Bone regeneration (BR) is an ongoing challenge in biomedical research. While recombinant human bone morphogenetic protein-2 (rhBMP-2) is available for clinical use, its side effects remain a concern. Patient-derived platelet-rich plasma has been proposed as an alternative, but its heterogeneity poses a major hurdle to standardization. Here, we evaluated the effectiveness of induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) and recombinant human bone morphogenetic protein-2 (rhBMP-2) as potential BR therapy in a rat lumbar bone graft model. We implanted artificial bones with iMPs and/or rhBMP-2 and performed computed tomography and histological analysis to assess new bone formation. iMPs and rhBMP-2 showed comparable efficacy in vivo, but rhBMP-2 induced significant inflammation. In vitro, iMPs promoted human bone marrow mesenchymal stem cell (BM-MSC) proliferation and migration, while rhBMP-2 enhanced osteodifferentiation. RNA sequencing revealed cell cycle-related gene upregulation by iMPs. Altogether, these findings suggest iMPs, alone or in combination with rhBMP-2, as a promising BR therapy for enhancing clinical efficacy.
{"title":"Bone morphogenetic protein-2-independent bone formation by human iPSC-derived megakaryocytes and platelets","authors":"Norichika Mizuki , Michiaki Mukai , Yasuhiro Shiga , Naoya Takayama , Sou Nakamura , Kentaro Kosaka , Si Jing Chen , Sudip Kumar Paul , Takahito Arai , Susumu Tashiro , Masashi Sato , Masaki Fukuyo , Bahityar Rahmutulla , Ikuko Tajiri , Kazuhide Inage , Miyako Suzuki-Narita , Yawara Eguchi , Sumihisa Orita , Atsushi Kaneda , Koji Eto , Seiji Ohtori","doi":"10.1016/j.bone.2025.117703","DOIUrl":"10.1016/j.bone.2025.117703","url":null,"abstract":"<div><div>Bone regeneration (BR) is an ongoing challenge in biomedical research. While recombinant human bone morphogenetic protein-2 (rhBMP-2) is available for clinical use, its side effects remain a concern. Patient-derived platelet-rich plasma has been proposed as an alternative, but its heterogeneity poses a major hurdle to standardization. Here, we evaluated the effectiveness of induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) and recombinant human bone morphogenetic protein-2 (rhBMP-2) as potential BR therapy in a rat lumbar bone graft model. We implanted artificial bones with iMPs and/or rhBMP-2 and performed computed tomography and histological analysis to assess new bone formation. iMPs and rhBMP-2 showed comparable efficacy in vivo, but rhBMP-2 induced significant inflammation. In vitro, iMPs promoted human bone marrow mesenchymal stem cell (BM-MSC) proliferation and migration, while rhBMP-2 enhanced osteodifferentiation. RNA sequencing revealed cell cycle-related gene upregulation by iMPs. Altogether, these findings suggest iMPs, alone or in combination with rhBMP-2, as a promising BR therapy for enhancing clinical efficacy.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"203 ","pages":"Article 117703"},"PeriodicalIF":3.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454146","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 : 2025-11-02DOI: 10.1016/j.bone.2025.117701
Evelien Gielen , Nadjia Amini , Désirée Coppens , Marian Dejaeger , Jolan Dupont , Kurt De Vlam , Maurizio Rossini , Ombretta Viapiana , Michaël R. Laurent , Giovanni Adami
Background
Romosozumab is approved in Europe for severe osteoporosis in postmenopausal women at high risk of fracture including older women, but whether bone mineral density (BMD) response varies with age remains unknown.
Purpose
To examine BMD changes in a real-world cohort of older women treated with romosozumab. We hypothesized that younger, treatment-naive patients and those with lower baseline BMD might experience greater BMD improvements.
Methods
Prospective observational study in one Italian and two Belgian centers. Multivariable linear and logistic regression models with imputation of missing data were used to determine the association between baseline variables and % BMD change or ≥ 3 % BMD increase after 12 months.
Results
We included 186 postmenopausal women with a median age of 76 years (range 52–96), lumbar spine T-score of −2.8 (interquartile range − 3.4;-1.8), mean total hip T-score of −2.4 (± standard deviation 0.95) and femoral neck T-score of −2.7 (−3.2;-2.2). After 12 months of romosozumab, BMD increased +9.16 % and + 3.00 % at the lumbar spine and total hip, respectively. A ≥ 3 % BMD increase was observed in 80.4 % at the spine, 51 % at the hip and 46 % at the femoral neck. Lower baseline BMD was independently associated with greater total hip BMD response. There was no significant association of BMD responses with age.
Conclusions
Baseline BMD was associated with total hip BMD response to romosozumab. Age itself was not associated with BMD differences. Our data support the effectiveness of romosozumab in older postmenopausal women in routine clinical practice.
{"title":"Bone mineral density response to romosozumab in post-menopausal women: A prospective observational real-world study","authors":"Evelien Gielen , Nadjia Amini , Désirée Coppens , Marian Dejaeger , Jolan Dupont , Kurt De Vlam , Maurizio Rossini , Ombretta Viapiana , Michaël R. Laurent , Giovanni Adami","doi":"10.1016/j.bone.2025.117701","DOIUrl":"10.1016/j.bone.2025.117701","url":null,"abstract":"<div><h3>Background</h3><div>Romosozumab is approved in Europe for severe osteoporosis in postmenopausal women at high risk of fracture including older women, but whether bone mineral density (BMD) response varies with age remains unknown.</div></div><div><h3>Purpose</h3><div>To examine BMD changes in a real-world cohort of older women treated with romosozumab. We hypothesized that younger, treatment-naive patients and those with lower baseline BMD might experience greater BMD improvements.</div></div><div><h3>Methods</h3><div>Prospective observational study in one Italian and two Belgian centers. Multivariable linear and logistic regression models with imputation of missing data were used to determine the association between baseline variables and % BMD change or ≥ 3 % BMD increase after 12 months.</div></div><div><h3>Results</h3><div>We included 186 postmenopausal women with a median age of 76 years (range 52–96), lumbar spine T-score of −2.8 (interquartile range − 3.4;-1.8), mean total hip T-score of −2.4 (± standard deviation 0.95) and femoral neck T-score of −2.7 (−3.2;-2.2). After 12 months of romosozumab, BMD increased +9.16 % and + 3.00 % at the lumbar spine and total hip, respectively. A ≥ 3 % BMD increase was observed in 80.4 % at the spine, 51 % at the hip and 46 % at the femoral neck. Lower baseline BMD was independently associated with greater total hip BMD response. There was no significant association of BMD responses with age.</div></div><div><h3>Conclusions</h3><div>Baseline BMD was associated with total hip BMD response to romosozumab. Age itself was not associated with BMD differences. Our data support the effectiveness of romosozumab in older postmenopausal women in routine clinical practice.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117701"},"PeriodicalIF":3.6,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446871","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 : 2025-11-02DOI: 10.1016/j.bone.2025.117704
Alexandra N. Krez , Nicole L. Levine , Kevin A. Wu , Robert J. French , Roy Colglazier , Emily M. Peairs , Elizabeth Sachs , Brian E. Brigman , William C. Eward , Julia D. Visgauss
Background
While megaprosthetic reconstructions have been instrumental in restoring patients' functional abilities, surgeons remain cautious of revision risk. This is the first study to assess the impacts of preoperative bone mineral density (BMD) on outcomes following lower extremity megaprosthetic reconstructions.
Methods
This was a retrospective cohort study of patients who underwent lower extremity oncologic megaprosthetic reconstruction between March 2005 and January 2022. Hounsfield units of the first lumbar vertebrae within a year prior to surgery were blindly collected for assessment of BMD. Patient demographics, megaprostheses characteristics and postoperative outcomes were recorded. Primary outcomes were complications according to the Henderson classification and implant survival rate.
Results
Eighty-four patients underwent a lower extremity megaprosthetic reconstruction. Mean age was 46.6 ± 22.5 years and average follow-up was 53.5 ± 52.9 months. Indication for surgery included primary bone tumor (81.3 %) and secondary bone tumor (18.8 %). Twenty-three patients (28.8 %) had low BMD. The rate of revision was 27.5 % in the total cohort and not significantly different between groups. The most common indication for revision was infection. While no patients with low BMD developed aseptic loosing or structural failure, they were more likely to receive femoral cement fixation (OR = 5.7; 95 %CI = 1.2,55.6). Five-year implant survivorship was 66.6 % (95 %CI [54.9 %- 80.8 %]).
Conclusion
There was no significant difference in revision rate following oncologic lower extremity megaprosthetic reconstruction in patients with or without low BMD. No patients with low BMD in this cohort experienced aseptic loosening or structural failure; however, there was a bias toward cement fixation in patients with low BMD. This may reflect calculated decisions by the surgeon when evaluating the patient's bone quality and their specific risk profile. Our findings suggest that patients with low BMD have similar outcomes to patients without low BMD undergoing oncologic megaprosthetic reconstructions by experienced surgeons. The specific effect of cemented vs uncemented fixation in patients with low BMD in the oncologic population deserves further investigation.
{"title":"The impact of preoperative bone mineral density on outcomes following lower extremity megaprosthetic reconstruction for oncologic resections","authors":"Alexandra N. Krez , Nicole L. Levine , Kevin A. Wu , Robert J. French , Roy Colglazier , Emily M. Peairs , Elizabeth Sachs , Brian E. Brigman , William C. Eward , Julia D. Visgauss","doi":"10.1016/j.bone.2025.117704","DOIUrl":"10.1016/j.bone.2025.117704","url":null,"abstract":"<div><h3>Background</h3><div>While megaprosthetic reconstructions have been instrumental in restoring patients' functional abilities, surgeons remain cautious of revision risk. This is the first study to assess the impacts of preoperative bone mineral density (BMD) on outcomes following lower extremity megaprosthetic reconstructions.</div></div><div><h3>Methods</h3><div>This was a retrospective cohort study of patients who underwent lower extremity oncologic megaprosthetic reconstruction between March 2005 and January 2022. Hounsfield units of the first lumbar vertebrae within a year prior to surgery were blindly collected for assessment of BMD. Patient demographics, megaprostheses characteristics and postoperative outcomes were recorded. Primary outcomes were complications according to the Henderson classification and implant survival rate.</div></div><div><h3>Results</h3><div>Eighty-four patients underwent a lower extremity megaprosthetic reconstruction. Mean age was 46.6 ± 22.5 years and average follow-up was 53.5 ± 52.9 months. Indication for surgery included primary bone tumor (81.3 %) and secondary bone tumor (18.8 %). Twenty-three patients (28.8 %) had low BMD. The rate of revision was 27.5 % in the total cohort and not significantly different between groups. The most common indication for revision was infection. While no patients with low BMD developed aseptic loosing or structural failure, they were more likely to receive femoral cement fixation (OR = 5.7; 95 %CI = 1.2,55.6). Five-year implant survivorship was 66.6 % (95 %CI [54.9 %- 80.8 %]).</div></div><div><h3>Conclusion</h3><div>There was no significant difference in revision rate following oncologic lower extremity megaprosthetic reconstruction in patients with or without low BMD. No patients with low BMD in this cohort experienced aseptic loosening or structural failure; however, there was a bias toward cement fixation in patients with low BMD. This may reflect calculated decisions by the surgeon when evaluating the patient's bone quality and their specific risk profile. Our findings suggest that patients with low BMD have similar outcomes to patients without low BMD undergoing oncologic megaprosthetic reconstructions by experienced surgeons. The specific effect of cemented vs uncemented fixation in patients with low BMD in the oncologic population deserves further investigation.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117704"},"PeriodicalIF":3.6,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446874","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}
A 2-month-old female child presented with a low-trauma femoral fracture, low bone mass, bowing of long bones, loss of height of a thoracic vertebra, and Wormian bones. Exome sequencing revealed the presence of a novel heterozygous 4006G > C pG1336R mutation in exon 25 of NOTCH2 in the child and her father. In silico analysis considered the variant as likely deleterious. CRISPR/Cas9 was used to introduce the Notch24006G>C mutation into Notch2 to create Notch2em1Ecan mutant mice. Homozygous Notch2em1Ecan mutant mice were active, appeared healthy, had normal femoral length, but lower weights than controls. μCT of the distal femur revealed a 25 % decrease in trabecular bone volume, and a decrease in total, bone and marrow area, in periosteal perimeter and polar moment of inertia, revealing the presence of small and potentially fragile bones. Three-point bend testing demonstrated decreased toughness in Notch2em1Ecan femurs. Cancellous bone histomorphometry demonstrated decreased eroded surface, and Raman spectroscopy revealed normal mineral to matrix ratios, carbonate:phosphate and collagen peak ratios. A structure homology model of NOTCH2 EGF33–36 repeats suggests that the G1336R mutation may disrupt the local structure, reducing the flexibility of the extracellular domain and thereby affecting receptor activation and signaling. Indeed, there was a modest decrease in Notch canonical target genes in osteoblasts from Notch2em1Ecan mice. Osteoblast and osteoclast differentiation were diminished in cells from Notch2em1Ecan mice. In conclusion, a novel mutation affecting the NOTCH2 extracellular domain is associated with small and apparently fragile bones, possibly due to altered Notch signaling.
一个2个月大的女婴表现为低创伤性股骨骨折，骨量低，长骨弯曲，胸椎高度下降，虫状骨。外显子组测序显示，在孩子及其父亲的NOTCH2外显子25上存在一种新的杂合4006G > C pG1336R突变。计算机分析认为这种变异可能是有害的。利用CRISPR/Cas9将Notch24006G>C突变引入Notch2中，构建Notch2em1Ecan突变小鼠。Notch2em1Ecan纯合子突变小鼠活跃，看起来健康，股骨长度正常，但体重低于对照组。μCT示股骨远端骨小梁体积减小25 %，总骨面积、骨髓面积、骨膜周长和极转动惯量减小，提示骨小且可能脆弱。三点弯曲试验显示Notch2em1Ecan股骨韧性下降。松质骨组织形态测量显示侵蚀面减少，拉曼光谱显示正常的矿物与基质比率，碳酸盐：磷酸盐和胶原蛋白峰值比率。NOTCH2 EGF33-36重复序列的结构同源性模型表明，G1336R突变可能会破坏局部结构，降低细胞外结构域的灵活性，从而影响受体的激活和信号传导。事实上，notch2em1can小鼠的成骨细胞中Notch标准靶基因有适度的减少。Notch2em1Ecan小鼠的成骨细胞和破骨细胞分化减弱。总之，一种影响NOTCH2细胞外结构域的新突变与小而明显脆弱的骨骼有关，可能是由于Notch信号通路的改变。
{"title":"A novel variant of NOTCH2 causes skeletal fragility","authors":"Ernesto Canalis , Jungeun Yu , Emily Denker , Lauren Schilling , Alix Deymier , Bing Hao , Thomas Carpenter","doi":"10.1016/j.bone.2025.117702","DOIUrl":"10.1016/j.bone.2025.117702","url":null,"abstract":"<div><div>A 2-month-old female child presented with a low-trauma femoral fracture, low bone mass, bowing of long bones, loss of height of a thoracic vertebra, and Wormian bones. Exome sequencing revealed the presence of a novel heterozygous 4006G > C pG1336R mutation in exon 25 of <em>NOTCH2</em> in the child and her father. In silico analysis considered the variant as likely deleterious. CRISPR/Cas9 was used to introduce the <em>Notch2</em><sup><em>4006G>C</em></sup> mutation into <em>Notch2</em> to create <em>Notch2</em><sup><em>em1Ecan</em></sup> mutant mice. Homozygous <em>Notch2</em><sup><em>em1Ecan</em></sup> mutant mice were active, appeared healthy, had normal femoral length, but lower weights than controls. μCT of the distal femur revealed a 25 % decrease in trabecular bone volume, and a decrease in total, bone and marrow area, in periosteal perimeter and polar moment of inertia, revealing the presence of small and potentially fragile bones. Three-point bend testing demonstrated decreased toughness in <em>Notch2</em><sup><em>em1Ecan</em></sup> femurs. Cancellous bone histomorphometry demonstrated decreased eroded surface, and Raman spectroscopy revealed normal mineral to matrix ratios, carbonate:phosphate and collagen peak ratios. A structure homology model of NOTCH2 EGF33–36 repeats suggests that the G1336R mutation may disrupt the local structure, reducing the flexibility of the extracellular domain and thereby affecting receptor activation and signaling. Indeed, there was a modest decrease in Notch canonical target genes in osteoblasts from <em>Notch2</em><sup><em>em1Ecan</em></sup> mice. Osteoblast and osteoclast differentiation were diminished in cells from <em>Notch2</em><sup><em>em1Ecan</em></sup> mice. In conclusion, a novel mutation affecting the NOTCH2 extracellular domain is associated with small and apparently fragile bones, possibly due to altered Notch signaling.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117702"},"PeriodicalIF":3.6,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446840","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 : 2025-11-02DOI: 10.1016/j.bone.2025.117697
Pin-Ru Chen , Kai-Ti Chuang , Po-Fang Wang , Chuan-Fong Yao , Pang-Yun Chou , Ying-An Chen , Clement Cheng-Hui Lin , Hong-Yuan Huang , Yu-Ray Chen
Background
Craniofacial fibrous dysplasia (CFD) is a non-malignant disease characterized by fibro-osseous lesions in the affected bones. Management is multidisciplinary, with surgery often serving as the mainstay of treatment and stratified according to four anatomical zones. This study aimed to evaluate the long-term outcomes and assess potential modifications to the algorithm.
Methods
This retrospective study included patients diagnosed with CFD or McCune–Albright syndrome (MAS) who received surgical intervention between 1972 and 2000, with a follow-up period exceeding 20 years. Demographic characteristics, surgical procedures, and follow-up computed tomographic scans and photographs were included in the analysis.
Results
Of 93 surgically treated patients with CFD/MAS, 13 were available for ≥20-year follow-up, with complete data and CT imaging (mean 30 ± 6 years, range 20–40 years). Ten patients underwent radical resection and immediate bone graft reconstruction, and two of them experienced recurrence. Three patients underwent therapeutic optic nerve decompression, and two patients experienced post-surgical vision improvement. One patient underwent surgery for hearing loss in the external auditory canal and experienced improved hearing post-surgery. One patient diagnosed with MAS experienced significant relief from craniofacial pain after receiving adjuvant hormone therapy.
Conclusions
Surgical strategies tailored to the four anatomical zones of CFD yield satisfactory outcomes. For Zone 1 lesions, based on our experience, radical resection followed by immediate bone graft reconstruction is a viable option. In Zone 3, therapeutic rather than prophylactic optic nerve decompression is suggested. Orthognathic surgery is also a viable option for such patients, improving occlusion and facial appearance.
{"title":"Craniofacial fibrous dysplasia: Long-term postoperative outcomes in a retrospective case series with up to 40 years of follow-up","authors":"Pin-Ru Chen , Kai-Ti Chuang , Po-Fang Wang , Chuan-Fong Yao , Pang-Yun Chou , Ying-An Chen , Clement Cheng-Hui Lin , Hong-Yuan Huang , Yu-Ray Chen","doi":"10.1016/j.bone.2025.117697","DOIUrl":"10.1016/j.bone.2025.117697","url":null,"abstract":"<div><h3>Background</h3><div>Craniofacial fibrous dysplasia (CFD) is a non-malignant disease characterized by fibro-osseous lesions in the affected bones. Management is multidisciplinary, with surgery often serving as the mainstay of treatment and stratified according to four anatomical zones. This study aimed to evaluate the long-term outcomes and assess potential modifications to the algorithm.</div></div><div><h3>Methods</h3><div>This retrospective study included patients diagnosed with CFD or McCune–Albright syndrome (MAS) who received surgical intervention between 1972 and 2000, with a follow-up period exceeding 20 years. Demographic characteristics, surgical procedures, and follow-up computed tomographic scans and photographs were included in the analysis.</div></div><div><h3>Results</h3><div>Of 93 surgically treated patients with CFD/MAS, 13 were available for ≥20-year follow-up, with complete data and CT imaging (mean 30 ± 6 years, range 20–40 years). Ten patients underwent radical resection and immediate bone graft reconstruction, and two of them experienced recurrence. Three patients underwent therapeutic optic nerve decompression, and two patients experienced post-surgical vision improvement. One patient underwent surgery for hearing loss in the external auditory canal and experienced improved hearing post-surgery. One patient diagnosed with MAS experienced significant relief from craniofacial pain after receiving adjuvant hormone therapy.</div></div><div><h3>Conclusions</h3><div>Surgical strategies tailored to the four anatomical zones of CFD yield satisfactory outcomes. For Zone 1 lesions, based on our experience, radical resection followed by immediate bone graft reconstruction is a viable option. In Zone 3, therapeutic rather than prophylactic optic nerve decompression is suggested. Orthognathic surgery is also a viable option for such patients, improving occlusion and facial appearance.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"203 ","pages":"Article 117697"},"PeriodicalIF":3.6,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446881","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 : 2025-10-31DOI: 10.1016/j.bone.2025.117694
Matthew Prideaux , Mathilde Palmier , Yukiko Kitase , Yuika Sone , Lynda F. Bonewald , Thomas M. O'Connell
Recent research has identified metabolic pathways which play key roles in the differentiation and function of osteoblasts and osteoclasts. However, the mechanisms by which osteocytes, the most numerous cells in bone, meet their energetic demands are still unknown. To address this, we used the IDG-SW3 osteocyte cell line to examine changes in metabolism during differentiation from late osteoblasts to mature osteocytes. There was a significant increase in the expression of glycolysis genes (including Pkm and Ldha), glucose consumption and lactate production during late differentiation of these cells. This was concurrent with the onset of the expression of mature osteocyte markers. Inhibition of glucose metabolism using the glucose analogue 2-deoxy-d-glucose (2-DG) inhibited IDG-SW3 cell mineralization and differentiation into osteocytes. To examine the effect of glucose metabolism inhibition on mature osteocytes, we treated differentiated IDG-SW3 cells and long bone osteocytes with 2-DG, which resulted in decreased expression of the bone formation inhibitor Sost and mineralization inhibitor Fgf23. Concurrently, there was an increase in genes associated with lipolysis (Lpl) fatty acid β-oxidation (Pparδ and Cpt1a). Treatment of differentiated IDG-SW3 cells with the unsaturated fatty acid oleic acid increased Cpt1a expression and downregulated Sost and Fgf23. Application of mechanical stress to IDG-SW3 cells resulted in upregulation of oxidative metabolism, Pparδ and Cpt1a expression. Long and short chain acylcarnitines were increased in the cortical bone of axially loaded tibiae compared to non-loaded controls, indicative of increased β-oxidation. Overall, our data suggests that while glucose metabolism is essential for osteocyte differentiation, mature osteocytes are metabolically flexible. Furthermore, β-oxidation may play an important role in the osteocyte response to mechanical stress.
{"title":"Osteocyte differentiation requires glucose metabolism, but mature osteocytes display metabolic flexibility","authors":"Matthew Prideaux , Mathilde Palmier , Yukiko Kitase , Yuika Sone , Lynda F. Bonewald , Thomas M. O'Connell","doi":"10.1016/j.bone.2025.117694","DOIUrl":"10.1016/j.bone.2025.117694","url":null,"abstract":"<div><div>Recent research has identified metabolic pathways which play key roles in the differentiation and function of osteoblasts and osteoclasts. However, the mechanisms by which osteocytes, the most numerous cells in bone, meet their energetic demands are still unknown. To address this, we used the IDG-SW3 osteocyte cell line to examine changes in metabolism during differentiation from late osteoblasts to mature osteocytes. There was a significant increase in the expression of glycolysis genes (including <em>Pkm</em> and <em>Ldha</em>), glucose consumption and lactate production during late differentiation of these cells. This was concurrent with the onset of the expression of mature osteocyte markers. Inhibition of glucose metabolism using the glucose analogue 2-deoxy-<span>d</span>-glucose (2-DG) inhibited IDG-SW3 cell mineralization and differentiation into osteocytes. To examine the effect of glucose metabolism inhibition on mature osteocytes, we treated differentiated IDG-SW3 cells and long bone osteocytes with 2-DG, which resulted in decreased expression of the bone formation inhibitor <em>Sost</em> and mineralization inhibitor <em>Fgf23</em>. Concurrently, there was an increase in genes associated with lipolysis (<em>Lpl</em>) fatty acid β-oxidation (<em>Pparδ</em> and <em>Cpt1a</em>). Treatment of differentiated IDG-SW3 cells with the unsaturated fatty acid oleic acid increased <em>Cpt1a</em> expression and downregulated <em>Sost</em> and <em>Fgf23</em>. Application of mechanical stress to IDG-SW3 cells resulted in upregulation of oxidative metabolism, <em>Pparδ</em> and <em>Cpt1a</em> expression. Long and short chain acylcarnitines were increased in the cortical bone of axially loaded tibiae compared to non-loaded controls, indicative of increased β-oxidation. Overall, our data suggests that while glucose metabolism is essential for osteocyte differentiation, mature osteocytes are metabolically flexible. Furthermore, β-oxidation may play an important role in the osteocyte response to mechanical stress.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"203 ","pages":"Article 117694"},"PeriodicalIF":3.6,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433442","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 : 2025-10-31DOI: 10.1016/j.bone.2025.117705
João Matheus Fonseca e Santos , Rafaela Sandro Stuque , Gabriel Conceição Brito , Edilson Ervolino , Letícia Helena Theodoro , Leonardo P. Faverani
Bone repairing is a complex mechanism that demands good bodily conditions to happen; however, some systemic conditions can negatively influence this process, such as some chronic inflammatory conditions and changes in the microarchitecture of bone tissue. This study aims to evaluate the potential of Photobiomodulation (PBM) therapy using an infrared diode laser (808 nm) in the bone repair of femoral fractures in osteoporotic rats. A total of 24 adult rats, aged 6 months old, were initially subjected to bilateral ovariectomy, to induce osteoporosis. After 90 days, the rats were subjected to femoral fractures and fixation with plates and screws of the 1.5 mm system. The rats were randomly divided into PBM (n = 9), those that were irradiated in the trans-surgical period with low-power laser, and WPBM (n = 9), those that were not irradiated. For the PBM group, a low-power laser with a 808 nm wavelength, 0.0283 cm2 spot area, 100 mW power was applied for 60 s, with 6 J/point energy, 212 J/cm2 energy density, single and punctual application in five determined points around the entire reparative “gap,” following the applications once per day, during eight days of the postoperative period. The animals were euthanized at 14 and 42 days after surgery, and the samples were sent for microtomographic, histometric, and immunohistochemical analyses. Data were analyzed using the two-way ANOVA test and the Holm-Sidak post-test when p < 0.05. The microtomographic analysis showed no differences between the groups analyzed in any experimental period (p > 0.05). Histometric analysis showed a greater area of newly formed bone for the PBM group compared to the WPBM group (p < 0.05), corroborating the immunohistochemical result, which shows greater labeling of TGF-B and VEGF. It can be concluded that the use of PBM therapy by infrared laser irradiation improved the repair of fractures in femurs of osteoporotic rats and it should be considered in future clinical research.
{"title":"Effect of photobiomodulation on femoral fracture specimens in rats with experimentally induced osteoporosis","authors":"João Matheus Fonseca e Santos , Rafaela Sandro Stuque , Gabriel Conceição Brito , Edilson Ervolino , Letícia Helena Theodoro , Leonardo P. Faverani","doi":"10.1016/j.bone.2025.117705","DOIUrl":"10.1016/j.bone.2025.117705","url":null,"abstract":"<div><div>Bone repairing is a complex mechanism that demands good bodily conditions to happen; however, some systemic conditions can negatively influence this process, such as some chronic inflammatory conditions and changes in the microarchitecture of bone tissue. This study aims to evaluate the potential of Photobiomodulation (PBM) therapy using an infrared diode laser (808 nm) in the bone repair of femoral fractures in osteoporotic rats. A total of 24 adult rats, aged 6 months old, were initially subjected to bilateral ovariectomy, to induce osteoporosis. After 90 days, the rats were subjected to femoral fractures and fixation with plates and screws of the 1.5 mm system. The rats were randomly divided into PBM (<em>n</em> = 9), those that were irradiated in the trans-surgical period with low-power laser, and WPBM (n = 9), those that were not irradiated. For the PBM group, a low-power laser with a 808 nm wavelength, 0.0283 cm<sup>2</sup> spot area, 100 mW power was applied for 60 s, with 6 J/point energy, 212 J/cm<sup>2</sup> energy density, single and punctual application in five determined points around the entire reparative “gap,” following the applications once per day, during eight days of the postoperative period. The animals were euthanized at 14 and 42 days after surgery, and the samples were sent for microtomographic, histometric, and immunohistochemical analyses. Data were analyzed using the two-way ANOVA test and the Holm-Sidak post-test when <em>p</em> < 0.05. The microtomographic analysis showed no differences between the groups analyzed in any experimental period (<em>p</em> > 0.05). Histometric analysis showed a greater area of newly formed bone for the PBM group compared to the WPBM group (<em>p</em> < 0.05), corroborating the immunohistochemical result, which shows greater labeling of TGF-B and VEGF. It can be concluded that the use of PBM therapy by infrared laser irradiation improved the repair of fractures in femurs of osteoporotic rats and it should be considered in future clinical research.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117705"},"PeriodicalIF":3.6,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433422","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 : 2025-10-30DOI: 10.1016/j.bone.2025.117698
Martin Munteanu , Frank Rutsch , Yvonne Nitschke , Uwe Kornak , Cordula Kiewert , Julia Spiekermann , Jakob Höppner , Corinna Grasemann
Introduction
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product.
Aim
To expand the phenotypic spectrum of ARHR2 and heterozygous ENPP1 variant carriers and to review safety concerns related to phosphate supplementation in affected individuals.
Case report
We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status.
Results
The patient was homozygous for the ENPP1 variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype.
Conclusion
This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk—potentially through combined treatment strategies or enzyme replacement therapy.
{"title":"Autosomal recessive hypophosphatemic rickets type 2 (ARHR2): Is phosphate supplementation safe?","authors":"Martin Munteanu , Frank Rutsch , Yvonne Nitschke , Uwe Kornak , Cordula Kiewert , Julia Spiekermann , Jakob Höppner , Corinna Grasemann","doi":"10.1016/j.bone.2025.117698","DOIUrl":"10.1016/j.bone.2025.117698","url":null,"abstract":"<div><h3>Introduction</h3><div>Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product.</div></div><div><h3>Aim</h3><div>To expand the phenotypic spectrum of ARHR2 and heterozygous <em>ENPP1</em> variant carriers and to review safety concerns related to phosphate supplementation in affected individuals.</div></div><div><h3>Case report</h3><div>We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status.</div></div><div><h3>Results</h3><div>The patient was homozygous for the <em>ENPP1</em> variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype.</div></div><div><h3>Conclusion</h3><div>This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk—potentially through combined treatment strategies or enzyme replacement therapy.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117698"},"PeriodicalIF":3.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427187","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 : 2025-10-30DOI: 10.1016/j.bone.2025.117695
Han Kyoung Choi , Thomas Kim , Xiaoxi Wei , Karl J. Jepsen , Yuji Mishina , Nicholas Auyeung , Fei Liu
Tuberous sclerosis complex 1 (Tsc1) negatively regulates mTORC1 signaling, but its role in postnatal skeletal development is not fully understood. Previous studies using various Cre drivers to target osteoblasts or mesenchymal lineage cells have generally shown higher bone mass accompanied by disorganized bone structure. However, our earlier study using Osx-Cre-mediated Tsc1 deletion demonstrated that conditional knockout mice (CKO) had lower femoral trabecular bone at one month of age, but early lethality prevented later-stage assessment. Furthermore, how postnatal mTOCRC1 hyperactivation affects bone accrual and mechanical properties remains unknown. In this report, we first evaluated the cortical bone phenotype of one-month-old CKO mice using nanoCT, immunostaining, and quantitative PCR (qPCR). CKO mice exhibited greater cortical bone mass, elevated osteoblast markers (Alpl, Bsp, Col1a1, Ocn) and transcription factors (Runx2, Osx), enhanced periosteal proliferation in vivo, and upregulated proliferation of primary femur cortical bone-derived osteoblasts in vitro. To overcome early lethality and assess the impact of postnatal mTORC1 hyperactivation, we utilized the built-in doxycycline (Dox) Turn-Off system in Osx-Cre mice to suppress Cre activity until 2 months of age. Postnatal Tsc1 deletion from 2 to 5 months led to robust cortical and trabecular bone gains in the femur, calvariae, and vertebrae. Picrosirius Red staining demonstrated that the femoral cortical bone in CKO mice exhibited organized collagen with lamellar features, indicating preserved tissue quality. Importantly, four-point bending tests demonstrated significantly improved femoral mechanical strength in CKO mice. In summary, our data reveal differential effects of Tsc1 deletion on trabecular and cortical bone at an early postnatal stage, and show that postnatal deletion results in robust bone gain with enhanced mechanical strength. These findings provide a more complete understanding of Tsc1-mTORC1 signaling as a key regulator of bone mass and challenge the assumption that mTORC1 hyperactivation yields mechanically inferior bone.
{"title":"Loss of Tsc1 in Osterix-expressing cells leads to greater bone mass and strength in mice","authors":"Han Kyoung Choi , Thomas Kim , Xiaoxi Wei , Karl J. Jepsen , Yuji Mishina , Nicholas Auyeung , Fei Liu","doi":"10.1016/j.bone.2025.117695","DOIUrl":"10.1016/j.bone.2025.117695","url":null,"abstract":"<div><div>Tuberous sclerosis complex 1 (<em>Tsc1</em>) negatively regulates mTORC1 signaling, but its role in postnatal skeletal development is not fully understood. Previous studies using various Cre drivers to target osteoblasts or mesenchymal lineage cells have generally shown higher bone mass accompanied by disorganized bone structure. However, our earlier study using Osx-Cre-mediated <em>Tsc1</em> deletion demonstrated that conditional knockout mice (CKO) had lower femoral trabecular bone at one month of age, but early lethality prevented later-stage assessment. Furthermore, how postnatal mTOCRC1 hyperactivation affects bone accrual and mechanical properties remains unknown. In this report, we first evaluated the cortical bone phenotype of one-month-old CKO mice using nanoCT, immunostaining, and quantitative PCR (qPCR). CKO mice exhibited greater cortical bone mass, elevated osteoblast markers (<em>Alpl, Bsp, Col1a1, Ocn</em>) and transcription factors (<em>Runx2, Osx</em>), enhanced periosteal proliferation in vivo, and upregulated proliferation of primary femur cortical bone-derived osteoblasts in vitro. To overcome early lethality and assess the impact of postnatal mTORC1 hyperactivation, we utilized the built-in doxycycline (Dox) Turn-Off system in Osx-Cre mice to suppress Cre activity until 2 months of age. Postnatal <em>Tsc1</em> deletion from 2 to 5 months led to robust cortical and trabecular bone gains in the femur, calvariae, and vertebrae. Picrosirius Red staining demonstrated that the femoral cortical bone in CKO mice exhibited organized collagen with lamellar features, indicating preserved tissue quality. Importantly, four-point bending tests demonstrated significantly improved femoral mechanical strength in CKO mice. In summary, our data reveal differential effects of <em>Tsc1</em> deletion on trabecular and cortical bone at an early postnatal stage, and show that postnatal deletion results in robust bone gain with enhanced mechanical strength. These findings provide a more complete understanding of <em>Tsc1</em>-mTORC1 signaling as a key regulator of bone mass and challenge the assumption that mTORC1 hyperactivation yields mechanically inferior bone.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"203 ","pages":"Article 117695"},"PeriodicalIF":3.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427149","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 : 2025-10-29DOI: 10.1016/j.bone.2025.117693
Tyler J. McNeill , Seoyeon Bok , Branden R. Sosa , Michelle Cung , Matthew B. Greenblatt , Marjolein C.H. van der Meulen
The ability of bone to adapt to external mechanical loads has been extensively studied, with mechanical stimuli increasing cortical and cancellous bone mass. However, the stem cell basis underlying this response is not well understood. To date, most studies focused on the role of differentiated cell populations in the skeletal response to loading. A recently discovered periosteal-specific skeletal stem cell marked by cathepsin K (CTSK) that drives intramembranous bone formation is a promising candidate to mediate load-induced bone formation. In this study, we sought to determine the influence of CTSK-lineage cells on the skeletal response to mechanical loading. We ablated cells expressing CTSK prior to initiating cyclic tibial compression for two weeks beginning at 16 weeks of age. We analyzed cortical and cancellous bone morphology at the tibial metaphysis and cortical bone morphology at the mid-diaphysis. Loading increased cortical, but not cancellous, bone mass. The amount of bone formed in response to loading did not differ when CTSK-expressing cells were ablated. CTSK-lineage cell ablation increased cortical bone mass primarily in regions subjected to tension and loading predominantly affected regions of bone under compression. To analyze the material composition of load-induced bone, we performed Raman spectroscopy along the periosteal surface of the diaphysis. CTSK-lineage cell ablation altered the influence of loading on B-type carbonate substation, a measure of tissue age. Overall, the amount of bone formed in response to loading did not differ in the absence of CTSK-lineage cells, but the material composition of load-induced cortical tissue was altered.
{"title":"Cathepsin K-lineage cells and mechanical loading independently modulate bone mass in the murine tibia","authors":"Tyler J. McNeill , Seoyeon Bok , Branden R. Sosa , Michelle Cung , Matthew B. Greenblatt , Marjolein C.H. van der Meulen","doi":"10.1016/j.bone.2025.117693","DOIUrl":"10.1016/j.bone.2025.117693","url":null,"abstract":"<div><div>The ability of bone to adapt to external mechanical loads has been extensively studied, with mechanical stimuli increasing cortical and cancellous bone mass. However, the stem cell basis underlying this response is not well understood. To date, most studies focused on the role of differentiated cell populations in the skeletal response to loading. A recently discovered periosteal-specific skeletal stem cell marked by cathepsin K (CTSK) that drives intramembranous bone formation is a promising candidate to mediate load-induced bone formation. In this study, we sought to determine the influence of CTSK-lineage cells on the skeletal response to mechanical loading. We ablated cells expressing CTSK prior to initiating cyclic tibial compression for two weeks beginning at 16 weeks of age. We analyzed cortical and cancellous bone morphology at the tibial metaphysis and cortical bone morphology at the mid-diaphysis. Loading increased cortical, but not cancellous, bone mass. The amount of bone formed in response to loading did not differ when CTSK-expressing cells were ablated. CTSK-lineage cell ablation increased cortical bone mass primarily in regions subjected to tension and loading predominantly affected regions of bone under compression. To analyze the material composition of load-induced bone, we performed Raman spectroscopy along the periosteal surface of the diaphysis. CTSK-lineage cell ablation altered the influence of loading on B-type carbonate substation, a measure of tissue age. Overall, the amount of bone formed in response to loading did not differ in the absence of CTSK-lineage cells, but the material composition of load-induced cortical tissue was altered.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117693"},"PeriodicalIF":3.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423588","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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