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Sex hormone deficiency in male and female mice expressing the Alzheimer's disease-associated risk-factor TREM2 R47H variant impacts the musculoskeletal system in a sex- and genotype-dependent manner. 表达阿尔茨海默病相关风险因子 TREM2 R47H 变体的雌雄小鼠缺乏性荷尔蒙会以性别和基因型依赖的方式影响肌肉骨骼系统。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-13 eCollection Date: 2025-01-01 DOI: 10.1093/jbmrpl/ziae144
Roquelina Pianeta, Padmini Deosthale, Natasha Sanz, Rachel Kohler, Chiebuka Okpara, Matthew Arnett, Iqra Asad, Amber Rogers, Madison Gerbig, Alyson Essex, Ziyue Liu, Joseph M Wallace, Lilian I Plotkin

The R47H variant of the triggering receptor expressed on myeloid cells 2 (TREM2) is a risk factor for Alzheimer's disease in humans and leads to lower bone mass accrual in female but not male 12-mo-old mice. To determine whether, as with aging, gonadectomy results in sex-specific musculoskeletal effects, gonad removal or SHAM surgery was performed in 4-mo-old TREM2R47H/+ mice and WT male and female littermates (n = 10-12/group), with sexes analyzed separately. Body weight was lower in males, but higher in females after gonadectomy, independently of their genotype. Gonadectomy also leads to decreased BMD in males at all sites and in the whole body (total) and spine in female mice for both genotypes. Total and femur BMD was lower in gonadectomized male mice 6-wk post-surgery, independently of the genotype. On the other hand, BMD was only lower in ovariectomized WT but not TREM2R47H/+ mice in all sites measured at this time point. Bone formation and resorption marker levels were not affected by orchiectomy, whereas CTX was higher 3 wk after surgery and P1NP showed a tendency toward lower values at the 6-wk time point only in ovariectomized WT mice. Micro-CT analyses showed no differences resulting from gonadectomy in structural parameters in femoral cortical bone for either sex, but lower tissue mineral density in males of either genotype 6-wk post-surgery. Nevertheless, biomechanical properties were overall lower in gonadectomized males of either genotype, and only for WT ovariectomized mice. Distal femur cancellous bone structure was also affected by gonadectomy in a genotype- and sex-dependent manner, with genotype-independent changes in males, and only in WT female mice. Thus, expression of the TREM2 R47H variant minimally alters the impact of gonadectomy in the musculoskeletal system in males, whereas it partially ameliorates the consequences of ovariectomy in female mice.

髓样细胞2 (TREM2)上表达的触发受体的R47H变体是人类阿尔茨海默病的一个危险因素,在雌性小鼠中导致骨量减少,而在雄性小鼠中则没有。为了确定性腺切除术是否会像衰老一样导致性别特异性肌肉骨骼效应,我们对4岁龄TREM2R47H/+小鼠和WT雌雄窝鼠(n = 10-12/组)进行了性腺切除术或SHAM手术,并分别对性别进行了分析。性腺切除术后,男性体重较低,但女性体重较高,与基因型无关。对于两种基因型,性腺切除术也会导致雄性小鼠所有部位的骨密度下降,以及雌性小鼠全身(总)和脊柱的骨密度下降。与基因型无关,性腺切除术后6周雄性小鼠的总骨密度和股骨骨密度均较低。另一方面,在该时间点测量的所有部位,BMD仅在卵巢切除的WT中较低,而在TREM2R47H/+小鼠中则没有。骨形成和骨吸收标志物水平不受睾丸切除术的影响,而CTX在手术后3周较高,P1NP仅在卵巢切除的WT小鼠中在6周时间点呈下降趋势。显微ct分析显示,性腺切除术后两性股骨皮质骨的结构参数没有差异,但术后6周两种基因型男性的组织矿物质密度均较低。然而,两种基因型的雄性性腺切除小鼠的生物力学特性总体上较低,并且仅对WT卵巢切除小鼠有效。性腺切除术也以基因型和性别依赖的方式影响股骨远端松质骨结构,在雄性小鼠中存在基因型无关的变化,仅在WT雌性小鼠中存在。因此,TREM2 R47H变体的表达对雄性肌肉骨骼系统中性腺切除术的影响最小,而它部分改善了雌性小鼠卵巢切除术的后果。
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引用次数: 0
In-depth clinical characterization of intravenous iron infusion-induced hypophosphatemic osteomalacia and its resolution. 静脉输铁致低磷性骨软化症的深入临床特征及解决方法。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-09 eCollection Date: 2024-12-01 DOI: 10.1093/jbmrpl/ziae139
Felix N von Brackel, Jonathan Grambeck, Florian Barvencik, Michael Amling, Ralf Oheim

Iron deficiency anemia is treated by iron supplementation. Increasing evidence has shown that the carbohydrate components in iron infusions can cause hypophosphatemia and subsequent osteomalacia due to excess intact fibroblast growth factor 23 (iFGF23). We here undertook an in-depth characterization of 13 patients with iron infusion-induced osteomalacia (IIIO). Patients were characterized (monocentric institutional practice) by means of laboratory, bone density, HR-pQCT, and virtual osteoid volume estimation. We additionally report a patient who was treated with burosumab because iron infusions had to be continued despite osteomalacia. All 13 patients received ferric carboxymaltose (FCM) infusions and presented with low phosphate levels. Stopping the FCM infusions and supportive treatment by substitution of phosphate, calcium, native, and/or active Vitamin D was the chosen therapeutic approach. Pain, mobility, and biochemical data, such as serum phosphate levels, BMD, bone microstructure, and virtual osteoid volume, were the main outcome measures. Our results indicate biochemical normalization (eg, phosphate levels pre: 0.50 mmol/L ± 0.23 mmol/L, post: 0.93 mmol/L ± 0.32 mmol/L, p<.001) after stopping the FCM infusion and establishing supportive treatment. Additionally, pain levels on the visual analog scale (VAS) decreased (VASpre 7.31 ± 1.22, VASpost 2.73 ± 1.27, p<.0001) and areal BMD (expressed by T-score) improved significantly (T-scorepre: -1.85 ± 1.84, T-scorepost: -0.91 ± 2.13, p<.05). One patient requiring ongoing FCM infusions experienced significant additional benefits from burosumab treatment. In conclusion, our results highlight the importance of monitoring phosphate in patients treated with FCM infusions. Stopping FCM infusions is effective in addressing the excess of iFGF23 and thereby phosphate wasting. Supportive therapy enables quick recovery of the musculoskeletal system and improves pain levels in these patients.

缺铁性贫血可以通过补充铁来治疗。越来越多的证据表明,铁输注中的碳水化合物成分可导致低磷血症和随后的骨软化,这是由于过量的完整成纤维细胞生长因子23 (iFGF23)。我们在此对13例铁输注诱导的骨软化症(IIIO)患者进行了深入的表征。通过实验室、骨密度、HR-pQCT和虚拟类骨体积估计对患者进行特征描述(单中心机构实践)。我们还报告了一位患者,他接受了布若单抗治疗,因为尽管有骨软化症,但必须继续输注铁。13例患者均接受三羧基麦芽糖铁(FCM)输注,均出现低磷酸盐水平。停止FCM输注和替代磷酸盐、钙、天然和/或活性维生素D的支持治疗是所选择的治疗方法。疼痛、活动能力和生化数据,如血清磷酸盐水平、骨密度、骨微结构和虚拟类骨体积是主要的结局指标。我们的结果表明生化正常化(例如,磷酸盐水平前:0.50 mmol/L±0.23 mmol/L,后:0.93 mmol/L±0.32 mmol/L, ppre: 7.31±1.22,VASpost: 2.73±1.27,ppre: -1.85±1.84,T-scorepost: -0.91±2.13,p
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引用次数: 0
Lysine specific demethylase 1 conditional myeloid cell knockout mice have decreased osteoclast differentiation due to increased IFN-β gene expression. 赖氨酸特异性去甲基化酶1条件性髓细胞敲除小鼠由于IFN-β基因表达增加而导致破骨细胞分化减少。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-09 eCollection Date: 2025-01-01 DOI: 10.1093/jbmrpl/ziae142
Kristina Astleford-Hopper, Juan E Abrahante Llorens, Elizabeth W Bradley, Kim C Mansky

Osteoclasts are large multinucleated cells that degrade bone mineral and extracellular matrix. Investigating the epigenetic mechanisms orchestrating osteoclast differentiation is key to our understanding of the pathogenesis of skeletal related diseases such as periodontitis and osteoporosis. Lysine specific demethylase 1 (LSD1/KDM1A) is a member of the histone demethylase family that mediates the removal of mono- and dimethyl groups from H3K4 and H3K9 to elicit dichotomous effects on gene expression. Prior to our study, little was known about the contributions of LSD1 to skeletal development and osteoclast differentiation. Here we show that conditional deletion of Lsd1 within the myeloid lineage or macrophage/osteoclast precursors results in enhanced bone mass of male and female mice accompanied by diminished osteoclast size in vivo. Furthermore, Lsd1 deletion decreased osteoclast differentiation and activity within in vitro assays. Our bulk RNA-SEQ data suggest Lsd1 ablation in male and female mice inhibits osteoclast differentiation due to enhanced expression of interferon-β target genes. Lastly, we demonstrate that LSD1 forms an immune complex with HDAC1 and HDAC2. These data suggest that the combination of methylation and acetylation of histone residues, facilitated by LSD1, mechanistically promotes osteoclast gene expression.

破骨细胞是一种能够降解骨矿物质和细胞外基质的大型多核细胞。研究调控破骨细胞分化的表观遗传机制是我们理解牙周炎和骨质疏松等骨骼相关疾病发病机制的关键。赖氨酸特异性去甲基酶1 (LSD1/KDM1A)是组蛋白去甲基酶家族的一员,它介导H3K4和H3K9中单甲基和二甲基的去除,从而引发基因表达的二分化效应。在我们的研究之前,人们对LSD1在骨骼发育和破骨细胞分化中的作用知之甚少。本研究表明,髓系或巨噬细胞/破骨细胞前体中Lsd1的条件缺失导致雄性和雌性小鼠的骨量增加,同时体内破骨细胞大小减小。此外,在体外实验中,Lsd1缺失降低了破骨细胞的分化和活性。我们的大量RNA-SEQ数据表明,雄性和雌性小鼠的Lsd1消融由于干扰素-β靶基因的表达增强而抑制破骨细胞分化。最后,我们证明了LSD1与HDAC1和HDAC2形成免疫复合物。这些数据表明,在LSD1的促进下,组蛋白残基的甲基化和乙酰化结合,在机制上促进了破骨细胞基因的表达。
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引用次数: 0
Altered post-fracture systemic bone loss in a mouse model of osteocyte dysfunction. 骨细胞功能障碍小鼠模型中骨折后全身骨质流失的改变。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-11-01 eCollection Date: 2024-12-01 DOI: 10.1093/jbmrpl/ziae135
Benjamin Osipov, Armaun J Emami, Hailey C Cunningham, Sophie Orr, Yu-Yang Lin, Elias H Jbeily, Ritvik S Punati, Deepa K Murugesh, Hannah M Zukowski, Gabriela G Loots, Randy Carney, Diego Vargas, Virginia L Ferguson, Blaine A Christiansen

Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.

股骨骨折会导致未受伤骨骼部位的骨质流失,这可能会增加后续骨折的风险。骨细胞是最丰富的骨细胞,可直接吸收骨基质并调节破骨细胞和成骨细胞的活性,但它们在骨折后全身骨质流失中的作用仍鲜为人知。在这项研究中,我们使用了一种转基因(TG+)小鼠模型,该模型在成骨细胞和骨细胞中过度表达人类 B 细胞淋巴瘤 2(BCL-2)。这会导致成骨细胞增殖增强,继而破坏裂隙-髓鞘连接,并在 10 周龄时造成大量成骨细胞死亡。我们假设,成活的骨细胞密度降低会减少股骨骨折后全身骨质流失的程度,减少髋关节周围的重塑,并改变胼胝体的形成。骨折后 5 d 时,我们使用血清中的骨形成和骨吸收生物标志物对骨重塑进行了评估。我们使用微型计算机断层扫描、高分辨率 X 射线显微镜、机械测试和拉曼光谱来量化全身骨质流失的程度,以及骨折后 2 周骨细胞裂隙体积、骨强度和骨成分的变化。在非转基因(TG-)动物中,骨折与骨吸收循环标志物的减少有关。TG+小鼠四肢骨质量高,皮质弹性模量大,屈服后位移减少。与 TG- 小鼠相比,TG+ 小鼠骨折后骨小梁损失较少,但相反,TG+ 小鼠骨折后屈服点呈下降趋势,股骨皮质厚度也有所减少,尽管这些趋势在统计学上并不显著。TG+小鼠的裂隙密度更大,但骨折并没有改变TG+或TG-小鼠的裂隙体积。这些研究结果表明,骨细胞可能在骨折创伤后的系统反应中发挥重要作用,尽管骨小梁和皮质骨的影响有所不同。
{"title":"Altered post-fracture systemic bone loss in a mouse model of osteocyte dysfunction.","authors":"Benjamin Osipov, Armaun J Emami, Hailey C Cunningham, Sophie Orr, Yu-Yang Lin, Elias H Jbeily, Ritvik S Punati, Deepa K Murugesh, Hannah M Zukowski, Gabriela G Loots, Randy Carney, Diego Vargas, Virginia L Ferguson, Blaine A Christiansen","doi":"10.1093/jbmrpl/ziae135","DOIUrl":"10.1093/jbmrpl/ziae135","url":null,"abstract":"<p><p>Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"8 12","pages":"ziae135"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739456","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
The uremic toxin indoxyl sulfate decreases osteocyte RANKL/OPG and increases Wnt inhibitor RNA expression that is reversed by PTH. 尿毒症毒素硫酸吲哚酚降低骨细胞RANKL/OPG,增加Wnt抑制剂RNA的表达,这种表达被甲状旁腺激素逆转。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-29 eCollection Date: 2025-01-01 DOI: 10.1093/jbmrpl/ziae136
Neal X Chen, Kalisha D O'Neill, Hannah E Wilson, Shruthi Srinivasan, Lynda Bonewald, Sharon M Moe

Renal osteodystrophy (ROD) leads to increased fractures, potentially due to underlying low bone turnover in chronic kidney disease (CKD). We hypothesized that indoxyl sulfate (IS), a circulating toxin elevated in CKD and a ligand for the aryl hydrocarbon receptor (AhR), may target the osteocytes leading to bone cell uncoupling in ROD. The IDG-SW3 osteocytes were cultured for 14 days (early) and 35 days (mature osteocytes) and incubated with 500 μM of IS after dose finding studies to confirm AhR activation. Long-term incubation of IS for 14 days led to decreased expression of Tnfsf11/Tnfrsf11b ratio (RANKL/OPG), which would increase osteoclast activity, and increased expression of Wnt inhibitors Sost and Dkk1, which would decrease bone formation in addition to decreased mineralization and alkaline phosphatase (ALP) activity. When osteocytes were incubated with IS and the AhR translocation inhibitor CH223191, mineralization and ALP activity were restored. However, the Tnfsf11/Tnfrsf11b ratio and Sost, Dkk1 expression were not altered compared with IS alone, suggesting more complex signaling. In both early and mature osteocytes, co-culture with parathyroid hormone (PTH) and IS reversed the IS-induced upregulation of Sost and Dkk1, and IS enhanced the PTH-induced increase of the Tnfsf11/Tnfrsf11b ratio. Co-culture of IS with PTH additively enhanced the AhR activity assessed by Cyp1a1 and Cyp1b1 expression. In summary, IS in the absence of PTH increased osteocyte messenger RNA (mRNA) Wnt inhibitor expression in both early and mature osteocytes, decreased mRNA expression ofTnfsf11/Tnfrsf11b ratio and decreased mineralization in early osteocytes. These changes would lead to decreased resorption and formation resulting in low bone remodeling. These data suggest IS may be important in the underlying low turnover bone disease observed in CKD when PTH is not elevated. In addition, when PTH is elevated, IS interacts to further increase Tnfsf11/Tnfrsf11b ratio for osteoclast activity in both early and mature osteocytes, which would worsen bone resorption.

肾性骨营养不良(ROD)导致骨折增加,可能是由于慢性肾脏疾病(CKD)中潜在的低骨转换。我们假设硫酸吲哚酚(IS),一种在CKD中升高的循环毒素和芳烃受体(AhR)的配体,可能靶向骨细胞,导致ROD中骨细胞解偶联。将IDG-SW3骨细胞培养14天(早期)和35天(成熟骨细胞),并在500 μM IS中进行剂量测定,确认AhR活化。IS长期孵育14天,导致Tnfsf11/Tnfrsf11b比值(RANKL/OPG)表达降低,从而增加破骨细胞活性;Wnt抑制剂Sost和Dkk1表达增加,除了矿化和碱性磷酸酶(ALP)活性降低外,还会减少骨形成。当骨细胞与IS和AhR易位抑制剂CH223191孵育时,矿化和ALP活性恢复。然而,与IS单独相比,Tnfsf11/Tnfrsf11b比值和Sost、Dkk1表达未发生改变,提示信号传导更为复杂。在早期和成熟骨细胞中,与甲状旁腺激素(PTH)和IS共培养逆转了IS诱导的Sost和Dkk1的上调,IS增强了PTH诱导的Tnfsf11/Tnfrsf11b比值的升高。通过Cyp1a1和Cyp1b1表达评估,IS与PTH共培养可增强AhR活性。综上所述,在没有PTH的情况下,IS增加了早期和成熟骨细胞中骨细胞信使RNA (mRNA) Wnt抑制剂的表达,降低了早期骨细胞中tnfsf11 /Tnfrsf11b比值的mRNA表达,降低了矿化。这些变化会导致骨吸收和骨形成减少,从而导致骨重塑降低。这些数据表明,当甲状旁腺激素不升高时,IS可能在CKD中观察到的潜在的低周转率骨病中起重要作用。此外,当PTH升高时,is相互作用进一步增加早期和成熟骨细胞中破骨细胞活性的Tnfsf11/Tnfrsf11b比值,从而加重骨吸收。
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引用次数: 0
Therapy with transitions from one bone-forming agent to another: a retrospective cohort study on teriparatide and romosozumab. 从一种骨形成剂过渡到另一种骨形成剂的治疗:一项关于特立帕肽和罗莫单抗的回顾性队列研究。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-23 eCollection Date: 2024-12-01 DOI: 10.1093/jbmrpl/ziae131
Tomonori Kobayakawa, Yasuhide Kanayama, Yuji Hirano, Toshitaka Yukishima, Yukio Nakamura

This study aimed to evaluate the effectiveness of sequential therapy with a bone formation-promoting agent (either teriparatide or romosozumab) for osteoporosis treatment following prior treatment with the other bone-forming agent (teriparatide or romosozumab). This is a multicenter retrospective cohort study observing 2 groups for comparison: one with 69 patients transitioning from teriparatide to romosozumab (the T2R group) and the other with 25 patients transitioning from romosozumab to teriparatide (the R2T group), monitored for 12 months on the second drug. Key outcomes included changes in bone mineral density (BMD), bone turnover marker changes, and adverse events. The mean ages of each group were 72.3 years in the T2R group and 67.6 years in the R2T group, with the proportions of women being 91.3% and 80.0%, respectively. The percent changes of BMD in the lumbar spine after 12 months of sequential therapy were +10.8% in the T2R group (p < .001 versus baseline) and -0.0% in the R2T group (p = .875). The percent changes in BMD in the total hip and femoral neck were +4.4% and +4.4% in the T2R group, and -1.3% and -0.8% in the R2T group, respectively. When comparing the 2 groups, BMD changes at all sites in the T2R group were significantly higher than those in the R2T group (p < .001). Furthermore, when examining the changes in the proportion of patients who achieved the osteoporosis treatment goal of a T-score exceeding -2.5, no significant increase was observed in the R2T group, whereas a significant increase was observed in the lumbar spine in the T2R group. Regarding therapy switching between bone-forming agents, this study suggests that transitioning from teriparatide to romosozumab increases BMD more effectively than transitioning in the opposite sequence.

本研究旨在评估在使用另一种骨形成药物(特立帕肽或罗莫索珠单抗)治疗骨质疏松症后,使用促进骨形成药物(特立帕肽或罗莫索珠单抗)进行序贯治疗的有效性。这是一项多中心回顾性队列研究,观察了两组患者进行比较:一组是 69 名从特立帕肽过渡到罗莫索珠单抗的患者(T2R 组),另一组是 25 名从罗莫索珠单抗过渡到特立帕肽的患者(R2T 组),对第二种药物进行为期 12 个月的监测。主要结果包括骨矿物质密度(BMD)变化、骨转换标志物变化和不良事件。T2R 组和 R2T 组的平均年龄分别为 72.3 岁和 67.6 岁,女性比例分别为 91.3% 和 80.0%。连续治疗 12 个月后,T2R 组的腰椎 BMD 变化百分比为 +10.8%(P = .875)。T2R 组全髋和股骨颈 BMD 的变化百分比分别为 +4.4% 和 +4.4%,R2T 组分别为 -1.3% 和 -0.8%。比较两组,T2R 组所有部位的 BMD 变化均显著高于 R2T 组(p
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引用次数: 0
Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity. 香叶二磷酸合成酶抑制可损害破骨细胞的分化、形态和吸收活性。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-23 eCollection Date: 2025-01-01 DOI: 10.1093/jbmrpl/ziae133
Molly E Muehlebach, Staci L Haney, Yashpal S Chhonker, Mamunur Rashid, Daryl J Murry, Geoffrey Talmon, Sarah A Holstein

Nitrogen bisphosphonates, such as zoledronic acid, target the enzyme farnesyl diphosphate synthase (FDPS) in the isoprenoid biosynthetic pathway (IBP), and are the frontline treatment for osteolytic bone diseases. A strong affinity of these agents for bone limits their distribution out of the skeleton. Geranylgeranyl diphosphate synthase (GGDPS) is directly downstream to FDPS in the IBP and novel GGDPS inhibitors such as RAM2061 have been shown to have key drug-like features including prolonged half-life, metabolic stability, and systemic distribution. Furthermore, RAM2061 exerts anti-neoplastic benefits in mouse models of multiple myeloma and Ewing sarcoma. Therefore, we are interested in determining the potential impact of RAM2061 on osteoclast biology and bone remodeling. Studies utilizing undifferentiated RAW264.7 cells demonstrated that treatment with RAM2061 depletes cells of geranylgeranyl diphosphate, impairs protein geranylgeranylation, and induces markers of the unfolded protein response pathway and apoptosis. Differentiation of RAW264.7 cells to mature osteoclasts is disrupted by RAM2061, resulting in decreased numbers of mature osteoclasts, altered morphology, and decreased tartrate-resistant acid phosphatase activity. Treatment of fully differentiated RAW264.7 cells with RAM2061 led to decreased resorptive activity. Confocal microscopy studies revealed that RAM2061 disrupts Cdc42 localization, inhibiting proper actin ring formation in osteoclasts. No significant impact on bone turnover markers or bone histomorphology was observed following a 3-week treatment of CD-1 mice with RAM2061, although decreased numbers of osteoclasts were observed. Liquid chromatography-tandem mass spectrometry studies confirmed accumulation of RAM2061 in bone from the in vivo studies as well as hydroxyapatite binding in vitro. In conclusion, these studies are the first to demonstrate the anti-osteoclastic activity of GGDPS inhibitor treatment and support future studies exploring the therapeutic benefit of this novel therapy in the setting of pathological bone remodeling.

氮双膦酸盐,如唑来膦酸,在类异戊二烯生物合成途径(IBP)中靶向法尼基二磷酸合成酶(FDPS),是溶骨性骨病的一线治疗药物。这些药物对骨骼的强亲和力限制了它们在骨骼外的分布。在IBP中,香叶二磷酸合成酶(GGDPS)直接位于FDPS的下游,RAM2061等新型GGDPS抑制剂已被证明具有关键的药物样特征,包括半衰期延长、代谢稳定性和全身分布。此外,RAM2061在多发性骨髓瘤和尤文氏肉瘤小鼠模型中具有抗肿瘤作用。因此,我们有兴趣确定RAM2061对破骨细胞生物学和骨重塑的潜在影响。利用未分化的RAW264.7细胞进行的研究表明,RAM2061处理可减少细胞中香叶基二磷酸的表达,损害蛋白香叶基化,诱导未折叠蛋白反应途径的标记物和细胞凋亡。RAM2061破坏RAW264.7细胞向成熟破骨细胞的分化,导致成熟破骨细胞数量减少,形态改变,抗酒石酸盐酸性磷酸酶活性降低。RAM2061处理完全分化的RAW264.7细胞导致吸收活性降低。共聚焦显微镜研究显示RAM2061破坏Cdc42的定位,抑制破骨细胞中适当的肌动蛋白环的形成。RAM2061对CD-1小鼠治疗3周后,虽然破骨细胞数量减少,但对骨转换标志物或骨组织形态学没有明显影响。液相色谱-串联质谱研究证实了RAM2061在体内的积累以及羟基磷灰石在体外的结合。总之,这些研究首次证明了GGDPS抑制剂治疗的抗破骨活性,并支持未来研究探索这种新疗法在病理性骨重塑中的治疗益处。
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引用次数: 0
Evaluating the relationship between glycemic control and bone fragility within the UK Biobank: observational and one-sample Mendelian randomization analyses. 评估英国生物库中血糖控制与骨脆性之间的关系:观察性分析和单样本孟德尔随机分析。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 eCollection Date: 2024-11-01 DOI: 10.1093/jbmrpl/ziae126
Samuel Ghatan, Fjorda Koromani, Katerina Trajanoska, Evert F S van Velsen, Maryam Kavousi, M Carola Zillikens, Carolina Medina-Gomez, Ling Oei, Fernando Rivadeneira

We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA1c was used to classify patients into "adequately-" (ACD; n = 17 078; HbA1c < 7.0%/53 mmol/mol) and "inadequately-" (ICD; n = 10 682; HbA1c ≥ 7.0%/53 mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11 mmol/mol) increase in HbA1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA1c. Fracture risk between the T2D ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA1c and eBMD. We obtained evidence that lower HbA1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.

我们的目的是(1) 研究 1 型糖尿病 (T1D) 和 2 型糖尿病 (T2D) 患者的血糖控制、足跟超声估测的 BMD(eBMD)和骨折风险之间的关系;(2) 进行单样本孟德尔随机化 (MR) 研究,探索血糖控制、eBMD 和骨折之间的潜在因果关系。这项研究包括英国生物库中的 452 131 名糖化血红蛋白 A1C (HbA1c) 和 eBMD 水平的个体。基线时,4078 名参与者被诊断为 T1D,23682 名参与者被诊断为 T2D。HbA1c 用于将患者划分为 "充分"(ACD;n = 17 078;HbA1c n = 10 682;HbA1c ≥ 7.0%/53 mmol/mol)控制的糖尿病患者。在 T1D 患者中,HbA1c 水平每增加 1%(11 mmol/mol),骨折风险就会增加 12%(HR:1.12,95% CI [1.05-1.19])。与没有糖尿病的受试者相比,患有 T1D 和 ICD 的受试者骨折风险最高(HR 2.84,95%CI [2.53,3.19]),其次是患有 ACD 的受试者(HR 2.26,95%CI [1.91,2.69])。在 T2D 患者中,有证据表明 HbA1c 与骨折风险之间存在非线性关系(F 检验方差分析 p 值 = 0.002),HbA1c 水平越低和越高,骨折风险越高。尽管 BMD 增加,但 T2D ACD 组和 ICD 组之间的骨折风险并无显著差异(HR:0.97,95%CI [0.91-1.16])。在 MR 分析中,遗传预测的较高 HbA1c 水平与骨折风险无显著相关性(因果风险比:1.04,95%CI [0.95-1.14])。我们确实观察到与 eBMD 存在非线性因果关系的证据(二次检验 p 值 = 0.0002),表明 HbA1c 与 eBMD 之间存在 U 型关系。我们获得的证据表明,降低 HbA1c 水平可降低 T1D 患者的骨折风险。对于 T2D 患者,降低 HbA1c 水平可减轻骨折风险,但需达到一定的临界值,超过该临界值,骨折风险可能会开始回升。
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引用次数: 0
Correction to: Evidence for peri-lacunar remodeling and altered osteocyte lacuno-canalicular network in mouse models of myeloma-induced bone disease. 更正:骨髓瘤诱发骨病小鼠模型中腔周重塑和骨细胞腔隙-颅骨网络改变的证据
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-24 eCollection Date: 2024-10-01 DOI: 10.1093/jbmrpl/ziae123

[This corrects the article DOI: 10.1093/jbmrpl/ziae093.].

[此处更正了文章 DOI:10.1093/jbmrpl/ziae093]。
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引用次数: 0
Healing sequelae following tooth extraction and dental implant placement in an aged, ovariectomy model. 老年卵巢切除模型拔牙和种植牙后的愈合后遗症。
IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-31 eCollection Date: 2024-10-01 DOI: 10.1093/jbmrpl/ziae113
Jessica M Latimer, Shogo Maekawa, Takahiko Shiba, Tobias Fretwurst, Michael Chen, Lena Larsson, James V Sugai, Paul Kostenuik, Bruce Mitlak, Beate Lanske, William V Giannobile

At present, a lack of consensus exists regarding the clinical impact of osteoporosis on alveolar bone metabolism during implant osseointegration. While limited preclinical and clinical evidence demonstrates a negative influence of osteoporosis on dental extraction socket healing, no preclinical studies offer data on the results of implant placement in 6-mo-old, ovariectomized (OVX) Sprague-Dawley rats. This study aimed to investigate the outcomes of dental tooth extraction socket healing and implant placement in a rodent model of osteoporosis following daily vehicle (VEH) or abaloparatide (ABL) administration. Micro-CT and histologic analysis demonstrated signs of delayed wound healing, consistent with alveolar osteitis in extraction sockets following 42 d of healing in both the VEH and ABL groups. In a semiquantitative histological analysis, the OVX-ABL group demonstrated a tendency for improved socket regeneration with a 3-fold greater rate for moderate socket healing when compared to the OVX-VEH group (43% vs 14%), however, this finding was not statistically significant (p=.11). No significant differences were observed between vehicle and test groups in terms of implant outcomes (BMD and bone volume/total volume) at 14- and 21-d post-implant placement. Abaloparatide (ABL) significantly increased BMD of the femoral shaft and intact maxillary alveolar bone sites in OVX animals, demonstrating the therapeutic potential for oral hard tissue regeneration. The present model involving estrogen-deficiency-induced bone loss demonstrated an impaired healing response to dental extraction and implant installation.

目前,关于骨质疏松症对种植体骨结合过程中牙槽骨代谢的临床影响还缺乏共识。虽然有限的临床前和临床证据表明骨质疏松症对拔牙窝愈合有负面影响,但没有临床前研究提供有关 6 个月大的卵巢切除(OVX)Sprague-Dawley 大鼠植入种植体的结果数据。本研究旨在调查在骨质疏松症啮齿动物模型中,每天服用药物(VEH)或阿巴拉帕肽(ABL)后,拔牙窝愈合和植入物植入的结果。显微 CT 和组织学分析表明,在 VEH 组和 ABL 组拔牙窝愈合 42 天后,出现了与牙槽骨炎一致的伤口延迟愈合迹象。在半定量组织学分析中,OVX-ABL 组显示出牙槽骨再生改善的趋势,与 OVX-VEH 组相比,中度牙槽骨愈合率增加了 3 倍(43% 对 14%),但这一结果并无统计学意义(P=.11)。在植入后 14 天和 21 天的植入结果(BMD 和骨量/总骨量)方面,载体组和试验组之间未观察到明显差异。阿巴帕肽(ABL)能显著增加卵巢功能缺失动物股骨柄和完整上颌骨牙槽骨部位的 BMD,证明了其在口腔硬组织再生方面的治疗潜力。本模型涉及雌激素缺乏引起的骨质流失,表明拔牙和安装种植体的愈合反应受损。
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