Bone最新文献

{"title":"Effects of aging on the immune and periosteal response to fracture injury","authors":"Justin S. King ,&nbsp;Matthew Wan ,&nbsp;Adam Kim ,&nbsp;Shagun Prabhu ,&nbsp;Sanja Novak ,&nbsp;Ivo Kalajzic ,&nbsp;Anne M. Delany ,&nbsp;Archana Sanjay","doi":"10.1016/j.bone.2025.117524","DOIUrl":"10.1016/j.bone.2025.117524","url":null,"abstract":"<div><div>Aging predisposes individuals to reduced bone mass and fragility fractures, which are costly and linked to high mortality. Understanding how aging affects fracture healing is essential for developing therapies to enhance bone regeneration in older adults. During the inflammatory phase of fracture healing, immune cells are recruited to the injury site as periosteal skeletal stem/progenitor cells (pSSPCs) rapidly proliferate and differentiate into osteochondral lineages, allowing for fibrocartilaginous callus formation and, subsequently, complete bone healing. Irrespective of age, how periosteal mesenchymal and immune cells interact during early fracture healing is incompletely understood, limiting our ability to modulate this process. To address this, we directly analyzed, in parallel, at a single-cell level, isolated murine CD45(+) and CD45(−) periosteal cells dissected from intact and fractured bones, collected three days after injury. Comprehensive analysis, corroborated by bulk RNA-sequencing, flow cytometry, and histology, demonstrated that aging decreased pSSPC proliferation, markedly reduced expression of genes required for callus formation, and increased senescence signature. During the regeneration phase, at 14 days post injury, aged mice demonstrated reduced mineralization of the callus, accompanied by elevated Sox9 expression and increased cartilage content, suggesting delayed repair. We also found that the chemokine <em>Cxcl9</em> was highly upregulated in aged intact Prrx1+ pSSPCs, which has the potential to directly regulate other pSSPCs, and was associated with increased recruitment of CD8+ T cells at the fracture site. Cell-to-cell communication analysis provided further appreciation of the complex interactions among the many mesenchymal and hematopoietic cell types regulating fracture healing and highlighted the impact of aging on these interactions. Together, these results provide insight into age-induced alterations in early fracture healing, which could facilitate the development of improved therapeutic approaches for fracture repair in the elderly.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117524"},"PeriodicalIF":3.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083989","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}

{"title":"Comparative effectiveness of romosozumab versus teriparatide for fracture prevention: A new-user, active comparator design","authors":"Ryoji Tominaga ,&nbsp;Tatsuyoshi Ikenoue ,&nbsp;Ryosuke Ishii ,&nbsp;Kakuya Niihata ,&nbsp;Tetsuro Aita ,&nbsp;Tadahisa Okuda ,&nbsp;Sayaka Shimizu ,&nbsp;Noriaki Kurita ,&nbsp;Masataka Taguri","doi":"10.1016/j.bone.2025.117523","DOIUrl":"10.1016/j.bone.2025.117523","url":null,"abstract":"<div><h3>Background</h3><div>Comparative evidence on the effectiveness of romosozumab and teriparatide in preventing osteoporotic fractures remains limited. This study evaluated their effectiveness in fracture prevention.</div></div><div><h3>Methods</h3><div>This observational new-user cohort study used the DeSC Healthcare database, a nationwide claims database in Japan. Patients aged ≥40 years with osteoporosis, defined by International Classification of Diseases, 10th Revision codes or prior fragility fractures, who newly initiated romosozumab or teriparatide between March 2019 and August 2021 were included. The primary outcome was the major osteoporotic fractures within 1 year. Secondary outcomes included 2-years fracture incidence and individual fracture types. Cox proportional hazards models, weighted by inverse probability-of-treatment derived from propensity scores, were used to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs), accounting for patient- and facility-level confounders.</div></div><div><h3>Results</h3><div>Among 35,547 observations (romosozumab: 9603; teriparatide: 25,944), the mean ages were 80.3 and 80.0 years, 85.2 % and 81.3 % were women, and 64.4 % and 71.9 % had a history of fragility fracture, respectively. The 1-year incidences of major osteoporotic fractures were 10.14 per 100 person-years (teriparatide) and 7.01 per 100 person-years (romosozumab) (HR: 0.80, 95 % CI: 0.71, 0.89). Romosozumab was also associated with lower rates of composite fractures over 2 years (HR: 0.81, 95 % CI: 0.72, 0.90); vertebral fractures over 1 and 2 years; and proximal humeral, distal forearm, and proximal femoral fractures over 1 year.</div></div><div><h3>Conclusions</h3><div>In this nationwide Japanese cohort, romosozumab use was associated with a lower incidence of major osteoporotic fractures compared to teriparatide over both 1- and 2-year follow-up periods among high-risk patients with osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117523"},"PeriodicalIF":3.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083988","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}

{"title":"Rest-activity circadian rhythms and osteoporosis: A prospective cohort and Mendelian randomization study","authors":"Hanhan Zhao ,&nbsp;Jiacheng Wang ,&nbsp;Yi Zheng ,&nbsp;Zhenqiu Liu ,&nbsp;Yanfeng Jiang ,&nbsp;Chen Suo ,&nbsp;Xingdong Chen ,&nbsp;Kelin Xu","doi":"10.1016/j.bone.2025.117521","DOIUrl":"10.1016/j.bone.2025.117521","url":null,"abstract":"<div><h3>Background</h3><div>Disruptions in rest-activity circadian rhythms (RAR) have been shown to be associated with an increased risk of osteoporosis. However, there remains a scarcity of prospective studies examining this association.</div></div><div><h3>Methods</h3><div>This longitudinal cohort study utilized data from the UK Biobank, including 90,029 participants who were initially free of OP and had reliable accelerometer data at baseline, with a median follow-up time of 8.1 years. Participants newly lost to follow-up within the first two years were excluded. We assessed the associations of eleven RAR variables including nonparametric variables relative amplitude (RA), most active 10-h period counts (M10), least active 5-h period counts (L5), interdaily stability (IS), and intradaily variability (IV), and parametric variables amplitude, mesor, pseudo-F statistic, acrophase, alpha, and beta with the risk of OP using Cox models adjusted for multiple confounders. Mediation analyses were conducted to determine whether inflammatory markers mediated the associations between RAR variables and OP incidence. Additionally, two-sample MR analyses were conducted to infer causality.</div></div><div><h3>Results</h3><div>In this study, 1702 new-onset OP cases were documented. Higher RA(adjusted hazard ratio 0.87 [95 % CI 0.83–0.92]) and M10 (0.73 [0.60–0.89]) were associated with a lower risk of osteoporosis, while higher L5 (1.09 [1.04–1.15]) was associated with an increased risk. The associations between these three RAR variables and osteoporosis risk were possibly mediated by leukocyte count and platelet-to-lymphocyte ratio, with mediation proportions ranging from 6.06 % to 13.84 %. Higher alpha of parametric variables (0.92 [0.88–0.97]) were associated with a lower risk of osteoporosis. Two-sample MR analyses suggested potential significant associations between RA, L5, pseudo-F and femoral neck bone mineral density, consistent with observational results.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that circadian rhythm disruption, as indicated by impaired RAR variables, was associated with higher osteoporosis risk. Circadian rhythm disruption may be a modifiable risk factor that could be targeted for osteoporosis prevention.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117521"},"PeriodicalIF":3.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068515","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}

{"title":"Different effects of moderate tibial loading and Yoda1 on breast cancer-induced osteolysis in aged mice","authors":"Murtaza Wasi ,&nbsp;Shubo Wang ,&nbsp;Rosa M. Guerra ,&nbsp;Tiankuo Chu ,&nbsp;Rory Kooker ,&nbsp;Kimberly Seaman ,&nbsp;Xin (Suzie) Song ,&nbsp;Amel Sassi ,&nbsp;Xuehua Li ,&nbsp;Jinhu Xiong ,&nbsp;Lidan You ,&nbsp;Liyun Wang","doi":"10.1016/j.bone.2025.117517","DOIUrl":"10.1016/j.bone.2025.117517","url":null,"abstract":"<div><div>Elderly breast cancer patients and survivors are at high risk of bone loss but experience obstacles to harness the known benefits of exercise due to aging, cancer, and cancer treatment. Previously, we and others showed that moderate mechanical loading suppressed breast cancer-induced osteolysis in young adult mice. To overcome the mechano-transduction deficits in aged skeletons, we recently tested a dual therapy combining mechanical and Yoda1 activation of mechanosensitive Piezo1 channels. We found that the dual therapy was more effective in mitigating bone loss due to aging and doxorubicin in mature mice than the individual interventions. In the present study, we further tested the hypothesis that dual therapy combining moderate tibial loading and Yoda1 protects aged skeleton from breast cancer-induced osteolysis better than individual treatments. Aged female C57BL/6 J mice (~74-week-old) receiving Py8119 breast cancer cells in both tibiae were assigned to the four experimental groups (<em>n</em> = 5–8 per group) to examine the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles per day, 5 days/week), individually or combined on bone structural integrity. At the end of 4 weeks' experiments, the dual therapy group had the lowest incidence of osteolytic perforation (56 %) compared to the non-treated group (80 %), loading only group (70 %), and Yoda1 only group (100 %). The relative drop of cortical polar moment of inertia (Ct.pMOI), calculated as [(Week 4- Week 0)/Week 0, %], were analyzed at the proximal end, mid-diaphysis, and tibial-fibular junction of the tibia. The average values over the three locations were − 12.7 %, −3.2 %, −24.0 %, −4.2 % for the non-treated, loading only, Yoda1 only, and dual therapy groups, respectively. Furthermore, the % of samples with decreased Ct.pMOI (indication of structural deterioration) was suppressed in the dual therapy group (33 %), compared with nontreated (100 %), loading only (80 %), and Yoda1 only (100 %) groups. Each treatment differentially affected the osteoclast activity, tumor proliferation, and apoptosis of osteocytes, marrow cells and tumor cells, revealing the complex interactions of bone, tumor, and mechanical stimulations. In summary, the dual therapy resulted in skeletal benefits comparable to or slightly better than loading only treatment. However, the exacerbated bone loss and cortical perforation associated with Yoda1 call for further investigation on safe and effective treatments of skeletal damages caused by metastatic breast cancers.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117517"},"PeriodicalIF":3.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923270","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}

{"title":"Expanding the genetic spectrum of short rib polydactyly syndrome: Novel DYNC2H1 variants and functional insights","authors":"Bilgesu Ak ,&nbsp;Mete Akısü ,&nbsp;Asude Durmaz ,&nbsp;Mehmet Yalaz ,&nbsp;Demet Terek ,&nbsp;Ece Sönmezler ,&nbsp;Yavuz Oktay ,&nbsp;Haluk Akın ,&nbsp;Ayça Aykut","doi":"10.1016/j.bone.2025.117511","DOIUrl":"10.1016/j.bone.2025.117511","url":null,"abstract":"<div><h3>Introduction</h3><div>Short rib polydactyly syndrome (SRPS), with or without polydactyly, also known as Verma-Naumoff/Saldino-Noonan syndrome, is a type of skeletal ciliopathy. Initially, variants in the <em>IFT80</em> gene were implicated; however, approximately half of the SRPS cases are associated with variants in the <em>DYNC2H1</em> gene. Additionally, digenic variants involving <em>DYNC2H1</em> and <em>NEK1</em> can contribute to the syndrome.</div></div><div><h3>Materials and methods</h3><div>This case report describes a male patient presenting with characteristic SRPS features, including a constricted thorax and shortened limbs. Exome sequencing was performed to identify causative variants, followed by functional analyses to assess the pathogenicity of the identified variants, including a synonymous variant.</div></div><div><h3>Results</h3><div>Exome sequencing identified compound heterozygous variants in the <em>DYNC2H1</em> gene: a novel missense variant c.6439G&gt;T p.(Asp2147Tyr) and a synonymous variant c.6477G&gt;A p.(Gln2159=). Functional analyses confirmed that the synonymous variant triggers nonsense-mediated decay of the affected allele.</div></div><div><h3>Conclusion</h3><div>This study expands the spectrum of <em>DYNC2H1</em> variants associated with SRPS and emphasizes the importance of functional analyses in genetic diagnostics. Demonstrating pathogenicity for a synonymous variant highlights the necessity for comprehensive variant assessments to improve diagnostic accuracy and enable early intervention. These findings have significant implications for molecular diagnostics and personalized therapy strategies in skeletal ciliopathies.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117511"},"PeriodicalIF":3.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924839","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}

{"title":"How to identify children with cerebral palsy at risk of low bone mineral density","authors":"Marianne Lindblad Pedersen ,&nbsp;Johan Sebastian Ohlendorf ,&nbsp;Thomas Alexander Gerds ,&nbsp;Nanette Mol Debes ,&nbsp;Christina Engel Hoei-Hansen ,&nbsp;Bo Zerahn ,&nbsp;Jesper Johannesen","doi":"10.1016/j.bone.2025.117515","DOIUrl":"10.1016/j.bone.2025.117515","url":null,"abstract":"<div><h3>Aim</h3><div>Cerebral palsy is a common chronic motorically disabling condition in children. The aim of this study was to determine prevalence of low bone mineral density (BMD) in children with cerebral palsy and to examine the association between BMD with risk factors.</div></div><div><h3>Methods</h3><div>Cross sectional study of children with cerebral palsy analyzing Dual X-ray Absorptiometry, blood tests, full clinical medical examination including Tanner stage and nutritional status, measurement of anthropometrics and assessment of physical activity.</div></div><div><h3>Results</h3><div>The 81 participants were aged 2.1–17.4 years (median 9 years) and 64 out of 81 had a mild cerebral palsy (Gross Motor Function Classification System score of I-II). Mean BMD z-score was −0.2 (SD = 1.05, range −4.6 to 2.0). GMFCS score was negatively associated with BMD (p &lt; 0.01) as higher score led to 1.43 SD lower BMD [−1.97 to −0.89]. Weight bearing activity was negatively associated with lower BMD z-score (p = 0.01), as having &lt;30 min of weight bearing activity per day lead to 0.98 SD lower BMD [−1.75; −0.22]. Use of anti-seizure medication was negatively associated with BMD (BMD z-score 0.7 SD lower; p = 0.02, [−1.28; −0.12]). Serum vitamin D levels or fracture rates were not statistically significantly associated with BMD changes.</div></div><div><h3>Conclusion</h3><div>We found 17 % of children have low BMD regardless of motoric impairment level. GMFCS score, Sparse weight bearing activity and use of anti-seizure medicine were negatively associated to BMD. No significant associations were found with vitamin D, sex, BMI, puberty.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117515"},"PeriodicalIF":3.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924840","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}

{"title":"Comparison of the bone remodeling in the midpalatal suture during maxillary expansion between young and middle-aged mice","authors":"Hyeran Helen Jeon ,&nbsp;Mary Cruz Contreras Salas ,&nbsp;Kyungjoon Park ,&nbsp;Lindsay Fisher ,&nbsp;Sara Ha ,&nbsp;Caroline Palmer ,&nbsp;Fionna Chan ,&nbsp;Dana T. Graves","doi":"10.1016/j.bone.2025.117512","DOIUrl":"10.1016/j.bone.2025.117512","url":null,"abstract":"<div><div>Maxillary expansion is a common orthodontic procedure for treating maxillary transverse deficiency. However, the cell responses to mechanical force may vary across different age groups, suggesting the need for age-specific treatment protocols. To compare the age-related responses to the mechanical force, we examined the 6-week- and 12-month-old mice undergoing maxillary expansion with 0.012-in. stainless steel orthodontic wire bonded to the maxillary first and second molars (25 g force). Mice were euthanized on days 0, 3, 7, and 14 for analysis. MicroCT analysis, tartrate-resistant acid phosphatase (TRAP) stain, and immunofluorescence/immunohistochemistry stain using antibodies to RUNX2, alkaline phosphatase (ALP), Gli1 and Ki67 along with the TUNEL assay, were conducted to evaluate suture width, osteoclast activity, new bone formation and mesenchymal stem cell (MSC) proliferation and apoptosis. Both 6-week- and 12-month-old mice exhibited successful midpalatal suture opening, but young mice demonstrated earlier and more intense osteoclast activity, along with higher expression of RUNX2 and ALP. Young mice also exhibited a higher percentage of Gli1+Ki67+ immunopositive cells, while middle-aged mice showed a higher percentage of Gli1+TUNEL+ positive cells on day 3 after maxillary expansion. Our findings suggest that aging negatively impacts mechanical force-induced bone remodeling by reducing osteoclastogenesis, osteogenesis, and MSC proliferation while increasing MSC apoptosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117512"},"PeriodicalIF":3.5,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907662","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}

{"title":"Label-free rapid diagnosis of jaw osteonecrosis via the intersection of Raman spectroscopy and deep learning","authors":"Xiaobo Dai ,&nbsp;Bowen Yang ,&nbsp;Liangjun Zhou ,&nbsp;Ran You ,&nbsp;Shuai Chen ,&nbsp;ZhongXu Li ,&nbsp;Xingzhi Zeng ,&nbsp;Zhining Wen ,&nbsp;Chunjie Li ,&nbsp;Bing Yan","doi":"10.1016/j.bone.2025.117510","DOIUrl":"10.1016/j.bone.2025.117510","url":null,"abstract":"<div><h3>Objectives</h3><div>To establish a precise and efficient diagnostic framework for distinguishing medication-related osteonecrosis of the jaw, radiation-induced osteonecrosis of the jaw, and normal bone tissue, thus enhancing clinical decision-making and enabling targeted therapeutic interventions.</div></div><div><h3>Methods</h3><div>Raman spectroscopy was applied to investigate bone mineral composition, organic matrix content, and crystallinity in ninety bone tissue samples (30 MRONJ, 30 ORN, 30 control). Each mandible underwent 10 randomized spectral acquisitions, yielding 900 spectra across 200–2200 cm⁻¹. The raw spectral data were preprocessed using Labspec6 software (Horiba Scientific). Principal component analysis (PCA) and linear discriminant analysis (LDA) were employed for feature extraction and classification. Additionally, a ResNet18 deep learning architecture was employed to enhance diagnostic accuracy. The model's performance was evaluated using precision, recall, and the area under the receiver operating characteristic curve to ensure robustness.</div></div><div><h3>Results</h3><div>The PCA-LDA integration achieved 90.3 % accuracy in differentiating MRONJ, ORN, and healthy bone， with leave-one-out cross-validation confirming 89.1 % classification robustness. Furthermore, the ResNet18 deep learning model outperformed traditional classification methods, achieving 0.926 ± 0.024 accuracy, 0.924 ± 0.026 precision, 0.926 ± 0.024 recall, and 0.985 ± 0.007 AUROC on the validation set.</div></div><div><h3>Significance</h3><div>These findings underscore the significant potential of combining Raman spectroscopy with advanced deep learning techniques as a rapid, noninvasive, and highly reliable diagnostic tool. This approach not only enhances the ability to differentiate between MRONJ and ORN but also offers substantial implications for improving patient management and therapeutic outcomes in clinical practice.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117510"},"PeriodicalIF":3.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923273","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}

{"title":"Automated micro-CT morphometry of femoral biopsies from hip arthroplasties: adaptive local thresholding, volume of interest wrapping and removal of debris","authors":"Deepti K. Sharma ,&nbsp;Agatha Labrinidis ,&nbsp;Xiangyu Dong ,&nbsp;Christopher Schultz ,&nbsp;Lucian B. Solomon ,&nbsp;Boopalan Ramasamy ,&nbsp;Stuart A. Callary ,&nbsp;Phil Salmon","doi":"10.1016/j.bone.2025.117502","DOIUrl":"10.1016/j.bone.2025.117502","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Bone biopsies are an important biological tool for investigating bone microarchitecture, which can be non-destructively imaged in 3D via micro-computed tomography (micro-CT). Image thresholding and delineation of a region of interest (ROI) are prerequisites for quantifying bone parameters. Validated automatic protocols enable quantification of biopsies that contain trabecular and cortical bone. However, irregularly shaped trabecular bone biopsies with peripheral and internal debris have required manual ROI delineation, which is time-intensive and subject to inter and intra-observer variance. We hypothesise that an automated workflow will be a suitable alternative to overcome these issues and objectively determine bone microarchitecture in surgical biopsies, at higher throughput suitable for clinical studies. Hence, the aim of this study was to develop an objective, reproducible and automated workflow to analyse microarchitecture of trabecular bone biopsies. To accomplish this aim, we tested six different methods of ROI delineation: a whole biopsy ROI, and both manual (slow) and automatically delineated (fast) reduced ROIs to remove peripheral debris, each with (adaptive thresholding and a set of morphological operations to remove debris) and without (global thresholding) processing in a subset (&lt;em&gt;n&lt;/em&gt; = 8) of intertrochanteric femoral biopsies obtained from patients undergoing hip arthroplasty. Number of objects, bone volume to tissue volume (BV/TV), trabecular separation (Tb.Sp), structure model index (SMI) and Euler number and trabecular pattern factor (Tb.Pf) were compared between the six workflows using Friedman's test and post-hoc pairwise comparisons with Bonferroni correction was performed. The two most reproducible techniques were tested for validation in a larger cohort of arthroplasty patients (&lt;em&gt;n&lt;/em&gt; = 60) and results were compared with appropriate &lt;em&gt;t&lt;/em&gt;-test. Subset analysis indicated that the manual and automated ROI with processing increased the ability to resolve real differences between these groups in parameters BV/TV, Tb.Sp and Euler number compared to with no processing and whole biopsy ROI approach. A validation cohort consisted of thirty osteoarthritis patients with a mean age 68.25 ± 8.64 and thirty neck of femur fracture with a mean age 82.4 ± 8.9. The manual technique failed to detect differences in BV/TV, SMI and Tb.Pf between the two patient groups (&lt;em&gt;p&lt;/em&gt; &gt; 0.05, for all) while the automated workflow demonstrated significant differences in these parameters between the OA and the NOF patients (&lt;em&gt;p&lt;/em&gt; &lt; 0.05). This is probably due to irregularity in the reference VOI volume introduced by manual ROI delineation reducing morphometric precision, compared to the automated method. In conclusion, our automated workflow performed better than customary practice; it represents a user-independent, high throughput technique to measure bone microarchitecture accurately in surgical biopsies.&lt;/div&gt;&lt;","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117502"},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886318","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}

{"title":"Rebound hypercalcaemia timing is associated with cumulative weight-based denosumab dose for central giant cell granuloma treatment in children despite a dose weaning regimen","authors":"Alexander D. Chesover ,&nbsp;Jeremy Allgrove ,&nbsp;Alistair Calder ,&nbsp;Catherine Campbell ,&nbsp;Emmeline Heffernan ,&nbsp;Kshitij Mankad ,&nbsp;Rhiannon McBayDoherty ,&nbsp;Dearbhla McKenna ,&nbsp;Caroline Mills ,&nbsp;Madeline Rooney ,&nbsp;Nadeem Saeed","doi":"10.1016/j.bone.2025.117501","DOIUrl":"10.1016/j.bone.2025.117501","url":null,"abstract":"<div><div>Central giant cell granulomas (CGCG) are locally destructive, non-neoplastic lesions that express receptor activator of nuclear factor-κB (RANK) and RANK ligand. Denosumab, a monoclonal antibody against RANK ligand, is licensed in skeletally mature patients, with less experience in children who are at risk of rebound hypercalcaemia.</div><div>We describe the response to denosumab in five skeletally immature children with CGCG. Denosumab was started aged 2.1 to 11.6 years, for 8 to 22 months, with a cumulative dose of 9.6 to 58.8 mg/kg. Three patients followed a weaning protocol (using reducing dose frequency and zoledronic acid).</div><div>Denosumab ossified all lesions. Three patients had subsequent surgery, and one had recurrence. All had rebound hypercalcaemia, 8.9–47 weeks (median 23.3 weeks) after the last treatment dose. Four presented with symptomatic hypercalcaemia and acute kidney injury. Cumulative denosumab treatment dose/kg positively correlated with (1) time to rebound after the last treatment dose (r² = 0.94, <em>p</em> = 0.006); and (2) length of admission for hypercalcaemia treatment (r² = 0.87, <em>p</em> = 0.02). All patients had increased bone mineral density and metaphyseal sclerosis that improved after stopping denosumab. One had a clavicular fracture at the intersection of normal and high-density bone.</div><div>We propose that rebound hypercalcaemia should be an anticipated consequence of stopping denosumab in skeletally immature patients and exists on a spectrum. A higher cumulative denosumab dose/kg increases the time to rebound hypercalcaemia and its severity. Further work is needed to establish the lowest dose and the shortest treatment duration to balance effective treatment with minimising side effects.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"197 ","pages":"Article 117501"},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895698","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}