雷奈酸锶的药理及临床研究进展

雷奈酸锶是一种新近上市的治疗骨质疏松药物,能够有效预防和治疗骨质疏松症及绝经后妇女骨质疏松引起的骨折。大量的动物实验和临床试验研究表明雷奈酸锶是一种既具有抗骨吸收,又能促进骨形成的药物。在迄今为止的临床试验中,雷奈酸锶显示了很好的安全性和有效性。本文就雷奈酸锶目前的药理及临床研究进展作一综述。     

抗骨质疏松药物雷奈酸锶的研究进展

雷奈酸锶是目前临床应用的一种兼具促进成骨和抑制破骨吸收双重作用的抗骨质疏松药物,具有优秀的抗骨质疏松效果。文章综述了雷奈酸锶基础和临床研究的研究进展,并讨论了近年来该药出现的毒副作用和新的应用前景,为今后进一步研究和临床用药选择提供依据。     

雷奈酸锶对绝经后妇女骨质疏松症性骨痛及骨密度和骨代谢的影响

目的:研究雷奈酸锶在绝经后妇女骨质疏松症治疗中对骨痛、骨密度、骨代谢及骨质疏松性骨折风险的作用,评价其疗效和安全性。方法:40例老年绝经后骨质疏松症妇女被随机分为雷奈酸锶组(20例)和对照组(20例),进行开放、对比研究。雷奈酸锶组:雷奈酸锶2 g.d-1,口服,同时口服钙剂600 mg.d-1;对照组:钙剂600 mg.d-1,口服。治疗前后分别测定2组患者腰背痛的VAS评分、L1-L4椎体、股骨颈、全髋的骨密度值及T值、骨代谢指标,并观察2组骨质疏松性骨折的发生率及服药后的不良反应。结果:治疗后雷奈酸锶组VAS评分明显改善,低于对照组,但骨痛缓解过程较为缓慢;雷奈酸锶组L1-L4椎体、股骨颈、全髋的骨密度值及T值在治疗6月后较治疗前上升显著,明显优于对照组(P<0.01);骨代谢指标在治疗6月后骨钙素(N-MID)明显上升,β-CTX明显下降,与对照组有显著性差异(P<0.01);骨质疏松脆性骨折的发生率对照组明显高于雷奈酸锶组;雷奈酸锶的主要不良反应为恶心、腹泻及皮疹,对照组主要为便秘。结论:雷奈酸锶能有效缓解骨质疏松症骨痛,但作用较为缓慢。它能有效提高骨质量,改善骨代谢标志物,降低骨质疏松脆性骨折的发生率,不良反应少。     

雷奈酸锶对抗地塞米松诱导大鼠骨质疏松的作用

目的 研究雷奈酸锶对地塞米松诱导骨质疏松大鼠的作用。方法 30只雌性SD大鼠采用随机数字表法分为5组:空白组,骨质疏松模型组,雷奈酸锶高、中、低剂量组。5周后进行骨形态学及血清指标检测,同时考察不同浓度雷奈酸锶对成骨细胞的体外增殖影响。结果 较模型组(38.00±2.36)μm,雷奈酸锶中、高剂量组的平均骨小梁厚度(48.50±4.05)μm、(52.00±4.44)μm明显升高(P＜0.05),较模型组(189.90±19.27)μm,雷奈酸锶中、高剂量组的骨小梁间距(154.26±13.86)μm、(150.02±20.86)μm明显降低(P＜0.05),表明雷奈酸锶的干预能明显改善骨显微结构指标。雷奈酸锶组高剂量较模型组大鼠血清白介素-6(IL-6)、骨性特异性磷酸酶(BALP)、抗酒石酸酸性磷酸酶(TRACP-5b)、Ⅰ型胶原C端肽(CTX-I)明显降低(P＜0.05),骨钙素(OCN)、25羟基维生素D(25-HVD)明显升高(P＜0.05)。体外实验表明雷奈酸锶可促进成骨细胞增殖。结论 雷奈酸锶可促进成骨细胞增殖,改善骨形态及多项血清指标,对激素性骨质疏松有一定治疗作用。     

锶制剂治疗骨质疏松的临床研究进展

雷奈酸锶在欧盟、亚太国家和地区是广泛应用于治疗绝经后妇女骨质疏松症及其并发症的一线药物。临床前期研究表明,以雷奈酸锶为代表的含锶制剂具有其他抗骨质疏松药物所不具备的双重药理机制,即既能促进骨的生成,又能抑制骨的吸收。多项临床试验表明,雷奈酸锶能有效防止骨质疏松后脊柱、髋骨和外周骨的骨折,增加骨密度,改善骨微结构,并且在长时间的临床观察中均未发现其明显的、固有的毒副作用。此文主要就上述各方面最新进展做一综述,旨在推进锶制剂在骨质疏松方面的应用,并为进一步开发其应用范围提出初步建议。     

锶抗骨质疏松的作用机制研究

目的:综述锶抗骨质疏松的作用机制,为其临床应用提供参考。方法:以"骨质疏松症机制""锶""骨细胞""雷奈酸锶""Osteoporosis""Strontium""Strontium Ranelate"等为关键词,组合查询2005-2018年中国知网、万方数据、PubMed等数据库中的相关文献,对锶抗骨质疏松的作用机制及含锶的药物进行归纳总结。结果与结论:共检索到相关文献978篇,其中有效文献38篇。锶抗骨质疏松的作用机制包括结合钙离子敏感受体、上调转化生长因子水平、调节成骨相关标志物表达等促进骨细胞形成;调节核因子κB受体活化因子/核因子κB受体活化因子配体/骨保护素(RANK/RANKL/OPG)信号通路、调节κB抑制蛋白α(IκBα)等抑制破骨细胞分化;诱导间充质干细胞(MSCs)表达成骨相关基因、激活Wnt/β-catenin信号通路促进MSCs成骨分化;改善骨的微观结构,增强骨强度。临床常用含锶药物为雷奈酸锶,其具有促进骨形成和抑制骨吸收的双重作用,与其他治疗骨质疏松症的药物相比,雷奈酸锶具有良好的治疗效果。     

雷奈酸锶的合成

目的研究雷奈酸锶的化学合成。方法以无水柠檬酸为起始原料,经脱羧、酯化、环合、烷基化、水解和成盐等多步反应生成最终产物雷奈酸锶。结果雷奈酸锶的结构经IR1、H-NMR1、3C-NMR得到证实,总产率为41.4%。结论本合成路线操作简单,成本低,纯度高,适合工业化生产。     

抗骨质疏松药物治疗原发性骨质疏松症有效性的网状Meta分析

目的：采用网状Meta分析方法系统评价不同抗骨质疏松药物治疗原发性骨质疏松症的临床疗效,为临床用药提供循证依据。方法：计算机检索PubMed、Embase、Cochrane Library、中国知网和万方数据库,搜集关于不同抗骨质疏松药物治疗原发性骨质疏松症患者的随机对照试验（randomized controlled trials, RCTs）,检索时限均为建库至2023年2月。由2名研究者对文献进行筛选、提取数据和质量评价,采用Stata16.0软件进行网状Meta分析。结果：该研究共纳入62篇RCTs,涉及10种干预措施,包括50 704名患者。网状Meta分析结果显示,在增加腰椎骨密度（bone mineral density, BMD）方面,SUCRA概率排序依次是罗莫单抗>阿巴洛肽>特立帕肽>雷奈酸锶>地舒单抗>唑来膦酸>阿仑膦酸>伊班膦酸>利塞磷酸>雷洛昔芬>安慰剂;在增加髋骨骨密度方面,SUCRA概率排序依次是罗莫单抗>地舒单抗>雷奈酸锶>阿巴洛肽>唑来膦酸>阿仑膦酸>伊班膦...     

雷奈酸锶治疗骨质疏松症的疗效及安全性的Meta分析

目的系统评价雷奈酸锶治疗骨质疏松症的疗效及安全性。方法检索Cochrane的RCT中心数据库、Embase、PubMed、CNKI数据库和维普数据库中雷奈酸锶治疗骨质疏松症的临床研究,按照纳入及排除标准筛选出随机对照试验,使用"Cochrane协作网的偏倚评论指标"评估搜集的文献质量。提取有效数据,采用RevMan 5.3软件进行Meta分析。结果共纳入双盲、随机对照试验6项,结果表明,雷奈酸锶治疗12个月后,腰椎、髋部及股骨颈骨密度提升度比安慰剂对照组分别高6.72%(95%CI:6.17%~7.27%,P<0.01)、3.97%(95%CI:3.53%~4.40%,P<0.01)及3.51%(95%CI:3.21%~3.81%,P<0.01)。雷奈酸锶组的不良反应发生率、因不良反应导致的患者退出率和安慰剂组相似,差异无统计学意义(P>0.05);雷奈酸锶组的皮肤和胃肠道不良反应事件发生率高于安慰剂组,差异有统计学意义(P<0.05)。结论相对于安慰剂对照,雷奈酸锶可显著提高腰椎、髋部及股骨颈骨密度,两者的安全性近似。     

骨质疏松髋部骨折的药物干预

骨质疏松最严重的危害来自于髋部骨折,骨质疏松髋部骨折的药物干预目的是髋部骨折或再骨折的风险降低,而不是针对骨折愈合或不愈合的治疗。钙和维生素D补充是骨质疏松髋部骨折干预的重要基础措施,阿仑膦酸和唑来膦酸干预老年髋部骨折疗效明显,雷奈酸锶和人单克隆抗体Denosumab在骨质疏松骨折干预方面也具有一定的作用。     

Strontium ranelate: a new paradigm in the treatment of osteoporosis

Not one of the currently available medications has, so far, unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once osteoporosis is established. Therefore, several new therapies are currently under development to optimize the risk/benefit ratio of osteoporosis treatment. Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable nonradioactive strontium. In vitro, strontium ranelate increases collagen and noncollagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cell replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cell and collagen, as well as noncollagenic protein synthesis in osteoblasts, provides substantial evidence to categorize strontium ranelate as a bone-forming agent. In the isolated rat osteoclast assay, a pre-incubation of bone slices with strontium ranelate induced a dose- dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both carbonic anhydrase II and the alpha-subunit of the vitronectin receptor. These effects showing that strontium ranelate significantly affects bone resorption due to a direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation, are compatible with the profile of an anti-resorptive drug. In normal rats, administration of strontium ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. Strontium ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg and 1 g of strontium ranelate were compared with a placebo. At the conclusion of the study, the percent variation of lumbar-adjusted bone mineral density from baseline was significantly different in the group receiving 1 g/day of strontium ranelate compared with placebo (+1.41% vs. -0.98%, respectively). Increase in total hip and neck bone mineral density averages, respectively, 3.2% and 2.5%. Strontium ranelate does not induce any significant adverse reaction compared with those observed in women receiving a placebo for the same duration. In a phase II study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was + 2.97%. This result was significantly different compared with placebo. A significant increase in bone alkaline phosphatase and, over a 6-month period, a significant decrease in urinary-pyridium crosslinks (NTX) were evidenced. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. The compound was further investigated in a large phase III program that included two extensive trials for the treatment of severe osteoporosis, one assessing the effects of strontium ranelate on the risk of vertebral fractures (SOTI) and one evaluating its effects on peripheral (nonspinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in the relative risk of expein the relative risk of experiencing a first new vertebral fracture with strontium ranelate, throughout the 3-year study, compared with placebo. The TROPOS study, showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population. A 41% reduction in the relative risk of experiencing a hip fracture was demonstrated in the per protocol population. All these results imply that strontium ranelate is a new, effective and safe treatment for vertebral and nonvertebral osteoporosis, with a unique mode of action.     

Comprehensive therapy in osteoporosis using a single drug: from ADFR to strontium ranelate

In vitro, strontium ranelate increases collagen and non-collagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated rat osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. In a phase II dose ranging trial Strontium ranelate (500 mg, 1000 mg, 2000 mg/day) or placebo were given to 353 postmenopausal women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving 2000 mg of strontium ranelate was + 7.3%, a significant increase in bone alkaline phosphatase, over a 6-month period and a significant decrease in N-telopeptide crosslinks throughout the 2-year period were seen. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patient experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture by 16% in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture by 36% was also demonstrated in the patients at high risk of hip fracture (age > or =74 years and Femoral Neck T score < or = -2.4 according to NHANES normative value). All these results suggest that strontium ranelate is a new, effective and safe treatment of vertebral and non-vertebral osteoporosis, with a unique mode of action.     

Strontium ranelate: a new paradigm in the treatment of osteoporosis

In vitro, strontium ranelate increases collagen and non-collagenic protein synthesis by mature osteoblast-enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. The drug was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomised study. At the conclusion of the study, the percentage variation of lumbar bone mineral density (BMD) from baseline was significantly different in the group receiving strontium ranelate 1000 mg/day as compared with placebo (+5.53 versus -0.75%, respectively). Increase in total hip and neck BMD averages were 3.2 and 2.5%, respectively. The effect of strontium ranelate in postmenopausal women with established osteoporosis was assessed during a multinational, prospective, double-blind, randomised, placebo-controlled trial. Strontium ranelate (500, 1000, 2000 mg/day) or placebo were given to 353 Caucasian women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving strontium ranelate 2000 mg was 7.3% (p < 0.001). A significant increase in bone alkaline phophatase (p = 0.002) over a 6-month period and a significant decrease in N-telopeptide crosslinks (p = 0.004) throughout the 2-year period were seen in the group receiving 2000 mg of strontium ranelate. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patients experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture was also demonstrated in the patients treated for ≥ 18 months.     

Strontium ranelate: a new paradigm in the treatment of osteoporosis

In vitro, strontium ranelate increases collagen and non-collagenic protein synthesis by mature osteoblast-enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. The drug was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomised study. At the conclusion of the study, the percentage variation of lumbar bone mineral density (BMD) from baseline was significantly different in the group receiving strontium ranelate 1000 mg/day as compared with placebo (+5.53 versus -0.75%, respectively). Increase in total hip and neck BMD averages were 3.2 and 2.5%, respectively. The effect of strontium ranelate in postmenopausal women with established osteoporosis was assessed during a multinational, prospective, double-blind, randomised, placebo-controlled trial. Strontium ranelate (500, 1000, 2000 mg/day) or placebo were given to 353 Caucasian women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving strontium ranelate 2000 mg was 7.3% (p < 0.001). A significant increase in bone alkaline phophatase (p = 0.002) over a 6-month period and a significant decrease in N-telopeptide crosslinks (p = 0.004) throughout the 2-year period were seen in the group receiving 2000 mg of strontium ranelate. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patients experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture was also demonstrated in the patients treated for > or = 18 months.     

雷奈酸锶研究现状

骨质疏松症是以低骨量和骨组织结构退化为特征,可以导致骨脆性增加和提升骨折风险,是一种骨骼紊乱性疾病。雷奈酸锶是首个上市的能同时抑制骨重吸收和促进骨形成的药物,在体内外有极好的生物活性以及良好的生物利用度和耐受性。本文对雷奈酸锶的研究情况作一简要概述。     

新型抗骨质疏松药物雷尼酸锶

雷尼酸锶是第一个具有双重药理作用的抗骨质疏松新药，在保持骨形成的同时抑制骨吸收，具有安全、耐受性好且服用方便等特点。现对其药理作用、药动学、临床评价及安全性等做一综述。     

Recent important clinical trials of drugs in osteoporosis

The antiresorptive therapies (raloxifene, bisphosphonates) commonly used to treat postmenopausal osteoporotic women, reduce the rate of bone remodeling and lowers the fracture rate, but do not increase bone mass. Strontium ranelate has the advantage of also stimulating bone formation. In the Spinal Osteoporosis Intervention study, at the end of 1 year, there was a lower incidence of fractures in the strontium ranelate group than the placebo group (12.2 and 6.4%, placebo and strontium, respectively) and this difference was maintained over the 3 years (32.8 and 20.9%, placebo and strontium, respectively). With the demise of oestrogen treatment for postmenopausal osteoporosis, it is useful that strontium ranelate is emerging as a promising drug in this condition. Secondary osteoporosis (e.g., due to glucocorticoid treatment after cardiac transplantation) tends to be more severe than primary osteoporosis. In a recent trial comparing calcitriol to alendronate after cardiac transplantation, both showed similar abilities to prevent bone loss. As hypercalcaemia is a relatively common adverse effect with calcitriol in the treatment of secondary osteoporosis, requiring monitoring of calcium levels, alendronate is the easier agent to use.     

Recent important clinical trials of drugs in osteoporosis

The antiresorptive therapies (raloxifene, bisphosphonates) commonly used to treat postmenopausal osteoporotic women, reduce the rate of bone remodeling and lowers the fracture rate, but do not increase bone mass. Strontium ranelate has the advantage of also stimulating bone formation. In the Spinal Osteoporosis Intervention study, at the end of 1 year, there was a lower incidence of fractures in the strontium ranelate group than the placebo group (12.2 and 6.4%, placebo and strontium, respectively) and this difference was maintained over the 3 years (32.8 and 20.9%, placebo and strontium, respectively). With the demise of oestrogen treatment for postmenopausal osteoporosis, it is useful that strontium ranelate is emerging as a promising drug in this condition. Secondary osteoporosis (e.g., due to glucocorticoid treatment after cardiac transplantation) tends to be more severe than primary osteoporosis. In a recent trial comparing calcitriol to alendronate after cardiac transplantation, both showed similar abilities to prevent bone loss. As hypercalcaemia is a relatively common adverse effect with calcitriol in the treatment of secondary osteoporosis, requiring monitoring of calcium levels, alendronate is the easier agent to use.