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Decomposing and simplifying fracture risk assessment tool 分解和简化骨折风险评估工具
IF 3.8 Q1 Medicine Pub Date : 2024-03-23 DOI: 10.1093/jbmrpl/ziae039
Chia-Chun Li, I. Liu, Tien-Tsai Cheng, Fu-Wen Liang, Zih‐Jie Sun, Yin-Fan Chang, Chin-Sung Chang, Yi-Ching Yang, Tsung-Hsueh Lu, Li-Chieh Kuo, Chih-Hsing Wu
The Fracture Risk Assessment tool (FRAX®) is a widely utilized country-specific calculator for identifying individuals with high fracture risk; its score is calculated from 12 variables, but its formulation is not publicly disclosed. We aimed to decompose and simplify the FRAX® by utilizing a nationwide community survey database as a reference module for creating a local assessment tool for osteoporotic fracture community screening in any country. Participants (n = 16 384: predominantly women (75%); mean age = 64.8 years) were enrolled from the Taiwan OsteoPorosis Survey, a nationwide cross-sectional community survey database collected from 2008–2011. We identified 11 other clinical risk factors from the health questionnaires. Bone mineral density (BMD) was assessed via dual-energy X-ray absorptiometry in a mobile DXA vehicle, and 10-year fracture risk scores, including major osteoporotic fracture (MOF) and hip fracture (HF) risk scores, were calculated using the FRAX®. The mean femoral neck BMD was 0.7 ± 0.1 g/cm2, the T-score was -1.9 ± 1.2, the MOF was 8.9 ± 7.1%, and the HF was 3.2 ± 4.7%. Following FRAX® decomposition with multiple linear regression, the adjusted R2 values were 0.9206 for MOF and 0.9376 for HF when BMD was included and 0.9538 for MOF and 0.9554 for HF when BMD was excluded. The FRAX® demonstrated better prediction for women and younger individuals than for men and elderly individuals after sex and age stratification analysis. Excluding femoral neck BMD, age, sex, and previous fractures emerged as three primary clinical risk factors for simplified FRAX® according to the decision tree analysis in this study population. The adjusted R2 values for the simplified country-specific FRAX® incorporating three premier clinical risk factors were 0.8210 for MOF and 0.8528 for HF. After decomposition, the newly simplified module provides a straightforward formulation for estimating 10-year fracture risk, even without femoral neck BMD, making it suitable for community or clinical osteoporotic fracture risk screening.
骨折风险评估工具(FRAX®)是一种广泛使用的针对特定国家的计算器,用于识别骨折高危人群;其分数由 12 个变量计算得出,但其制定方法并未公开披露。我们的目的是利用一个全国性的社区调查数据库作为参考模块,对 FRAX® 进行分解和简化,从而为任何国家的骨质疏松性骨折社区筛查创建一个本地评估工具。参与者(n = 16 384:主要为女性(75%);平均年龄 = 64.8 岁)来自台湾骨质疏松症调查,这是一个 2008-2011 年收集的全国性横断面社区调查数据库。我们还从健康问卷中确定了 11 项其他临床风险因素。我们使用移动式 DXA 车通过双能 X 射线吸收仪评估了骨质密度(BMD),并使用 FRAX® 计算了 10 年骨折风险评分,包括主要骨质疏松性骨折(MOF)和髋部骨折(HF)风险评分。平均股骨颈 BMD 为 0.7 ± 0.1 g/cm2,T 评分为 -1.9 ± 1.2,MOF 为 8.9 ± 7.1%,HF 为 3.2 ± 4.7%。在使用多重线性回归对 FRAX® 进行分解后,当包括 BMD 时,MOF 的调整 R2 值为 0.9206,HF 为 0.9376;当不包括 BMD 时,MOF 为 0.9538,HF 为 0.9554。在对性别和年龄进行分层分析后,FRAX® 对女性和年轻人的预测效果优于男性和老年人。根据本研究人群的决策树分析,排除股骨颈 BMD 后,年龄、性别和既往骨折成为简化 FRAX® 的三个主要临床风险因素。包含三个主要临床风险因素的简化版国别 FRAX® 的调整 R2 值为:MOF 为 0.8210,HF 为 0.8528。经过分解后,即使没有股骨颈 BMD,新的简化模块也能直接估算出 10 年骨折风险,因此适用于社区或临床骨质疏松性骨折风险筛查。
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引用次数: 0
Week-by-week changes in serum levels of bone-related circulating microRNAs and bone turnover markers. 骨相关循环 microRNA 和骨转换标志物的血清水平逐周变化。
IF 3.8 Q1 Medicine Pub Date : 2024-03-22 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae035
Patryk Zarecki, Fatma Gossiel, Johannes Grillari, Miguel Debono, Matthias Hackl, Richard Eastell

MicroRNAs are involved in post-transcriptional regulation of gene expression. Due to their regulatory role, microRNAs are differently expressed during specific conditions in healthy and diseased individuals, so microRNAs circulating in the blood could be used as diagnostic and prognostic biomarkers for various diseases and conditions. We want to investigate the variability of circulating microRNAs and bone turnover markers in weekly time intervals in older women. In a single-site longitudinal study, a panel of 19 bone-related miRNAs was measured using the osteomiR RT-qPCR assay in serum samples of 35 postmenopausal women divided into 3 groups: healthy controls (n = 12), low BMD (n = 14), and vertebral fractures (n = 9). Blood samples for measurement of CTX, PINP, OC, and bone ALP were collected once per week for 8 weeks at 9:00 AM after overnight fasting. Serum samples from all participants were analyzed for 19 microRNA bone biomarkers and 4 bone turnover markers over 8 weeks. We analyzed the data using a mixed model analysis of variance and found no significant changes between week-by-week time points in any of the groups. To estimate intraindividual variability between weekly time points, we have calculated the median coefficient of variation (CV). This was between 28.4% and 80.2% for microRNA, with an assay CV of 21.3%. It was between 8.5% and 15.6% for bone turnover markers, with an assay CV of 3.5% to 6.5%. The intraindividual variability was similar between groups. Circulating microRNAs measured in serum had a higher weekly intraindividual variability than bone turnover markers due in part to a higher assay CV.

microRNA 参与基因表达的转录后调控。由于其调控作用,microRNA 在健康和患病个体的特定条件下会有不同的表达,因此血液中循环的 microRNA 可用作各种疾病和病症的诊断和预后生物标志物。我们希望研究老年妇女每周时间间隔内循环 microRNAs 和骨转换标志物的变化情况。在一项单点纵向研究中,我们使用 osteomiR RT-qPCR 分析法对 35 名绝经后妇女的血清样本中的 19 种骨相关 miRNA 进行了测定,这些妇女分为 3 组:健康对照组(12 人)、低 BMD 组(14 人)和椎体骨折组(9 人)。测量 CTX、PINP、OC 和骨 ALP 的血液样本每周采集一次,连续采集 8 周,采集时间为一夜禁食后的上午 9:00。我们对所有参与者的血清样本进行了为期 8 周的分析,以检测 19 种 microRNA 骨生物标记物和 4 种骨转换标记物。我们采用混合方差分析模型对数据进行了分析,结果发现各组在各周时间点之间均无明显变化。为了估计每周时间点之间的个体内部变异性,我们计算了中位变异系数(CV)。微 RNA 的变异系数介于 28.4% 和 80.2% 之间,化验变异系数为 21.3%。骨转换标记物的变异系数介于 8.5% 和 15.6% 之间,检测 CV 为 3.5% 至 6.5%。各组之间的个体内变异性相似。与骨转换标志物相比,血清中测定的循环微RNA每周的个体内变异性更高,部分原因是测定CV更高。
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引用次数: 0
The Anti-HIV Drug Abacavir stimulates β-catenin activity in osteoblast lineage cells 抗艾滋病毒药物阿巴卡韦刺激成骨细胞系细胞中β-catenin的活性
IF 3.8 Q1 Medicine Pub Date : 2024-03-19 DOI: 10.1093/jbmrpl/ziae037
Arnold Z. Olali, Jennillee Wallace, Hemil Gonzalez, K. A. Carpenter, Niyati Patel, Lee C Winchester, A. Podany, Ishwarya Venkatesh, S. Narasipura, Lena Al-Harthi, Ryan D Ross
Bone mineral density (BMD) loss in people living with HIV (PLWH) occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/β-catenin in bone formation, we further investigated ARV effects on the Wnt/β-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic β-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) β-catenin staining, and β-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/β-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/β-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.
艾滋病病毒感染者(PLWH)在开始接受联合抗逆转录病毒疗法(cART),尤其是含有富马酸替诺福韦二吡呋酯(TDF)的 cART 治疗时,会出现骨密度(BMD)降低的情况。从 TDF 改用阿巴卡韦 (ABC) 或多罗替拉韦 (DTG) 会导致 BMD 增加。BMD增加是由于停用TDF,还是由于ABC或DTG的合成代谢作用,目前尚不清楚。我们在体外和体内研究了 ABC 和 DTG 对成骨细胞系细胞的影响。原代人类成骨细胞和雄性 C57BL/6 小鼠接受了单个抗逆转录病毒药物(ARV)或 ABC/DTG/lamivudine (3TC) 组合的治疗。几乎所有抗逆转录病毒药物和 cART 都抑制体外成骨活性。由于 Wnt/β-catenin 在骨形成中的重要性,我们进一步研究了 ARV 对 Wnt/β-catenin 通路的影响。ABC(单独或作为ABC/DTG/3TC的一部分)增加了成骨细胞β-catenin的活性,表现为TOPFlash活性增加、低磷酸化(活性)β-catenin染色和β-catenin靶基因表达。接受TDF治疗的小鼠腰椎BMD和椎骨小梁连接密度降低,而接受ABC/DTG/3TC治疗的小鼠股骨皮质面积和厚度减少。单用 ABC 治疗的小鼠没有骨结构变化,骨形成标志物 P1NP 的循环水平升高,Wnt/β-catenin 靶基因 Lef1 在骨细胞富集样本中的表达升高。此外,还分离了接受过 ARV 治疗的小鼠骨骼,以评估 ARV 的分布情况。在包括骨髓在内的骨组织中检测到了所有抗逆转录病毒药物,但当骨髓被移除时,只检测到了TDF、ABC和DTG,其含量约为循环水平的0.1%。总之,我们的研究结果表明,ABC能激活Wnt/β-catenin信号,但这是否会导致骨形成增加还需要进一步研究。评估抗逆转录病毒药物对骨骼的影响对于选择抗逆转录病毒药物和/或发现不会对骨骼产生负面影响的治疗方案至关重要。
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引用次数: 0
Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case–control study 维生素 D 缺乏症日本婴儿骨形成和吸收指标的不一致反应:一项全面的匹配病例对照研究
IF 3.8 Q1 Medicine Pub Date : 2024-03-18 DOI: 10.1093/jbmrpl/ziae033
Keigo Takahashi, Kazushige Ikeda, Kaori Hara-Isono, Akihisa Nitta, Nobuhiko Nagano, T. Arimitsu
Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25(OH)D, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 months born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. 116 infants (147 samples) were classified as having vitamin D deficiency (25(OH)D < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25(OH)D ≥ 12.0 ng/mL). In addition to 25(OH)D and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b only measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (p = <0.0001, 0.0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the two groups (p = 0.19, 0.08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.
婴儿期维生素 D 缺乏与骨转换率增加和骨矿物质流失有关。然而,很少有研究对维生素 D 缺乏婴儿骨形成和骨吸收的骨转换标志物(BTMs)进行研究。在此,我们分析了 2021 年 1 月至 2022 年 12 月期间在日本琦玉县市立医院(北纬 35.9°)出生的 456 名年龄小于 12 个月的婴儿(626 个样本)的血清 25(OH)D、完整副泌乳素(iPTH)和 BTMs(包括总碱性磷酸酶(ALP)、抗酒石酸磷酸酶同工酶 5b (TRACP-5b)和血清 I 型胶原 N-十肽(NTx))浓度以及基本临床特征。116名婴儿(147个样本)被归类为维生素D缺乏(25(OH)D < 12.0 ng/mL),340名婴儿(479个样本)维生素D水平充足(25(OH)D ≥ 12.0 ng/mL)。除 25(OH)D 和 ALP 外,331 名婴儿(418 个样本)同时测量了 TRACP-5b 和 sNTx,90 名婴儿(105 个样本)只测量了 TRACP-5b,101 名婴儿(103 个样本)只测量了 sNTx。对维生素 D 缺乏组和维生素 D 充足组各 104 名受试者进行背景特征匹配后的统计比较发现,维生素 D 缺乏组的 ALP 和 iPTH 水平明显高于维生素 D 充足组(p = <0.0001,0.0012)。然而,两组之间的 TRACP-5b 和 NTx 水平没有明显差异(分别为 p = 0.19 和 0.08)。我们的研究结果表明,在亚临床维生素 D 缺乏的婴儿期,骨形成和骨吸收标志物之间的反应并不一致。
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引用次数: 0
Development of an opportunistic diagnostic prediction algorithm for osteoporosis and fragility fracture risk estimates from forearm radiographs (The OFFER1 Study). 根据前臂 X 射线照片开发骨质疏松症和脆性骨折风险评估的机会性诊断预测算法(OFFER1 研究)。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-03-15 eCollection Date: 2024-04-01 DOI: 10.1093/jbmrpl/ziae020
Robert Meertens, Ben Lopez, Ben Crone, Mike Gundry, Emma Metcalfe-Smith, Warren Gibbard, Thomas Jubb, Fay Manning, Paul Scott, Richard McWilliam

Osteoporosis and associated fractures are an increasingly prevalent concern with an ageing population. This study reports testing of IBEX Bone Health (IBEX BH) software, applied following acquisition of forearm radiographs. IBEX Bone Health analyses the radiograph to measure areal bone mineral density (aBMD) at the examination site. A non-randomized cross-sectional study design was performed involving 261 (254 after exclusions) participants (112/142 m/f; mean age 70.8 years (SD+/-9.0); 53 with osteoporosis). They underwent posterior-anterior distal forearm radiographs; dual X-ray absorptiometry (DXA) of the wrists, hips, and lumbar spine; and questionnaires exploring clinical risk factors. IBEX Bone Health automatically identifies regions of interest (ROI) at the ultra-distal (UD) and distal third (TD) regions of the radius. Analysis investigated area under the receiver operating characteristics curve performance of IBEX BH for prediction of (i) osteoporosis (based on clinical reporting of the hip and spine DXA) and (ii) treatment recommendations by Fracture Risk Assessment Tool (FRAX) inclusive of neck of femur (NoF) areal bone mineral density (aBMD) results following National Osteoporosis Guideline Group (NOGG) guidelines. Area under the receiver operating characteristics curve for osteoporosis prediction at the UD and TD ROIs were 0.86 (99% confidence interval (CI) [0.80, 0.91]) and 0.81 (99% CI [0.75, 0.88]), respectively. Area under the receiver operating characteristics curve for treatment recommendation using FRAX inclusive of NoF aBMD at the UD and TD ROIs were 0.95 (99% CI [0.91, 1.00]) and 0.97 (99% CI [0.93,1.00]), respectively. With a matched sensitivity to FRAX (without NoF aBMD) 0.93 (99% CI [0.78, 0.99]), IBEX BH predicted at the UD and TD ROIs recommended treatment outcomes by NOGG guidelines using FRAX (with NoF aBMD) with specificity 0.89 (99% CI 0.83, 0.94]) and 0.93 (99% CI [0.87, 0.97]), respectively. This is compared with 0.60 (99% CI [0.51, 0.69]) for FRAX (without NoF aBMD). Results demonstrate the potential clinical utility of IBEX BH as an opportunistic screening tool.

随着人口老龄化,骨质疏松症和相关骨折问题日益突出。本研究报告对 IBEX Bone Health(IBEX BH)软件进行了测试,该软件是在采集前臂X光片后应用的。IBEX Bone Health 通过分析射线照片来测量检查部位的平均骨矿物质密度 (aBMD)。该研究采用非随机横断面研究设计,共有 261 人(排除 254 人后)参加(男性/女性 112/142;平均年龄 70.8 岁(SD+/-9.0);53 人患有骨质疏松症)。他们接受了前臂远端后前位片检查;腕部、髋部和腰椎的双 X 射线吸收测定(DXA);以及临床风险因素调查问卷。IBEX Bone Health能自动识别桡骨超远端(UD)和远端三分之一(TD)区域的感兴趣区(ROI)。分析调查了 IBEX BH 在预测 (i) 骨质疏松症(基于髋关节和脊柱 DXA 的临床报告)和 (ii) 骨折风险评估工具 (FRAX) 治疗建议(包括股骨颈 (NoF) 平均骨矿密度 (aBMD) 结果)方面的接收器操作特征曲线下面积性能,这些预测均遵循国家骨质疏松症指导小组 (NOGG) 指南。UD 和 TD ROI 的骨质疏松症预测接收器操作特征曲线下面积分别为 0.86(99% 置信区间 (CI) [0.80, 0.91])和 0.81(99% CI [0.75, 0.88])。使用 FRAX(包括 UD 和 TD ROI 的 NoF aBMD)进行治疗推荐的接收器操作特征曲线下面积分别为 0.95(99% CI [0.91,1.00])和 0.97(99% CI [0.93,1.00])。与 FRAX(无 NoF aBMD)相匹配的灵敏度为 0.93(99% CI [0.78,0.99]),IBEX BH 在 UD 和 TD ROI 预测 NOGG 指南使用 FRAX(无 NoF aBMD)推荐的治疗结果的特异性分别为 0.89(99% CI 0.83,0.94])和 0.93(99% CI [0.87,0.97])。而 FRAX(无 NoF aBMD)的特异性为 0.60(99% CI [0.51,0.69])。结果表明,IBEX BH 作为一种机会性筛查工具具有潜在的临床实用性。
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引用次数: 0
Molecular and functional mapping of Plekhm1-Rab7 interaction in osteoclasts 破骨细胞中Plekhm1-Rab7相互作用的分子和功能图谱
IF 3.8 Q1 Medicine Pub Date : 2024-03-12 DOI: 10.1093/jbmrpl/ziae034
Bhaba K Das, Tarun Minocha, Mikaela D. Kunika, Aarthi Kannan, Ling Gao, S. Mohan, Weirong Xing, Kottayil I Varughese, Haibo Zhao
Mutations in PLEKHM1 cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of Plekhm1 gene in mice lead to defective osteoclast bone resorption and increased trabecular bone mass without overt abnormalities in other organs. As an adaptor protein, PLEKHM1 interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study of the PLEKHM1 RH domain and RAB7 interaction in osteoclasts in vitro. The single mutations of the key residues in the Plekhm1 RH predicted from the crystal structure of the RUBICON RH domain and RAB7 interface failed to disrupt the Plekhm1-Rab7 binding, lysosome trafficking, and bone resorption. The compound alanine mutations at Y949-R954 and L1011-I1018 regions decreased Plekhm1 protein stability and Rab7-binding, respectively, thereby attenuated lysosome trafficking and bone resorption in osteoclasts. In contrast, the compound alanine mutations at R1060-Q1068 region were dispensable for Rab7-binding and Plekhm1 function in osteoclasts. These results indicate that the regions spanning Y949-R954 and L1011-I1018 of Plekhm1 RH domain are functionally important for Plekhm1 in osteoclasts and offer the therapeutical targets for blocking bone resorption in treatment of osteoporosis and other metabolic bone diseases.
PLEKHM1 基因突变会导致人类和大鼠骨质软化症。在小鼠中,Plekhm1 基因的种系和破骨细胞条件性缺失导致破骨细胞骨吸收缺陷和骨小梁骨量增加,但其他器官无明显异常。作为一种适配蛋白,PLEKHM1通过其C端RUBICON同源(RH)结构域与溶酶体关键调控因子小GTP酶RAB7相互作用。本研究对破骨细胞中 PLEKHM1 RH 结构域与 RAB7 的相互作用进行了体外结构-功能研究。根据RUBICON RH结构域和RAB7界面的晶体结构预测的Plekhm1 RH关键残基的单突变未能破坏Plekhm1-Rab7的结合、溶酶体贩运和骨吸收。Y949-R954和L1011-I1018区域的复合丙氨酸突变分别降低了Plekhm1蛋白的稳定性和Rab7的结合力,从而减弱了溶酶体的转运和破骨细胞的骨吸收。相比之下,R1060-Q1068区域的复合丙氨酸突变对破骨细胞中的Rab7结合和Plekhm1功能没有影响。这些结果表明,Plekhm1 RH结构域中横跨Y949-R954和L1011-I1018的区域对Plekhm1在破骨细胞中的功能非常重要,为治疗骨质疏松症和其他代谢性骨病提供了阻断骨吸收的治疗靶点。
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引用次数: 0
Local application of zoledronate inhibits early bone resorption and promotes bone formation. 局部使用唑来膦酸钠可抑制早期骨吸收,促进骨形成。
IF 3.8 Q1 Medicine Pub Date : 2024-03-09 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae031
Ming-Kai Hsieh, Chi-Yun Wang, Fu-Cheng Kao, Hui-Ting Su, Mei-Feng Chen, Tsung-Ting Tsai, Po-Liang Lai

Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with β-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro, zolendronate concentrations below 2.5 × 10-7 M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cell‑specific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo, histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 μM and 2000 μM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo, soaking β-TCP artificial bone with 500 μM or 2000 μM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.

骨移植手术后,因早期骨吸收而导致的不愈合很常见。在这些患者中,不稳定性或骨质疏松症会导致相对于合成代谢的过度分解代谢,从而导致移植物吸收而非融合。全身应用唑来膦酸盐可抑制破骨细胞生成,被广泛用于预防骨质疏松症;然而,由于成骨细胞细胞毒性、不可控的剂量方案和局部释放方法,有关局部应用唑来膦酸盐的证据还存在争议。我们研究了唑伦膦酸钠对破骨细胞生成和成骨细胞生成的影响,并探索了相应的信号通路。我们用不同浓度的唑伦膦酸评估了MC3T3E1细胞、大鼠骨髓基质细胞(BMSCs)和破骨细胞前期(RAW264.7细胞)的体外细胞毒性和分化。将不同浓度的唑仑膦酸盐与β-磷酸三钙(TCP)骨替代物一起移植到大鼠股骨临界大小骨缺损处,测试体内骨再生能力。在体外,低于 2.5 × 10-7 M 的唑伦膦酸浓度不会影响三种细胞系的活力,也不会促进 MC3T3E1 细胞和 BMSCs 的成骨分化。在 RAW264.7 细胞中,唑来膦酸盐抑制了细胞外调节蛋白激酶和 c-Jun n 端激酶的信号转导,下调了 c-Fos 和 NFATc1 的表达,降低了融合相关树突状细胞特异性跨膜蛋白和破骨细胞特异性 Ctsk 和酒石酸抗性酸性磷酸酶()的表达。 在体内,组织学染色显示,使用 500 μM 和 2000 μM 的唑来膦酸盐后,骨形成和新生血管增加,纤维化组织减少。6 周后,在正常生理盐水组中发现了更多的破骨细胞,唑来膦酸盐处理后出现了连续的破骨细胞形成,这表明在早期胼胝体形成期间抑制了骨吸收,但没有抑制后期的骨重塑。在体内,用500 μM或2000 μM唑来膦酸盐浸泡β-TCP人工骨是一种很有前景的骨再生方法,有望应用于骨移植。
{"title":"Local application of zoledronate inhibits early bone resorption and promotes bone formation.","authors":"Ming-Kai Hsieh, Chi-Yun Wang, Fu-Cheng Kao, Hui-Ting Su, Mei-Feng Chen, Tsung-Ting Tsai, Po-Liang Lai","doi":"10.1093/jbmrpl/ziae031","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae031","url":null,"abstract":"<p><p>Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with β-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro<i>,</i> zolendronate concentrations below 2.5 × 10<sup>-7</sup> M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cell‑specific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo<i>,</i> histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 μM and 2000 μM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo<i>,</i> soaking β-TCP artificial bone with 500 μM or 2000 μM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11008729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis. 确定成人慢性非细菌性骨炎的影像诊断标准。
IF 3.8 Q1 Medicine Pub Date : 2024-03-08 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae024
Ashna I E Ramautar, Ana Navas, Elizabeth M Winter, Herman M Kroon, Frits Smit, Dennis Vriens, Neveen A T Hamdy, Natasha M Appelman-Dijkstra

Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (n = 103, 89.2%); median age at first symptoms 45 years (range 20-73). The diagnosis was excluded in the remaining 51 "non-CNO" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (P < 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages.

胸骨锁骨(SCC)区骨炎被称为胸骨锁骨骨质增生症(SCCH),是慢性非细菌性骨炎(CNO)的临床表现,成年人会患有这种罕见的慢性轴性骨骼自身炎症性疾病。诊断的依据是计算机断层扫描(CT)显示的SCC区域硬化和骨质增生的明显特征,以及骨骼闪烁扫描显示的放射性灯塔高摄取率所显示的局部骨质形成增加,但目前尚缺乏明确的放射学诊断标准。在一项横断面研究中,2 名骨骼放射科医生和 2 名核医学医生对 2008 年至 2018 年期间在莱顿大学医学中心骨质中心就诊的 169 名疑似 SCC 区 CNO 患者的 CT 扫描和全身骨骼闪烁扫描图像进行了重新评估。确诊的 118 例(70%)患者主要为女性(n = 103,89.2%);首次出现症状时的中位年龄为 45 岁(范围为 20-73)。其余 51 名 "非 CNNO "患者未被确诊。在82%的CNO患者中观察到SCC区域的放射性灯塔摄取增加,在两种成像模式中,胸骨嵴的预测鉴别能力最高。在 CNO 患者中,锁骨、胸骨和第一肋骨硬化的发生率明显更高(P<0.05)。
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引用次数: 0
Skeletal fluorosis secondary to methoxyflurane use for chronic pain 因使用甲氧氟醚治疗慢性疼痛而继发的骨骼氟中毒
IF 3.8 Q1 Medicine Pub Date : 2024-03-07 DOI: 10.1093/jbmrpl/ziae032
Yeung-Ae Park, Walter E Plehwe, Kapilan Varatharajah, Sophie Hale, Michael Christie, Christopher J Yates
Skeletal fluorosis is rare and occurs secondary to chronic high amounts of fluoride consumption, manifesting as diffuse osteosclerosis, skeletal pain, connective tissue calcification, and increased fracture risk. Methoxyflurane is a volatile fluorinated hydrocarbon inhaled analgesic, and the maximum recommended dose is 15 mL (99.9 % w/w) per week. A rodent study found increased skeletal fluoride after methoxyflurane exposure. However, skeletal fluorosis secondary to methoxyflurane use in humans has rarely been reported. We present the case of a 47-year-old female with diffuse osteosclerosis secondary to fluorosis from methoxyflurane use for chronic pain presenting with three years of generalized bony pain and multiple fragility fractures. Lumbar spine bone mineral density was elevated. CT and radiographs demonstrated new-onset marked diffuse osteosclerosis, with calcification of interosseous membranes and ligaments and a bone scan demonstrated grossly increased uptake throughout the skeleton. Biochemistry revealed an elevated alkaline phosphatase and bone turnover markers, mild secondary hyperparathyroidism with vitamin D deficiency and mild renal impairment. Zoledronic acid, prescribed for presumed Paget’s disease, severely exacerbated bony pain. Urinary fluoride was elevated (7.3 mg/L; reference range <3.0 mg/L) and the patient revealed using methoxyflurane 9 mL per week for eight years for chronic pain. A decalcified bone biopsy revealed haphazardly arranged cement lines and osteocytes lacunae and canaliculi, consistent with an osteosclerotic process. Focal subtle basophilic stippling around osteocyte lacunae was suggestive of fluorosis. Although fluorosis is not a histological diagnosis, the presence of compatible histology features was supportive of the diagnosis in this case with clinical-radiological-pathological correlation. Skeletal fluorosis should be considered as a cause of acquired diffuse osteosclerosis. Methoxyflurane should not be recommended for chronic pain. The risk of repeated low-dose exposure to fluoride from methoxyflurane use as analgesia may be greater than expected, and the maximum recommended dose for methoxyflurane may require re-evaluation to minimize skeletal complications.
骨骼氟中毒十分罕见,是由于长期大量摄入氟而继发的,表现为弥漫性骨硬化、骨骼疼痛、结缔组织钙化和骨折风险增加。甲氧氟醚是一种挥发性含氟碳氢化合物吸入镇痛剂,建议的最大剂量为每周 15 毫升(99.9% w/w)。一项啮齿动物研究发现,接触甲氧氟烷后骨骼氟化物增加。然而,人类因使用甲氧氟烷而继发骨骼氟中毒的报道却很少见。我们介绍了一例因使用甲氧氟烷治疗慢性疼痛而继发氟中毒的弥漫性骨硬化症患者,该患者 47 岁,三年来出现全身骨痛和多处脆性骨折。腰椎骨矿物质密度升高。CT和X光片显示新近出现明显的弥漫性骨硬化,骨间膜和韧带钙化,骨扫描显示整个骨骼的摄取量明显增加。生化检查显示碱性磷酸酶和骨转换标志物升高,继发性甲状旁腺功能亢进伴维生素 D 缺乏,肾功能轻度受损。唑来膦酸是治疗假定的帕吉特氏病的处方药,它严重加剧了骨痛。尿氟升高(7.3 毫克/升;参考值范围小于 3.0 毫克/升),患者透露因慢性疼痛每周使用 9 毫升甲氧氟烷,已持续八年。脱钙骨活检显示,骨水泥线和骨细胞裂隙及管状突起杂乱排列,与骨硬化过程一致。骨细胞裂隙周围的局部细微嗜碱性斑纹提示为氟中毒。虽然氟中毒不是一种组织学诊断,但该病例的组织学特征与临床、放射学和病理学的相关性支持了这一诊断。骨骼氟中毒应被视为获得性弥漫性骨硬化症的病因之一。慢性疼痛患者不宜使用甲氧氟醚。使用甲氧氟烷镇痛时反复低剂量接触氟化物的风险可能比预期的要大,因此可能需要重新评估甲氧氟烷的最大推荐剂量,以尽量减少骨骼并发症。
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引用次数: 0
Identification of a novel genetic variant associated with osteoporosis: insights from the Taiwan biobank study 确定与骨质疏松症相关的新型基因变异:台湾生物库研究的启示
IF 3.8 Q1 Medicine Pub Date : 2024-03-05 DOI: 10.1093/jbmrpl/ziae028
Yi-Ching Liaw, Koichi Matsuda, Y. Liaw
The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB). The TWBB dataset was divided into two subsets: We first used 60% of the data as discovery data, and 40% as replication data. Following data quality control measures, GWAS analysis was conducted using an additive genetic model adjusted for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model (SAIGE) approach. The meta-analysis of TWBB1 and TWBB2 was further carried out. The Functional Mapping and Annotation (FUMA) platform was used to identify genetic loci associated with osteoporosis based on GWAS summary statistics. Manhattan and quantile-quantile plots were generated using the FUMA platform to visualize the association results. Independent significant single nucleotide polymorphisms (SNPs) were selected based on genome-wide significance (P < 5 × 10−8) and independence from each other (r2 < 0.6) within a 1 Mb window. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions. Positional, eQTL and Chromatin interaction mapping are used to map SNPs to genes. A total of 29 084 individuals (3154 osteoporosis cases and 25 930 controls) were used for GWAS analysis (TWBB1 data), and 18 918 individuals (1917 cases and 17 001 controls) were utilized for replication studies (TWBB2 data). We identified a new independent significant SNP for osteoporosis in TWBB1, with the lead SNP rs76140829 (minor allele frequency = 0.055, P-value = 1.15 × 10-08). This SNP is located within the VTI1A gene on chromosome 10, specifically in its intronic region (10q25.2). Replication of the association was performed in TWBB2, yielding a P-value of 6.56 × 10-3. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (P-value = 7.52 × 10-10). In the positional mapping of rs76140829, six genes (HABP2, RP11-481H12.1, RNU7-165P, RP11-139 K1.2, RP11-57H14.3, and RP11-214 N15.5) were identified through chromatin interaction mapping in mesenchymal stem cells, indicating potential regulatory involvement. Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the VTI1A gene as a key risk variant associated with osteoporosis. This finding expands our understanding of the genetic basis of osteoporosis and highlights the potential regulatory role of this SNP in mesenchymal stem cells. Further research on the associated genes may contribute to future advancements in personalized treatments and drug development for osteoporosis.
本研究的目的是利用台湾生物库(TWBB)的数据,找出与骨质疏松症相关的新的独立重要 SNPs。 TWBB 数据集被分为两个子集:我们首先将 60% 的数据作为发现数据,40% 作为复制数据。在采取数据质量控制措施后,采用可扩展和精确实现的广义混合模型(SAIGE)方法,使用加性遗传模型对性别、年龄和前5个主成分进行调整,进行GWAS分析。进一步对 TWBB1 和 TWBB2 进行了荟萃分析。利用功能图谱和注释(FUMA)平台,根据 GWAS 的汇总统计数据确定与骨质疏松症相关的基因位点。利用 FUMA 平台生成了曼哈顿图和量纲-量纲图,以直观显示关联结果。根据全基因组的显著性(P < 5 × 10-8)和 1 Mb 窗口内的相互独立性(r2 < 0.6),筛选出独立的重要单核苷酸多态性(SNPs)。全球基因组研究的结果通常不能直接转化为因果变异,因为大多数结果位于非编码区或基因间区。定位、eQTL 和染色质相互作用图谱用于将 SNP 映射到基因上。 共有 29 084 人(3154 例骨质疏松症病例和 25 930 例对照)被用于 GWAS 分析(TWBB1 数据),18 918 人(1917 例病例和 17 001 例对照)被用于复制研究(TWBB2 数据)。我们在 TWBB1 中发现了一个新的骨质疏松症独立显著 SNP,其主要 SNP 为 rs76140829(小等位基因频率 = 0.055,P 值 = 1.15 × 10-08)。该 SNP 位于 10 号染色体上的 VTI1A 基因,特别是其内隐区(10q25.2)。在 TWBB2 中复制了这一关联,得出的 P 值为 6.56 × 10-3。对 TWBB1 和 TWBB2 数据的荟萃分析表明,SNP rs76140829 具有高度显著的关联性(P 值 = 7.52 × 10-10)。在rs76140829的定位图谱中,通过间充质干细胞染色质相互作用图谱发现了6个基因(HABP2、RP11-481H12.1、RNU7-165P、RP11-139 K1.2、RP11-57H14.3和RP11-214 N15.5),表明这些基因可能参与调控。 我们利用台湾生物库数据集进行的 GWAS 分析揭示了 VTI1A 基因中的 rs76140829 是与骨质疏松症相关的关键风险变异。这一发现拓展了我们对骨质疏松症遗传基础的理解,并强调了该 SNP 在间充质干细胞中的潜在调控作用。对相关基因的进一步研究可能有助于未来骨质疏松症个性化治疗和药物开发的进步。
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