Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss

Introduction: Pharmacological options to address the imbalance between bone resorption and accrual in osteoporosis include anti-resorptive and osteoanabolic agents. Unique biologic pathways such as the Wnt/β-catenin pathway have been targeted in the quest for new emerging therapeutic strategies.

Areas covered: This review provides an overview of existing pharmacotherapy for osteoporosis in women and explore state-of–the-art and emerging therapies to prevent bone loss, with an emphasis on the mechanism of action, indications and side effects.

Expert opinion: Bisphosphonates appear to be a reliable and cost-effective option, whereas denosumab has introduced a simpler dosing regimen and may achieve a linear increase in bone mineral density (BMD) with no plateau being observed, along with continuous anti-fracture efficacy. Abaloparatide, a parathyroid-hormone-related peptide (PTHrP)-analogue, approved by the FDA in April 2017, constitutes the first new anabolic osteoporosis drug in the US for nearly 15 years and has also proven its anti-fracture efficacy. Romosozumab, a sclerostin inhibitor, which induces bone formation and suppresses bone resorption, has also been developed and shown a significant reduction in fracture incidence; however, concerns have arisen with regard to increased cardiovascular risk.     

血清骨膜蛋白和骨硬化蛋白对老年2型糖尿病患者骨质疏松的诊断价值

目的 探讨血清骨膜蛋白(PN)和骨硬化蛋白(SOST)与老年 2 型糖尿病(T2DM)患者骨密度的关系。方法 选取2020年8月—2022年3月海南医学院第二附属医院收治的192例老年T2DM患者作为研究对象,依据骨密度值分为骨量正常组、骨量减少组及骨质疏松组,每组64例。比较3组患者的临床资料,血清PN、SOST、25羟维生素D₃[25(OH)D₃]、骨钙素(OST)及I型胶原氨基端前肽(PINP)水平。多因素Logistic回归分析影响老年T2DM患者骨质疏松发生的危险因素。绘制受试者工作特征(ROC)曲线,以ROC曲线下面积(AUC)评价血清PN、SOST及两者联合对老年T2DM患者骨质疏松的诊断价值。结果 骨量正常组、骨量减少组及骨质疏松组HbA1c、HDL-C、PN、SOST、25(OH)D₃、OST及PINP水平比较,差异有统计学意义(P <0.05),骨质疏松组HbA1c、PN、SOST、OST及PINP水平高于骨量正常组和骨量减少组(P <0.05),骨质疏松组HDL-C、25(OH)D     

FGF23、sclerostin蛋白、fetuin-A与慢性肾脏病患者血管钙化的相关性研究

目的探讨成纤维细胞生长因子23(FGF23)、骨硬化蛋白(sclerostin蛋白)、胎球蛋白A(fetuin-A)与慢性肾脏病患者血管钙化的相关性。方法选取2018年2月至2020年2月该院诊治的200例慢性肾脏病患者,根据冠状动脉有无钙化分为观察组(102例)与对照组(98例),比较两组FGF23、sclerostin蛋白、fetuin-A水平,评估FGF23、sclerostin蛋白、fetuin-A诊断血管钙化的效能。其中,观察组根据冠状动脉钙化积分分为3组,每组34例,比较不同钙化组的FGF23、sclerostin蛋白、fetuin-A水平,以及分析血管不同钙化程度与FGF23、sclerostin蛋白、fetuin-A的相关性,以及评估FGF23、sclerostin蛋白、fetuin-A诊断血管重度钙化的效能。结果观察组患者FGF23、sclerostin蛋白水平高于对照组,而fetuin-A水平低于对照组(P<0.05)。受试者工作特征曲线分析显示,FGF23、sclerostin蛋白、fetuin-a的曲线下面积(AUC)分别为0.990、0.967、0.722(P<0.05)。在不同钙化组中,FGF23、sclerostin蛋白水平均为轻度钙化组<中度钙化组<重度钙化组,而fetuin-A水平为轻度钙化组>中度钙化组>重度钙化组,差异均有统计学意义(P<0.05)。Spearman相关分析显示,慢性肾脏病患者的血管钙化严重程度与FGF23、sclerostin蛋白呈正相关(P<0.05),与fetuin-A呈负相关(P<0.05)。血管重度钙化患者的FGF23、sclerostin蛋白、fetuin-A的AUC分别为0.917、0.926、0.749(P<0.05)。结论FGF23、sclerostin蛋白、fetuin-A水平与慢性肾脏病患者血管钙化的严重程度有关,可将以上指标作为临床诊断血管钙化的参考指标。     

Osteocytic Sclerostin Expression in Alveolar Bone in Rats With Diabetes Mellitus and Ligature‐Induced Periodontitis

Background: Osteocytic sclerostin inhibits bone formation, and its expression is stimulated by tumor necrosis factor (TNF)‐α. This study investigates sclerostin and TNF‐α expression in rats with diabetes mellitus (DM) and periodontitis. Methods: Rats were divided into control (C), periodontitis (P), and DM + periodontitis (DP) groups. After induction of DM by streptozotocin, periodontitis was induced by ligature. At day 0 (control) and at days 3 and 20 after induction of periodontitis, alveolar bone, osteoclasts, osteoid area, and TNF‐α and sclerostin expression were evaluated. Results: The distance between the cemento‐enamel junction and the alveolar bone crest of the DP group was longer than that of the P group at day 20 after induction of periodontitis, but the number of osteoclasts was not different. Osteoid area decreased in both the P and DP groups by day 3, but whereas sustained osteoid suppression was observed in the DP group at day 20, osteoid formation was increased in the P group. The number of sclerostin‐positive osteocytes increased in both groups at day 3, but the increased number of sclerostin‐positive osteocytes was maintained only in the DP group through day 20. The number of TNF‐α–positive cells increased more in the DP group than in the P group. Conclusions: Enhanced alveolar bone loss, suppressed bone formation, and prevalent TNF‐α expression were characteristic of the DP group compared with the P group. Suppressed bone formation in the DP group was observed simultaneously with increased sclerostin and TNF‐α expression. These results suggest that upregulated osteocytic sclerostin expression in periodontitis accompanied by DM may play a role in suppressed bone formation.     

Vitamin D and spondyloarthritis

In cross-sectional studies, vitamin D deficiency is frequent in spondyloarthritic patients and associated with increased spondyloarthritis (SpA) activity and structural damage. Experimental studies also show that vitamin D interferes with molecular pathways critically involved in SpA, especially regarding entheseal inflammation and ossification (involving cytokines such as IL-23 and sclerostin). Vitamin D deficiency might also affect the course of the disease through periodontal and gut inflammation, leading to increased functional impairment. Therefore, Vitamin D receptor selective agonists could represent a promising therapeutic pathway in this pathology. Randomised-controlled intervention studies are required in order to further elucidate complex relationships between vitamin D deficiency and SpA.     

Effects of sclerostin antibody on healing of a non‐critical size femoral bone defect

Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl‐AbIII) would accelerate the healing of a murine femoral non‐critical size bone defect model. A unilateral and unicortical 0.8 mm‐sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl‐AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl‐AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl‐AbIII group, indicating early bone maturation following treatment with Scl‐AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl‐AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl‐AbIII resulted in earlier healing and maturation of a non‐critical size bone defect. These findings underscore the potential use of Scl‐AbIII for treatment of complicated fractures, non‐unions, and other clinical scenarios. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:155–163, 2012     

脉冲电磁场磁疗与骨硬化蛋白单克隆抗体联合干预绝经后新西兰大白兔骨代谢和骨微结构的变化

文题释义：低频脉冲电磁场(pulsed electromagnetic fields,PEMFs)疗法：是目前常用的骨质疏松症物理治疗方法。脉冲电磁场治疗骨质疏松症的原理是采用低频脉冲电磁场改变人体生物电、改善生物场,促使成骨细胞增生,增强成骨能力,提高骨密度治疗骨质疏松。 骨硬化蛋白的单克隆抗体(sclerostin antibody,Scl-Ab)：对骨代谢的影响集中体现在对骨硬化蛋白的拮抗作用上。骨硬化蛋白单克隆抗体在刺激成骨活动的同时,不会刺激破骨活动,对骨合成代谢有显著刺激作用,其已经成为治疗骨质疏松的潜在方法。 背景：脉冲电磁场与骨硬化蛋白单克隆抗体皆能对绝经后新西兰大白兔骨代谢产生良好影响,但关于两者联合干预的效果至今少有报道。 目的：探讨脉冲电磁场联合骨硬化蛋白单克隆抗体对绝经后新西兰大白兔骨代谢的影响,探索其对骨质疏松症的治疗价值。 方法：采用卵巢切除法建立新西兰大白兔绝经后骨质疏松动物模型。将实验动物随机分为4组：卵巢切除组、脉冲电磁场组、骨硬化蛋白单克隆抗体组和脉冲电磁场+骨硬化蛋白单克隆抗体组,每组10只。术后第1天起,脉冲电磁场组给予脉冲电磁场磁疗每天1次;骨硬化蛋白单克隆抗体组给予骨硬化蛋白单克隆抗体皮下注射每周2次;脉冲电磁场+骨硬化蛋白单克隆抗体组接受脉冲电磁场磁疗每天1次、每周5次,骨硬化蛋白单克隆抗体皮下注射每周2次;卵巢切除组皮下注射相同剂量的生理盐水每周2次,干预共8周。8周后行骨代谢指标检查、骨密度测定、MicroCT骨微结构参数检测。动物研究中的所有程序经复旦大学实验动物科学部批准(20171263A193)。 结果与结论：①卵巢切除6个月新西兰大白兔骨密度显著下降,提示骨质疏松模型建立成功;②与卵巢切除组相比,3个治疗组L₃椎体的骨密度均显著增加(P < 0.05);③3个治疗组血清骨特异性碱性磷酸酶水平均显著高于卵巢切除组,血清抗酒石酸酸性磷酸酶5b水平均显著低于卵巢切除组;脉冲电磁场+骨硬化蛋白单克隆抗体组血清抗酒石酸酸性磷酸酶5b的水平明显低于脉冲电磁场组、骨硬化蛋白单克隆抗体组;④脉冲电磁场+骨硬化蛋白单克隆抗体组骨微结构参数(骨体积分数､骨小梁厚度､骨小梁数量､骨小梁分离度)均优于脉冲电磁场组、骨硬化蛋白单克隆抗体组(均P < 0.05);⑤骨硬化蛋白单克隆抗体和脉冲电磁场联合治疗可以增强去势新西兰大白兔骨密度,改善骨代谢和骨微结构。 ORCID: 0000-0001-7052-4262(钱光) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Anatomical similarity between the Sost-knockout mouse and sclerosteosis in humans

Sclerosteosis, a rare autosomal recessive genetic disorder caused by a mutation of the Sost gene, manifests in the facial skeleton by gigantism, facial distortion, mandibular prognathism, cranial nerve palsy, and, in extreme cases, compression of the medulla oblongata. Mice lacking sclerostin reflect some symptoms of sclerosteosis, but this is the first report of the effect on the facial skeleton. We used geometric morphometrics (GMM) to analyze the deformations of the murine facial skeleton from the wild-type to the Sost gene knockout. Landmark coordinates were obtained by surface reconstructions from micro-computed tomography. Centroid size, principal component scores in shape space and form space, and asymmetry were computed by the standard GMM formulas, and dental and skeletal jaw lengths were examined as ratios. We show here that, compared to wild type controls, mice lacking Sost have larger centroid size (effect size, p-value: 4.59, <.001), higher mean asymmetry (1.14, .065), dental and skeletal mandibular prognathism (1.36, .010 and 5.92, <.001), a smaller foramen magnum (−1.71, .015), and calvaria that are more highly curved (form space p = 4.09, .002; shape space p = 12.82, .002). These features of mice lacking sclerostin largely correspond to the changes of the facial skeleton observed in sclerosteosis. This alignment further supports claims that the Sost gene plays a fundamental role in bony facial development in rodents and humans alike.