Osteogenesis Imperfecta (OI) is a rare hereditary brittle bone disorder typically caused by COL1A1 and COL1A2 variants impairing type I collagen. However, gross deletions involving COL1A1 are uncommon. Here, we report a family with type I OI harboring a 101-kbp deletion encompassing COL1A1, identified through whole genome analysis. Affected individuals presented mild phenotypes. Breakpoint analysis revealed a 5-bp microhomology-mediated end joining involving an Alu element. This report expands the understanding of genetic mechanisms underlying OI.
{"title":"Osteogenesis Imperfecta with a gross deletion including the COL1A1 gene, induced by Alu-driven microhomology-mediated end joining","authors":"Kenichi Yamamoto , Hirofumi Nakayama , Yusaku Ito , Masaya Hattori , Takaaki Shimada , Ikumi Ueda , Takeshi Ishimi , Chieko Yamada , Yukako Nakano , Makoto Fujiwara , Takuo Kubota , Yasuhisa Ohata , Yasuji Kitabatake","doi":"10.1016/j.bonr.2026.101901","DOIUrl":"10.1016/j.bonr.2026.101901","url":null,"abstract":"<div><div>Osteogenesis Imperfecta (OI) is a rare hereditary brittle bone disorder typically caused by <em>COL1A1</em> and <em>COL1A2</em> variants impairing type I collagen. However, gross deletions involving <em>COL1A1</em> are uncommon. Here, we report a family with type I OI harboring a 101-kbp deletion encompassing <em>COL1A1</em>, identified through whole genome analysis. Affected individuals presented mild phenotypes. Breakpoint analysis revealed a 5-bp microhomology-mediated end joining involving an Alu element. This report expands the understanding of genetic mechanisms underlying OI.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"28 ","pages":"Article 101901"},"PeriodicalIF":2.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073559","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 : 2025-12-01Epub Date: 2025-09-10DOI: 10.1016/j.bonr.2025.101876
Honey Hendesi , Dana A. Godfrey , Ana Ferreira Ruble , Aaron M. Tran , David A. Villani , Samantha H. Landgrave , Nur A. Hasan , Douglas J. Adams , Michael J. Zuscik
Intermittent Fasting (IF) is a dietary strategy with metabolic benefits that can reverse certain obesity-related pathologies. This study aimed to investigate whether IF can mitigate delayed bone fracture healing associated with obesity. Using cohorts of mice on high-fat or control diets, we applied either an ad libitum feeding or an alternate-day fasting regimen to animals from both diet groups. We assessed bone healing outcomes by evaluating callus mineralization and adipocyte accumulation within the callus through micro computed tomography (micro-CT), histology, and immunohistochemical analyses. Since IF is known to modulate gut microbiome composition, often associated with improvement in various metabolic and inflammatory processes, particularly in high-fat-fed mice, we also explored the microbial community changes in IF mice through 16S rRNA sequencing of cecal samples. Metabolically, IF led to reduced body weight and improved glucose tolerance in obese mice. Regarding fracture healing outcomes, reduced/delayed mineralization and adipocyte accumulation in fracture callus tissue in the high-fat-fed cohort were significantly attenuated when the high-fat-fed mice were subjected to alternate-day fasting. These benefits of IF were not observed in lean mice fed a control diet. Furthermore, IF significantly altered the gut microbiota of mice on a high-fat diet, including an increased abundance of short-chain fatty acid producing bacteria, known for their positive effect on bone density, and a reduction in various pro-inflammatory taxa. While the mechanistic role remains unknown, these findings suggest that the improved fracture healing observed in obese mice following IF may be associated with alterations in gut microbiome composition and function.
{"title":"Intermittent fasting alleviates obesity-associated impairments in bone fracture healing: Exploring the role of gut microbiome","authors":"Honey Hendesi , Dana A. Godfrey , Ana Ferreira Ruble , Aaron M. Tran , David A. Villani , Samantha H. Landgrave , Nur A. Hasan , Douglas J. Adams , Michael J. Zuscik","doi":"10.1016/j.bonr.2025.101876","DOIUrl":"10.1016/j.bonr.2025.101876","url":null,"abstract":"<div><div>Intermittent Fasting (IF) is a dietary strategy with metabolic benefits that can reverse certain obesity-related pathologies. This study aimed to investigate whether IF can mitigate delayed bone fracture healing associated with obesity. Using cohorts of mice on high-fat or control diets, we applied either an ad libitum feeding or an alternate-day fasting regimen to animals from both diet groups. We assessed bone healing outcomes by evaluating callus mineralization and adipocyte accumulation within the callus through micro computed tomography (micro-CT), histology, and immunohistochemical analyses. Since IF is known to modulate gut microbiome composition, often associated with improvement in various metabolic and inflammatory processes, particularly in high-fat-fed mice, we also explored the microbial community changes in IF mice through 16S rRNA sequencing of cecal samples. Metabolically, IF led to reduced body weight and improved glucose tolerance in obese mice. Regarding fracture healing outcomes, reduced/delayed mineralization and adipocyte accumulation in fracture callus tissue in the high-fat-fed cohort were significantly attenuated when the high-fat-fed mice were subjected to alternate-day fasting. These benefits of IF were not observed in lean mice fed a control diet. Furthermore, IF significantly altered the gut microbiota of mice on a high-fat diet, including an increased abundance of short-chain fatty acid producing bacteria, known for their positive effect on bone density, and a reduction in various pro-inflammatory taxa. While the mechanistic role remains unknown, these findings suggest that the improved fracture healing observed in obese mice following IF may be associated with alterations in gut microbiome composition and function.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101876"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047410","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 : 2025-12-01Epub 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":"2025-12-01","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}
Pub Date : 2025-12-01Epub Date: 2025-10-06DOI: 10.1016/j.bonr.2025.101879
Charu Jain , Neharika Bhadouria , Justin Tiao , Jonathan J. Huang , Yunsoo Lee , Saad Chaudhary , Andrew C. Hecht , Nilsson Holguin , James C. Iatridis
Background
Human bone quality varies with age and spinal level, with upper lumbar vertebrae more prone to fracture. Mouse studies of bone health often focus on a single lumbar vertebral level and limited regional analysis with no comprehensive study evaluating how sex, lumbar level, vertebral region, and reconstruction method contribute to patterns of age-related vertebral bone loss in mice.
Methods
This micro-computed tomography (μCT) study measured lumbar spinal level- and vertebral region of interest (ROI)-specific patterns of bone quantity, structure, and density in relation to age and sex in mice. Lumbar vertebrae (L1–L6; n = 4/sex/age) from young adult (4-month), middle-aged (12-month), and old (24-month) mice were analyzed for trabecular bone volume fraction (BV/TV), volumetric bone mineral density (vBMD), cortical thickness (Ct.Th), and tissue mineral density (TMD). Parameters were measured for full vertebrae, cranial, middle, and caudal vertebral regions, comparing both 1/3-vertebral and standardized 30-slice reconstruction approaches.
Results
Age was associated with a reduction in vBMD and BV/TV in both sexes, with bone volume, structure, and density most significantly reduced at L1 and cranial vertebral regions. Females exhibited greater declines than males, particularly in BV/TV and vBMD. Ct.Th was the greatest mid-spine but declined with age at L1 and L5. Regional differences were observed for both cortical parameters.
Conclusions
Trabecular bone is affected by age, sex, lumbar level, and vertebral region in mice. The greatest sensitivity to age-related bone loss was detected in the L1 lumbar level and cranial vertebral regions in female mice. These findings highlight the need for region- and method- specific analysis in bone research and exhibit age-related changes in vertebrate by level and region that exhibit similarities to humans.
人的骨骼质量随年龄和脊柱水平而变化，上腰椎更容易骨折。对小鼠骨骼健康的研究通常集中在单个腰椎水平和有限的区域分析上，没有全面的研究来评估性别、腰椎水平、椎体区域和重建方法如何影响小鼠年龄相关的椎体骨质流失模式。方法微计算机断层扫描（μCT）研究测量了小鼠腰椎水平和椎体感兴趣区（ROI）特异性骨数量、结构和密度与年龄和性别的关系。对年轻成年（4个月）、中年（12个月）和老年（24个月）小鼠腰椎（L1-L6, n = 4/性别/年龄）进行骨小梁体积分数（BV/TV）、体积骨矿物质密度（vBMD）、皮质厚度(Ct。Th)和组织矿物质密度（TMD）。测量全椎体、颅骨、中段和尾椎区域的参数，比较1/3椎体和标准化30层重建方法。结果年龄与男女vBMD和BV/TV的降低有关，L1和颅椎区的骨体积、结构和密度降低最为显著。女性表现出比男性更大的下降，尤其是BV/TV和vBMD。Ct。腰椎中部最大，但随着L1和L5年龄的增长而下降。两种皮质参数均存在区域差异。结论小鼠的骨梁受年龄、性别、腰椎水平和椎体区域的影响。在雌性小鼠中，L1腰椎水平和颅椎区域对年龄相关的骨质流失最敏感。这些发现强调了在骨骼研究中对区域和方法进行特定分析的必要性，并展示了脊椎动物在水平和区域上与人类相似的年龄相关变化。
{"title":"Age-related bone loss in mouse lumbar vertebrae is affected by region, sex, and level: Implications for spinal loading and analysis methods","authors":"Charu Jain , Neharika Bhadouria , Justin Tiao , Jonathan J. Huang , Yunsoo Lee , Saad Chaudhary , Andrew C. Hecht , Nilsson Holguin , James C. Iatridis","doi":"10.1016/j.bonr.2025.101879","DOIUrl":"10.1016/j.bonr.2025.101879","url":null,"abstract":"<div><h3>Background</h3><div>Human bone quality varies with age and spinal level, with upper lumbar vertebrae more prone to fracture. Mouse studies of bone health often focus on a single lumbar vertebral level and limited regional analysis with no comprehensive study evaluating how sex, lumbar level, vertebral region, and reconstruction method contribute to patterns of age-related vertebral bone loss in mice.</div></div><div><h3>Methods</h3><div>This micro-computed tomography (μCT) study measured lumbar spinal level- and vertebral region of interest (ROI)-specific patterns of bone quantity, structure, and density in relation to age and sex in mice. Lumbar vertebrae (L1–L6; <em>n</em> = 4/sex/age) from young adult (4-month), middle-aged (12-month), and old (24-month) mice were analyzed for trabecular bone volume fraction (BV/TV), volumetric bone mineral density (vBMD), cortical thickness (Ct.Th), and tissue mineral density (TMD). Parameters were measured for full vertebrae, cranial, middle, and caudal vertebral regions, comparing both 1/3-vertebral and standardized 30-slice reconstruction approaches.</div></div><div><h3>Results</h3><div>Age was associated with a reduction in vBMD and BV/TV in both sexes, with bone volume, structure, and density most significantly reduced at L1 and cranial vertebral regions. Females exhibited greater declines than males, particularly in BV/TV and vBMD. Ct.Th was the greatest mid-spine but declined with age at L1 and L5. Regional differences were observed for both cortical parameters.</div></div><div><h3>Conclusions</h3><div>Trabecular bone is affected by age, sex, lumbar level, and vertebral region in mice. The greatest sensitivity to age-related bone loss was detected in the L1 lumbar level and cranial vertebral regions in female mice. These findings highlight the need for region- and method- specific analysis in bone research and exhibit age-related changes in vertebrate by level and region that exhibit similarities to humans.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101879"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145263211","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 : 2025-12-01Epub Date: 2025-09-06DOI: 10.1016/j.bonr.2025.101877
Guido Filler , Harry Chandrakumaran , Funmbi Babalola , Dougenie Emile , Shih-Han Susan Huang , Robert Stein
Background
Burosumab, a monoclonal antibody to fibroblast growth factor 23 (FGF23), is effective for X-linked hypophosphatemic rickets (XLH). Renal effects, particularly calciuria and nephrocalcinosis, remain incompletely characterized.
Methods
In this retrospective cohort, 13 children with genetically confirmed XLH (7 females, 6 males; 0.6–16.3 years) were evaluated after conversion from conventional therapy to burosumab. Longitudinal changes in serum phosphate, TmP/GFR, TRP, 1,25(OH)₂D, intact parathyroid hormone (PTH), and urinary calcium/creatinine (Ca:Cr) were assessed. Hypercalciuria was defined using age-specific SI thresholds; Ca:Cr was also expressed as ×ULN (Ca:Cr divided by the age-specific upper limit).
Results
Burosumab improved serum phosphate (p < 0.001), TmP/GFR (p < 0.001), and TRP (p = 0.007). Despite normalized phosphate handling, two patients developed de novo nephrocalcinosis. No child was hypercalciuric at washout or Day 14; two had ≥1 episode later. A repeated-measures analysis of log10(×ULN) showed no overall time effect from washout to Day 56 (F(4,29) = 1.66, p = 0.185). A larger decline in PTH correlated with higher Ca:Cr (p < 0.05), whereas 1,25(OH)₂D did not.
Conclusion
Burosumab improves phosphate homeostasis in children with XLH, but a minority may develop hypercalciuria and nephrocalcinosis, potentially linked to PTH suppression. Vigilant biochemical and ultrasound monitoring—particularly early after conversion—and consideration of prophylaxis in high-risk cases are advisable.
{"title":"Effect of burosumab conversion on calciuria and nephrocalcinosis in children with XLH: A real-world cohort study","authors":"Guido Filler , Harry Chandrakumaran , Funmbi Babalola , Dougenie Emile , Shih-Han Susan Huang , Robert Stein","doi":"10.1016/j.bonr.2025.101877","DOIUrl":"10.1016/j.bonr.2025.101877","url":null,"abstract":"<div><h3>Background</h3><div>Burosumab, a monoclonal antibody to fibroblast growth factor 23 (FGF23), is effective for X-linked hypophosphatemic rickets (XLH). Renal effects, particularly calciuria and nephrocalcinosis, remain incompletely characterized.</div></div><div><h3>Methods</h3><div>In this retrospective cohort, 13 children with genetically confirmed XLH (7 females, 6 males; 0.6–16.3 years) were evaluated after conversion from conventional therapy to burosumab. Longitudinal changes in serum phosphate, TmP/GFR, TRP, 1,25(OH)₂D, intact parathyroid hormone (PTH), and urinary calcium/creatinine (Ca:Cr) were assessed. Hypercalciuria was defined using age-specific SI thresholds; Ca:Cr was also expressed as ×ULN (Ca:Cr divided by the age-specific upper limit).</div></div><div><h3>Results</h3><div>Burosumab improved serum phosphate (<em>p</em> < 0.001), TmP/GFR (p < 0.001), and TRP (<em>p</em> = 0.007). Despite normalized phosphate handling, two patients developed de novo nephrocalcinosis. No child was hypercalciuric at washout or Day 14; two had ≥1 episode later. A repeated-measures analysis of log10(×ULN) showed no overall time effect from washout to Day 56 (F(4,29) = 1.66, <em>p</em> = 0.185). A larger decline in PTH correlated with higher Ca:Cr (<em>p</em> < 0.05), whereas 1,25(OH)₂D did not.</div></div><div><h3>Conclusion</h3><div>Burosumab improves phosphate homeostasis in children with XLH, but a minority may develop hypercalciuria and nephrocalcinosis, potentially linked to PTH suppression. Vigilant biochemical and ultrasound monitoring—particularly early after conversion—and consideration of prophylaxis in high-risk cases are advisable.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101877"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145107001","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-11-26DOI: 10.1016/j.bonr.2025.101890
David Castro Corredor , Luis Ángel Calvo Pascual
Objective
To evaluate the real-world effectiveness of Romosozumab in postmenopausal women with severe osteoporosis and to identify baseline clinical and biochemical predictors of clinically meaningful bone mineral density (BMD) gains (≥10 %, used for exploratory classification) using an explainable machine-learning approach.
Methods
We conducted a retrospective, observational multicentre study across seven hospitals in Castilla-La Mancha, Spain. Postmenopausal women aged ≥50 years who initiated romosozumab between May 2023 and November 2024 for severe osteoporosis or high fracture risk were included. Lumbar-spine, femoral-neck, and total-hip BMD were assessed by dual-energy X-ray absorptiometry (DXA) at baseline and 12 months. Baseline biochemical variables included serum P1NP, CTX, PTH, vitamin D, calcium, phosphate, alkaline phosphatase, and creatinine. Predictors of a ≥ 10 % BMD gain were examined using elastic-net logistic regression combined with SHapley Additive exPlanations (SHAP) for model interpretability.
Results
Fifty-eight women were analysed (mean ± SD age 71.7 ± 10.0 years; BMI 26.1 ± 4.8 kg/m2; mean age at menopause 47.3 ± 6.0 years). Mean 12-month BMD increases were + 15,35 % at the lumbar spine, +12,42 % at the femoral neck, and + 8,62 % at the total hip. The proportion achieving a ≥ 10 % gain was 39 %, 38.1 %, and 31.7 %, respectively. SHAP analysis identified consistent predictors of response: lower baseline BMD, higher phosphate levels, and younger age at menopause were associated with greater gains, whereas elevated PTH and alkaline phosphatase predicted a reduced response. Patients who had not received corticosteroids or NSAIDs in the six months prior to treatment initiation, typically for pain or inflammation, also showed greater increases in BMD.
Conclusions
Romosozumab was effective and well-tolerated in routine clinical practice, yielding meaningful and site-specific gains in BMD. Explainable machine-learning analysis identified physiologically coherent and consistent clinical predictors of ≥10 % response.
{"title":"Predictors of clinically meaningful bone mineral density gains with romosozumab: An explainable machine leaning analysis of a real-world cohort","authors":"David Castro Corredor , Luis Ángel Calvo Pascual","doi":"10.1016/j.bonr.2025.101890","DOIUrl":"10.1016/j.bonr.2025.101890","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the real-world effectiveness of Romosozumab in postmenopausal women with severe osteoporosis and to identify baseline clinical and biochemical predictors of clinically meaningful bone mineral density (BMD) gains (≥10 %, used for exploratory classification) using an explainable machine-learning approach.</div></div><div><h3>Methods</h3><div>We conducted a retrospective, observational multicentre study across seven hospitals in Castilla-La Mancha, Spain. Postmenopausal women aged ≥50 years who initiated romosozumab between May 2023 and November 2024 for severe osteoporosis or high fracture risk were included. Lumbar-spine, femoral-neck, and total-hip BMD were assessed by dual-energy X-ray absorptiometry (DXA) at baseline and 12 months. Baseline biochemical variables included serum P1NP, CTX, PTH, vitamin D, calcium, phosphate, alkaline phosphatase, and creatinine. Predictors of a ≥ 10 % BMD gain were examined using elastic-net logistic regression combined with SHapley Additive exPlanations (SHAP) for model interpretability.</div></div><div><h3>Results</h3><div>Fifty-eight women were analysed (mean ± SD age 71.7 ± 10.0 years; BMI 26.1 ± 4.8 kg/m<sup>2</sup>; mean age at menopause 47.3 ± 6.0 years). Mean 12-month BMD increases were + 15,35 % at the lumbar spine, +12,42 % at the femoral neck, and + 8,62 % at the total hip. The proportion achieving a ≥ 10 % gain was 39 %, 38.1 %, and 31.7 %, respectively. SHAP analysis identified consistent predictors of response: lower baseline BMD, higher phosphate levels, and younger age at menopause were associated with greater gains, whereas elevated PTH and alkaline phosphatase predicted a reduced response. Patients who had not received corticosteroids or NSAIDs in the six months prior to treatment initiation, typically for pain or inflammation, also showed greater increases in BMD.</div></div><div><h3>Conclusions</h3><div>Romosozumab was effective and well-tolerated in routine clinical practice, yielding meaningful and site-specific gains in BMD. Explainable machine-learning analysis identified physiologically coherent and consistent clinical predictors of ≥10 % response.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101890"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620177","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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-11-28DOI: 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}
Pub Date : 2025-12-01Epub 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":"2025-12-01","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}
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