter assay validated the direct interaction between miR-133b-3p and TGF-β1 3’-UTR. Dual-energy X-ray bone densitometry was used to detect bone mineral density (BMD) after 4 weeks of treatment with miR-133b-3p-enriched exosomes (200 μg weekly via tail vein injection). Micro-CT was used to analyze the BV/TV, Tb.N, Tb.Th, SMI, Ct.Th, BA/TA, and Tb.Sp. In vitro experiments using isolated CD4+ T cells were conducted to assess TGF-β1 expression and CD4+CD25+Foxp3+ Treg cell differentiation via Western blot, RT-PCR, and flow cytometry. Osteoclast marker enzymes TRAP, MMP-9, and Cathepsin K were identified using immunohistochemistry.
Results
Bioinformatics analysis revealed 27 differentially expressed miRNAs. Target prediction of miR-133b-3p identified 44 high-confidence genes, with TGF-β1 emerging as a key target. BMSCs expressing CD29, CD44, and CD106 (but not CD34 and CD45) were isolated from both control and OP rats. The identified exosomes were roughly spherical with a double-layered membrane, they had a size distribution of about 103.5 ± 8.2 nm and 105.8 ± 10.6 nm, respectively, and had a positive expression of CD9 CD63, and TSG101. qRT-PCR analysis revealed significantly decreased miR-133b-3p expression in OP group exosomes (P < 0.001). D
{"title":"Exosomal miR-133b-3p modulates TGF-β1/Treg immunomodulation to ameliorate osteoporosis","authors":"Yun Zhao , Xingyao Yang , Jialun Wang , Fangdong Chen , Guojia Shi , Jun Cheng , Shuxing Xing , Xiao Liu","doi":"10.1016/j.bone.2025.117658","DOIUrl":"10.1016/j.bone.2025.117658","url":null,"abstract":"<div><h3>Purpose</h3><div>Osteoporosis (OP) is influenced by dysregulated miRNAs, particularly during osteoblast differentiation. The precise mechanisms are still under debate. This study aimed to explore the impact of bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-133b-3p on the TGF-β1/Treg-mediated immune pathway, offering insights into OP's pathogenesis and potential therapeutic targets.</div></div><div><h3>Materials and methods</h3><div>Bioinformatics analysis of GEO dataset (<span><span>GSE64433</span><svg><path></path></svg></span>) identified differentially expressed miRNAs in osteoporosis. Target genes were predicted using TargetScan, miRDB, miRTarBase, and miRWalk databases, followed by GO and KEGG pathway enrichment analyses. An OP rat model was constructed by ovariectomy (<em>n</em> = 36, randomly allocated into three groups: control, OP, and OP+exosomal <em>miR-133b-3p</em>, <em>n</em> = 12 per group). BMSCs were isolated at 12 weeks post-OVX.Flow cytometry was used to identify the surface markers of BMSCs, <em>CD29, CD44, CD106, CD34,</em> and <em>CD45</em>. Exosomes were isolated from passages 3–5 BMSCs using ExoQuick kit. Transmission electron microscopy and nanoparticle tracking analysis were used to observe the morphology and size distribution of exosomes, and the expression of exosomal protein markers <em>CD9, CD63,</em> and <em>TSG101</em> was detected by Western blot. qRT-PCR was performed to detect <em>miR-133b-3p</em> and <em>TGF-β1</em> expression in exosomes. Dual-luciferase reporter assay validated the direct interaction between <em>miR-133b-3p</em> and <em>TGF-β1</em> 3’-UTR. Dual-energy X-ray bone densitometry was used to detect bone mineral density (BMD) after 4 weeks of treatment with <em>miR-133b-3p</em>-enriched exosomes (200 μg weekly via tail vein injection). Micro-CT was used to analyze the BV/TV, Tb.N, Tb.Th, SMI, Ct.Th, BA/TA, and Tb.Sp. In vitro experiments using isolated CD4+ T cells were conducted to assess <em>TGF-β1</em> expression and <em>CD4</em> <em>+</em> <em>CD25</em> <em>+</em> <em>Foxp3+</em> Treg cell differentiation via Western blot, RT-PCR, and flow cytometry. Osteoclast marker enzymes <em>TRAP, MMP-9,</em> and <em>Cathepsin K</em> were identified using immunohistochemistry.</div></div><div><h3>Results</h3><div>Bioinformatics analysis revealed 27 differentially expressed miRNAs. Target prediction of <em>miR-133b-3p</em> identified 44 high-confidence genes, with <em>TGF-β1</em> emerging as a key target. BMSCs expressing <em>CD29, CD44,</em> and CD106 (but not CD34 and CD45) were isolated from both control and OP rats. The identified exosomes were roughly spherical with a double-layered membrane, they had a size distribution of about 103.5 ± 8.2 nm and 105.8 ± 10.6 nm, respectively, and had a positive expression of <em>CD9 CD63,</em> and <em>TSG101</em>. qRT-PCR analysis revealed significantly decreased <em>miR-133b-3p</em> expression in OP group exosomes (<em>P</em> < 0.001). D","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117658"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.bone.2025.117659
Elena Ghotbi , Quincy A. Hathaway , Roham Hadidchi , Michael P. Bancks , David A. Bluemke , Mei Wan , R. Graham Barr , Wendy S. Post , Matthew Budoff , Benjamin M. Smith , João A.C. Lima , Shadpour Demehri
Background
Existing reports on the protective effects of statins on bone health have been conflicting, which may have been related to the diverse selectivity of studied populations. We aimed to evaluate the association between statin initiation and longitudinal changes in vertebral bone mineral density (BMD) over six years.
Methods
This emulated target trial used data from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants with a baseline 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5 % at MESA Exam 4 or 5 and no history of prevalent statin use were included. Statin initiators were propensity score matched to non-initiators.
The primary outcome was longitudinal change in CT-derived multilevel vertebral (T1–T10) BMD, assessed using linear mixed-effects models. Prespecified interaction terms and subsequent subgroup analyses were performed by age, sex, race/ethnicity, body mass index, high-sensitivity C-reactive protein (hs-CRP), physical activity, diabetes status, smoking, and alcohol use. We used an array approach to evaluate the magnitude and prevalence of residual confounding necessary to fully explain our main observation.
Results
A total of 384 participants (173 statin initiators; 211 non-initiators) were included in the per-protocol analysis. Statin initiation was associated with a slower decline in vertebral BMD (estimated difference, β = 1.00 g/cm3/year; 95 % CI, 0.65–1.35; p < 0.001), corresponding to a 0.47 % slower annual decline. An unmeasured confounder associated with a 1 % annual relative difference in BMD change would need to be at least three times as prevalent among statin initiators compared with non-initiators to nullify the observed effect size. Subgroup analyses suggested stronger protective associations among participants with impaired fasting glucose or diabetes, lower hs-CRP, and higher physical activity.
Conclusions
In this emulated target trial, statin initiation was associated with beneficial bone health effects.
关于他汀类药物对骨骼健康的保护作用的现有报告存在矛盾，这可能与研究人群的不同选择性有关。我们的目的是评估他汀类药物起始治疗与6年内椎体骨密度（BMD）纵向变化之间的关系。方法本模拟靶试验采用多民族动脉粥样硬化研究（MESA）的数据。在MESA检查4或5时，基线10年动脉粥样硬化性心血管疾病（ASCVD）风险≥7.5%且无他汀类药物流行史的参与者被纳入研究。他汀类药物启动者倾向评分与非启动者相匹配。主要终点是ct衍生的多节段椎体（T1-T10）骨密度的纵向变化，使用线性混合效应模型进行评估。预先指定的相互作用项和随后的亚组分析按年龄、性别、种族/民族、体重指数、高敏c反应蛋白（hs-CRP）、身体活动、糖尿病状况、吸烟和饮酒进行。我们使用阵列方法来评估充分解释我们的主要观察结果所必需的残留混淆的大小和流行程度。结果384名受试者（173名他汀类药物启动者，211名非他汀类药物启动者）被纳入方案分析。开始服用他汀类药物与椎体骨密度下降较慢相关（估计差异，β = 1.00 g/cm3/年；95% CI, 0.65-1.35; p < 0.001），相当于年下降速度减慢0.47%。未测量的混杂因素与每年1%的BMD变化相对差异相关，在他汀类药物启动者中与非启动者相比，至少需要三倍的流行率才能使观察到的效应大小无效。亚组分析表明，空腹血糖受损或糖尿病患者、hs-CRP较低和体力活动较多的参与者之间存在更强的保护关联。结论在这个模拟靶试验中，他汀类药物起始与有益的骨健康效应相关。
{"title":"Statins and longitudinal changes in vertebral bone mineral density in an emulated target trial: the multi-ethnic study of atherosclerosis","authors":"Elena Ghotbi , Quincy A. Hathaway , Roham Hadidchi , Michael P. Bancks , David A. Bluemke , Mei Wan , R. Graham Barr , Wendy S. Post , Matthew Budoff , Benjamin M. Smith , João A.C. Lima , Shadpour Demehri","doi":"10.1016/j.bone.2025.117659","DOIUrl":"10.1016/j.bone.2025.117659","url":null,"abstract":"<div><h3>Background</h3><div>Existing reports on the protective effects of statins on bone health have been conflicting, which may have been related to the diverse selectivity of studied populations. We aimed to evaluate the association between statin initiation and longitudinal changes in vertebral bone mineral density (BMD) over six years.</div></div><div><h3>Methods</h3><div>This emulated target trial used data from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants with a baseline 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5 % at MESA Exam 4 or 5 and no history of prevalent statin use were included. Statin initiators were propensity score matched to non-initiators.</div><div>The primary outcome was longitudinal change in CT-derived multilevel vertebral (T1–T10) BMD, assessed using linear mixed-effects models. Prespecified interaction terms and subsequent subgroup analyses were performed by age, sex, race/ethnicity, body mass index, high-sensitivity C-reactive protein (hs-CRP), physical activity, diabetes status, smoking, and alcohol use. We used an array approach to evaluate the magnitude and prevalence of residual confounding necessary to fully explain our main observation.</div></div><div><h3>Results</h3><div>A total of 384 participants (173 statin initiators; 211 non-initiators) were included in the per-protocol analysis. Statin initiation was associated with a slower decline in vertebral BMD (estimated difference, β = 1.00 g/cm<sup>3</sup>/year; 95 % CI, 0.65–1.35; <em>p</em> < 0.001), corresponding to a 0.47 % slower annual decline. An unmeasured confounder associated with a 1 % annual relative difference in BMD change would need to be at least three times as prevalent among statin initiators compared with non-initiators to nullify the observed effect size. Subgroup analyses suggested stronger protective associations among participants with impaired fasting glucose or diabetes, lower hs-CRP, and higher physical activity.</div></div><div><h3>Conclusions</h3><div>In this emulated target trial, statin initiation was associated with beneficial bone health effects.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117659"},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.bone.2025.117654
Łukasz Jaśkiewicz , Anna Romaszko-Wojtowicz , Grzegorz Chmielewski , Jakub Kuna , Magdalena Krajewska-Włodarczyk
Myokines are cytokines secreted by skeletal muscle cells. These are cytokines with pleiotropic effects, which have receptors in different organs. Increased secretion of myokines is closely linked to physical activity, through which they affect metabolic processes, signalling pathways, protein expression or cell differentiation.
This study aimed to demonstrate the possible impact of myokines on bone tissue metabolism based on a review of published scientific papers and to disseminate knowledge on myokines among the clinician community. To carry out an analysis in accordance with the PRISMA guidelines, publications were searched in PubMed, Web of Science and ScienceDirect databases. Out of the total of 644 papers identified in the databases, 18 original studies were analysed.
The paper outlined the importance of irisin, myostatin, fibroblast growth factor 2, myonectin, and interleukins 6 and 15 in the regulation of bone tissue metabolism. Based on the reviewed studies, irisin consistently demonstrates a pro-osteoblastic effect via the p38 MAPK pathway, while myostatin generally shows an inhibitory effect on bone formation by decreasing muscle mass. Myonectin exhibits a dual role, inhibiting both osteoblast and osteoclast differentiation in murine models, suggesting a complex regulatory function. This analysis considers both pre-clinical studies on cell cultures and animal models, as well as clinical trials in humans. The findings suggest that further research is needed to fully elucidate the in vivo functions and clinical relevance of myokines in bone metabolism, identifying potential therapeutic targets.
肌因子是骨骼肌细胞分泌的细胞因子。这些细胞因子具有多效性，在不同的器官中都有受体。肌因子的分泌增加与身体活动密切相关，通过身体活动影响代谢过程、信号通路、蛋白质表达或细胞分化。本研究旨在通过对已发表的科学论文的回顾，证明肌因子对骨组织代谢的可能影响，并在临床医学界传播有关肌因子的知识。为了根据PRISMA指南进行分析，在PubMed、Web of Science和ScienceDirect数据库中检索了出版物。在数据库中确定的644篇论文中，分析了18篇原创研究。本文概述了鸢尾素、肌生长抑制素、成纤维细胞生长因子2、肌连接素和白细胞介素6和15在骨组织代谢调节中的重要性。根据所回顾的研究，鸢尾素通过p38 MAPK途径一直显示出促成骨作用，而肌肉生长抑制素通常通过减少肌肉质量来抑制骨形成。Myonectin具有双重作用，在小鼠模型中抑制成骨细胞和破骨细胞的分化，表明其具有复杂的调节功能。该分析考虑了细胞培养和动物模型的临床前研究，以及人体临床试验。这些发现表明，需要进一步的研究来充分阐明肌因子在骨代谢中的体内功能和临床相关性，并确定潜在的治疗靶点。
{"title":"Effect of myokines on bone tissue metabolism: a systematic review","authors":"Łukasz Jaśkiewicz , Anna Romaszko-Wojtowicz , Grzegorz Chmielewski , Jakub Kuna , Magdalena Krajewska-Włodarczyk","doi":"10.1016/j.bone.2025.117654","DOIUrl":"10.1016/j.bone.2025.117654","url":null,"abstract":"<div><div>Myokines are cytokines secreted by skeletal muscle cells. These are cytokines with pleiotropic effects, which have receptors in different organs. Increased secretion of myokines is closely linked to physical activity, through which they affect metabolic processes, signalling pathways, protein expression or cell differentiation.</div><div>This study aimed to demonstrate the possible impact of myokines on bone tissue metabolism based on a review of published scientific papers and to disseminate knowledge on myokines among the clinician community. To carry out an analysis in accordance with the PRISMA guidelines, publications were searched in PubMed, Web of Science and ScienceDirect databases. Out of the total of 644 papers identified in the databases, 18 original studies were analysed.</div><div>The paper outlined the importance of irisin, myostatin, fibroblast growth factor 2, myonectin, and interleukins 6 and 15 in the regulation of bone tissue metabolism. Based on the reviewed studies, irisin consistently demonstrates a pro-osteoblastic effect via the p38 MAPK pathway, while myostatin generally shows an inhibitory effect on bone formation by decreasing muscle mass. Myonectin exhibits a dual role, inhibiting both osteoblast and osteoclast differentiation in murine models, suggesting a complex regulatory function. This analysis considers both pre-clinical studies on cell cultures and animal models, as well as clinical trials in humans. The findings suggest that further research is needed to fully elucidate the in vivo functions and clinical relevance of myokines in bone metabolism, identifying potential therapeutic targets.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117654"},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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