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Decoding fracture healing: A scoping review of mechanistic pathways derived from transcriptional analysis in murine studies
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/j.bone.2025.117444
Nazanin Nafisi , Ahmad Hedayatzadeh Razavi , Mohammad Javad Shariyate , Maria V. Velasquez , Mohammad Khak , David Manoukian , Arthur Klujian , Hamid Mirzamohammadi , Tom Cummiskey , Mahboubeh R. Rostami , Fatemeh Mirzamohammadi , Ara Nazarian
Fracture healing is a complex biological process involving orchestrated interactions among cells, growth factors, and transcriptional pathways. Despite significant advancements in understanding bone repair, non-union and delayed healing remain prevalent, especially in patients with comorbidities such as aging, diabetes, or substance use. Murine models serve as a cornerstone in fracture healing research, offering genetic manipulability, cost-effectiveness, and biological relevance to humans. This scoping review consolidates findings from studies conducted between 2010 and 2024, focusing on mechanistic pathways derived from transcriptional analysis in secondary bone healing as identified through bulk RNA sequencing of murine models.
Key mechanistic pathways were categorized and analyzed across the distinct phases of fracture healing—reactive, reparative, and remodeling—highlighting their unique roles in inflammation, ECM remodeling, cell proliferation, and tissue mineralization. The most recurrent mechanistic pathways included ECM-receptor interaction, focal adhesion, and signaling mechanisms such as MAPK and TGF-beta. Variability in methodologies and limited overlap among studies underscore the need for standardized protocols in RNA sequencing analysis. Additionally, comparisons across long bone fractures, hole defects, and craniofacial bone healing revealed shared molecular mechanisms alongside unique challenges, particularly in craniofacial models.
This scoping review underscores the promise of integrating systems biology approaches with transcriptomic data to elucidate the intricate regulatory networks governing fracture repair. Addressing the identified gaps in early-phase healing and harmonizing research methodologies will advance therapeutic strategies to reduce non-union rates and improve clinical outcomes.
{"title":"Decoding fracture healing: A scoping review of mechanistic pathways derived from transcriptional analysis in murine studies","authors":"Nazanin Nafisi ,&nbsp;Ahmad Hedayatzadeh Razavi ,&nbsp;Mohammad Javad Shariyate ,&nbsp;Maria V. Velasquez ,&nbsp;Mohammad Khak ,&nbsp;David Manoukian ,&nbsp;Arthur Klujian ,&nbsp;Hamid Mirzamohammadi ,&nbsp;Tom Cummiskey ,&nbsp;Mahboubeh R. Rostami ,&nbsp;Fatemeh Mirzamohammadi ,&nbsp;Ara Nazarian","doi":"10.1016/j.bone.2025.117444","DOIUrl":"10.1016/j.bone.2025.117444","url":null,"abstract":"<div><div>Fracture healing is a complex biological process involving orchestrated interactions among cells, growth factors, and transcriptional pathways. Despite significant advancements in understanding bone repair, non-union and delayed healing remain prevalent, especially in patients with comorbidities such as aging, diabetes, or substance use. Murine models serve as a cornerstone in fracture healing research, offering genetic manipulability, cost-effectiveness, and biological relevance to humans. This scoping review consolidates findings from studies conducted between 2010 and 2024, focusing on mechanistic pathways derived from transcriptional analysis in secondary bone healing as identified through bulk RNA sequencing of murine models.</div><div>Key mechanistic pathways were categorized and analyzed across the distinct phases of fracture healing—reactive, reparative, and remodeling—highlighting their unique roles in inflammation, ECM remodeling, cell proliferation, and tissue mineralization. The most recurrent mechanistic pathways included ECM-receptor interaction, focal adhesion, and signaling mechanisms such as MAPK and TGF-beta. Variability in methodologies and limited overlap among studies underscore the need for standardized protocols in RNA sequencing analysis. Additionally, comparisons across long bone fractures, hole defects, and craniofacial bone healing revealed shared molecular mechanisms alongside unique challenges, particularly in craniofacial models.</div><div>This scoping review underscores the promise of integrating systems biology approaches with transcriptomic data to elucidate the intricate regulatory networks governing fracture repair. Addressing the identified gaps in early-phase healing and harmonizing research methodologies will advance therapeutic strategies to reduce non-union rates and improve clinical outcomes.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117444"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544755","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}
引用次数: 0
Accuracy and precision of segmentation and quantification of wrist bone microarchitecture using photon-counting computed tomography ex vivo
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/j.bone.2025.117443
Jilmen Quintiens , Sarah L. Manske , Steven K. Boyd , Walter Coudyzer , Melissa Bevers , Evie Vereecke , Joop van den Bergh , G. Harry van Lenthe
<div><div>The quantification of bone microarchitecture provides insight into bone health and the effects of disease or treatment, and is therefore highly relevant clinical information. Nonetheless, in vivo quantification of bone microarchitecture is mostly limited to high-resolution peripheral quantitative CT (HR-pQCT). This is a small field of view CT modality of which the gantry size only allows scanning of distal radius and tibia. Photon-counting CT (PCCT) is a novel clinical full-body CT with improved image resolution and quality compared to other clinical CT modalities, yet data on its capabilities in quantifying bone microarchitecture are limited. The aim of this study was to quantify the accuracy of two methods for trabecular bone segmentation on PCCT images as compared to the segmentations on micro-CT (μCT) and to use these segmentations to quantify the accuracy and agreement of trabecular bone morphometry measurements as compared to μCT, as well as the short-term precision.</div><div>This study analysed multimodal CT data, obtained from eight cadaveric forearms; the data includes two repeated PCCT scans, as well as a single HR-pQCT scan from the forearm, and μCT scans of all individual carpal bones. For each carpal bone, trabecular volumes of interest (VOI) were delineated on the μCT images, and the μCT reference segmentations and VOIs were resampled onto the PCCT and HR-pQCT images. HR-pQCT images were segmented with a global threshold of 320 mgHA/cm<sup>3</sup>; PCCT images were segmented with either an identical global threshold or with an adaptive thresholding algorithm. Trabecular bone-volume fraction (Tb.BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) were quantified for all segmented VOIs. Accuracy and agreement were calculated relative to μCT as the gold standard, short-term precision was calculated from the repeated PCCT scan.</div><div>For PCCT, adaptive threshold segmentation had significantly increased sensitivity compared to global threshold segmentation, along with a lower variance in its sensitivity and specificity. Concerning the microarchitecture quantification, for global threshold segmentation of PCCT images, correlations with μCT were significant, except for Tb.Sp. Correlation coefficients of Tb.BV/TV and Tb.N were not significantly different from those between HR-pQCT and μCT. Adaptive threshold segmentation led to higher correlation coefficients between PCCT and μCT of Tb.Th, Tb.N and Tb.Sp, although correlations of Tb.N remained poor for both PCCT and HR-pQCT. Moreover, adaptive thresholding led to a constant bias of Tb.BV/TV, Tb.Th and Tb.Sp, unlike the bias of HR-pQCT which was proportionally increasing with the size of the measurement. Finally, adaptive threshold segmentation led to a higher short-term precision than global threshold segmentation, with a root-mean-squared coefficient of variation below 0.65 % for all parameters.</div><div>We conclude that adaptive
{"title":"Accuracy and precision of segmentation and quantification of wrist bone microarchitecture using photon-counting computed tomography ex vivo","authors":"Jilmen Quintiens ,&nbsp;Sarah L. Manske ,&nbsp;Steven K. Boyd ,&nbsp;Walter Coudyzer ,&nbsp;Melissa Bevers ,&nbsp;Evie Vereecke ,&nbsp;Joop van den Bergh ,&nbsp;G. Harry van Lenthe","doi":"10.1016/j.bone.2025.117443","DOIUrl":"10.1016/j.bone.2025.117443","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The quantification of bone microarchitecture provides insight into bone health and the effects of disease or treatment, and is therefore highly relevant clinical information. Nonetheless, in vivo quantification of bone microarchitecture is mostly limited to high-resolution peripheral quantitative CT (HR-pQCT). This is a small field of view CT modality of which the gantry size only allows scanning of distal radius and tibia. Photon-counting CT (PCCT) is a novel clinical full-body CT with improved image resolution and quality compared to other clinical CT modalities, yet data on its capabilities in quantifying bone microarchitecture are limited. The aim of this study was to quantify the accuracy of two methods for trabecular bone segmentation on PCCT images as compared to the segmentations on micro-CT (μCT) and to use these segmentations to quantify the accuracy and agreement of trabecular bone morphometry measurements as compared to μCT, as well as the short-term precision.&lt;/div&gt;&lt;div&gt;This study analysed multimodal CT data, obtained from eight cadaveric forearms; the data includes two repeated PCCT scans, as well as a single HR-pQCT scan from the forearm, and μCT scans of all individual carpal bones. For each carpal bone, trabecular volumes of interest (VOI) were delineated on the μCT images, and the μCT reference segmentations and VOIs were resampled onto the PCCT and HR-pQCT images. HR-pQCT images were segmented with a global threshold of 320 mgHA/cm&lt;sup&gt;3&lt;/sup&gt;; PCCT images were segmented with either an identical global threshold or with an adaptive thresholding algorithm. Trabecular bone-volume fraction (Tb.BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) were quantified for all segmented VOIs. Accuracy and agreement were calculated relative to μCT as the gold standard, short-term precision was calculated from the repeated PCCT scan.&lt;/div&gt;&lt;div&gt;For PCCT, adaptive threshold segmentation had significantly increased sensitivity compared to global threshold segmentation, along with a lower variance in its sensitivity and specificity. Concerning the microarchitecture quantification, for global threshold segmentation of PCCT images, correlations with μCT were significant, except for Tb.Sp. Correlation coefficients of Tb.BV/TV and Tb.N were not significantly different from those between HR-pQCT and μCT. Adaptive threshold segmentation led to higher correlation coefficients between PCCT and μCT of Tb.Th, Tb.N and Tb.Sp, although correlations of Tb.N remained poor for both PCCT and HR-pQCT. Moreover, adaptive thresholding led to a constant bias of Tb.BV/TV, Tb.Th and Tb.Sp, unlike the bias of HR-pQCT which was proportionally increasing with the size of the measurement. Finally, adaptive threshold segmentation led to a higher short-term precision than global threshold segmentation, with a root-mean-squared coefficient of variation below 0.65 % for all parameters.&lt;/div&gt;&lt;div&gt;We conclude that adaptive","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117443"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544751","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}
引用次数: 0
Novel estrogen receptor-α gene inactivating missense variant in a woman: Therapeutic challenge and long-term follow-up data 一名女性体内的新型雌激素受体-α基因失活错义变异:治疗挑战和长期随访数据
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/j.bone.2025.117427
Eva Feigerlova

Background

Rare mutations of the ESR1 gene, encoding the estrogen receptor alpha (ERα), have been shown to cause estrogen resistance in humans. Phenotypic features include impaired maturation of epiphyseal cartilage, osteoporosis, and infertility. Clinical phenotype is not well described and the available data reflect inconsistency. To date, there are no effective therapeutic options.

Method

This retrospective study provides a detailed description of bone and metabolic phenotype and 8-year follow-up data of a female with a novel p.Met543Thr missense variant in the homozygous state, localized in the ligand-binding domain.

Results

The patient, first seen at the age of 21.3 years, presented with a tall stature (+2.2 SD), a delayed bone age (13 years). She had no breast development, normal axillary and pubic pilosity and bilateral axillary acanthosis nigricans. The metabolic phenotype included insulin resistance, decreased insulin sensitivity and increased leptinemia. The patient presented a continuous linear growth (height + 3SD at the age of 28.6 years). She had a severe osteoporosis of the lumbar spine (Z-score −3.9) and osteopenia of the femoral neck (Z-score −1.8). Osteoporosis worsened (Z-score −5.6 at the lumbar spine; Z-score −4.4 at the femoral neck) despite successive treatments with ethinyl-estradiol and tamoxifen (selective estrogen modulator). Markers of bone turnover were increased and unresponsive to treatment. Treatment with ethinyl-estradiol improved insulin sensitivity, lowered leptinemia, increased some estrogen-regulated liver proteins and the E2/T ratio.

Conclusion

This report brings new insights to the estrogen resistance syndrome and improves our understanding of the skeletal and tissue specific roles of ERα in humans.
{"title":"Novel estrogen receptor-α gene inactivating missense variant in a woman: Therapeutic challenge and long-term follow-up data","authors":"Eva Feigerlova","doi":"10.1016/j.bone.2025.117427","DOIUrl":"10.1016/j.bone.2025.117427","url":null,"abstract":"<div><h3>Background</h3><div>Rare mutations of the <em>ESR1</em> gene, encoding the estrogen receptor alpha (ERα), have been shown to cause estrogen resistance in humans. Phenotypic features include impaired maturation of epiphyseal cartilage, osteoporosis, and infertility. Clinical phenotype is not well described and the available data reflect inconsistency. To date, there are no effective therapeutic options.</div></div><div><h3>Method</h3><div>This retrospective study provides a detailed description of bone and metabolic phenotype and 8-year follow-up data of a female with a novel p.Met543Thr missense variant in the homozygous state, localized in the ligand-binding domain.</div></div><div><h3>Results</h3><div>The patient, first seen at the age of 21.3 years, presented with a tall stature (+2.2 SD), a delayed bone age (13 years). She had no breast development, normal axillary and pubic pilosity and bilateral axillary acanthosis nigricans. The metabolic phenotype included insulin resistance, decreased insulin sensitivity and increased leptinemia. The patient presented a continuous linear growth (height + 3SD at the age of 28.6 years). She had a severe osteoporosis of the lumbar spine (<em>Z</em>-score −3.9) and osteopenia of the femoral neck (Z-score −1.8). Osteoporosis worsened (Z-score −5.6 at the lumbar spine; Z-score −4.4 at the femoral neck) despite successive treatments with ethinyl-estradiol and tamoxifen (selective estrogen modulator). Markers of bone turnover were increased and unresponsive to treatment. Treatment with ethinyl-estradiol improved insulin sensitivity, lowered leptinemia, increased some estrogen-regulated liver proteins and the E2/T ratio.</div></div><div><h3>Conclusion</h3><div>This report brings new insights to the estrogen resistance syndrome and improves our understanding of the skeletal and tissue specific roles of ERα in humans.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117427"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528703","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}
引用次数: 0
RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice RANKL 衍生肽 MHP1-AcN 通过靶向 RANK 和 TNFR1 减轻小鼠卵巢切除术诱发的骨质疏松症
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/j.bone.2025.117440
Takuya Kurihara , Munehisa Shimamura , Yuki Etani , Takaaki Noguchi , Yuji Fukuda , Nagahiro Ochiai , Atsushi Goshima , Taihei Miura , Makoto Hirao , Atsushi Sugimoto , Nan Ju , Satoshi Yamakawa , Takashi Kanamoto , Ken Nakata , Seiji Okada , Kosuke Ebina

Purpose

Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin expression in osteocytes, thereby inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis.

Methods

We developed microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), a modified RANKL peptide with N-terminal acetylation and C-terminal amidation lacking the osteoclast activating CD loop. Given the structural similarities of RANK and TNF receptor 1 (TNFR1), we hypothesized that MHP1-AcN could inhibit both the RANKL–RANK and TNFα–TNFR1 pathways to address the pathophysiology of osteoporosis, as evaluated in vitro and in vivo using an ovariectomized mouse model.

Results

In ovariectomized mice, MHP1-AcN inhibited osteoclastogenesis, reduced osteocytic sclerostin expression, prevented bone loss, and improved the femoral cancellous and cortical bone microarchitecture. Unlike anti-RANKL antibody, MHP1-AcN considerably preserved bone formation by osteoblasts and enhanced bone strength, as evidenced by increases in energy absorption capacity. In vitro, MHP1-AcN bound to both RANK and TNFR1, suppressing osteoclast activity via the RANKL–RANK pathway and reducing sclerostin expression through the TNFα–TNFR1–nuclear factor-kappa B pathway. MHP1-AcN did not affect osteoblast proliferation and differentiation or RANKL expression.

Conclusion

MHP1-AcN effectively inhibits osteoclastogenesis and sclerostin-mediated suppression of bone formation while considerably preserving osteoblast function. These findings suggest that MHP1-AcN, which targets dual pathways critical for bone homeostasis, is a promising uncoupling therapeutic agent for osteoporosis.
{"title":"RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice","authors":"Takuya Kurihara ,&nbsp;Munehisa Shimamura ,&nbsp;Yuki Etani ,&nbsp;Takaaki Noguchi ,&nbsp;Yuji Fukuda ,&nbsp;Nagahiro Ochiai ,&nbsp;Atsushi Goshima ,&nbsp;Taihei Miura ,&nbsp;Makoto Hirao ,&nbsp;Atsushi Sugimoto ,&nbsp;Nan Ju ,&nbsp;Satoshi Yamakawa ,&nbsp;Takashi Kanamoto ,&nbsp;Ken Nakata ,&nbsp;Seiji Okada ,&nbsp;Kosuke Ebina","doi":"10.1016/j.bone.2025.117440","DOIUrl":"10.1016/j.bone.2025.117440","url":null,"abstract":"<div><h3>Purpose</h3><div>Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin expression in osteocytes, thereby inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis.</div></div><div><h3>Methods</h3><div>We developed microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), a modified RANKL peptide with N-terminal acetylation and C-terminal amidation lacking the osteoclast activating CD loop. Given the structural similarities of RANK and TNF receptor 1 (TNFR1), we hypothesized that MHP1-AcN could inhibit both the RANKL–RANK and TNFα–TNFR1 pathways to address the pathophysiology of osteoporosis, as evaluated in vitro and in vivo using an ovariectomized mouse model.</div></div><div><h3>Results</h3><div>In ovariectomized mice, MHP1-AcN inhibited osteoclastogenesis, reduced osteocytic sclerostin expression, prevented bone loss, and improved the femoral cancellous and cortical bone microarchitecture. Unlike anti-RANKL antibody, MHP1-AcN considerably preserved bone formation by osteoblasts and enhanced bone strength, as evidenced by increases in energy absorption capacity. In vitro, MHP1-AcN bound to both RANK and TNFR1, suppressing osteoclast activity via the RANKL–RANK pathway and reducing sclerostin expression through the TNFα–TNFR1–nuclear factor-kappa B pathway. MHP1-AcN did not affect osteoblast proliferation and differentiation or RANKL expression.</div></div><div><h3>Conclusion</h3><div>MHP1-AcN effectively inhibits osteoclastogenesis and sclerostin-mediated suppression of bone formation while considerably preserving osteoblast function. These findings suggest that MHP1-AcN, which targets dual pathways critical for bone homeostasis, is a promising uncoupling therapeutic agent for osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117440"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the dynamics of osteoblast differentiation in MC3T3-E1 cells: Transcriptomic insights into matrix mineralization and cell proliferation 揭示 MC3T3-E1 细胞成骨细胞分化的动态过程:从转录组深入了解基质矿化和细胞增殖
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/j.bone.2025.117442
Heein Yoon , Seung Gwa Park , Hye-Rim Shin , Ki-Tae Kim , Young-Dan Cho , Jae-I Moon , Woo-Jin Kim , Hyun-Mo Ryoo
Unraveling the intricacies of osteoblast differentiation is crucial for advancing our comprehension of bone biology. This study investigated the complicated molecular events orchestrating osteoblast differentiation in MC3T3-E1 cells, a well-established in vitro culture model. Employing longitudinal RNA-sequencing analysis, we explored transcriptomic changes at the pivotal time points of 0, 1, 4, 7, 10, 14, and 21 days and categorized osteogenic differentiation into proliferation, matrix maturation, and mineralization stages. Notably, we observed a simultaneous increase in matrix mineralization and cell proliferation during the mineralization stage, accompanied by a positive correlation between proliferation-associated genes and those enriched in ossification. Additionally, we identified the presence of proliferating cells over the mineralizing matrix layers. These results could serve as a model for understanding the principles by which bone lining cells are formed on the calcified bone matrix and the mechanism by which new osteoblasts are recruited during the bone remodeling process.
{"title":"Unraveling the dynamics of osteoblast differentiation in MC3T3-E1 cells: Transcriptomic insights into matrix mineralization and cell proliferation","authors":"Heein Yoon ,&nbsp;Seung Gwa Park ,&nbsp;Hye-Rim Shin ,&nbsp;Ki-Tae Kim ,&nbsp;Young-Dan Cho ,&nbsp;Jae-I Moon ,&nbsp;Woo-Jin Kim ,&nbsp;Hyun-Mo Ryoo","doi":"10.1016/j.bone.2025.117442","DOIUrl":"10.1016/j.bone.2025.117442","url":null,"abstract":"<div><div>Unraveling the intricacies of osteoblast differentiation is crucial for advancing our comprehension of bone biology. This study investigated the complicated molecular events orchestrating osteoblast differentiation in MC3T3-E1 cells, a well-established in vitro culture model. Employing longitudinal RNA-sequencing analysis, we explored transcriptomic changes at the pivotal time points of 0, 1, 4, 7, 10, 14, and 21 days and categorized osteogenic differentiation into proliferation, matrix maturation, and mineralization stages. Notably, we observed a simultaneous increase in matrix mineralization and cell proliferation during the mineralization stage, accompanied by a positive correlation between proliferation-associated genes and those enriched in ossification. Additionally, we identified the presence of proliferating cells over the mineralizing matrix layers. These results could serve as a model for understanding the principles by which bone lining cells are formed on the calcified bone matrix and the mechanism by which new osteoblasts are recruited during the bone remodeling process.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117442"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528704","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}
引用次数: 0
Human cortical bone intrinsic permeability distribution based on 3D canalicular morphology
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-28 DOI: 10.1016/j.bone.2025.117441
Remy Gauthier , Hélène Follet , Cécile Olivier , Thibault Lemaire , David Mitton , Francoise Peyrin
Bone permeability is a key parameter that drives osteocyte-based mechanobiological modelling and remodelling. While previous experimental and numerical studies have estimated bone permeability based on the morphology of the lacuno-canalicular network, these studies often relied on simplified geometries. In the current study, bone permeability was characterized using more realistic canalicular geometry for the morphological data. Bone samples harvested from 27 human femoral bones were investigated using synchrotron radiation-based nano-computed tomography with a voxel size of 100 nm. After segmenting the canaliculi and lacunae, each canaliculus was investigated individually by applying a distance map and watershed algorithms. Bone permeability based on canalicular morphology was then assessed using the Kozeny relation, which defines the permeability of a porous medium with capillary-like pores. An averaged intrinsic permeability value of 8.8 10−18 m2 was obtained. It should be noted that this study considered an empty canalicular network, however in vivo, both cellular and peri-cellular matrices decrease space for interstitial fluid flow and thus permeability. Furthermore, a voxel size of 100 nm does not allow for the detection of smaller canaliculi, which may also modify average permeability. With the current data set and the analytic process applied, the results showed a heterogeneous permeability distribution within bone tissue, both when comparing osteonal and interstitial tissues and within an individual osteon. A difference was observed between male and female samples, and permeability appeared to significantly decrease with age. Finally, a significant correlation was found between permeability and canalicular length density, defined as canalicular length per unit bone volume. This study proposes a new form of the Kozeny law to express bone canalicular permeability as a proportional relationship with the canalicular length density. Importantly, this parameter can be directly quantified through confocal fluorescence microcopy, which is more convenient than synchrotron radiation-based nano-computed tomography. In conclusion, the current study confirms that confocal microscopy can be serve as a reliable tool to estimate bone permeability. However, the permeability values calculated here are solely based on canalicular morphology and do not consider cellular and peri-cellular intra-canalicular features.
{"title":"Human cortical bone intrinsic permeability distribution based on 3D canalicular morphology","authors":"Remy Gauthier ,&nbsp;Hélène Follet ,&nbsp;Cécile Olivier ,&nbsp;Thibault Lemaire ,&nbsp;David Mitton ,&nbsp;Francoise Peyrin","doi":"10.1016/j.bone.2025.117441","DOIUrl":"10.1016/j.bone.2025.117441","url":null,"abstract":"<div><div>Bone permeability is a key parameter that drives osteocyte-based mechanobiological modelling and remodelling. While previous experimental and numerical studies have estimated bone permeability based on the morphology of the lacuno-canalicular network, these studies often relied on simplified geometries. In the current study, bone permeability was characterized using more realistic canalicular geometry for the morphological data. Bone samples harvested from 27 human femoral bones were investigated using synchrotron radiation-based nano-computed tomography with a voxel size of 100 nm. After segmenting the canaliculi and lacunae, each canaliculus was investigated individually by applying a distance map and watershed algorithms. Bone permeability based on canalicular morphology was then assessed using the Kozeny relation, which defines the permeability of a porous medium with capillary-like pores. An averaged intrinsic permeability value of 8.8 10<sup>−18</sup> m<sup>2</sup> was obtained. It should be noted that this study considered an empty canalicular network, however <em>in vivo</em>, both cellular and peri-cellular matrices decrease space for interstitial fluid flow and thus permeability. Furthermore, a voxel size of 100 nm does not allow for the detection of smaller canaliculi, which may also modify average permeability. With the current data set and the analytic process applied, the results showed a heterogeneous permeability distribution within bone tissue, both when comparing osteonal and interstitial tissues and within an individual osteon. A difference was observed between male and female samples, and permeability appeared to significantly decrease with age. Finally, a significant correlation was found between permeability and canalicular length density, defined as canalicular length per unit bone volume. This study proposes a new form of the Kozeny law to express bone canalicular permeability as a proportional relationship with the canalicular length density. Importantly, this parameter can be directly quantified through confocal fluorescence microcopy, which is more convenient than synchrotron radiation-based nano-computed tomography. In conclusion, the current study confirms that confocal microscopy can be serve as a reliable tool to estimate bone permeability. However, the permeability values calculated here are solely based on canalicular morphology and do not consider cellular and peri-cellular intra-canalicular features.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117441"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bone proliferation in osteoporotic experimental animals using alginate-pullulan-bioactive glass‑gold nanoparticles composite
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-28 DOI: 10.1016/j.bone.2025.117439
Andreea Niculina Aștilean (Pertea) , Alexandra Dreancă , Sidonia Gog-Bogdan , Bogdan Sevastre , Andrei Ungur , Andrada Negoescu , Marian Taulescu , Oana Rotar , Maximilian Dindelegan , Luciana-Mădălina Gherman , Klara Magyari , Liviu Oana
In the present study, scaffold composites based on alginate-pullulan-bioactive glass‑gold nanoparticles were orthotopically implanted in an experimental model of delayed bone union, in rats, given by a metabolic pathology, namely osteoporosis. Differences between treated and untreated groups were observed and the efficacy of our biomaterial was evaluated by applying micro-CT imaging, together with histological evaluation of the osteoporotic animals with sub-critical bone defects, at 30 and 60 days. Osteoporosis was successfully induced by ovariectomy in 9-month-old rats, confirmed by micro-CT and histopathological analysis. A secondary complication from a cortical bone defect was further induced to study bone proliferation in such a delayed environment. The studied composite presents osteointegration and angiogenesis properties at 60 days post-implantation in the osteoporotic animals. These results are given by the micro-CT analysis in which higher bone mineral density and bone volume fraction were observed, alongside histopathology, stating a lack of tissue necrosis and inflammatory reaction and the presence of new woven islands within and around the implanted biomaterial. This is the first endeavor to treat cortical bone defects in osteoporotic animals using scaffold biopolymers containing bioactive glass‑gold nanoparticles instead of cement.
{"title":"Bone proliferation in osteoporotic experimental animals using alginate-pullulan-bioactive glass‑gold nanoparticles composite","authors":"Andreea Niculina Aștilean (Pertea) ,&nbsp;Alexandra Dreancă ,&nbsp;Sidonia Gog-Bogdan ,&nbsp;Bogdan Sevastre ,&nbsp;Andrei Ungur ,&nbsp;Andrada Negoescu ,&nbsp;Marian Taulescu ,&nbsp;Oana Rotar ,&nbsp;Maximilian Dindelegan ,&nbsp;Luciana-Mădălina Gherman ,&nbsp;Klara Magyari ,&nbsp;Liviu Oana","doi":"10.1016/j.bone.2025.117439","DOIUrl":"10.1016/j.bone.2025.117439","url":null,"abstract":"<div><div>In the present study, scaffold composites based on alginate-pullulan-bioactive glass‑gold nanoparticles were orthotopically implanted in an experimental model of delayed bone union, in rats, given by a metabolic pathology, namely osteoporosis. Differences between treated and untreated groups were observed and the efficacy of our biomaterial was evaluated by applying micro-CT imaging, together with histological evaluation of the osteoporotic animals with sub-critical bone defects, at 30 and 60 days. Osteoporosis was successfully induced by ovariectomy in 9-month-old rats, confirmed by micro-CT and histopathological analysis. A secondary complication from a cortical bone defect was further induced to study bone proliferation in such a delayed environment. The studied composite presents osteointegration and angiogenesis properties at 60 days post-implantation in the osteoporotic animals. These results are given by the micro-CT analysis in which higher bone mineral density and bone volume fraction were observed, alongside histopathology, stating a lack of tissue necrosis and inflammatory reaction and the presence of new woven islands within and around the implanted biomaterial. This is the first endeavor to treat cortical bone defects in osteoporotic animals using scaffold biopolymers containing bioactive glass‑gold nanoparticles instead of cement.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117439"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Automatic phantom-less calibration of routine CT scans for the evaluation of osteoporosis and hip fracture risk
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-25 DOI: 10.1016/j.bone.2025.117431
Wen Li , Yuanzhi Weng , Renfei Zong , Miao Wei , Chen Zheng , Minghao Wu , Wenqin Zhou , Jiayi Pu , William Lu , Fajin Lv
Background/Purpose.
The diagnosis of osteoporosis remains a paramount concern for orthopedic surgeons worldwide. We aim to (1) evaluate the efficacy of automatic phantom-less quantitative computed tomography (PL-QCT) in diagnosing osteoporosis and (2) investigate its clinical value in predicting hip fracture risk.

Methods

A cohort of 705 patients was included in the study. Hip CT scans from 310 patients and spinal CT scans from 315 patients were analyzed using automatic PL-QCT. The consistency of bone mineral density (BMD) measurement obtained by dual-energy X-ray absorptiometry (DXA), phantom-based QCT (PB-QCT), and automatic PL-QCT was examined through linear regression analysis and Bland-Altman plots. The ability of automatic PL-QCT to predict osteoporosis and hip fracture risk was assessed using ROC analysis.

Results

Linear regression and Bland-Altman plots demonstrated a high level of agreement between BMD measurements from PL-QCT and those from hip DXA and lumbar PB-QCT. The AUC values for PL-QCT and PB-QCT in diagnosing osteoporosis were 0.903 (95 % CI 0.852–0.955) and 0.900 (95 % CI 0.847–0.953). The AUC values for predicting hip fracture risk, based on femoral neck BMD measured by PL-QCT and DXA, were 0.869 (95 % CI 0.823–0.915) and 0.831(95 % CI 0.778–0.885), respectively. When the femoral neck BMD was combined with the percentage of inter-muscular adipose tissue area, the AUC increased to 0.929 (95 % CI 0.897–0.961).

Conclusion

Automatic PL-QCT has shown superior performance in predicting hip fracture risk compared to DXA. Furthermore, the novel PL-QCT demonstrates comparable predictive efficacy to that of PB-QCT, suggesting its potential as a valuable tool in clinical practice.
{"title":"Automatic phantom-less calibration of routine CT scans for the evaluation of osteoporosis and hip fracture risk","authors":"Wen Li ,&nbsp;Yuanzhi Weng ,&nbsp;Renfei Zong ,&nbsp;Miao Wei ,&nbsp;Chen Zheng ,&nbsp;Minghao Wu ,&nbsp;Wenqin Zhou ,&nbsp;Jiayi Pu ,&nbsp;William Lu ,&nbsp;Fajin Lv","doi":"10.1016/j.bone.2025.117431","DOIUrl":"10.1016/j.bone.2025.117431","url":null,"abstract":"<div><div>Background/Purpose.</div><div>The diagnosis of osteoporosis remains a paramount concern for orthopedic surgeons worldwide. We aim to (1) evaluate the efficacy of automatic phantom-less quantitative computed tomography (PL-QCT) in diagnosing osteoporosis and (2) investigate its clinical value in predicting hip fracture risk.</div></div><div><h3>Methods</h3><div>A cohort of 705 patients was included in the study. Hip CT scans from 310 patients and spinal CT scans from 315 patients were analyzed using automatic PL-QCT. The consistency of bone mineral density (BMD) measurement obtained by dual-energy X-ray absorptiometry (DXA), phantom-based QCT (PB-QCT), and automatic PL-QCT was examined through linear regression analysis and Bland-Altman plots. The ability of automatic PL-QCT to predict osteoporosis and hip fracture risk was assessed using ROC analysis.</div></div><div><h3>Results</h3><div>Linear regression and Bland-Altman plots demonstrated a high level of agreement between BMD measurements from PL-QCT and those from hip DXA and lumbar PB-QCT. The AUC values for PL-QCT and PB-QCT in diagnosing osteoporosis were 0.903 (95 % CI 0.852–0.955) and 0.900 (95 % CI 0.847–0.953). The AUC values for predicting hip fracture risk, based on femoral neck BMD measured by PL-QCT and DXA, were 0.869 (95 % CI 0.823–0.915) and 0.831(95 % CI 0.778–0.885), respectively. When the femoral neck BMD was combined with the percentage of inter-muscular adipose tissue area, the AUC increased to 0.929 (95 % CI 0.897–0.961).</div></div><div><h3>Conclusion</h3><div>Automatic PL-QCT has shown superior performance in predicting hip fracture risk compared to DXA. Furthermore, the novel PL-QCT demonstrates comparable predictive efficacy to that of PB-QCT, suggesting its potential as a valuable tool in clinical practice.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117431"},"PeriodicalIF":3.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511712","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}
引用次数: 0
Use of double-echo ultrashort echo time magnetic resonance imaging to assess proximal femoral cortical bone changes in axial spondyloarthritis
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-25 DOI: 10.1016/j.bone.2025.117430
Yitong Li, Bowen Hou, Yao Zhang, Yi Wang, Yongqiang Chu, Jing Zhang, Xiaoming Li
<div><h3>Objective</h3><div>We quantitatively evaluated proximal femoral cortical bone changes associated with generalized bone loss in axial spondyloarthritis (axSpA) patients using double-echo ultrashort echo time (UTE) MRI. To achieve non-radiation, clinically available visualization of cortical microstructural deterioration in the proximal femur of axSpA and to determine the factors influencing it.</div></div><div><h3>Materials and methods</h3><div>Patients with axSpA (<em>n</em> = 83) and age- and sex-matched healthy controls (<em>n</em> = 61) were recruited and underwent double-echo UTE MR scan of the nondominant proximal femur. Porosity index (PI) and cortical bone thickness (CbTh) were measured by two radiologists and their average measurements were used for subsequent analyses. Additionally, demographic characteristics of all subjects and disease-specific characteristics of axSpA patients were recorded. Proximal femoral cortical bone PI and CbTh values were compared between axSpA patients and healthy controls using independent samples <em>t</em>-test. Correlation analyses (Pearson or Spearman or Point-biserial correlation coefficients) were conducted to investigate factors potentially associated with UTE measurements in axSpA patients, and Bonferroni correction was applied at the α = 0.002 level for more stringent correction. Multiple linear regression analyses were performed to further identify influencing factors of UTE measurements with multiple correlated variables.</div></div><div><h3>Results</h3><div>A total of 72 axSpA patients and 52 healthy control subjects were finally included. Patients and control subjects were comparable in sex, age, and body mass index (BMI). Proximal femoral cortical PI was higher (<em>p</em> < 0.001) and CbTh was lower (<em>p</em> < 0.001) in axSpA patients than in healthy controls. Sex (<em>p</em> < 0.001), BMI (<em>p</em> = 0.003), disease duration (<em>p</em> = 0.044), onset age (<em>p</em> = 0.01), alkaline phosphatase (ALP) (<em>p</em> < 0.001), radiographic axSpA (r-axSpA) (<em>p</em> = 0.02), Sacroiliac Joint Structural Score (<em>SSS</em>)-backfill (<em>p</em> = 0.03), SSS-ankylosis (<em>p</em> = 0.01), and nonsteroidal anti-inflammatory drugs (NSAIDs) use (<em>p</em> = 0.03) were potentially correlated to proximal femoral cortical PI, and among them, sex (<em>p</em> < 0.001) and BMI (<em>p</em> = 0.01) were independently associated demographic characteristics, and ALP (<em>p</em> = 0.02), SSS-backfill (<em>p</em> = 0.044) and SSS-ankylosis (<em>p</em> = 0.01) were independently associated disease-specific characteristics, and when all types of variables were considered, sex (<em>p</em> < 0.001), BMI (<em>p</em> = 0.016), and SSS-ankylosis (<em>p</em> = 0.042) were independently associated with PI. BMI (<em>p</em> = 0.043) and NSAIDs use (<em>p</em> = 0.041) were potentially negatively associated with CbTh.</div></div><div><h3>Conclusion</h3><div>Double-echo UTE measurements reve
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引用次数: 0
Comment on “Characteristics of patients with very high fracture risk in a community-dwelling geriatric cohort” 关于 "社区老年群体中骨折风险极高的患者特征 "的评论
IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-02-24 DOI: 10.1016/j.bone.2025.117429
Jian Tong
{"title":"Comment on “Characteristics of patients with very high fracture risk in a community-dwelling geriatric cohort”","authors":"Jian Tong","doi":"10.1016/j.bone.2025.117429","DOIUrl":"10.1016/j.bone.2025.117429","url":null,"abstract":"","PeriodicalId":9301,"journal":{"name":"Bone","volume":"194 ","pages":"Article 117429"},"PeriodicalIF":3.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511713","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}
引用次数: 0
期刊
Bone
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