Strontium ranelate: a look back at its use for osteoporosis

Importance of the field: Osteoporosis is now considered a major health problem in all developed and in most developing (non-African) countries.

Areas covered in this review: In this review, we provide an extensive literature survey (MEDLINE, PubMed, Cochrane Controlled Register), for articles dealing with osteoporosis management and/or strontium ranelate, from 1920 to 2010.

What the reader will gain : The objective is to provide an extensive, unbiased assessment of the available data allowing strontium ranelate to be placed in perspective with other anti-osteoporosis treatments.

Take home message : Owing to a positive benefit-to-risk ratio, strontium ranelate may now be considered a first-line treatment in the management of osteoporosis.     

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.     

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.     

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。     

雷奈酸锶对大鼠应力缺失性骨丢失的防治作用

摘要： 目的 探讨雷奈酸锶对尾悬吊导致的应力缺失性大鼠骨质疏松的防治效果。方法 6 月龄 SD 大鼠 30 只, 随机均分为 3 组： 正常对照组（A 组）、 尾悬吊组（B 组）、 雷奈酸锶干预组（C 组）。B、 C 两组大鼠采用尾悬吊法制 备应力缺失型骨质疏松大鼠模型, C 组给予 1 g/(kg·d） 雷奈酸锶干预, 4 周后处死所有大鼠, 取左侧股骨检测骨密度, 取左侧胫骨制备非脱钙组织切片并行骨形态计量学检测, 取右侧股骨和胫骨骨髓细胞体外培养并向成骨细胞诱导 分化, 取第 4 代细胞及血清检测骨钙素 （OCN） 的表达。结果 B 组骨密度低于 A 组, C 组高于 B 组 （P＜0.05）。 B 组 骨小梁体积（BV/TV）、 骨小梁数量（Tb.N）、 骨小梁厚度（Tb.Th）低于 A、 C 组, 破骨细胞数（Oc.N）、 骨吸收长度比（Er. Pm）高于 A 组, C 组骨形成率（BFR/BV）、 矿化长度比（L.Pm）高于 B 组, Er.Pm、 Oc.N 低于 B 组（P＜0.05）。B、 C 组 OCN mRNA 表达水平高于 A 组, 但血清中 OCN 水平 B 组低于 A、 C 组 （P＜0.05）。结论 尾悬吊 4 周可造成大鼠骨 丢失, 雷奈酸锶可抑制其骨量丢失, 作用机制可能与其通过上调 OCN 的表达促进骨形成有关。     

雷奈酸锶临床研究进展

目的 对抗骨质疏松药物雷奈酸锶的整个研究过程进行分析,评价其各阶段研究的有效性.方法 简要总结雷奈酸锶各个阶段研究试验情况,系统概括近10年来雷奈酸锶的研究结论.结果 雷奈酸锶具有双重抗骨质疏松作用,能够有效地预防骨质疏松患者骨密度下降,显著降低骨质疏松骨折发生危险.结论 口服雷奈酸锶是治疗骨质疏松症的一种有效办法,应当成为抗骨质疏松治疗的一种新选择.     

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。     

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。     

Cardiac concerns associated with strontium ranelate

Introduction: Strontium ranelate is proven to reduce vertebral and non-vertebral fracture risk in osteoporosis. Concerns about cardiac safety have led to a new contraindication to strontium ranelate in patients with uncontrolled hypertension and/or current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Areas covered: A literature search was performed; data were also collected from the European Medicines Agency website. Randomised controlled trial (RCT) data indicate a higher incidence of non-adjudicated myocardial infarction (MI) with strontium ranelate versus placebo (1.7 vs 1.1%; odds ratio [OR]: 1.6; 95% CI: 1.07 – 2.38; p = 0.020) (Mantel-Haenzel estimate of the OR). There was no increase in cardiovascular mortality. MI risk was mitigated by excluding patients with cardiovascular contraindications (OR: 0.99; 95% CI: 0.48 – 2.04; p = 0.988). Three observational studies performed in the context of real-life medical practice in the UK and Denmark did not report a signal.

Expert opinion: The increased risk for cardiac events with strontium ranelate has been detected in RCTs but not in real life. Excluding patients with cardiovascular contraindications appears to be an effective measure for controlling the risk of MI. Strontium ranelate remains a useful therapeutic alternative in patients with severe osteoporosis without cardiovascular contraindications who are unable to take another osteoporosis treatment.     

New findings with old drugs for osteoporosis

Background: Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods: This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results: Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions: As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.     

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.     

Strontium ranelate,a promising disease modifying osteoarthritis drug

Introduction: The articular cartilage and subchondral bone may have potential crosstalk in the development and progression of osteoarthritis (OA). Strontium ranelate (SrR) has the ability to dissociate the bone remodeling process and to change the balance between bone resorption and bone formation. Its effect on subchondral bone makes it a potential disease- modifying osteoarthritis drug (DMOAD) in the treatment of OA. The aim of the current review is to summarize up-to-date pharmacological and clinical data of SrR for OA treatment.

Areas covered: A literature search was performed on PubMed and European Medicines Agency (EMA) website for all publications and documents related to SrR and OA. References of related studies were searched by hand. Treatment with SrR, especially at the dosage of 2 g/day, was associated with reduced radiographic knee OA progression, and with meaningful clinical improvement. It was also significantly associated with decreased MRI-assessed cartilage volume loss (CVL) and bone marrow lesions (BMLs).

Expert opinion: SrR could be a promising DMOAD particularly for OA patients with bone phenotypes. The clinical efficacy and side effects of SrR for OA treatment need to be further investigated in future clinical trials before clinical application.     

原子吸收分光光度法测定雷尼酸锶的含量

目的:建立原子吸收分光光度法测定雷尼酸锶含量的方法。方法:样品不经消化;在含有1.488g·L~(-1) EDTA-2Na及0.076g·L~(-1)氯化钾的0.15%的硝酸中,火焰法测定样品中锶的含量,并以锶的含量计算雷尼酸锶含量。结果:锶的线性范围为2～10μg·mL~(-1),回归方程为A=5.57×10~(-2)C 0.0028,r=0.9999;高、中、低三浓度的回收率分别为103.1%,97.5%,101.5%,RSD分别为2.7%,2.8%,3.1%;最低检出限为0.02μg·mL~(-1)。结论:该方法简单、快速、准确,可用于评价雷尼酸锶质量。     

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。     

雷尼酸锶的合成

1,3-丙酮二羧酸二乙酯与硫和内二腈环合后，与氯乙酸乙酯缩合得5-[N，N-二（乙氧羰甲基）氨基]-4-氰基-3-乙氧羰甲基-2-噻吩甲酸乙酯，再用氢氧化锶水解、成盐制得抗骨质疏松症药物雷尼酸锶，总收率34％。     

火焰原子吸收分光光度法测定雷奈酸锶干混悬剂中的锶含量

目的：建立测定雷奈酸锶干混悬剂中锶含量的火焰原子吸收分光光度法。方法：使用含有0．1g·L-1铯离子和5．0g·L-1镧离子的0．1％硝酸溶液对样品进行溶解和稀释,采用空气一乙炔火焰原子吸收光谱法在460．7nm波长处进行测定。结果：当锶的质量浓度在6．30～25．20mg·L-1范围内时,其吸光度和质量浓度线性关系良好,相关系数为0．9997;平均加样回收率为101．4％,RSD为1．8％;测得3批雷奈酸锶干混悬剂中锶含量分别为制剂中锶标示含量的98．7％、99．3％和99．8％。结论：该方法便捷、准确、灵敏度高,适用于雷奈酸锶干混悬剂中锶含量的测定。     

Effect of a sequential treatment combining abaloparatide and alendronate for the management of postmenopausal osteoporosis

The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 µg/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non-vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis.