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.     

~(89)锶治疗乳腺癌转移性骨痛临床观察

目的评价89SrC l2对乳腺癌转移性骨痛的临床疗效。方法观察乳腺癌骨转移并伴有不同程度骨痛患者88例,使用89SrC l2静脉注射治疗,观察其镇痛效果、骨转移灶的变化及不良反应等。结果治疗后骨痛减轻或消失75例,总有效率为85.2%;治疗后骨显像有53.4%(47例)骨转移灶代谢减低,治疗前后RO I比值差异具有统计学意义(P<0.05)。未见明显骨髓抑制与肝肾脏功能损伤。结论89Sr对缓解乳腺癌骨转移瘤疼痛有较好疗效,并有一定的治疗作用,副作用小,可重复用药。     

Fabrication of strontium-releasable inorganic cement by incorporation of bioactive glass

Objectives

Bioactive glass (BG) is widely used as a bioactive material for various clinical applications, and effective and efficient elemental release and an increase in mechanical strength are expected with further development. The purpose of this study is to clarify the physicochemical and biological characteristics of Sr-doped BG-incorporated glass ionomer cements.

89Sr治疗肺癌骨转移96例疗效观察

目的探讨89SrCl2对肺癌骨转移疼痛的治疗效果及毒副作用。方法96例肺癌多发骨转移患者予以肘静脉注射89SrCl2 148MBq／例次,治疗后第28天观察疼痛强度,根据治疗前后骨显像显示的病灶大小或数目的变化,对病灶疗效进行分级,并观察治疗前后白细胞和血小板的变化。结果疼痛程度缓解的患者占70．0％,其中疼痛消失21例,占21．9％。治疗后病灶部分消退15例,缩小或变浅27例,总有效率为43．6％。白细胞和血小板在治疗后1个月降至最低,白细胞降低幅度约34．5％,血小板降低47．8％,3个月时血象正常率为94．8％（91／96）。结论89SrCl2可有效缓解肺癌多发骨转移的骨痛,减少骨转移灶数量,毒副作用轻微,可提高患者生活质量。     

What about strontium ranelate in osteoarthritis? Doubts and securities

Abstract

Osteoarthritis (OA) is the most common disabling joint disease worldwide and its treatment is based on a combination of non-pharmacological and pharmacological modalities. Commonly prescribed OA medications include symptomatic drugs (non-steroidal anti-inflammatory drugs, analgesics, locally administered corticosteroids, viscosupplementation) and new compounds that are potentially able to reduce or stop the disease progression, called “Disease Modifying Osteoarthritis Drugs (DMOADs)”. Strontium ranelate (SR) is an anti-osteoporotic treatment that increases bone formation, while decreasing bone resorption and it potentially acts as a new DMOAD. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of SR in OA. We have examined two post hoc analysis conducted on the large, randomized Treatment of Peripheral Osteoporosis study and the double-blind, randomized, controlled trial about SR in knee OA. Furthermore, we analyzed three studies in animal models and two in vitro experiments to better understand the mechanism of action of SR in OA. The available data demonstrate that SR could be considered a new promising symptomatic and disease-modifying agent in the treatment of OA and was safe and well tolerated. Additionally, there is a need for further investigations to establish the optimal dosage and to better clarify the mechanism of action of SR in OA.     

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.     

Effects of Strontium on the Physicochemical Characteristics of Hydroxyapatite

In a previous experimental study using a chronic renal failure rat model, a dose-related multiphasic effect of strontium (Sr) on bone formation was found that could be reproduced in an in vitro set-up using primary rat osteoblasts. The results from the latter study allowed us to distinguish between a reduced nodule formation in the presence of an intact mineralization at low Sr-doses (1 g/ml) and an interference of the element with the hydroxyapatite (HA) formation at high doses (20–100 g/ml). To further investigate the latter effect of Sr on physicochemical bone mineral properties, an in vitro study was set up in which the UMR-106 rat osteosarcoma cell line was exposed to Sr, added to the cell culture medium in a concentration range varying between 0–100 g/ml. Temporal growth and functionality of the culture was investigated by measurement of the alkaline phosphatase activity and calcium (Ca) concentration in the culture medium (used as an index of Ca-incorporation, i.e., HA formation) at various time points. At the end of the culture period (14 days post-confluence), samples of the mineralized cultures were taken for further analysis using X-ray diffraction (XRD) and Fourier Transform Infra-Red Spectroscopy (FTIR). Synthetic HA doped with various Sr concentrations (based on the cell culture and previous experimental studies and yielding Sr/(Sr+Ca) ratios ranging from 0–60%), was prepared and examined for crystal growth and solubility. Crystal size was assessed using scanning electron microscopy (SEM). Ca incorporation indicated a reduced mineralization in the 20 and 100 g/ml Sr groups vs. controls. Sr-doped synthetic HA showed a significant dose-dependent reduction in crystal growth, as assessed by SEM, and an increase in solubility, apparent from 12.7% Sr/(Sr+Ca) on. Moreover, in both mineralized cultures and synthetic HA, XRD and FTIR analysis showed a reduced crystallinity and altered crystal lattice at similar concentrations. These new data support our previous in vivo and in vitro findings and point to a potential physicochemical interference of Sr with HA formation and crystal properties in vivo.     

Exercise-Trained Young Men Have Higher Calcium Absorption Rates and Plasma Calcitriol Levels Compared with Age-Matched Sedentary Controls

The effect of physical activity on human calcium (Ca) metabolism is still not completely understood. Thus, we investigated fractional Ca absorption using a stable strontium test (Fc₂₄₀), calciotropic hormones, and renal Ca excretion in 31 young men with a high activity level (GH) and in 26 age-matched sedentary control subjects (GL). Weekly hours spent on physical activity, obtained with a questionnaire were 15.0 ± 6.6 (GH) and 1.0 ± 1.4 (GL), respectively. Serum testosterone levels were significantly lower in GH compared with GL (P < 0.005). Dietary Ca intake (4-day food record) was twice as high in GH compared with GL men (P < 0.001). GH had significantly higher serum calcitriol levels and Fc₂₄₀ values than GL (P < 0.001 and P < 0.01, respectively). In a stepwise multiple regression analysis including serum levels of 25-hydroxyvitamin D, calcitriol, testosterone, and dietary Ca intake, only calcitriol was significantly correlated with Fc₂₄₀ (P= 0.017). Twenty-four hour renal Ca excretion was only slightly higher in GH compared with GL (P < 0.05). However, additional Ca losses might have occurred through the extensive sweating of GH, as indicated by a difference of 1.7 liter between fluid intake and renal fluid excretion (P < 0.001). In summary, we observed a higher fractional Ca absorption rate in physically active young men compared with sedentary controls which is probably mediated by calcitriol. The low testosterone serum levels of the athletes were obviously not a limiting factor in Ca absorption efficiency. An additional Ca retention might, however, only be obtained if absorbed Ca exceeded total obligatory Ca losses. Received: 30 September 1999 / Accepted: 22 March 2000     

Does strontium play a role in the cariostatic activity of glass ionomer?: Strontium diffusion and antibacterial activity

Objectives

The aim of this work was to evaluate the activity of strontium ions on the main pathogens of the oral flora. The leaching of strontium from resin modified glass ionomer cements (RMGIC) was evaluated together with its uptake by superficial dental enamel.

Methods

The antibacterial activity was measured by the growth inhibition method following exposure of supra- and sub-gingival bacteria to a range of strontium concentrations (0.19 mol l⁻¹, 0.37 mol l⁻¹, 0.74 mol l⁻¹ and 1.11 mol l⁻¹). Strontium concentrations were analyzed chemically and migration at 5 μm and 15 μm depths was quantified by microprobe following Fuji Ortho LC application on the vestibular enamel of extracted teeth.

Results

Strontium was found in appreciable amounts (0.8 wt.%) in superficial enamel, but in insignificant concentrations deeper in. At the same time, 8% fluoroapatite was formed in the enamel. Under our experimental conditions, strontium had no significant antibacterial activity; only one log reduction of activity was observed at the highest concentrations tested.

Conclusions

RMGIC releases strontium ions which are rapidly exchanged for calcium ions in the superficial enamel. No significant antibacterial activity was observed for strontium ions alone at the concentrations considered. However synergistic effects with fluoride could promote antibacterial activity.     

Hedgehog/Gli1通路在雷奈酸锶促进骨髓间充质干细胞成骨分化过程中的作用

目的:探讨Hedgehog/Gli1信号通路在雷奈酸锶(strontium ranelate,Sr)促进骨髓间充质干细胞(BMSCs)向成骨细胞分化中的作用。方法:体外分离培养大鼠BMSCs,诱导其成骨分化,根据实验目的加入不同浓度的Sr、Hedgehog受体拮抗剂cyclopamine(Cy)及Gli1小干扰RNA(Gli1-siRNA)。用Western blotting法检测Gli1及Runx2的表达,酶标法检测碱性磷酸酶(ALP)活性,茜素红染色法检测钙结节水平。结果:应用不同浓度的Sr(0.1~5 mmol/L)处理BMSCs细胞7 d后,细胞内Gli1蛋白表达增高,Sr的浓度为3 mmol/L时,Gli1表达达到高峰;使用Cy与Sr共处理BMSCs 7 d,能拮抗Sr对Gli1蛋白表达的上调作用;应用Gli1-siRNA转染细胞后,能下调Gli1蛋白的表达,并抑制Sr对Gli1下游Runx2蛋白表达的上调作用,还可拮抗Sr对ALP活性及钙化结节形成的促进作用。结论:Hedgehog/Gli1通路参与了Sr促进骨髓间充质干细胞向成骨分化的过程。