Journal of Bone and Mineral Research最新文献

{"title":"Targeting FGFR3 gain-of-function with Infigratinib, a promising precision therapy for Hypochondroplasia.","authors":"Antonella Forlino","doi":"10.1093/jbmr/zjaf121","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf121","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005669","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":"Fractures are Highly Correlated with Bone Density and Inversely Correlated with Bone Turnover Markers in Autosomal Dominant Osteopetrosis.","authors":"Michael J Econs, Stuart J Warden, Ziyue Liu, Paul Niziolek, Corinne Parks-Schenck, Netsanet Gebregziabher, Rita Gerard-O'Riley, Marian Hart, Lynda E Polgreen, Erik A Imel","doi":"10.1093/jbmr/zjaf123","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf123","url":null,"abstract":"<p><p>Autosomal Dominant Osteopetrosis (ADO) is a rare, osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, resulting in impaired osteoclastic bone resorption. Penetrance is incomplete and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline bone mineral density and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z scores for both volumetric (r = 0.87, p < .001) and areal bone mineral density (aBMD) of the lumbar spine, and Z scores for femoral neck, and total hip aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD and bone turnover markers were similar when limited to the 37 adults with disease causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005665","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":"Use of DXA-derived 3D-modeling, as implemented by 3D-shaper®, for the assessment of fracture risk in a population-based setting.","authors":"K Huininga, F Koromani, M C Zillikens, E F S van Velsen, F Rivadeneira","doi":"10.1093/jbmr/zjaf120","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf120","url":null,"abstract":"<p><strong>Introduction: </strong>3D-modeling of hip DXA scans has been proposed to partition BMD into cortical surface (csBMD) and trabecular \"volumetric\" (tvBMD). We assessed in a population-based cohort whether such partitioning contributes to fracture risk assessment compared to aBMD alone.</p><p><strong>Methods: </strong>Participants (N = 4908) from the Rotterdam Study comprised 56% women, mean age 67.4 (SD = 10.1) years. Hip DXA scans were analyzed with enCore (GE Lunar) and 3D Shaper software. Pearson partial correlation was calculated between aBMD, csBMD and tvBMD at the total hip, femoral neck and trochanter. Incident fractures were collected from GP or hospital records. During a mean follow-up of 6.8 (SD = 2.5) years, 171 sustained a hip fracture, and 1019 any-type fractures. Fracture risk estimates were determined as hazard ratios (HR) per SD decrease in BMD, from Cox-regression adjusted for multiple confounders.</p><p><strong>Results: </strong>High correlation (r= > 0.81; p < .001) was observed between aBMD and the modeled 3D parameters; also, between csBMD and tvBMD (r = 0.85; p < .001 at total hip). Lower aBMD was associated with higher incidence of any-type (HR = 1.60, 95%CI 1.43-1.78) and hip (HR = 2.46, 95%CI 1.90-3.17) fracture; lower csBMD with increased risk of any-type (HR = 1.44, 95%CI 1.30-1.60) and hip (csBMD HR = 1.76, 95%CI 1.39-2.23) fracture, and tvBMD with increased risk of any-type (HR = 1.62, 95%CI 1.45-1.80) and hip fracture (HR = 2.44, 95%CI 1.88-3.15). Inclusion of aBMD in models with tvBMD or csBMD resulted in high multicollinearity and unreliable coefficient parameters (VIF > 5). The effect of csBMD was largely attenuated after inclusion of tvBMD in the same model for both any-type (csBMD HR = 0.96, 95%CI 0.81-1.13; tvBMD HR = 1.67, 95%CI 1.41-1.98) and hip (csBMD HR = 0.83, 95%CI 0.58-1.21, tvBMD HR = 2.82, 95%CI 1.94-4.10) fractures. Similar results were observed at the neck and intertrochanteric regions.</p><p><strong>Conclusions: </strong>DXA-derived 3D modeled parameters are highly correlated to aBMD and do not provide additional value for the estimation of fracture risk beyond aBMD alone.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937416","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":"Artificial gravity protects bone and prevents bone marrow adipose tissue accumulation in humans during 60 days of bed rest.","authors":"K Culliton, G Melkus, A Sheikh, T Liu, A Berthiaume, G Armbrecht, G Trudel","doi":"10.1093/jbmr/zjaf119","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf119","url":null,"abstract":"<p><p>Inactivity has been associated with increased bone marrow adipose tissue (BMAT) and bone loss. Artificial gravity (AG) may prevent these complications. This randomized controlled trial investigated the effectiveness of AG at 2g at the feet to prevent lumbar vertebral BMAT accumulation and bone loss. Twenty-four participants (16 male, 8 female) were bedridden for 60 days at 6° head down tilt. They were randomly assigned to bedrest only (n=8), continuous supine centrifugation (cAG; 30 minutes/day), or intermittent supine centrifugation (iAG; 6 bouts of 5 minutes/day). Serial 3T magnetic resonance (MR) measured BMAT while Dual Energy X-ray Absorptiometry measured bone mineral density (BMD) in the lumbar vertebrae before, during, and after bedrest. After 60 days of bedrest, vertebral BMAT was higher in controls, +3.93% (95%CI -0.28 to 8.14), compared to cAG and iAG interventions. After 60 days of bedrest, male controls BMAT increased 5.81% (95%CI 2.01 to 9.61) compared to -1.35% (95%CI -5.74 to 3.04) and 1.23% (95%CI -1.53 to 3.99) for male cAG and iAG participants respectively. This difference between interventions was significant: X2(2)=8.487, p=0.014. In addition, while control male participants showed decreased BMD after 60 days of bedrest (-0.02g/cm2; 95%CI -0.05 to 0.00), the male participants receiving iAG showed no decrease in BMD during bedrest (0.00g/cm2; 95%CI -0.04 to 0.05). The modulation of BMAT was inversely correlated with BMD at the same vertebrae. Recreating an axial force vector mechanically on horizontalized participants prevented BMAT accumulation and demineralization. These findings suggest exploring technological advances to translate these clinical benefits to populations at risk of acute or chronic bone loss.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937295","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":"Letter in response to \"atypical fractures at non-classical sites associated with anti-resorptive therapy: a systematic review\".","authors":"Lucy E Collins, Alec Ronan, Evelyn Hutcheon, Peter R Ebeling, Vivian Grill, Hanh H H Nguyen","doi":"10.1093/jbmr/zjaf116","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf116","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937322","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":"Improvements in hearing loss with bone-targeted enzyme replacement therapy are associated with corrected hypomineralization and osteocyte properties of auditory ossicles in Enpp1-deficient mice.","authors":"Ana Ocokoljic, Shivani Srivastava, Simon von Kroge, Paul R Stabach, Björn Busse, Keith Weise, Ralf Oheim, Tim Rolvien, Demetrios T Braddock","doi":"10.1093/jbmr/zjaf082","DOIUrl":"10.1093/jbmr/zjaf082","url":null,"abstract":"<p><p>Hearing loss is common in conditions caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency, such as generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. Mechanistically, it is hypothesized that poor mineralization of the auditory ossicles leads to impaired sound transmission in the middle ear. Here we investigated whether enzyme replacement therapy (ERT) improves hearing loss in an Enpp1-deficient mouse model and whether this is associated with corrected bone properties in the ossicles. For this purpose, male Enpp1asj/asj mice were subjected to either a soluble or bone-targeted ERT of ENPP1-Fc. Hearing function and bone properties of the malleus, the first bone of the ossicular chain, were evaluated and compared to untreated Enpp1asj/asj and WT mice at the age of 17 wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32 kHz, suggesting a generalized impairment of hearing. The hearing deficits observed in Enpp1asj/asj mice were partially or fully corrected by both soluble and bone-targeted ERT, as evidenced by the restoration of auditory brainstem response thresholds, with dose dependence and generally stronger effect of bone-targeted ERT. This was not only associated with corrected blood plasma markers of mineral metabolism but also improved matrix mineralization and restored osteocyte properties in the malleus. In addition, for the first time in mice, we were able to demonstrate the occurrence of mineralized osteocyte lacunae in Enpp1asj/asj mice, a phenomenon that was corrected by bone-targeted but not soluble ERT, underscoring the need for targeted delivery for effective treatment. In contrast to osteocyte lacunar mineralization in humans (ie, micropetrosis), the intra-lacunar mineral was overall less mineralized than the adjacent bone. In conclusion, our results point toward the potential benefit of correcting ossicular mineralization to prevent hearing loss in ENPP1 deficiency.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1077-1086"},"PeriodicalIF":5.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking fracture prevention after DO-HEALTH.","authors":"Kelsey M Mangano, Sabrina E Noel","doi":"10.1093/jbmr/zjaf081","DOIUrl":"10.1093/jbmr/zjaf081","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1015-1016"},"PeriodicalIF":5.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256919","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":"Denosumab discontinuation in the clinic: implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures.","authors":"Shejil Kumar, Mawson Wang, Albert S Kim, Jacqueline R Center, Michelle M McDonald, Christian M Girgis","doi":"10.1093/jbmr/zjaf037","DOIUrl":"10.1093/jbmr/zjaf037","url":null,"abstract":"<p><p>Denosumab is a highly effective treatment for osteoporosis, and its long-term use is associated with incremental gains in BMD and sustained fracture risk reduction. Stopping denosumab, however, results in a rebound increase in bone turnover, loss of treatment-associated BMD gains, and in the worst case, spontaneous vertebral fractures (VFs). Insights into the risk factors, the underlying mechanisms for rebound-associated bone loss, and true incidence of rebound VFs are emerging. Conventional strategies using bisphosphonates to mitigate post-denosumab rebound display mixed success. Bisphosphonates may preserve bone density following short-term denosumab but the optimal sequential approach after longer-term denosumab remains elusive. Patients at particular risk of are those with prevalent VFs or greater on-treatment BMD gains. To greater understand these risks and strategies to preserve bone after denosumab, an emerging body of translational and preclinical work is shedding new light on the biology of RANKL inhibition and withdrawal. Discovering an effective \"exit strategy\" to control rebound bone turnover and avoid bone loss after denosumab will improve confidence among patients and clinicians in this highly effective and otherwise safe treatment for osteoporosis. This perspective characterizes the clinical problem of post-denosumab rebound, provides a comprehensive update on human studies examining the use of bisphosphonates following denosumab and explores mechanistic insights from preclinical studies that will be critical in the design of definitive human trials.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1017-1034"},"PeriodicalIF":5.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-type natriuretic peptide and collagen X marker are aberrant in skeletal dysplasias.","authors":"Ricki S Carroll, Robert C Olney, Angela L Duker, Ryan F Coghlan, Andrea J Schelhaas, William G Mackenzie, Colleen P Ditro, Cassondra J Brown, David A O'Connell, William A Horton, Brian Johnstone, Eric A Espiner, Timothy C R Prickett, Michael B Bober","doi":"10.1093/jbmr/zjaf085","DOIUrl":"10.1093/jbmr/zjaf085","url":null,"abstract":"<p><p>Skeletal dysplasias (SD) are rare genetic disorders affecting skeletal development and bone growth. Whereas specific gene mutations have been identified in many, however, the molecular signaling pathways contributing to the phenotype are poorly understood. The C-type natriuretic peptide (CNP) signaling pathway is a driver of normal endochondral bone growth and underlies the impact of several genetic disorders of bone growth, including achondroplasia, the most common form of SD. In this cross-sectional study of 73 children with SD, comprising 7 distinct forms, we have examined the association of plasma concentrations of bioactive CNP and bio-inactive NTproCNP (recognized bio markers driving growth) and of collagen X marker (CXM) (an established biomarker of the growth plate response) with age and with annualized height velocity (HV). Although significant associations were identified with age in several disorders, the association of NTproCNP and of CXM with HV was aberrant except in type II collagen disorders and MOPD II. In OI, CNP and NTproCNP were reduced in proportion to severity of OI phenotype. Reduction in CNP exceeded NTproCNP, suggesting that higher rate of clearance/degradation of bioactive CNP occurs in OI. Across a wide range of HV in subjects with OI, biomarkers were dissociated and unrelated to HV. Similar changes were observed in 3 other forms of SD (multiple epiphyseal dysplasia, microcephalic osteodysplastic primordial dwarfism type II, and Morquio A syndrome). Although limited numbers of affected individuals within each group were studied employing a single sample at one time point, the results indicate aberrant responses both within biomarkers and when related to HV. Importantly, we identify enhanced rates of CNP clearance in OI and other forms of SD, which suggests CNP agonists could have therapeutic benefits.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1052-1060"},"PeriodicalIF":5.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen loss activates memory T-cells to compromise bone integrity through distinct cortical compartments in mice.","authors":"Di Wu, Anna Cline-Smith, Daniel Goering, Aarushi Choudhary, Deborah Veis, Rajeev Aurora","doi":"10.1093/jbmr/zjaf089","DOIUrl":"10.1093/jbmr/zjaf089","url":null,"abstract":"<p><p>Fragility fractures are a significant cause of morbidity and mortality in postmenopausal women. Menopause leads to a drastic decline in bone mass and quality with over half of women sustaining fragility fractures without reaching the osteoporotic threshold (T-score < -2.5), underscoring the pivotal role of bone quality in fracture risk. Previous studies have shown that estrogen (E₂) deficiency following ovariectomy (OVX) in mice activates memory T-cells (TM) to produce TNFα and IL-17A, resulting in trabecular bone loss. This study extends these findings to cortical bone, revealing that under habitual load osteoclasts are predominantly localized on the posterior endosteal surface. Post-OVX, mice exhibited enlarged lacunae, indicative of osteocytic osteolysis, and reduced dendrite density in osteocytes (Ocy) adjacent to T-cells. These effects were more pronounced on the posterior side, where osteoclast-T-cell interactions are heightened. Additionally, osteoblast (OB) function analysis revealed that while bone formation at the mid-diaphysis remained unchanged, the collagen matrix became more disorganized, particularly in the posterior cortical compartment. Importantly, OVX increased bone fragility without altering cortical thickness or mineral density. These detrimental changes were absent in OVX mice lacking TNFα and IL-17A expression in TM cells (IL15RAΔT), suggesting that these cytokines specifically impair the osteolineage (Ocy and OB), compromising bone quality in ways undetectable by μCT. Our findings reveal a novel mechanism, where T-cell-mediated inflammation reduced cortical bone quality by targeting the osteolineage, leading to disrupted matrix organization and Ocy dendrite density. Clinically, these results highlight the potential of targeting T-cell responses to maintain bone quality and strength in estrogen-deficient states. Additionally, estrogen loss adversely affects endosteal bone quality in distinct cortical compartments without impacting bone mass, a deficit that may remain undetected by DXA scans.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1087-1099"},"PeriodicalIF":5.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12475993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}