雷尼酸锶对尾吊大鼠失重性骨质疏松的防治作用

目的观察雷尼酸锶(SR)对尾吊大鼠血清骨代谢指标、骨密度、骨生物力学的影响。方法选用3月龄雄性健康SD大鼠30只,随机分为5组:全程对照组(A组)、尾吊时服用SR组(B组)、尾吊后服用SR组(C组)、全程服用SR组(D组)、尾吊后对照组(E组),共8周(其中尾吊4周)。分别检测血清骨代谢指标,行骨密度检查及骨生物力学实验。结果尾吊后对照组碱性磷酸酶和骨钙素活性明显高于其余各组(P0.05)。骨密度、最大压缩载荷、最大三点弯曲载荷均比A组低,经过SR治疗后各组指标均有不同程度提高(P0.05),但尾吊后服用SR组和全程服用SR组效果相当且优于尾吊时服用SR组。结论雷尼酸锶对尾吊大鼠骨质疏松有防治作用。     

雷尼酸锶促进大鼠股骨骨质疏松性骨折愈合的研究

目的 探讨雷尼酸锶(strontium ranelate,SR)对大鼠股骨骨质疏松性骨折愈合的影响。方法 6个月龄Wistar雌性处鼠66只,切除双侧卵巢制作骨质疏松动物模型,模型建立成功后,在大鼠股骨中段横行截骨,制作大鼠股骨骨质疏松性骨折动物模型,术后死亡6只,然后将剩余60只大鼠随机分为实验组(SR干预治疗组）和空白对照组,每组30只。骨折术后第一天起,实验组给予SR 400 mg/(kg d)灌胃,对照组给予同等体积的生理盐水灌胃。通过影像学、组织学和免疫组织化学（骨形态发生蛋白-2,BMP-2)观察,骨组织形态计量学、骨密度（bone mineral density,BMD)和生物力学测量,观察骨折愈合情况。结果 实验组腰4、5椎体BMD、BMP-2阳性表达细胞数、骨小梁面积比、骨小梁平均宽度、最大负荷和最大桡度高于同时期对照组,差异有统计学意义(P <0. 01);骨小梁平均间隔小于同期对照组,差异有统计学意义(P <0. 01)。结论 SR具有抑制骨吸收和促进骨形成的双重作用,能增加BMD,加快骨痴形成,促进骨质疏松性骨折愈合,改善骨的显微结构,提高骨折愈合后骨的生物力学特性。     

雷尼酸锶治疗骨质疏松症的研究进展

雷尼酸锶（Strontium Ranelate，SR）由一个有机酸（雷尼酸）和两个非放射性锶原子组成。SR具有双向调节作用，能诱导骨重建的解偶联，增加骨形成，减少骨吸收，但不抑制骨转换，是非常有潜力的新药，目前被认为是有效治疗骨质疏松症的药物之一。但国内相关研究还很少。     

金乌骨胶囊联合雷尼酸锶治疗绝经后妇女 骨质疏松症的临床观察

目的 评价金乌骨胶囊联合雷尼酸锶治疗绝经后骨质疏松症有效性和安全性.方法 选70例绝经后妇女骨质疏松患者随机分治疗组与对照组各35例;对照组给金乌骨胶囊,口服,3次/d,3粒/次;治疗组在对照组基础上加用雷尼酸锶2mg/d,疗程14周;治疗前后检测采用超声骨密度仪测左侧跟骨低骨量.结果 两组绝经后妇女治疗后症状均有所减轻,骨密度较治疗前明显增加,骨折风险减少(P＜0.05);临床疗效优于单用金乌骨胶囊组(P＜0.05),临床症状好转达97.14％.结论 金乌骨胶囊联合雷尼酸锶治疗骨质疏松疗效比单一用药治疗效果及安全性更确切.     

雷尼酸锶对局部肌麻痹大鼠的骨量丢失及微结构退变的影响

目的 研究雷尼酸锶对局部肌肉麻痹大鼠的骨量丢失及微结构退变的影响。方法 21只3.5月龄的雌性SD大鼠随机分三组,每组各7只：肉毒素组(BTX组),右侧股四头肌肌注肉毒素建立局部肌肉麻痹废用模型;肉毒素+雷尼酸锶组(BTX+SR组),肌注肉毒素并予以雷尼酸锶灌胃处理;对照组。所有大鼠干预9周后处死,取双侧股骨,行显微CT扫描分析。结果 BTX组与对照组相比较,废用侧的股骨皮质骨矿物盐含量、皮质骨骨密度、皮质骨面积和截面总面积以及松质骨的骨体积分数、骨小梁厚度、骨小梁数量和骨小梁联接密度均明显下降;骨小梁面积分数、骨小梁间隔和结构模型指数显著增加(P＜0.05)。BTX+SR组与BTX组相比较,皮质骨骨密度、皮质骨面积和截面总面积以及松质骨的组织骨密度、骨体积分数、骨小梁厚度、骨小梁数量和骨小梁联接密度明显增加,骨小梁面积分数、骨小梁间隔和结构模型指数显著下降(P＜0.05)。BTX+SR组与BTX组和对照组比较,健侧松质骨的表观骨密度、组织骨密度、骨体积分数和骨小梁厚度均明显增加(P＜0.05)。结论 雷尼酸锶可阻止因局部肌肉麻痹导致的大鼠骨量丢失和微结构的退变。     

雷奈酸锶对大鼠骨质疏松性骨折愈合的骨密度及骨微结构影响

目的 观察雷奈酸锶对大鼠胫骨骨质疏松性骨折愈合过程中的骨密度、骨微结构及愈合后生物力学特性的影响.方法 72只雌性SD大鼠卵巢去势制造骨质疏松模型,造模成功后制造开放性骨折并予克氏针内固定.术后分为对照组和治疗组,分别给予生理盐水和雷奈酸锶625mg/( kg·d)灌胃给药.结果 在治疗后6、8w时两组骨性愈合率并无明显差异,但Micro CT检验数据结果显示治疗组骨密度(BMD);骨小梁体积(BV)、组织体积(TV)、骨体积分数(BV/TV)、平均骨小梁厚度(Tb.Th)、平均骨小梁数目(Tb.N)均明显高于对照组(P＜0.05),且治疗组最大压缩荷载在治疗后4w(48.1±:5.6(治疗组)vs 21.8±4.8(对照组))、8w时亦明显高于对照组(96.5±9.7(治疗组)vs68.2±7.4(对照组)).结论 雷奈酸锶能够抑制骨折后的骨量丢失,增加骨密度,促进骨折愈伤组织的生长,改善骨小梁三维结构及骨组织的力学性能,可用来促进骨质疏松性骨折的愈合并改善骨质量,预防再骨折.     

抗骨质疏松药物的研究进展

骨质疏松(osteoporosis)是一种最为常见的代谢性骨病,主要表现为骨量减少、骨组织微结构破坏从而导致骨痛、骨脆性及骨折危险性增加。目前临床常用抗骨质疏松药物可分为骨吸收抑制剂、骨形成剌激剂及骨矿化药物。选择性雌激素受体调节剂（SERMs)作为一种新型骨吸收抑制剂,于骨骼系统表现为雌激素激动剂作用,于乳腺等组织表现为雌激素拮抗剂作用,从而不增加致癌风险。骨保护素（OPG)及抗RANKL单克隆抗体可与核因子KB受体活化因子（RANK)竞争结合其配体 (RANKL),从而抑制破骨细胞骨重吸收作用。C-src激酶抑制剂可阻断破骨细胞的细胞内信号转导通路从而不能形成完整的细胞骨架,氯离子通道阻滞剂可破坏破骨细胞骨吸收酸性微环境,αVβ3整合素抗体及其受体拮抗剂可减弱破骨细胞与骨组织粘附,组织蛋白酶K抑制剂可减少骨胶原裂解,从而均有待于成为新一代骨吸收抑制剂。新型骨形成剌激剂主要包括PTH 片段制剂、钙离子敏感受体激动剂、骨硬化蛋白中和抗体、他汀类药物等。其中钙离子敏感受体激动剂于成骨细胞可通过促分裂原活化蛋白激酶(MAPK)通路来促进成骨细胞的骨形成作用,于破骨细胞可能通过RANKL信号通路以诱导破骨细胞凋亡。骨硬化蛋白中和抗体可抑制骨硬化蛋白与低密度脂蛋白受体相关蛋白（LRP)5/6结合,从而保证Wnt信号通路在骨形成及重建中发挥作用。他汀类药物则通过增强机体内骨形态发生蛋白-2基因表达以增加骨强度,减少骨折发生。本文就目前新型骨吸收抑制剂及新型骨形成剌激剂的研究进展作一综述。     

微量元素锶与骨质疏松症

随着世界范围内老龄人口的不断增加,骨质疏松症已经成为严重危害中老年人健康的常见病、多发病。骨质疏松症患者不仅易于发生骨折,他们在接受牙种植、人工关节置换等治疗时,还经常存在生物植入材料骨整合不佳、甚至松动脱落的问题,严重限制了中老年患者生活质量的提高。因此,探索各种科学、合理的方法改善骨质疏松症患者的骨代谢状况,预防骨质疏松性骨折的发生,促进骨质疏松性骨折的愈合,改善骨质疏松状态下植入体的骨整合已经成为骨科、矫形外科、口腔颌面外科以及老年医学等多学科领域内亟待解决的难题。近期的研究发现,微量元素锶是一种具有促进成骨和抑制骨吸收双重作用的抗骨质疏松药物,本文就微量元素锶治疗骨质疏松症的研究进展作一综述。     

骨形成蛋白联合雷奈酸锶对成骨细胞增殖和分化的影响

目的探索骨形成蛋白(bone morphogenetic protein,BMP)联合雷奈酸锶(strontium ranelate,SR)对成骨细胞增殖和分化的影响,为临床上两者联合使用可行性提供细胞学基础。方法获取SD大鼠成骨细胞,随机分为对照组、SR组、BMP组和BMP-SR组等4组,培养基中分别添加安慰剂、SR、BMP-2和SR联合BMP-2干预,培养12 d后,通过MTT法检测细胞的增殖情况,碱性磷酸酶(alkaline phosphatase,ALP)及茜素红染色观察细胞的功能状态,蛋白电泳观察骨钙素(osteocalcin,OCN)及Runx2蛋白的表达情况。结果 SR及BMP-2单独作用于成骨细胞时,都可以明显促进成骨细胞的增殖,增加ALP活性及矿化能力,同时明显促进OCN及Runx2蛋白的表达;联合使用效果明显优于单独使用,比较差异有统计学意义(P0.05)。结论 BMP-2及SR都可以明显促进成骨细胞增殖和分化,且联合使用效果更佳。     

雷奈酸锶对骨质疏松性骨痛及骨密度疗效评价

目的研究雷奈酸锶联合钙剂在骨质疏松症治疗中对骨痛、骨密度及骨质疏松性骨折风险的作用,评价其疗效和安全性。方法 124例老年骨质疏松症患者被随机分为雷奈酸锶+钙剂组(SR+Ca组,62例)和钙剂组(Ca组,62例),进行开放、对比研究。雷奈酸锶+钙剂组:雷奈酸锶2g/d,口服,同时口服钙剂600mg/d;Ca组:钙剂600mg/d,口服。治疗前后分别测定两组患者腰背部自发性疼痛的VAS评分、L1-L4椎体、股骨颈、Wards三角、桡骨远端的BMD值及T值,并观察两组骨质疏松性骨折的发生率及服药后的不良反应。结果治疗后雷奈酸锶+钙剂组VAS评分明显改善,低于钙剂组,但骨痛缓解过程较为缓慢;雷奈酸锶+钙剂组L1-L4椎体、股骨颈、Wards三角、桡骨远端的BMD值及T值在治疗后6月及12月较治疗前上升显著,明显优于钙剂组(P<0.01)。骨质疏松脆性骨折的发生率钙剂组明显高于雷奈酸锶+钙剂组。雷奈酸锶的主要不良反应为恶心及腹泻,钙剂组主要为便秘。结论雷奈酸锶对骨痛的缓解作用较为缓慢,但经过足够的疗程依然能达到令人满意的效果。它能有效提高骨质量,降低骨质疏松脆性骨折的发生率,副反应少,是治疗骨质疏松症的良好选择。     

Strontium ranelate does not stimulate bone formation in ovariectomized rats

INTRODUCTION: Strontium ranelate (SrR) is suggested to function as a dual-acting agent in the treatment of postmenopausal osteoporosis with anti-resorptive and anabolic skeletal benefits. We evaluated the effects of SrR on the skeleton in ovariectomized (OVX) rats and evaluated the influence of dietary calcium. METHODS: Three-month old virgin female rats underwent ovariectomy (OVX, n = 50) or SHAM surgery (SHAM, n = 10). Four weeks post-surgery, rats were treated daily by oral gavage with distilled water (10 ml/kg/day) or SrR (25 or 150 mg/kg/day) for 90 days. Separate groups of animals for each dose of SrR were fed a low (0.1%) or normal (1.19%) calcium (Ca) diet. Static and dynamic histomorphometry, DXA, mu-CT, mechanical testing, and serum and skeletal concentrations of strontium were assessed. RESULTS: SrR at doses of 25 and 150 mg/kg/day did not increase bone formation on trabecular or periosteal bone surfaces, and failed to inhibit bone resorption of trabecular bone regardless of Ca intake. There were no improvements in bone mass, volume or strength with either dose of SrR given normal Ca. CONCLUSION: These findings demonstrate that SrR at dosages of 25 and 150 mg/kg/day did not stimulate an anabolic bone response, and failed to improve the bone biomechanical properties of OVX rats.     

The Effects of Strontium Ranelate in Asian Women with Postmenopausal Osteoporosis

The aim of this study was to assess the efficacy and safety of strontium ranelate in the treatment of postmenopausal women with osteoporosis in Taiwan. In this 12-month multicenter, randomized, double-blind, placebo-controlled study, 125 women with osteoporosis were randomly given either strontium ranelate 2 g daily or placebo. Lumbar spine, femoral neck, and total-hip bone mineral density (BMD) and biochemical markers of bone turnover were measured; adverse events and tolerability were recorded and assessed. Subjects treated with strontium ranelate showed significant increases in BMD of 5.9% at the lumbar spine, 2.6% at the femoral neck, and 2.7% at the total hip, while the placebo group exhibited no significant change at 12 months. Serum level of a formation marker (bone-specific alkaline phosphatase) was also significantly increased at 6 and 12 months. Thus, although the sample size and the treatment duration of this study could not show its effect of reducing osteoprotic fractures, strontium ranelate showed bone protection effects by increasing BMD and concentrations of a bone formation marker. Safety assessment revealed adverse events were mild and not significantly different from placebo. An erratum to this article can be found at     

Strontium ranelate improves bone strength in ovariectomized rat by positively influencing bone resistance determinants

Summary  Treatment of adult ovariectomized (OVX) rats with strontium ranelate prevented vertebral biomechanics degradation as a result of the prevention of bone loss and micro-architecture deterioration associated to an effect on intrinsic bone material quality. Strontium ranelate influenced the determinants of bone strength by prevention of ovariectomy-induced changes which contribute to explain strontium ranelate antifracture efficacy. Introduction  Strontium ranelate effects on the determinants of bone strength in OVX rats were evaluated. Methods  Adult female Sprague–Dawley rats were OVX, then treated daily for 52 weeks with 125, 250, or 625 mg strontium ranelate/kg. Bone strength, mass, micro-architecture, turnover, and intrinsic quality were assessed. Results  Strontium ranelate prevented ovariectomy-induced deterioration in mechanical properties with energy necessary for fracture completely maintained vs. SHAM at 625 mg/kg/day, which corresponds to the clinical dose. This was related to a dose-dependent effect on bone volume, higher trabeculae number, and lower trabecular separation in strontium ranelate vs. OVX. Load and energy required to induce lamella deformation were higher with strontium ranelate than in OVX and in SHAM, indicating that the bone formed with strontium ranelate is able to withstand greater damage before fracture. Bone formation was maintained high or even increased in strontium ranelate as shown by mineralizing surfaces and alkaline phosphatase while strontium ranelate led to reductions in deoxypyridinoline. Conclusion  Strontium ranelate administered at 625 mg/kg/day for 52 weeks prevented OVX-induced biomechanical properties deterioration by influencing the determinants of bone strength: it prevented bone loss and micro-architecture degradation in association with an effect on intrinsic bone quality. These beneficial effects on bone contribute to explain strontium ranelate antifracture efficacy.     

Strontium ranelate prevents quality of life impairment in post-menopausal women with established vertebral osteoporosis

Summary

Strontium ranelate reduces the risk of fracture in post-menopausal osteoporotic women with prevalent fractures for whom quality of life is severely impaired. The SOTI study, which used the SF-36® questionnaire and disease-specific QUALIOST® module, demonstrated that treatment with strontium ranelate improved osteoporotic women’s quality of life compared with placebo.

Introduction

The Spinal Osteoporosis Therapeutic Intervention (SOTI) study demonstrated the effect of orally administered strontium ranelate versus placebo on the incidence of new vertebral fractures and compared impact on quality of life (QoL).

Methods

QoL was assessed 6 monthly over 3 years using the QUALIOST® and SF-36® questionnaires in post-menopausal osteoporotic women with prevalent fracture taking strontium ranelate or placebo 2 g/day. A total of 1,240 women were included (strontium ranelate: n?=?618 and placebo: n?= 622).

Results

The QUALIOST® total score decreased in the strontium ranelate group, indicating preserved QoL compared with a deterioration in the placebo group (P?=?0.016). Strontium ranelate patients had reduced QUALIOST® emotional and physical dimension scores (P?=?0.019 and 0.032, respectively, versus placebo), indicating beneficial effects on emotional and physical functioning. There was a trend towards better SF-36® scores in the strontium ranelate group, although there were no significant between-group differences. More strontium ranelate patients (+ 31%) were free from back pain over 3 years versus placebo (P?=?0.005), with a significant effect from the first year of treatment (P?=?0.023).

Conclusion

Strontium ranelate has beneficial effects on QoL in women with post-menopausal osteoporosis compared with placebo.     

Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response

Summary  The effect of strontium ranelate (SR) on human osteoblast differentiation was tested. SR induced osteoblastic proliferation, in vitro mineralization, and increased the expression of osteocyte markers. SR also elicited an osteoprotegerin (OPG) secretory response. We conclude that SR promotes the osteoblast maturation and osteocyte differentiation while promoting an additional antiresorptive effect. Introduction  SR is a new treatment for osteoporosis that reduces the risk of hip and vertebral fractures in postmenopausal women. This study sought to investigate the extent, to which SR modulates human osteoblast differentiation. Methods  Adult human primary osteoblasts (NHBC) were exposed to SR under mineralizing conditions in long-term cultures. Osteoblast differentiation status was investigated by cell-surface phenotypic analysis. Expression of genes associated with osteoblast/osteocyte differentiation was examined using real-time RT-PCR. Secreted OPG was assayed by enzyme-linked immunosorbent assay. Results  SR significantly increased osteoblast replication. SR time- and dose-dependently induced an osteocyte-like phenotype, as determined by cell surface alkaline phosphatase and STRO-1 expression. SR at 5 mM or greater dramatically increased in vitro mineralization. In parallel, mRNA levels of dentin matrix protein (DMP)-1 and sclerostin were higher under SR treatment, strongly suggestive of the presence of osteocytes. SR also increased the OPG/RANKL ratio throughout the culture period, consistent with an effect to inhibit osteoblast-induced osteoclastogenesis. Conclusions  This study suggests that SR can promote osteoblast maturation and an osteocyte-like phenotype. Coupled with its effect on the OPG/RANKL system, these findings are consistent with in vivo effects in patients receiving SR for the treatment of osteoporosis.     

雷奈酸锶结合钙剂对颈髓损伤合并骨质疏松症影响的临床研究

目的观察雷奈酸锶结合钙剂对颈髓损伤合并骨质疏松症的疼痛评分(VAS)、骨密度及骨代谢的影响。方法 2010年2月至2015年11月本科收治的颈髓损伤合并骨质疏松症患者80例,按随机数字表法将其分为治疗组(n=40)及对照组(n=40)。对照组给予钙剂治疗,治疗组给予雷奈酸锶联合钙剂进行治疗,共6个月。测定治疗不同时间段患者疼痛视觉模拟评分(VAS),腰椎及股骨颈骨密度(BMD)及1型前胶原N端前肽(P1NP)及1型胶原羧基端降解产物(β-CTX)的变化情况。结果治疗1个月、3个月及6个月后治疗组患者VAS评分显著低于对照组。治疗后6个月后,治疗组腰椎及股骨颈骨密度均显著高于对照组,比较差异有统计学意义(P0.05);β-CTX显著低于对照组,而P1NP显著高于对照组(P0.05),比较差异有统计学意义(P0.05)。结论雷奈酸锶联合钙剂可有效减轻颈髓损伤合并骨质疏松症患者的骨性疼痛程度,提升患者骨密度,改变骨代谢状态,值得临床推广。     

雷奈酸锶治疗原发性骨质疏松症慢性腰背痛的前瞻性随机双盲对照研究

目的：比较雷奈酸锶与阿仑膦酸钠治疗原发性骨质疏松症慢性腰背痛患者的临床疗效。方法采用前瞻性随机双盲对照观察,从2009年3月至2011年8月,94例被确诊为原发性骨质疏松症并获得知情同意的患者进入研究,所有入选者均按照随机码对应的治疗方案进行治疗,治疗完成后,所有患者均随访6个月以上,分别观察记录两组患者治疗前后的临床疗效、视觉疼痛模拟评分（ VAS）、日常活动功能情况（ Barthel指数和SF-36评分）和药物不良反应。所有资料都登记和记录在标准化病例报告表（ CRF）上,每月递交给研究组统计中心。结果研究结束时共有78例患者完成了观察,其中实验组38例,对照组40例。实验组的临床疗效明显优于对照组（P＜0.05）,治疗后两组患者骨密度均有改善,治疗后与治疗前相比,差异有统计学意义（P＜0.05）,但治疗组的改善程度比对照组更明显（P＜0.05）。两组患者的VAS评分治疗后均有明显改善（P＜0.01或P＜0.05）,两组患者之间比较,各个时段的VAS评分均有显著性差异（P＜0.05）,但两组患者治疗前后评价日常活动功能的Barthel指数和SF-36评分之间无显著性差异（ P＞0.05）。结论雷奈酸锶治疗原发性骨质疏松症慢性腰背痛患者效果理想,其最大优点是见效快,缓解疼痛明显,应用方便,患者依从性好,因而值得临床推广应用。