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The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia 阿斯福太酶α对一名成人型低磷血症患者血浆和尿液焦磷酸盐水平以及假性骨折的影响
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-20 DOI: 10.1002/jbm4.10842
Naoko Hidaka, Hiroaki Murata, Kanako Tachikawa, Keiichi Osaki, Takashi Sekiyama, Yuka Kinoshita, Hajime Kato, Yoshitomo Hoshino, Soichiro Kimura, Takashi Sunouchi, So Watanabe, Masaomi Nangaku, Noriko Makita, Toshimi Michigami, Nobuaki Ito

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

低磷酸盐血症(HPP)是一种遗传性疾病,由编码组织非特异性碱性磷酸酶的 ALPL 基因变异引起。成人发病型 HPP(成人 HPP)是一种轻型 HPP,在 18 岁以后出现骨软化症状。阿斯福太酶α(AA)是一种调节型重组人碱性磷酸酶(ALP),已被确定为围产期和婴儿期等严重型 HPP 的一线疗法。我们描述了一名 64 岁女性的病例,她出现双侧股骨骨骺假性骨折,行动不便。低血清 ALP 活性和高浓度尿磷乙醇胺表明她被诊断为 HPP,而 ALPL 基因的同源变异(c.319G > A; p.Val107Ile)也证实了这一诊断。通过体外转染实验测量了这种新型变异蛋白的 ALP 活性,结果发现与野生型相比,该变异蛋白的剩余酶活性降低了 40%。为了促进假骨折的结合并改善活动度,患者开始接受 AA 治疗。6 个月后,放射影像显示骨折线消失,6 分钟步行测试(525 米至 606 米)证实患者的活动能力得到改善。EQ-5D-5L 指数也有所改善(从 0.757 升至 0.895)。在随访期间,尿肌酐校正尿焦磷酸水平(uPPi/Cre)与血浆 PPi 水平同步下降(血浆 PPi:6.34 降至 1.04 μM,uPPi/Cre:226.8 降至 75.4 nmol/mg)。尽管 AA 的应用应仅限于表现相对严重的患者,但它对成人 HPP 假性骨折愈合的有利影响还是显现出来了。此外,研究还发现了 ALPL 基因的一种新型致病变体,并通过功能分析得出了支持性结果。此外,在监测接受 AA 治疗的 HPP 患者时,uPPi/Cre 可能是血浆 PPi 的方便替代品,因为血浆 PPi 需要在采血后立即过滤。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC.代表美国骨矿研究学会出版。
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引用次数: 0
Utility and Limitations of TALLYHO/JngJ as a Model for Type 2 Diabetes–Induced Bone Disease TALLYHO/JngJ 作为 2 型糖尿病诱发骨病模型的实用性和局限性
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-17 DOI: 10.1002/jbm4.10843
Lejla Emini, Juliane Salbach-Hirsch, Johannes Krug, Katharina Jähn-Rickert, Björn Busse, Martina Rauner, Lorenz C. Hofbauer

Type 2 diabetes mellitus (T2DM) increases risk of fractures due to bone microstructural and material deficits, though the mechanisms remain unclear. Preclinical models mimicking diabetic bone disease are required to further understand its pathogenesis. The TALLYHO/JngJ (TH) mouse is a polygenic model recapitulating adolescent-onset T2DM in humans. Due to incomplete penetrance of the phenotype ~25% of male TH mice never develop hyperglycemia, providing a strain-matched nondiabetic control. We performed a comprehensive characterization of the metabolic and skeletal phenotype of diabetic TH mice and compared them to either their nondiabetic TH controls or the recommended SWR/J controls to evaluate their suitability to study diabetic bone disease in humans. Compared to both controls, male TH mice with T2DM exhibited higher blood glucose levels, weight along with impaired glucose tolerance and insulin sensitivity. TH mice with/without T2DM displayed higher cortical bone parameters and lower trabecular bone parameters in the femurs and vertebrae compared to SWR/J. The mechanical properties remained unchanged for all three groups except for a low-energy failure in TH mice with T2DM only compared to SWR/J. Histomorphometry analyses only revealed higher number of osteoclasts and osteocytes for SWR/J compared to both groups of TH. Bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and tartrate-resistant acid phosphatase (TRAP) were low for both groups of TH mice compared to SWR/J. Silver nitrate staining of the femurs revealed low number of osteocyte lacunar and dendrites in TH mice with T2DM. Three-dimensional assessment showed reduced lacunar parameters in trabecular and cortical bone. Notably, osteocyte morphology changed in TH mice with T2DM compared to SWR/J. In summary, our study highlights the utility of the TH mouse to study T2DM, but not necessarily T2DM-induced bone disease, as there were no differences in bone strength and bone cell parameters between diabetic and non-diabetic TH mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

2 型糖尿病(T2DM)会因骨骼微结构和材料缺陷而增加骨折风险,但其机制仍不清楚。为进一步了解糖尿病骨病的发病机制,需要建立模拟糖尿病骨病的临床前模型。TALLYHO/JngJ(TH)小鼠是一种重现人类青春期发病的 T2DM 的多基因模型。由于表型的不完全渗透性,约有 25% 的雄性 TH 小鼠从未发生过高血糖,从而提供了一个品系匹配的非糖尿病对照。我们对糖尿病 TH 小鼠的代谢和骨骼表型进行了全面鉴定,并将其与非糖尿病 TH 对照组或推荐的 SWR/J 对照组进行了比较,以评估它们是否适合研究人类糖尿病骨病。与两个对照组相比,患有 T2DM 的雄性 TH 小鼠表现出较高的血糖水平、体重以及葡萄糖耐量和胰岛素敏感性受损。与 SWR/J 小鼠相比,患有/不患有 T2DM 的 TH 小鼠的股骨和椎骨的皮质骨参数较高,而骨小梁参数较低;与 SWR/J 小鼠相比,除了患有 T2DM 的 TH 小鼠出现低能衰竭外,其他三组小鼠的机械性能均保持不变。与SWR/J相比,两组TH小鼠的骨转换标志物1型胶原蛋白N端前肽(P1NP)和耐酒石酸磷酸酶(TRAP)都较低。硝酸银染色显示,患有T2DM的TH小鼠股骨中的骨细胞裂隙和树突数量较少。三维评估显示,骨小梁和皮质骨的裂隙参数降低。总之,我们的研究强调了TH小鼠在研究T2DM的实用性,但不一定是T2DM诱导的骨病,因为糖尿病和非糖尿病TH小鼠的骨强度和骨细胞参数没有差异。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨与矿物质研究学会出版。
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引用次数: 0
Transitory Activation and Improved Transition from Erosion to Formation within Intracortical Bone Remodeling in Hypoparathyroid Patients Treated with rhPTH(1–84) 接受 rhPTH(1-84) 治疗的甲状旁腺功能减退症患者骨皮质内骨重塑过程中的短暂活化和从侵蚀到形成的过渡得到改善
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-17 DOI: 10.1002/jbm4.10829
Pernille van Dijk Christiansen, Tanja Sikjær, Christina Møller Andreasen, Jesper Skovhus Thomsen, Annemarie Brüel, Ellen Margrethe Hauge, Jean-Marie Delaisse, Lars Rejnmark, Thomas Levin Andersen

In hypoparathyroidism, lack of parathyroid hormone (PTH) leads to low calcium levels and decreased bone remodeling. Treatment with recombinant human PTH (rhPTH) may normalize bone turnover. This study aimed to investigate whether rhPTH(1–84) continued to activate intracortical bone remodeling after 30 months and promoted the transition from erosion to formation and whether this effect was transitory when rhPTH(1–84) was discontinued. Cortical histomorphometry was performed on 60 bone biopsies from patients (aged 31 to 78 years) with chronic hypoparathyroidism randomized to either 100 μg rhPTH(1–84) a day (n = 21) (PTH) or similar placebo (n = 21) (PLB) for 6 months as add-on to conventional therapy. This was followed by an open-label extension, where patients extended their rhPTH(1–84) (PTH) (n = 5), continued conventional treatment (CON) (n = 5), or withdrew from rhPTH(1–84) and resumed conventional therapy (PTHw) for an additional 24 months (n = 8). Bone biopsies were collected at months 6 (n = 42) and 30 (n = 18). After 6 and 30 months, the overall cortical microarchitecture (cortical porosity, thickness, pore density, and mean pore diameter) in the PTH group did not differ from that of the PLB/CON and PTHw groups. Still, the PTH group had a significantly and persistently higher percentage of pores undergoing remodeling than the PLB/CON groups. A significantly higher percentage of these pores was undergoing bone formation in the PTH compared with the PLB/CON groups, whereas the percentage of pores with erosion only was not different. This resulted in a shift in the ratio between formative and eroded pores, reflecting a faster transition from erosion to formation in the PTH-treated patients. In the rhPTH(1–84) withdrawal group PTHw, the latter effects of PTH were completely reversed in comparison to those of the PLB/CON groups. In conclusion, rhPTH(1–84) replacement therapy in hypoparathyroidism patients promotes intracortical remodeling and its transition from erosion to formation without affecting the overall cortical microstructure. The effect persists for at least 30 months and is reversible when treatment is withdrawn. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

在甲状旁腺功能减退症患者中,甲状旁腺激素(PTH)的缺乏会导致低血钙水平和骨重塑减少。使用重组人PTH(rhPTH)治疗可使骨转换恢复正常。本研究旨在探讨rhPTH(1-84)是否在30个月后继续激活皮质内骨重塑并促进从侵蚀到形成的转变,以及当rhPTH(1-84)停用时这种作用是否会短暂消失。研究人员对60例慢性甲状旁腺功能减退症患者(年龄在31至78岁之间)的骨活检组织进行了皮质组织形态测量,这些患者被随机分配到每天100微克的rhPTH(1-84)(n = 21)(PTH)或类似的安慰剂(n = 21)(PLB)中,为期6个月,作为常规治疗的补充。随后是开放标签延长期,患者延长rhPTH(1-84) (PTH)(5例),继续常规治疗(CON)(5例),或停用rhPTH(1-84),恢复常规治疗(PTHw),延长24个月(8例)。在第 6 个月(n = 42)和第 30 个月(n = 18)收集骨活检。6 个月和 30 个月后,PTH 组的整体皮质微结构(皮质孔隙率、厚度、孔密度和平均孔直径)与 PLB/CON 组和 PTHw 组没有差异。不过,PTH 组发生重塑的孔隙比例明显且持续高于 PLB/CON 组。与 PLB/CON 组相比,PTH 组正在进行骨形成的孔隙比例明显更高,而仅发生侵蚀的孔隙比例则没有差异。这导致形成孔和侵蚀孔之间的比例发生了变化,反映出 PTH 治疗组患者从侵蚀到形成的转变速度更快。在停用 rhPTH(1-84) 的 PTHw 组中,与 PLB/CON 组相比,PTH 的后一种效应被完全逆转。总之,甲状旁腺功能减退症患者的rhPTH(1-84)替代疗法可促进皮质内重塑及其从侵蚀向形成的转变,而不会影响整体皮质微结构。这种效应可持续至少30个月,并且在停止治疗时是可逆的。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨与矿物质研究学会出版。
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引用次数: 0
Increased Osteoblast GαS Promotes Ossification by Suppressing Cartilage and Enhancing Callus Mineralization During Fracture Repair in Mice 在小鼠骨折修复过程中,成骨细胞 GαS 的增加通过抑制软骨和增强胼胝体矿化促进骨化
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-15 DOI: 10.1002/jbm4.10841
Kathy K Lee, Adele Changoor, Marc D Grynpas, Jane Mitchell

S, the stimulatory G protein α-subunit that raises intracellular cAMP levels by activating adenylyl cyclase, plays a vital role in bone development, maintenance, and remodeling. Previously, using transgenic mice overexpressing GαS in osteoblasts (GS-Tg), we demonstrated the influence of osteoblast GαS level on osteogenesis, bone turnover, and skeletal responses to hyperparathyroidism. To further investigate whether alterations in GαS levels affect endochondral bone repair, a postnatal bone regenerative process that recapitulates embryonic bone development, we performed stabilized tibial osteotomy in male GS-Tg mice at 8 weeks of age and examined the progression of fracture healing by micro-CT, histomorphometry, and gene expression analysis over a 4-week period. Bone fractures from GS-Tg mice exhibited diminished cartilage formation at the time of peak soft callus formation at 1 week post-fracture followed by significantly enhanced callus mineralization and new bone formation at 2 weeks post-fracture. The opposing effects on chondrogenesis and osteogenesis were validated by downregulation of chondrogenic markers and upregulation of osteogenic markers. Histomorphometric analysis at times of increased bone formation (2 and 3 weeks post-fracture) revealed excess fibroblast-like cells on newly formed woven bone surfaces and elevated osteocyte density in GS-Tg fractures. Coincident with enhanced callus mineralization and bone formation, GS-Tg mice showed elevated active β-catenin and Wntless proteins in osteoblasts at 2 weeks post-fracture, further substantiated by increased mRNA encoding various canonical Wnts and Wnt target genes, suggesting elevated osteoblastic Wnt secretion and Wnt/β-catenin signaling. The GS-Tg bony callus at 4 weeks post-fracture exhibited greater mineral density and decreased polar moment of inertia, resulting in improved material stiffness. These findings highlight that elevated GαS levels increase Wnt signaling, conferring an increased osteogenic differentiation potential at the expense of chondrogenic differentiation, resulting in improved mechanical integrity. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

GαS是刺激性G蛋白α亚基,通过激活腺苷酸环化酶提高细胞内cAMP水平,在骨骼发育、维持和重塑过程中发挥着重要作用。此前,我们利用在成骨细胞中过表达 GαS 的转基因小鼠(GS-Tg)证明了成骨细胞 GαS 水平对骨生成、骨转换和骨骼对甲状旁腺功能亢进反应的影响。为了进一步研究GαS水平的改变是否会影响软骨内骨修复(一种重现胚胎骨发育的产后骨再生过程),我们在雄性GS-Tg小鼠8周龄时对其进行了稳定的胫骨截骨术,并在4周时间内通过显微CT、组织形态学和基因表达分析检查了骨折愈合的进展。GS-Tg小鼠的骨折在骨折后1周达到软茧形成高峰时软骨形成减少,随后在骨折后2周胼胝矿化和新骨形成明显增强。软骨生成标志物的下调和成骨标志物的上调验证了对软骨生成和成骨的相反影响。在骨形成增加时(骨折后2周和3周)进行的组织形态学分析显示,GS-Tg骨折患者新形成的编织骨表面有过量的成纤维细胞,骨细胞密度升高。在胼胝体矿化和骨形成增强的同时,GS-Tg 小鼠在骨折后 2 周显示成骨细胞中活性 β-catenin 和 Wntless 蛋白升高,编码各种典型 Wnts 和 Wnt 靶基因的 mRNA 增加进一步证实了这一点,表明成骨细胞 Wnt 分泌和 Wnt/β-catenin 信号传导增强。骨折后4周的GS-Tg骨性胼胝体显示出更高的矿物质密度和更低的极性惯性矩,从而改善了材料的硬度。这些发现突出表明,GαS水平升高会增加Wnt信号传导,从而提高成骨分化潜能,牺牲软骨分化,从而改善机械完整性。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC.代表美国骨与矿物质研究学会出版。
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引用次数: 0
Fruit and Vegetable Consumption and the Risk of Bone Fracture: A Grading of Recommendations, Assessment, Development, and Evaluations (GRADE)-Assessed Systematic Review and Dose–Response Meta-Analysis 水果和蔬菜摄入量与骨折风险:建议、评估、发展和评价分级(GRADE)评估的系统性综述和剂量反应元分析
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-10 DOI: 10.1002/jbm4.10840
Sheida Zeraattalab-Motlagh, Seyed Mojtaba Ghoreishy, Arman Arab, Sara Mahmoodi, Amirhossein Hemmati, Hamed Mohammadi

Researchers have examined the link between consuming fruit and vegetables and the incidence of fractures for many years. Nevertheless, their findings have been unclear. Furthermore, the dose-dependent relationship has not been examined, and the level of certainty in the evidence was not evaluated. We carried out a dose-dependent meta-analysis examining the relation between fruit and vegetables intake and fracture incidence. PubMed, Web of Sciences, and Scopus were searched until April 2023 for cohort studies evaluating the relation between fruit and vegetables and fracture incidence. Summary relative risks (RRs) were computed from complied data by applying random effects analysis. To examine the level of evidence, we utilized the approach called the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Ten cohort studies comprising 511,716 individuals were entered. There was a nonsignificant relation between fruit and vegetables, as well as only fruit intake and any fracture risk. In contrast, high versus low analysis presented that vegetables consumption was linked to a 16% decrease in any type of fracture incidence (RR 0.84; 95% confidence interval [CI], 0.75 to 0.95; I2 = 83.1%; n = 6). Also, per one serving/day (200 g/day) increments in vegetables consumption, there was a 14% decline in the fracture risk (RR 0.86; 95% CI, 0.77 to 0.97; I2 = 84.7%; n = 5; GRADE = moderate). With moderate certainty, a greater consumption of only vegetables, but not total fruit and vegetables or only fruit, might reduce the risk of fracture. These associations were also evident in dose–response analysis. Large intervention trials are demanded to approve our findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

多年来,研究人员一直在研究食用水果和蔬菜与骨折发生率之间的联系。然而,他们的研究结果并不明确。此外,还没有研究过剂量依赖关系,也没有评估过证据的确定性水平。我们进行了一项剂量依赖性荟萃分析,研究水果和蔬菜摄入量与骨折发生率之间的关系。截至 2023 年 4 月,我们在 PubMed、Web of Sciences 和 Scopus 上检索了评估水果和蔬菜与骨折发生率之间关系的队列研究。通过应用随机效应分析法,从汇总的数据中计算出汇总相对风险(RRs)。为了考察证据的水平,我们采用了名为 "建议、评估、发展和评价分级"(GRADE)的方法。十项队列研究共涉及 511 716 人。水果和蔬菜之间以及仅水果摄入量与任何骨折风险之间的关系均不显著。相比之下,高与低的分析表明,蔬菜摄入量与任何类型骨折发病率下降 16% 有关(RR 0.84;95% 置信区间 [CI],0.75 至 0.95;I2 = 83.1%;n = 6)。此外,蔬菜消费量每增加一份/天(200 克/天),骨折风险就会下降 14%(RR 0.86;95% CI,0.77 至 0.97;I2 = 84.7%;n = 5;GRADE = 中等)。在中度确定性的情况下,多吃蔬菜,而不是多吃水果和蔬菜或只吃水果,可能会降低骨折风险。这些关联在剂量反应分析中也很明显。我们需要大型干预试验来验证我们的研究结果。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨与矿物质研究学会出版。
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引用次数: 0
Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia 小儿骨骼发育不良的血清细胞因子表达趋势
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-09 DOI: 10.1002/jbm4.10816
David A. O'Connell, Ricki S. Carroll, Angela L. Duker, Andrea J. Schelhaas, Marjorie M. Postell, Paul T. Fawcett, Michael B. Bober

The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold (p < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower (p < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

骨骼发育不良是一组由骨骼和软骨的生长、发育和维护异常引起的遗传性疾病。人们对细胞因子在骨骼发育不良的炎症性和非炎症性病理生理学中的作用知之甚少。我们试图验证我们的假设,即与生长发育正常的对照组相比,骨骼发育不良儿童体内细胞因子的表达会有所不同。我们使用细胞因子人类磁性 25-Plex Panel(Invitrogen,Waltham,MA,USA)分析了 136 名生长发育中的骨骼发育不良患者体内的细胞因子水平,并与 275 名健康儿科对照组受试者进行了比较。我们重点研究了九个发育不良队列中 12 种细胞因子的表达情况。最常见的骨骼发育不良诊断为:软骨发育不全(58 例)、成骨不全(19 例)、II 型胶原病(11 例)、多发性骺发育不良(MED:9 例)、灾难性发育不良(8 例)、变性发育不良(8 例)和小头骨发育不良性原始侏儒症 II 型(MOPDII:8 例)。在 108 项具体观察结果中,45 项(41.7%)表明对照组与骨骼发育不良患者之间存在统计学意义上的表达差异。在分析的 12 种细胞因子中,有 4 种细胞因子在所有发育不良队列中的表达均高于对照组水平(白细胞介素 12 [IL-12]、IL-13、干扰素 γ 诱导蛋白 10 kDa [IP-10]、活化调节、正常 T 细胞表达和分泌 [RANTES]),有两种细胞因子在所有发育不良队列中的表达均低于对照组水平(单核细胞趋化蛋白 1 [MCP-1]、巨噬细胞炎症蛋白-1β [MIP-1β])。MOPDII 的过表达水平最高,IP-10 的表达水平增加了 3.8 倍(p < 0.0001)。具有统计学意义的最低表达水平出现在 II 型胶原病中,MCP-1 的表达水平降低了 0.43 倍(p < 0.005)。我们希望通过这些数据为发育不良研究的未来方向奠定基础,从而加深我们对这些复杂信号通路的理解。展望未来,验证细胞因子表达的这些早期趋势,并将观察到的变化与发育不良的进展趋势联系起来,可能会为临床生物标记物甚至新疗法提供新的候选者。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC.代表美国骨矿研究学会出版。
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引用次数: 0
Changes in Vertebral Bone Density and Paraspinal Muscle Morphology Following Spaceflight and 1 Year Readaptation on Earth 太空飞行和在地球上重新适应 1 年后脊椎骨密度和脊柱旁肌肉形态的变化
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-08 DOI: 10.1002/jbm4.10810
Jennifer C. Coulombe, Fjola Johannesdottir, Katelyn A. Burkhart, Henriette Brummer, Brett T. Allaire, Mary L. Bouxsein

Astronauts have an increased risk of back pain and disc herniation upon returning to Earth. Thus, it is imperative to understand the effects of spaceflight and readaptation to gravity on the musculoskeletal tissues of the spine. Here we investigated whether ~6 months of spaceflight led to regional differences in bone loss within the vertebral body. Additionally, we evaluated the relationships between vertebral bone density and paraspinal muscle morphology before flight, after flight, and after readaptation on Earth. We measured vertebral trabecular bone mineral density (Tb.BMD), paraspinal muscle cross-sectional area (CSA), and muscle density in 17 astronauts using computed tomography (CT) images of the lumbar spine obtained before flight (before flight, n = 17), after flight (spaceflight, n = 17), and ~12 months of readaptation to gravitational loading on Earth (follow-up, n = 15). Spaceflight-induced declines in Tb.BMD were greater in the superior region of the vertebral body (−6.7%) than the inferior (−3.1%, p = 0.052 versus superior region) and transverse regions (−4.3%, p = 0.057 versus superior region). After a year of readaptation to Earth's gravity, Tb.BMD in the transverse region remained significantly below preflight levels (−4.66%, p = 0.0094). Paraspinal muscle CSA and muscle density declined −1.0% (p = 0.005) and −0.83% (p = 0.001) per month of spaceflight, respectively. Ultimately, bone loss in the superior vertebral body, along with fatty infiltration of paraspinal muscles and incomplete recovery even after a year of readaptation on Earth, may contribute to spinal pathology in long-duration astronauts. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

宇航员返回地球后患背痛和椎间盘突出症的风险会增加。因此,了解太空飞行和重新适应重力对脊柱肌肉骨骼组织的影响势在必行。在此,我们研究了约 6 个月的太空飞行是否会导致椎体内骨质流失的区域性差异。此外,我们还评估了飞行前、飞行后和在地球上重新适应后脊椎骨密度与脊柱旁肌肉形态之间的关系。我们使用飞行前(飞行前,n = 17)、飞行后(太空飞行,n = 17)和在地球上重新适应重力负荷约 12 个月后(随访,n = 15)获得的腰椎计算机断层扫描(CT)图像,测量了 17 名宇航员的椎体骨小梁骨矿物质密度(Tb.BMD)、脊柱旁肌肉横截面积(CSA)和肌肉密度。太空飞行引起的椎体上部 Tb.BMD 下降率(-6.7%)大于下部(-3.1%,与上部相比 p = 0.052)和横向区域(-4.3%,与上部相比 p = 0.057)。在重新适应地球重力一年后,横向区域的 Tb.BMD 仍明显低于飞行前水平(-4.66%,p = 0.0094)。每飞行一个月,脊柱旁肌肉CSA和肌肉密度分别下降-1.0%(p = 0.005)和-0.83%(p = 0.001)。最终,椎体上部的骨质流失,加上脊柱旁肌肉的脂肪浸润以及在地球上重新适应一年后仍未完全恢复,可能会导致长期宇航员的脊柱病变。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨矿研究学会出版。
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引用次数: 0
Anisotropy, Anatomical Region, and Additional Variables Influence Young's Modulus of Bone: A Systematic Review and Meta-Analysis 各向异性、解剖区域和其他变量对骨质杨氏模量的影响:系统综述与元分析
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-31 DOI: 10.1002/jbm4.10835
Krisztián Kovács, Szilárd Váncsa, Gergely Agócs, Andrea Harnos, Péter Hegyi, Viktor Weninger, Katinka Baross, Bence Kovács, Gergely Soós, György Kocsis

The importance of finite element analysis (FEA) is growing in orthopedic research, especially in implant design. However, Young's modulus (E) values, one of the most fundamental parameters, can range across a wide scale. Therefore, our study aimed to identify factors influencing E values in human bone specimens. We report our systematic review and meta-analysis based on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline. We conducted the analysis on November 21, 2021. We included studies investigating healthy human bone specimens and reported on E values regarding demographic data, specimen characteristics, and measurement specifics. In addition, we included study types reporting individual specimen measurements. From the acquired data, we created a cohort in which we performed an exploratory data analysis that included the explanatory variables selected by random forest and regression trees methods, and the comparison of groups using independent samples Welch's t test. A total of 756 entries were included from 48 articles. Eleven different bones of the human body were included in these articles. The range of E values is between 0.008 and 33.7 GPa. The E values were most heavily influenced by the cortical or cancellous type of bone tested. Measuring method (compression, tension, bending, and nanoindentation), the anatomical region within a bone, the position of the bone within the skeleton, and the bone specimen size had a decreasing impact on the E values. Bone anisotropy, specimen condition, patient age, and sex were selected as important variables considering the value of E. On the basis of our results, E values of a bone change with bone characteristics, measurement techniques, and demographic variables. Therefore, the evaluation of FEA should be performed after the standardization of in vitro measurement protocol. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

有限元分析(FEA)在整形外科研究中的重要性与日俱增,尤其是在植入物设计方面。然而,作为最基本的参数之一,杨氏模量(E)值的范围很广。因此,我们的研究旨在确定影响人体骨标本 E 值的因素。我们根据《2020 年系统综述和荟萃分析首选报告项目》(Preferred Reporting Items for Systematic Reviews and Meta-Analyses,PRISMA)指南的建议报告了我们的系统综述和荟萃分析。我们于 2021 年 11 月 21 日进行了分析。我们纳入了调查健康人体骨骼标本的研究,并报告了有关人口统计学数据、标本特征和测量细节的 E 值。此外,我们还纳入了报告单个标本测量结果的研究类型。根据获得的数据,我们创建了一个队列,并在其中进行了探索性数据分析,包括通过随机森林和回归树方法选择解释变量,以及使用独立样本韦尔奇 t 检验进行组间比较。共收录了 48 篇文章中的 756 个条目。这些文章包括人体 11 种不同的骨骼。E 值范围在 0.008 到 33.7 GPa 之间。E值受测试骨骼的皮质或松质类型影响最大。测量方法(压缩、拉伸、弯曲和纳米压痕)、骨内的解剖区域、骨在骨骼中的位置以及骨试样大小对 E 值的影响依次递减。根据我们的研究结果,骨骼的 E 值会随着骨骼特征、测量技术和人口统计学变量的变化而变化。因此,应在体外测量方案标准化后再对 FEA 进行评估。© 2023 作者。JBMR Plus 由 Wiley Periodicals LLC 代表美国骨与矿物质研究学会出版。
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引用次数: 0
Antiresorptive Versus Anabolic Therapy in Managing Osteoporosis in People with Type 1 and Type 2 Diabetes 抗吸收与合成代谢治疗在治疗1型和2型糖尿病患者骨质疏松症中的作用
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-29 DOI: 10.1002/jbm4.10838
Tatiane Vilaca, Richard Eastell

Diabetes is characterized by hyperglycemia, but the two main types, type 1 diabetes (T1D) and type 2 diabetes (T2D), have distinct pathophysiology and epidemiological profiles. Individuals with T1D and T2D have an increased risk of fractures, particularly of the hip, upper arm, ankle, and nonvertebral sites. The risk of fractures is higher in T1D compared to T2D. The diagnosis of osteoporosis in individuals with T1D and T2D follows similar criteria as in the general population, but treatment thresholds may differ. Antiresorptive therapies, the first-line treatment for osteoporosis, are effective in individuals with T2D. Observational studies and post hoc analyses of previous trials have indicated that antiresorptive drugs, such as bisphosphonates and selective estrogen receptor modulators, are equally effective in reducing fracture risk and increasing bone mineral density (BMD) in individuals with and without T2D. Denosumab has shown similar effects on vertebral fracture risk but increases the risk of nonvertebral fractures. Considering the low bone turnover observed in T1D and T2D, anabolic therapies, which promote bone formation and resorption, have emerged as a potential treatment option for bone fragility in this population. Data from observational studies and post hoc analyses of previous trials also showed similar results in increasing BMD and reducing the risk of fractures in people with or without T2D. However, no evidence suggests that anabolic therapy has greater efficacy than antiresorptive drugs. In conclusion, there is an increased risk of fractures in T1D and T2D. Reductions in BMD cannot solely explain the relationship between T1D and T2D and fractures. Bone microarchitecture and other factors play a role. Antiresorptive and anabolic therapies have shown efficacy in reducing fracture risk in individuals with T2D, but the evidence is more robust for antiresorptive drugs. Evidence in T1D is scant. Further research is needed to fully understand the underlying mechanisms and optimize management strategies for bone fragility in T1D and T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

糖尿病的特征是高血糖,但两种主要类型,1型糖尿病(T1D)和2型糖尿病(T2D),具有不同的病理生理和流行病学特征。T1D和T2D患者骨折的风险增加,尤其是髋部、上臂、踝关节和非椎体部位。与T2D相比,T1D发生骨折的风险更高。T1D和T2D患者骨质疏松症的诊断标准与一般人群相似,但治疗阈值可能不同。抗吸收疗法是治疗骨质疏松的一线疗法,对T2D患者有效。观察性研究和对先前试验的事后分析表明,抗吸收药物,如双膦酸盐和选择性雌激素受体调节剂,在有和没有T2D的个体中,在降低骨折风险和增加骨密度(BMD)方面同样有效。Denosumab对椎体骨折风险有类似的影响,但增加了非椎体骨折的风险。考虑到在T1D和T2D中观察到的低骨转换,促进骨形成和吸收的合成代谢疗法已成为该人群骨脆弱性的潜在治疗选择。来自观察性研究的数据和先前试验的事后分析也显示了类似的结果,增加骨密度,降低患有或不患有T2D的人的骨折风险。然而,没有证据表明合成代谢治疗比抗吸收药物更有效。总之,T1D和T2D的骨折风险增加。骨密度降低不能单独解释T1D和T2D与骨折之间的关系。骨微结构和其他因素起作用。抗再吸收和合成代谢治疗已显示出降低T2D患者骨折风险的疗效,但抗再吸收药物的证据更为有力。T1D的证据不足。需要进一步的研究来充分了解T1D和T2D骨脆性的潜在机制并优化管理策略。©2023作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。
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引用次数: 0
Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus 2型糖尿病患者微血管疾病与皮质骨较大骨细胞腔隙相关
IF 3.8 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-27 DOI: 10.1002/jbm4.10832
Sebastian Zanner, Elliott Goff, Samuel Ghatan, Eva Maria Wölfel, Charlotte Ejersted, Gisela Kuhn, Ralph Müller, Morten Frost

Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62–72 years). The participants were included based on c-peptide levels >700 pmol L−1, absence of anti-GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol−1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro-computed tomography (micro-CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

临床研究表明,微血管疾病(MVD)影响2型糖尿病(T2D)患者的骨微结构并降低骨强度。骨细胞被安置在骨基质和骨陷窝内的小空隙中,充当骨内机械力的传感器。这些细胞调节破骨细胞骨吸收和成骨细胞骨形成以及骨细胞腔周围重塑。我们假设MVD改变了T2D患者的骨细胞腔隙参数。我们收集了35例T2D合并MVD(15%)或无MVD(21%)患者的髂骨活检(10名女性,25名男性),中位年龄为67岁(四分位间距[IQR] 62-72岁)。参与者的c肽水平为700 pmol L−1,抗gad65抗体的缺乏,糖化血红蛋白(HbA1c)水平分别为40至82 mmol mol−1或5.8%和9.7%。我们使用1.2 μm体素尺寸的微计算机断层扫描(micro-CT)评估骨小梁和骨皮质区域的骨细胞腔隙形态测量参数。皮质骨细胞腔隙体积(Lc. v)增大7.7% (p = 0.05),呈球形(Lc. v)。Sr, p < 0.01)。通过线性回归,我们发现骨小梁的腔隙密度(Lc.N/BV)与HbA1c无关,与MVD无关(p < 0.05, R2 = 0.067)。此外,信用证。V更大,Lc。骨小梁中心区Sr高于骨小梁周围区和骨皮质区(p < 0.05)。总之,这些数据表明MVD可能损害骨骼完整性,可能导致T2D合并MVD时骨骼脆性增加。©2023作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。
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