Pub Date : 2025-12-01DOI: 10.1016/j.bonr.2025.101891
Brianna G. Bowden , Brett Klamer , Robin Alexander , Mariah Eisner , Garey Noritz
Introduction
Patients with cerebral palsy (CP) and spinal muscular atrophy (SMA) with immobility are at risk for low bone mineral density (BMD) and fragility fractures. This study investigates whether BMD differs between these two groups given their distinct pathological mechanisms.
Methods
Data were collected from non-ambulatory patients diagnosed with CP (GMFCS IV-V) and SMA (type I–II), aged five years and older, who were seen at a metabolic bone clinic between January 2012 and July 2023. Dual-energy X-ray absorptiometry (DXA) assessed BMD at the lumbar spine (LS) and lateral distal femur (LDF), region 3 (R3). Z-scores were calculated and compared between groups using the Wilcoxon rank sum test.
Results
This study included 274 children with CP and 16 with SMA. Unadjusted LS Z-scores were low and comparable in both groups (CP: −2.3, SMA: −2.6; p = 0.7). After adjusting for height, LS Z-scores were in the normal range (CP: −0.9, SMA: −1.6; p = 0.3). However, the SMA group had significantly lower BMD in R3 of the LDF compared to the CP group (CP: −2.9, SMA: −3.9; p = 0.047).
Conclusion
Both groups had normal height adjusted LS BMD and low R3 LDF BMD, with the SMA group significantly lower. We theorize that it may be due to the differences in muscle tonicity on the bone. We recommend including the distal femur bone density in routine bone health assessments and that BMD should be adjusted for height when possible.
{"title":"A comparative analysis of bone mineral density in cerebral palsy and spinal muscular atrophy","authors":"Brianna G. Bowden , Brett Klamer , Robin Alexander , Mariah Eisner , Garey Noritz","doi":"10.1016/j.bonr.2025.101891","DOIUrl":"10.1016/j.bonr.2025.101891","url":null,"abstract":"<div><h3>Introduction</h3><div>Patients with cerebral palsy (CP) and spinal muscular atrophy (SMA) with immobility are at risk for low bone mineral density (BMD) and fragility fractures. This study investigates whether BMD differs between these two groups given their distinct pathological mechanisms.</div></div><div><h3>Methods</h3><div>Data were collected from non-ambulatory patients diagnosed with CP (GMFCS IV-V) and SMA (type I–II), aged five years and older, who were seen at a metabolic bone clinic between January 2012 and July 2023. Dual-energy X-ray absorptiometry (DXA) assessed BMD at the lumbar spine (LS) and lateral distal femur (LDF), region 3 (R3). Z-scores were calculated and compared between groups using the Wilcoxon rank sum test.</div></div><div><h3>Results</h3><div>This study included 274 children with CP and 16 with SMA. Unadjusted LS Z-scores were low and comparable in both groups (CP: −2.3, SMA: −2.6; p = 0.7). After adjusting for height, LS Z-scores were in the normal range (CP: −0.9, SMA: −1.6; p = 0.3). However, the SMA group had significantly lower BMD in R3 of the LDF compared to the CP group (CP: −2.9, SMA: −3.9; p = 0.047).</div></div><div><h3>Conclusion</h3><div>Both groups had normal height adjusted LS BMD and low R3 LDF BMD, with the SMA group significantly lower. We theorize that it may be due to the differences in muscle tonicity on the bone. We recommend including the distal femur bone density in routine bone health assessments and that BMD should be adjusted for height when possible.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101891"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rheumatoid arthritis (RA) causes bone destruction by activating inflammatory cytokines and osteoclasts. Cyclin-dependent kinase inhibitor 1 (p21), a cell cycle regulator, may influence this process; however, its role remains unclear. Therefore, we investigated the effect and potential mechanisms of p21 deficiency in bone loss in a mouse model of arthritis. Collagen antibody-induced arthritis (CAIA) was established in p21 knockout (p21−/−) and wild-type mice. Bone destruction was analyzed using histology, micro-computed tomography, and bone strength testing; osteoclast formation and activity were evaluated using tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry for cathepsin K. The expression of inflammatory cytokines and osteoclast-related genes was examined using immunohistochemistry and real-time polymerase chain reaction, respectively. p21−/− mice exhibited greater bone destruction and lower bone strength than wild-type mice. Additionally, TRAP and cathepsin K staining revealed significantly higher osteoclast count in p21−/− mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), and phosphorylated signal transducer and activator of transcription 3 (STAT3) levels were considerably higher in bone tissues of p21−/− mice than in those of wild-type mice. In vitro osteoclast differentiation in bone marrow macrophages (BMMs) was examined after IL-6 stimulation; osteoclast differentiation and osteoclast marker gene expression were significantly enhanced in p21−/− BMMs. Western blotting confirmed increased STAT3 phosphorylation in p21−/− BMMs; IL-6 treatment further amplified osteoclastogenesis in p21−/− BMMs. In conclusion, p21 deficiency exacerbates bone destruction in arthritis by promoting osteoclast differentiation and inflammatory cytokine expression via the IL-6/STAT3 pathway. Targeting p21 may offer therapeutic potential for preventing arthritis-related bone loss, such as in RA.
{"title":"Cyclin-dependent kinase inhibitor-1 deficiency enhances bone destruction in a mouse model of arthritis","authors":"Kensuke Wada , Shinya Hayashi , Yuma Onoi , Shotaro Tachibana , Yoshihito Suda , Akira Saito , Takuma Maeda , Shotaro Araki , Kohei Motono , Tomoyuki Kamenaga , Masanori Tsubosaka , Yuichi Kuroda , Naoki Nakano , Tomoyuki Matsumoto , Ryosuke Kuroda","doi":"10.1016/j.bonr.2025.101892","DOIUrl":"10.1016/j.bonr.2025.101892","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) causes bone destruction by activating inflammatory cytokines and osteoclasts. Cyclin-dependent kinase inhibitor 1 (p21), a cell cycle regulator, may influence this process; however, its role remains unclear. Therefore, we investigated the effect and potential mechanisms of p21 deficiency in bone loss in a mouse model of arthritis. Collagen antibody-induced arthritis (CAIA) was established in p21 knockout (<em>p21</em><sup><em>−/−</em></sup>) and wild-type mice. Bone destruction was analyzed using histology, micro-computed tomography, and bone strength testing; osteoclast formation and activity were evaluated using tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry for cathepsin K. The expression of inflammatory cytokines and osteoclast-related genes was examined using immunohistochemistry and real-time polymerase chain reaction, respectively. <em>p21</em><sup><em>−</em></sup><em>/</em><sup><em>−</em></sup> mice exhibited greater bone destruction and lower bone strength than wild-type mice. Additionally, TRAP and cathepsin K staining revealed significantly higher osteoclast count in <em>p21</em><sup><em>−</em></sup><em>/</em><sup><em>−</em></sup> mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), and phosphorylated signal transducer and activator of transcription 3 (STAT3) levels were considerably higher in bone tissues of <em>p21</em><sup><em>−</em></sup><em>/</em><sup><em>−</em></sup> mice than in those of wild-type mice. In vitro osteoclast differentiation in bone marrow macrophages (BMMs) was examined after IL-6 stimulation; osteoclast differentiation and osteoclast marker gene expression were significantly enhanced in <em>p21</em><sup><em>−/−</em></sup> BMMs. Western blotting confirmed increased STAT3 phosphorylation in <em>p21</em><sup><em>−/−</em></sup> BMMs; IL-6 treatment further amplified osteoclastogenesis in <em>p21</em><sup><em>−/−</em></sup> BMMs. In conclusion, p21 deficiency exacerbates bone destruction in arthritis by promoting osteoclast differentiation and inflammatory cytokine expression via the IL-6/STAT3 pathway. Targeting p21 may offer therapeutic potential for preventing arthritis-related bone loss, such as in RA.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101892"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1016/j.bonr.2025.101889
Anton Gorodov , Albert Kolomansky , Lior Lezerovich , Michelle Piper , Nathalie Ben-Califa , Yankel Gabet , Drorit Neumann
Erythropoietin (EPO) is a key regulator of erythropoiesis, and it is mainly used to treat anemia. However, it is also administered prophylactically to non-anemic patients in certain clinical settings and is known to be used illicitly by athletes. The effect of EPO is controversial but emerging evidence indicates that EPO treatment induces bone loss in healthy mice. Here, we investigated the immediate and short-term skeletal effects of a single high-dose EPO injection in young mature (9 weeks) female mice. Cellular and molecular markers of bone turnover were evaluated at multiple time points post-injection. EPO administration led to a rapid increase in macrophage colony-stimulating factor (M-CSF) levels within the bone marrow (BM) microenvironment and in the serum, accompanied by an increase in BM CD115-positive cells and osteoclast precursors, as assessed by flow cytometry. This early cellular response to EPO was followed by an increase in tartrate-resistant acid phosphatase 5b (TRAP5b) and a decrease in procollagen type 1 N-terminal propeptide (P1NP), as determined by serum ELISA analyses, suggesting increased osteoclast numbers and decreased bone formation, respectively. Micro-computed tomography (μCT) revealed a significant reduction in trabecular bone volume. These findings demonstrate that even a single high-dose EPO injection disrupts bone homeostasis and induces significant bone loss through early modulation of the BM niche and osteoclastogenic pathways. Our results have important clinical implications for the prophylactic use of EPO and highlight potential skeletal risks.
{"title":"Erythropoietin and bone health: Single high-dose administration triggers bone loss in mice","authors":"Anton Gorodov , Albert Kolomansky , Lior Lezerovich , Michelle Piper , Nathalie Ben-Califa , Yankel Gabet , Drorit Neumann","doi":"10.1016/j.bonr.2025.101889","DOIUrl":"10.1016/j.bonr.2025.101889","url":null,"abstract":"<div><div>Erythropoietin (EPO) is a key regulator of erythropoiesis, and it is mainly used to treat anemia. However, it is also administered prophylactically to non-anemic patients in certain clinical settings and is known to be used illicitly by athletes. The effect of EPO is controversial but emerging evidence indicates that EPO treatment induces bone loss in healthy mice. Here, we investigated the immediate and short-term skeletal effects of a single high-dose EPO injection in young mature (9 weeks) female mice. Cellular and molecular markers of bone turnover were evaluated at multiple time points post-injection. EPO administration led to a rapid increase in macrophage colony-stimulating factor (M-CSF) levels within the bone marrow (BM) microenvironment and in the serum, accompanied by an increase in BM CD115-positive cells and osteoclast precursors, as assessed by flow cytometry. This early cellular response to EPO was followed by an increase in tartrate-resistant acid phosphatase 5b (TRAP5b) and a decrease in procollagen type 1 N-terminal propeptide (P1NP), as determined by serum ELISA analyses, suggesting increased osteoclast numbers and decreased bone formation, respectively. Micro-computed tomography (μCT) revealed a significant reduction in trabecular bone volume. These findings demonstrate that even a single high-dose EPO injection disrupts bone homeostasis and induces significant bone loss through early modulation of the BM niche and osteoclastogenic pathways. Our results have important clinical implications for the prophylactic use of EPO and highlight potential skeletal risks.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"28 ","pages":"Article 101889"},"PeriodicalIF":2.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.bonr.2025.101886
Shiho Kinoshita , Yasuhiro Omata , Kojiro Sato
Background
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive bone destruction. Although osteoclasts mediate bone resorption in RA, recent evidence suggests that inflammatory osteoclasts differ from physiological osteoclasts in various aspects, including their progenitor origins. This study aimed to compare the osteoclastogenic potential of monocyte-derived dendritic cells (moDCs) and other granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced cells to identify potential progenitor populations involved in inflammatory bone damage.
Methods
Classical monocytes were isolated from human peripheral blood mononuclear cells and cultured under four conditions: (i) M-CSF, (ii) GM-CSF, (iii) GM-CSF + interleukin (IL)-4, and (iv) GM-CSF + tumor necrosis factor-alpha (TNF-α). Subsequently, to induce osteoclast differentiation, the cells were cultured with M-CSF and receptor activator of NF-κB ligand (RANKL) with or without the presence of GM-CSF, IL-4, and TNF-α, followed by evaluations via tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays.
Results
Cells cultured with M-CSF, GM-CSF, and GM-CSF + TNF-α differentiated into TRAP-positive multinucleated osteoclasts with bone-resorbing activity. In contrast, moDCs (condition iii) exhibited minimal osteoclast differentiation without any bone-resorbing activity. Introduction of an intermediate M-CSF culture step induces adhesion of moDCs and partially induces osteoclastogenesis. However, their differentiation efficiency and bone resorption capacity remained inferior to those under other conditions. Notably, IL-4 and GM-CSF, but not TNF-α, suppressed osteoclast differentiation.
Conclusions
moDCs exhibit limited potential as osteoclast precursors under inflammatory conditions. Comparatively, GM-CSF (+ TNF-α)-induced progenitors represent a more viable inflammatory osteoclast precursor population. Overall, our results provide insights into osteoclast heterogeneity and RA-associated bone destruction mechanisms.
{"title":"Distinct osteoclastogenic potential of granulocyte-macrophage colony-stimulating factor-induced monocyte subsets","authors":"Shiho Kinoshita , Yasuhiro Omata , Kojiro Sato","doi":"10.1016/j.bonr.2025.101886","DOIUrl":"10.1016/j.bonr.2025.101886","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive bone destruction. Although osteoclasts mediate bone resorption in RA, recent evidence suggests that inflammatory osteoclasts differ from physiological osteoclasts in various aspects, including their progenitor origins. This study aimed to compare the osteoclastogenic potential of monocyte-derived dendritic cells (moDCs) and other granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced cells to identify potential progenitor populations involved in inflammatory bone damage.</div></div><div><h3>Methods</h3><div>Classical monocytes were isolated from human peripheral blood mononuclear cells and cultured under four conditions: (i) M-CSF, (ii) GM-CSF, (iii) GM-CSF + interleukin (IL)-4, and (iv) GM-CSF + tumor necrosis factor-alpha (TNF-α). Subsequently, to induce osteoclast differentiation, the cells were cultured with M-CSF and receptor activator of NF-κB ligand (RANKL) with or without the presence of GM-CSF, IL-4, and TNF-α, followed by evaluations via tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays.</div></div><div><h3>Results</h3><div>Cells cultured with M-CSF, GM-CSF, and GM-CSF + TNF-α differentiated into TRAP-positive multinucleated osteoclasts with bone-resorbing activity. In contrast, moDCs (condition iii) exhibited minimal osteoclast differentiation without any bone-resorbing activity. Introduction of an intermediate M-CSF culture step induces adhesion of moDCs and partially induces osteoclastogenesis. However, their differentiation efficiency and bone resorption capacity remained inferior to those under other conditions. Notably, IL-4 and GM-CSF, but not TNF-α, suppressed osteoclast differentiation.</div></div><div><h3>Conclusions</h3><div>moDCs exhibit limited potential as osteoclast precursors under inflammatory conditions. Comparatively, GM-CSF (+ TNF-α)-induced progenitors represent a more viable inflammatory osteoclast precursor population. Overall, our results provide insights into osteoclast heterogeneity and RA-associated bone destruction mechanisms.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101886"},"PeriodicalIF":2.6,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic non-bacterial osteomyelitis of the skull is a rare entity that should be taken into account in the differential diagnosis of lacunar lesions of the skull. Here, we present four challenging cases of non-infectious inflammatory lytic lesions of the neurocranium with a diagnostic delay of one to five years.
{"title":"Pediatric non-infectious inflammatory lytic lesions of the skull: The pitfalls of diagnosis","authors":"Peggy Alkefrawi , Sylvain Breton , Geneviève Baujat , Isabelle Melki , Benjamin Fournier , Brigitte Bader-Meunier","doi":"10.1016/j.bonr.2025.101888","DOIUrl":"10.1016/j.bonr.2025.101888","url":null,"abstract":"<div><div>Chronic non-bacterial osteomyelitis of the skull is a rare entity that should be taken into account in the differential diagnosis of lacunar lesions of the skull. Here, we present four challenging cases of non-infectious inflammatory lytic lesions of the neurocranium with a diagnostic delay of one to five years.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101888"},"PeriodicalIF":2.6,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-09DOI: 10.1016/j.bonr.2025.101887
Santosh Thapa , Jake Newberry , S.V.V.S. Ravi Mangu , Ron C.M. Helderman , Ananya Nandy , Cameron Fawcett , Sasidhar Uppuganti , Jeffry S. Nyman , Elizabeth Rendina-Ruedy
Osteoporosis is a major public health problem which results in reduced bone mineral density (BMD) and increased fracture risk. Osteoporosis-related fractures often lead to multiple comorbidities which can significantly reduce longevity and diminish one's quality of life. While anabolic agents that increase bone formation, such as parathyroid hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects along with variations in therapeutic response. Therefore, continued development of refined therapeutic interventions as well as improving efficacy is necessary. Relative to this, the current experiments report on the ability to harness PTH's impact to modulate osteoblast bioenergetic capacity to promote bone formation by supplying fatty acid substrates to meet this energetic demand. To accomplish this, mice were fed a moderately ‘high’ fat diet (2.5×) or control fat, as to not induce metabolic perturbations, while treating with or without PTH for 4 weeks. This dietary regimen resulted in improved bone parameters in mice fed the high fat diet compared to control diet. To directly test the contribution of increased exogenous fatty acid substrates during PTH treatment, we next introduced oleic acid simultaneous to PTH treatment for 4 weeks, and again showed improved skeletal parameters compared to the vehicle-control treated mice. These data support previous publications that demonstrate the osteoanabolic responsiveness of osteoblasts to PTH requires fatty acid substrates. These data further expand on these findings, by providing evidence that PTH efficacy can be improved by supplying exogenous fatty acid substrates, either by dietary or direct interventions.
{"title":"Increased fatty acid availability improves the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) in murine models","authors":"Santosh Thapa , Jake Newberry , S.V.V.S. Ravi Mangu , Ron C.M. Helderman , Ananya Nandy , Cameron Fawcett , Sasidhar Uppuganti , Jeffry S. Nyman , Elizabeth Rendina-Ruedy","doi":"10.1016/j.bonr.2025.101887","DOIUrl":"10.1016/j.bonr.2025.101887","url":null,"abstract":"<div><div>Osteoporosis is a major public health problem which results in reduced bone mineral density (BMD) and increased fracture risk. Osteoporosis-related fractures often lead to multiple comorbidities which can significantly reduce longevity and diminish one's quality of life. While anabolic agents that increase bone formation, such as parathyroid hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects along with variations in therapeutic response. Therefore, continued development of refined therapeutic interventions as well as improving efficacy is necessary. Relative to this, the current experiments report on the ability to harness PTH's impact to modulate osteoblast bioenergetic capacity to promote bone formation by supplying fatty acid substrates to meet this energetic demand. To accomplish this, mice were fed a moderately ‘high’ fat diet (2.5×) or control fat, as to not induce metabolic perturbations, while treating with or without PTH for 4 weeks. This dietary regimen resulted in improved bone parameters in mice fed the high fat diet compared to control diet. To directly test the contribution of increased exogenous fatty acid substrates during PTH treatment, we next introduced oleic acid simultaneous to PTH treatment for 4 weeks, and again showed improved skeletal parameters compared to the vehicle-control treated mice. These data support previous publications that demonstrate the osteoanabolic responsiveness of osteoblasts to PTH requires fatty acid substrates. These data further expand on these findings, by providing evidence that PTH efficacy can be improved by supplying exogenous fatty acid substrates, either by dietary or direct interventions.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101887"},"PeriodicalIF":2.6,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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.bonr.2025.101885
Sarah A. Ackah , Boaz Karmazyn , Alden Dewey , Michael J. Econs , Gang Peng , Corinne Parks-Schenck , Jodi L. Skiles , Paul Niziolek , Linda A. DiMeglio , Stuart J. Warden , Erik A. Imel
Osteosclerosis in infancy requires careful evaluation as it may indicate the presence of osteopetrosis. Osteopetrosis is a rare disorder of high bone density due to impaired osteoclast resorption. Infantile forms of osteopetrosis have neurological and hematopoietic defects. However, some infants may present with a transient neonatal osteosclerosis (TNO) appearance without skeletal consequences. The aim of this case series is to compare TNO with infantile osteopetrosis.
Radiographic reports of infants less than 12 months old were searched for the terms osteosclerosis and osteopetrosis from 2006 to 2025 at a single tertiary care children's hospital. Serial radiographs performed clinically were extracted and assessed for resolution and the clinical features described.
TNO was identified in 7 infants and osteopetrosis was identified in 6 infants. The children with TNO presented at younger age (median age 6 days) than those with osteopetrosis (median age 73 days). All infants with osteopetrosis had genetic confirmation (TCIRG1 n = 3, CLCN7 n = 2 [one dominant, one recessive], IKBKG n = 1). Four of 6 infants with autosomal recessive osteopetrosis had thrombocytopenia and 3 had hypocalcemia, 5 had elevated parathyroid hormone, and 3 had elevated alkaline phosphatase. One of the 7 infants with TNO had thrombocytopenia and 2 had mild hypocalcemia. Rachitic changes were present in 3 infants with osteopetrosis, and metaphyseal widening in all 6 infants, but none of the TNO infants had these features. In TNO, resolution was evident by mean age of 8.5 months (range 1 to 31 months).
TNO and infantile osteopetrosis have distinguishing clinical, radiographic and laboratory features.
婴儿期的骨硬化需要仔细评估，因为它可能表明存在骨质疏松症。骨质疏松症是一种罕见的因破骨细胞吸收受损而引起的高骨密度疾病。婴儿形式的骨质疏松症有神经和造血缺陷。然而，一些婴儿可能会出现短暂的新生儿骨硬化（TNO）外观，没有骨骼后果。本病例系列的目的是比较TNO与婴儿骨质疏松症。对2006年至2025年在一家三级保健儿童医院的12个月以下婴儿的影像学报告进行骨硬化和骨质疏松的检索。提取临床拍摄的系列x线片并评估分辨率和描述临床特征。7例婴儿发现TNO， 6例婴儿发现骨质疏松。TNO患儿比骨质疏松患儿（中位年龄73天）出现的年龄更小（中位年龄6天）。所有患有骨质疏松症的婴儿均有遗传证实（TCIRG1 n = 3, CLCN7 n = 2[1显性，1隐性]，IKBKG n = 1）。6例常染色体隐性骨质疏松症患儿中4例伴血小板减少症，3例伴低钙血症，5例伴甲状旁腺激素升高，3例伴碱性磷酸酶升高。7例TNO患儿中1例有血小板减少症，2例有轻度低钙血症。3例患有骨质疏松症的婴儿出现脊柱曲张改变，6例婴儿均出现干骺端变宽，但TNO婴儿均无这些特征。在TNO中，平均年龄为8.5个月（1至31个月），缓解明显。TNO与婴儿骨质疏松症具有不同的临床、影像学和实验室特征。
{"title":"Can transient neonatal osteosclerosis be differentiated from malignant infantile osteopetrosis?","authors":"Sarah A. Ackah , Boaz Karmazyn , Alden Dewey , Michael J. Econs , Gang Peng , Corinne Parks-Schenck , Jodi L. Skiles , Paul Niziolek , Linda A. DiMeglio , Stuart J. Warden , Erik A. Imel","doi":"10.1016/j.bonr.2025.101885","DOIUrl":"10.1016/j.bonr.2025.101885","url":null,"abstract":"<div><div>Osteosclerosis in infancy requires careful evaluation as it may indicate the presence of osteopetrosis. Osteopetrosis is a rare disorder of high bone density due to impaired osteoclast resorption. Infantile forms of osteopetrosis have neurological and hematopoietic defects. However, some infants may present with a transient neonatal osteosclerosis (TNO) appearance without skeletal consequences. The aim of this case series is to compare TNO with infantile osteopetrosis.</div><div>Radiographic reports of infants less than 12 months old were searched for the terms osteosclerosis and osteopetrosis from 2006 to 2025 at a single tertiary care children's hospital. Serial radiographs performed clinically were extracted and assessed for resolution and the clinical features described.</div><div>TNO was identified in 7 infants and osteopetrosis was identified in 6 infants. The children with TNO presented at younger age (median age 6 days) than those with osteopetrosis (median age 73 days). All infants with osteopetrosis had genetic confirmation (TCIRG1 <em>n</em> = 3, CLCN7 <em>n</em> = 2 [one dominant, one recessive], IKBKG <em>n</em> = 1). Four of 6 infants with autosomal recessive osteopetrosis had thrombocytopenia and 3 had hypocalcemia, 5 had elevated parathyroid hormone, and 3 had elevated alkaline phosphatase. One of the 7 infants with TNO had thrombocytopenia and 2 had mild hypocalcemia. Rachitic changes were present in 3 infants with osteopetrosis, and metaphyseal widening in all 6 infants, but none of the TNO infants had these features. In TNO, resolution was evident by mean age of 8.5 months (range 1 to 31 months).</div><div>TNO and infantile osteopetrosis have distinguishing clinical, radiographic and laboratory features.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101885"},"PeriodicalIF":2.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145473901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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.bonr.2025.101884
Mathieu Simon , Sasidhar Uppuganti , Jeffry S. Nyman , Philippe Zysset
Type 2 diabetes (T2D) is a chronic disease leading to an elevated glucose level in the blood and increased fracture risk. Because T2D individuals tend to have normal to higher areal bone mineral density (aBMD) than healthy individuals, their fracture risk is often underestimated. As an alternative, high-resolution peripheral quantitative computed tomography (HR-pQCT) is an attractive tool to investigate bone morphology in vivo and estimate fracture risk. Based on HR-pQCT scans, bone strength can be estimated using micro finite element (FE) analysis or homogenized finite element (hFE) analysis. While FE is computationally expensive, hFE provides an accurate estimation of bone mechanical properties within reasonable efforts. However, the hFE scheme is based on relationships between the local fabric (anisotropy) and elasticity. These relationships have been shown to hold for healthy controls as well as in the case of osteogenesis imperfecta. Nevertheless, whether these relationships are also valid for T2D-diagnosed patients remains unclear. Therefore, the present work aims to compare fabric–elasticity relationships between T2D and non-diabetic controls.
The present study collected 56 trabecular bone cores from the femoral head of 28 T2D and 28 control donors. These cadaveric samples were scanned in a micro-CT system at an isotropic 14.8 m voxel size. Three cubic regions of interest (ROIs) were selected in each scan. The resolution of these ROIs was coarsened by a factor of 4, mimicking clinical HR-pQCT resolution, and the ROIs were subsequently segmented. Standard morphometric parameters were computed from the segmented ROIs using medtool (v4.8; Dr. Pahr Ingenieurs e.U., Pfaffstätten, Austria). Additionally, their fabric tensor and their apparent stiffness tensors were computed. The ROIs were compared between T2D and control regarding their morphometric and mechanical properties. Finally, ROIs were matched between T2D and control for bone volume fraction () and degree of anisotropy (DA). The matched dataset allowed the comparison of fabric–elasticity relationships between T2D and control samples.
No significant difference was observed between T2D and control samples, both regarding their morphology and their mechanical properties. Specifically, fabric–elasticity relationships were shown to hold for both the control and the T2D groups. A comparison of the resulting exponents related to and DA has highlighted different trends but no important difference between T2D and control samples.
In conclusion, trabecular bone architecture was similar between T2D and non-T2D donors. Additionally, fabric–elasticity relationships, i.e. morphology-mechanical relationships, are also similar between donors with and without diabetes. Accordingly, HR-p
2型糖尿病（T2D）是一种导致血液中葡萄糖水平升高和骨折风险增加的慢性疾病。由于T2D患者的面骨矿物质密度（aBMD）往往高于健康人群，因此他们的骨折风险往往被低估。作为替代方案，高分辨率周边定量计算机断层扫描（HR-pQCT）是一种有吸引力的工具，用于研究体内骨形态和估计骨折风险。基于HR-pQCT扫描结果，可采用微有限元（μFE）分析或均质有限元（hFE）分析估算骨强度。虽然μFE在计算上是昂贵的，但hFE在合理的努力下提供了骨力学性能的准确估计。然而，hFE方案是基于局部结构（各向异性）和弹性之间的关系。这些关系已被证明适用于健康对照以及成骨不全症。然而，这些关系是否也适用于t2d诊断患者仍不清楚。因此，本研究旨在比较T2D和非糖尿病对照之间的织物弹性关系。本研究从28例T2D供体和28例对照供体的股骨头中收集了56个骨小梁核心。这些尸体样品在微ct系统中以各向同性14.8 μm体素尺寸进行扫描。在每次扫描中选择三个立方感兴趣区域（roi）。这些roi的分辨率被粗化4倍，模仿临床HR-pQCT分辨率，随后对roi进行分割。使用medtool （v4.8; Dr. Pahr Ingenieurs e.U, Pfaffstätten，奥地利）从分割的roi中计算标准形态计量参数。此外，还计算了它们的织物张量和表观刚度张量。比较了T2D和对照组在形态计量学和力学性能方面的roi。最后，在骨体积分数（ρ）和各向异性程度（DA）方面，将T2D与对照组的roi进行匹配。匹配的数据集允许比较T2D和对照样本之间的织物弹性关系。在T2D和对照样品之间，无论是形貌还是力学性能都没有观察到显著差异。具体来说，织物弹性关系被证明对对照组和T2D组都有效。与ρ和DA相关的结果指数的比较突出了不同的趋势，但在T2D和控制样本之间没有重要差异。总之，T2D和非T2D供体的骨小梁结构相似。此外，织物-弹性关系，即形态-力学关系，在有和没有糖尿病的供体之间也相似。因此，基于hr - pqct的hFE分析也可用于估计T2D患者的骨力学特性和评估其骨折风险。
{"title":"Fabric–elasticity relationships of femoral head trabecular bone are similar in Type 2 diabetes and non-diabetic individuals","authors":"Mathieu Simon , Sasidhar Uppuganti , Jeffry S. Nyman , Philippe Zysset","doi":"10.1016/j.bonr.2025.101884","DOIUrl":"10.1016/j.bonr.2025.101884","url":null,"abstract":"<div><div>Type 2 diabetes (T2D) is a chronic disease leading to an elevated glucose level in the blood and increased fracture risk. Because T2D individuals tend to have normal to higher areal bone mineral density (aBMD) than healthy individuals, their fracture risk is often underestimated. As an alternative, high-resolution peripheral quantitative computed tomography (HR-pQCT) is an attractive tool to investigate bone morphology in vivo and estimate fracture risk. Based on HR-pQCT scans, bone strength can be estimated using micro finite element (<span><math><mi>μ</mi></math></span>FE) analysis or homogenized finite element (hFE) analysis. While <span><math><mi>μ</mi></math></span>FE is computationally expensive, hFE provides an accurate estimation of bone mechanical properties within reasonable efforts. However, the hFE scheme is based on relationships between the local fabric (anisotropy) and elasticity. These relationships have been shown to hold for healthy controls as well as in the case of osteogenesis imperfecta. Nevertheless, whether these relationships are also valid for T2D-diagnosed patients remains unclear. Therefore, the present work aims to compare fabric–elasticity relationships between T2D and non-diabetic controls.</div><div>The present study collected 56 trabecular bone cores from the femoral head of 28 T2D and 28 control donors. These cadaveric samples were scanned in a micro-CT system at an isotropic 14.8 <span><math><mi>μ</mi></math></span>m voxel size. Three cubic regions of interest (ROIs) were selected in each scan. The resolution of these ROIs was coarsened by a factor of 4, mimicking clinical HR-pQCT resolution, and the ROIs were subsequently segmented. Standard morphometric parameters were computed from the segmented ROIs using medtool (v4.8; Dr. Pahr Ingenieurs e.U., Pfaffstätten, Austria). Additionally, their fabric tensor and their apparent stiffness tensors were computed. The ROIs were compared between T2D and control regarding their morphometric and mechanical properties. Finally, ROIs were matched between T2D and control for bone volume fraction (<span><math><mi>ρ</mi></math></span>) and degree of anisotropy (DA). The matched dataset allowed the comparison of fabric–elasticity relationships between T2D and control samples.</div><div>No significant difference was observed between T2D and control samples, both regarding their morphology and their mechanical properties. Specifically, fabric–elasticity relationships were shown to hold for both the control and the T2D groups. A comparison of the resulting exponents related to <span><math><mi>ρ</mi></math></span> and DA has highlighted different trends but no important difference between T2D and control samples.</div><div>In conclusion, trabecular bone architecture was similar between T2D and non-T2D donors. Additionally, fabric–elasticity relationships, i.e. morphology-mechanical relationships, are also similar between donors with and without diabetes. Accordingly, HR-p","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101884"},"PeriodicalIF":2.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyperglycemia in diabetes leads to the formation of methylglyoxal (MG) and accumulation of advanced glycation end-products (AGEs). We previously reported that exogenous MG exposure deteriorated osteoblastic differentiation in vitro and diabetic mice showed delayed bone defect healing along with elevated MG-derived AGE levels. However, whether endogenously formed MG is involved in impaired bone repair and remodeling in diabetes remains unclear. In this study, we investigated the effects of hyperglycemia-induced MG formation on bone quality and defect healing in mice. Using a synthetic MG probe [Ir(ppy)2(DA-phen)], we found that endogenous MG formation deteriorated osteoblastic and osteoclastic differentiation under hyperglycemic conditions in cultured cells. In the bone defect site of streptozotocin (STZ)-induced diabetic mice, along with impaired defect healing, we observed elevated endogenous MG levels and downregulation of alkaline phosphatase (ALP) compared with that in non-diabetic control mice; however, these alterations were alleviated by managing blood glucose levels through insulin supplementation. Furthermore, treatment with pyridoxamine (PM), an MG scavenger, ameliorated these impairments by suppressing MG elevation and upregulating the expression of osteocalcin, osteoprotegerin, and osteoclast-associated receptor genes without improving the diabetic status. These findings suggest that endogenously formed MG is detrimental to hyperglycemia-related delayed bone defect healing in type 1 diabetes mellitus (T1DM). Collectively, this study suggests that MG scavenging by PM and suppression of MG formation by glycemic control are potential therapeutic strategies for T1DM-associated bone disorders.
{"title":"Scavenging methylglyoxal improves bone quality and defect healing in diabetic mice","authors":"Toshifumi Hikichi , Kumi Kimura , Seiichi Munesue , Yu Oshima , Ai Harashima , Tomo Hamada , Kanu Shimokawa , Yuki Fushitani , Hisanori Goto , Hiroyuki Tsuchiya , Satoru Demura , Hidenori Matsubara , Yasuhiko Yamamoto","doi":"10.1016/j.bonr.2025.101883","DOIUrl":"10.1016/j.bonr.2025.101883","url":null,"abstract":"<div><div>Hyperglycemia in diabetes leads to the formation of methylglyoxal (MG) and accumulation of advanced glycation end-products (AGEs). We previously reported that exogenous MG exposure deteriorated osteoblastic differentiation in vitro and diabetic mice showed delayed bone defect healing along with elevated MG-derived AGE levels. However, whether endogenously formed MG is involved in impaired bone repair and remodeling in diabetes remains unclear. In this study, we investigated the effects of hyperglycemia-induced MG formation on bone quality and defect healing in mice. Using a synthetic MG probe [Ir(ppy)<sub>2</sub>(DA-phen)], we found that endogenous MG formation deteriorated osteoblastic and osteoclastic differentiation under hyperglycemic conditions in cultured cells. In the bone defect site of streptozotocin (STZ)-induced diabetic mice, along with impaired defect healing, we observed elevated endogenous MG levels and downregulation of alkaline phosphatase (ALP) compared with that in non-diabetic control mice; however, these alterations were alleviated by managing blood glucose levels through insulin supplementation. Furthermore, treatment with pyridoxamine (PM), an MG scavenger, ameliorated these impairments by suppressing MG elevation and upregulating the expression of osteocalcin, osteoprotegerin, and osteoclast-associated receptor genes without improving the diabetic status. These findings suggest that endogenously formed MG is detrimental to hyperglycemia-related delayed bone defect healing in type 1 diabetes mellitus (T1DM). Collectively, this study suggests that MG scavenging by PM and suppression of MG formation by glycemic control are potential therapeutic strategies for T1DM-associated bone disorders.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101883"},"PeriodicalIF":2.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145473900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1016/j.bonr.2025.101882
Ellie H. Northall , Liam M. Grover , Helen M. McGettrick , Matthew Newton Ede , Amy J. Naylor , Simon W. Jones
Adolescent Idiopathic Scoliosis (AIS) is a common paediatric spinal disorder of incompletely understood aetiology. Current interventions include bracing and invasive surgery. However, determining which patients will benefit from observation, bracing, or surgery remains challenging due to the difficulty in predicting disease progression. A number of factors have previously been purported to play a causative role including hormones and biomechanics. However, recently GWAS and in vitro studies have provided insight into the underlying signalling pathways and intrinsic factors that act as drivers of AIS pathology across different tissue types, including spinal bone tissue, paraspinal muscles and cartilage. This review will explore these recent findings and evaluate their links to systemic factors as possible intrinsic drivers underpinning AIS pathophysiology and development.
{"title":"Integrating intrinsic musculoskeletal pathology and genetics: Recent advances in unravelling the causative factors of adolescent idiopathic scoliosis","authors":"Ellie H. Northall , Liam M. Grover , Helen M. McGettrick , Matthew Newton Ede , Amy J. Naylor , Simon W. Jones","doi":"10.1016/j.bonr.2025.101882","DOIUrl":"10.1016/j.bonr.2025.101882","url":null,"abstract":"<div><div>Adolescent Idiopathic Scoliosis (AIS) is a common paediatric spinal disorder of incompletely understood aetiology. Current interventions include bracing and invasive surgery. However, determining which patients will benefit from observation, bracing, or surgery remains challenging due to the difficulty in predicting disease progression. A number of factors have previously been purported to play a causative role including hormones and biomechanics. However, recently GWAS and in vitro studies have provided insight into the underlying signalling pathways and intrinsic factors that act as drivers of AIS pathology across different tissue types, including spinal bone tissue, paraspinal muscles and cartilage. This review will explore these recent findings and evaluate their links to systemic factors as possible intrinsic drivers underpinning AIS pathophysiology and development.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101882"},"PeriodicalIF":2.6,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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