双重抗骨质疏松药雷尼酸锶

不同于其他抗骨质疏松药,雷尼酸锶是新型具有双重药理作用的抗骨质疏松药物,即抑制骨吸收和促进骨形成.雷尼酸锶可改变骨微结构,增加骨密度和骨强度,从而降低骨折风险,改善患者生活质量.临床研究显示,它能降低绝经后骨质疏松患者椎体和非椎体骨折的风险,并具有作用长久、安全性好、耐受性好的特点.     

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。     

骨质疏松症药物治疗进展

骨质疏松症是一个严峻的公共健康问题,其主要特征是骨强度下降和骨折风险增高。目前,治疗骨质疏松症的药物分为两类:抑制骨吸收药物和促进骨形成药物。抑制骨吸收药物通过减少破骨细胞数量和/或抑制破骨细胞活性到达抑制骨吸收的目的。目前,上市的骨吸收药物包括:二磷酸盐制剂、雌激素和选择性雌激素受体调节剂、降钙素和Denosumab。其中,Denosumab是在2010年刚被美国食品药品管理局和欧洲议会批准而上市的。重组人类甲状旁腺激素是唯一的上市的促进骨形成药物。雷尼酸锶是唯一已上市的具有双重作用机制的新型抗骨质疏松症药物,其在刺激新骨形成的同时抑制骨吸收。在对骨代谢途径的深刻认识上,涌现了一批新型的制剂比如胰高血糖素样肽2、组织蛋白酶K阻滞剂、钙离子受体拮抗剂、抗-Sclerostin单克隆抗体等等。随着这些制剂逐步通过临床试验的检验,将会给骨质疏松症的治疗带来新的希望。     

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.     

骨质疏松性骨折药物治疗的研究进展

骨质疏松症(osteoporosis,OP)是一种以低骨量和骨组织微结构破坏为特征,导致骨质脆性增加和易于骨折的全身性骨代谢性疾病。骨质疏松症患者最终结局常常是脆性骨折。骨质疏松症不利于骨折愈合,主要是由于骨质疏松症导致患者的骨吸收作用增强、新骨形成能力下降造成的。为了缩短骨质疏松症个体的骨折愈合时间、提高愈合质量,抑制骨吸收或促进骨形成的药物成为研究热点。而抗骨质疏松的治疗药物主要是通过抑制骨吸收或促进骨形成促进骨质疏松性骨折的愈合。所以现在已有大量的实验探讨了抗骨质疏松治疗药物对骨质疏松性骨折愈合的影响。同时还有关于抗骨质疏松药对骨修复影响的研究。这些研究的结果总结来说,指出了抗骨质疏松药可能对骨质疏松性骨折治疗有一定的作用。同时现在还没有明确的证据证明抗骨质疏松治疗不利于骨修复,故抗骨质疏松药在骨质疏松性骨折上有很大的应用前景。本文回顾综述了当下骨质疏松性骨折治疗的研究进展,总结了双膦酸盐、地诺单抗、雌激素、雷洛昔芬、特立帕肽、雷尼酸锶、他汀类药物以及一些正在研究中的抗骨质疏松药物对骨折愈合的影响及其作用机制。     

绝经后骨质疏松症的治疗进展

骨质疏松症是一个与老龄化进程息息相关的全球性健康问题，骨质疏松症患者不仅经常被漏诊，而且常常不能得到及时治疗。正因为如此，骨质疏松症直接导致了高发病率、高死亡率以及生活质量的下降。雌激素缺乏是绝经后骨量丢失的一个主要影响因素，50岁女性其一生中发生骨折风险的概率大约是50 %，对骨质疏松症进行针对性的治疗可以预防这些骨折的发生。除此之外，非药物性的治疗还包括健康饮食、防止跌倒以及适当的体育锻炼；药物治疗主要包括钙剂、维生素D以及抗骨吸收药物（选择性雌激素受体调节剂、激素替代治疗、双膦酸盐类药物、狄迪诺塞麦）、骨形成药物（特立帕肽）和混合型制剂（雷尼酸锶）在内的骨活性药物。双膦酸盐类药物（阿仑膦酸钠、利塞膦酸钠、伊班膦酸钠和唑来膦酸钠）是目前骨质疏松症治疗中最常应用的抗骨吸收药物，但由于其依从性、耐受性较差，加之不良反应的影响，会限制其从抗骨吸收治疗中的获益。目前已在研发针对骨细胞信号传导研究基础上的一些新药，并且正在进行疗效评估的临床试验。     

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。     

雷奈酸锶治疗老年男性骨质疏松性骨痛的疗效和安全性评价

【摘要】〓目的〓观察雷奈酸锶在男性骨质疏松症治疗中对骨痛的疗效,并评价其安全性。方法〓共纳入58例男性骨质疏松症患者,其中26例雷奈酸锶组,32例为钙剂组,分别测定两组患者治疗前后腰背部视觉疼痛模拟评分(VAS评分)、L1~L4椎体和Wards三角的骨密度值,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〓雷奈酸锶组患者治疗后6月及12月的VAS评分明显改善,低于钙剂组(P<0.001);雷奈酸锶组L1~L4椎体和Wards三角的骨密度值及T值在治疗后较治疗前上升显著,明显优于钙剂组(P<0.001)。雷奈酸锶组患者的主要不良反应为恶心及腹泻,钙剂组主要为便秘。结论〓雷奈酸锶能有效地提高骨质量和缓解骨痛,副反应少,是治疗男性骨质疏松性骨痛的良好选择。     

治疗骨质疏松症靶向药物研究进展

骨质疏松症(Osteoporosis,OP)是世界性高发生率的、易于引发骨折为特征的代谢性疾病。其治疗药物主要有促骨合成药和抑制骨吸收药。随着对其发病机制研究的不断深入,多肽、激素、细胞因子等靶向药物成为研究的热点。本文阐述的促骨合成药有:PTH、钙敏感受体负向调节剂calcilytics、雷尼酸锶、PYK2抑制剂;抑制骨吸收药有OPG、Denosumab;抑制骨基质降解的组织蛋白K等新型药物。它们有的已经上市,有的处于临床研究中。     

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。     

Strontium ranelate: A new treatment for postmenopausal osteoporosis with a dual mode of action

In vitro, strontium ranelate increases collagen and noncollagen protein synthesis by mature osteoblast-enriched cells. Its effects on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, preincubation of bone slices with strontium ranelate-induced dose-dependent inhibition of the bone-resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. Its effect in postmenopausal women with established osteoporosis was assessed during an international, prospective, double-blind, randomized, placebo-controlled phase 3 program comparing strontium ranelate 2 g daily with placebo. The 3-year analysis of the phase 3 study, Spinal Osteoporosis Therapeutic Intervention, evaluating the effect of strontium ranelate 2 g/day on vertebral fracture rates, revealed a significant 41% reduction in the relative risk of patients experiencing new vertebral fracture with strontium ranelate over 3 years. A second phase 3 study showed a significant reduction in the relative risk of experiencing a nonvertebral fracture in the group treated with strontium ranelate over 3 years. These results show that strontium ranelate is a new, effective, and safe treatment for vertebral and hip osteoporosis, with a unique mode of action, increasing bone formation and decreasing bone resorption leading to a rebalance of bone turnover in favor of bone formation.     

Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro

Strontium ranelate is a newly developed drug that has been shown to significantly reduce the risk of vertebral and non-vertebral fractures, including those of the hip, in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate increases bone formation and decreases resorption. In this study, the dual mode of action of strontium ranelate in bone was tested in vitro, on primary murine osteoblasts and osteoclasts derived from calvaria and spleen cells, respectively. We show that strontium ranelate treatment, either continuously or during proliferation or differentiation phases of mouse calvaria cells, stimulates osteoblast formation. Indeed after 22 days of continuous treatment with strontium ranelate, the expression of the osteoblast markers ALP, BSP and OCN was increased, and was combined with an increase in bone nodule numbers. On the other hand, the number of mature osteoclasts strongly decreased after strontium ranelate treatment. Similarly to previous studies, we confirm that osteoclasts resorbing activity was also reduced but we found that strontium ranelate treatment was associated with a disruption of the osteoclast actin-containing sealing zone. Therefore, our in vitro assays performed on primary murine bone cells confirmed the dual action of strontium ranelate in vivo as an anabolic agent on bone remodeling. It stimulates bone formation through its positive action on osteoblast differentiation and function, and decreases osteoclast differentiation as well as function by disrupting actin cytoskeleton organization.     

Strontium ranelate—Data on vertebral and nonvertebral fracture efficacy and safety: Mechanism of action

Strontium ranelate is a novel therapy for the treatment of postmenopausal osteoporosis with actions to reduce bone resorption and increase bone formation. In vitro, strontium ranelate has anabolic and antiresorptive activity, increasing collagen and non-collagen protein synthesis, enhancing pre-osteoblast differentiation, inhibiting osteoclast differentiation, and reducing osteoclast function. In animal models, the increase in bone density is closely correlated with increases in biomechanical bone strength. Histomorphometry demonstrates reduced osteoclast surfaces with increased bone formation. Clinical trials in postmenopausal women have demonstrated 3-year fracture efficacy. Reductions in vertebral fracture were seen in patients with and without prevalent vertebral fracture. Nonvertebral fractures were also significantly reduced. In a subgroup of patients at high risk for hip fracture, there was a significant reduction in hip fracture risk. Strontium ranelate is well tolerated with nausea, diarrhea, headache, and dermatitis more frequent in treated patients only for the first 3 months of therapy. Together, these data suggest that strontium ranelate is a well-tolerated and effective therapy for postmenopausal osteoporosis reducing vertebral and nonvertebral fracture by a novel dual antiresorptive and anabolic action on bone.     

Strontium ranelate related Stevens–Johnson syndrome: a case report

Strontium ranelate is a relatively new medication with good safety profile for the treatment of postmenopausal osteoporosis. However, severe cutaneous adverse drug reactions have been reported, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We report the case of a 70-year-old woman who developed multiple itching erythematous macules and plaques about 1 month after beginning strontium ranelate medication. The cutaneous lesions progressed over the entire body with severe oral and ocular mucosa involvement. Probable mild SJS was diagnosed, compatible with the pathology findings, and strontium ranelate was discontinued immediately. Systemic methylprednisolone was administered to suppress the overactive immune system and ameliorate cutaneous symptoms. With early recognition and prompt treatment, the patient’s prognosis was good.     

Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis

Summary

Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.

Introduction

Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate.

Methods

A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated.

Results

Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction?=?0.67, p?<?0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p?<?0.001). QoL, assessed by the QUALIOST®, was significantly better (p?=?0.025), and patients without back pain were greater (p?=?0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups.

Conclusion

In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.     

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 increases cartilage matrix formation.

Based on previous studies showing that strontium ranelate (S12911) modulates bone loss in osteoporosis, it could be hypothesized that this drug also is effective on cartilage degradation in osteoarthritis (OA). This was investigated in vitro on normal and OA human chondrocytes treated or not treated with interleukin-1beta (IL-1beta). This model mimics, in vitro, the imbalance between chondroformation and chondroresorption processes observed in vivo in OA cartilage. Chondrocytes were isolated from cartilage by enzymatic digestion and cultured for 24-72 h with 10(-4)-10(-3) M strontium ranelate, 10(-3) M calcium ranelate, or 2 x 10(-3) M SrCl2 with or without IL-1beta or insulin-like growth factor I (IGF-I). Stromelysin activity and stromelysin quantitation were assayed by spectrofluorometry and enzyme amplified sensitivity immunoassay (EASIA), respectively. Proteoglycans (PG) were quantified using a radioimmunoassay. Newly synthesized glycosaminoglycans (GAGs) were quantified by labeled sulfate (Na2(35)SO4) incorporation. This method allowed the PG size after exclusion chromatography to be determined. Strontium ranelate, calcium ranelate, and SrCl2 did not modify stromelysin synthesis even in the presence of IL-1beta. Calcium ranelate induced stromelysin activation whereas strontium compounds were ineffective. Strontium ranelate and SrCl2 both strongly stimulated PG production suggesting an ionic effect of strontium independent of the organic moiety. Moreover, 10(-3) M strontium ranelate increased the stimulatory effect of IGF-I (10(-9) M) on PG synthesis but did not reverse the inhibitory effect of IL-1beta. Strontium ranelate strongly stimulates human cartilage matrix formation in vitro by a direct ionic effect without stimulating the chondroresorption processes. This finding provides a preclinical basis for in vivo testing of strontium ranelate in OA.     

A review of strontium ranelate and its effect on DXA scans.

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and nonvertebral fractures. This review article examines the evidence for the antifracture efficacy and safety of strontium ranelate treatment and discusses the effect of DXA scans, biochemical markers of bone turnover, and bone histology. In the SOTI trial, three years treatment with strontium ranelate led to a 41% reduction in vertebral fracture risk (relative risk [RR]=0.59; 95% CI: 0.48-0.73; p<0.001), while in the TROPOS study there was a 16% reduction in nonvertebral fractures (RR=0.84; 95% CI 0.702-0.995; p=0.04). Compared with alternative osteoporosis therapies, strontium ranelate treated patients show large increases in BMD coupled with comparatively modest changes in biochemical markers of bone turnover and bone histology. While the large BMD changes provide a useful way of monitoring patients' response to treatment, it is important to appreciate that much of the increase is a purely physical effect due to the increased attenuation of X-ray when some of the calcium in bone is replaced by strontium. Strontium ranelate is a useful addition to the range of antifracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and nonvertebral fractures in women aged 80 yr and older.     

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis)

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years. Treatment for 6 months with strontium ranelate resulted in an increase in plasma strontium concentration. Histomorphometric analyses of indices of bone formation and resorption were determined in standardized areas of alveolar bone. Treatment with strontium ranelate decreased the histomorphometric indices of bone resorption (osteoclast surface and number) with a maximal significant effect at the highest dose tested. In contrast to this inhibitory effect on bone resorption, strontium ranelate maintained bone formation. Although the amount of osteoid tended to increase, strontium ranelate, even at the highest dose, had no deleterious effect on bone mineralization, as evaluated by mineral apposition rate and osteoid thickness. These findings show that strontium ranelate decreases indices of bone resorption while maintaining bone formation in the alveolar bone in monkeys.