Long-term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralization of bone.

In monkeys, long-term strontium ranelate administration results in a dose-dependent bone strontium uptake (mainly into newly formed bone) that preserves the degree of mineralization of bone and the bone mineral at the crystal level, showing its safety at bone mineral level. INTRODUCTION: Strontium ranelate simultaneously increases bone formation and decreases bone resorption, leading to prevention of bone loss and increase in bone mass and bone strength in normal and ovariectomized rats. This study investigated the interactions of stable strontium (Sr) with bone mineral in monkeys after long-term strontium ranelate treatment and after a period of treatment withdrawal. MATERIALS AND METHODS: Iliac bone was obtained from untreated monkeys, monkeys at the end of a 52-week strontium ranelate administration (200, 500, 1250 mg/kg/day orally), and in parallel groups 10 weeks after the end of strontium ranelate administration (same three doses; n = 3-7). Sr uptake and distribution in bone mineral were quantified by X-ray microanalysis, changes at the crystal level by X-ray diffraction, and the degree of mineralization of bone (DMB) by quantitative microradiography. RESULTS: After strontium ranelate administration, dose-dependent Sr uptake occurred into cortical and cancellous bone, with higher content (1.6 times) in new than in old bone. This Sr uptake decreased (50%) 10 weeks after treatment withdrawal; the decrease occurred almost exclusively in new bone. At the end of strontium ranelate treatment and after its withdrawal, a preservation of crystal characteristics was observed, suggesting that Sr was only faintly linked to crystals by ionic substitution and of DMB. CONCLUSIONS: These results show the absence of a deleterious effect of long-term strontium ranelate treatment on bone mineralization, confirming the histomorphometric observations made in postmenopausal osteoporotic women treated with strontium ranelate.     

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.     

雷尼酸锶治疗骨质疏松症的研究进展

目的 对雷尼酸锶在骨质疏松症中的临床应用、作用机制进行综述和评价.方法 从人群试验、动物试验、细胞培养和不良反应等方面进行综述.结果 雷尼酸锶具有抗骨吸收和增进骨形成双重作用,其作用可能通过CaSR和增加血清IGF-1、降低高半胱氨酸.结论 雷尼酸锶作为一种新型抗骨质疏松药物,对骨质疏松症具有良好的疗效,代表了骨质疏松症治疗的一个重要发展方向,但应注意其不良反应.     

Strontium ranelate promotes osteoblastic differentiation and mineralization of murine bone marrow stromal cells: involvement of prostaglandins.

Strontium ranelate is a new anti-osteoporosis treatment. This study showed that strontium ranelate stimulated PGE(2) production and osteoblastic differentiation in murine marrow stromal cells, which was markedly reduced by inhibition of COX-2 activity or disruption of COX-2 gene expression. Hence, some anabolic effects of strontium ranelate may be mediated by the induction of COX-2 and PGE(2) production. INTRODUCTION: Strontium ranelate is an orally active drug that reduces vertebral and hip fracture risk by increasing bone formation and reducing bone resorption. Strontium ranelate effects on bone formation are the result of increased osteoblastic differentiation and activity, but the mechanisms governing these effects are unknown. Based on previous work, we hypothesized that strontium ranelate increases cyclooxygenase (COX)-2 expression and that, consequently, the prostaglandin E(2) (PGE(2)) produced could mediate some effects of strontium ranelate on osteoblasts. MATERIALS AND METHODS: Marrow stromal cells (MSCs) from COX-2 wildtype (WT) and knockout (KO) mice were cultured with and without low-dose dexamethasone. Osteoblastic differentiation was characterized by alkaline phosphatase (ALP) activity, real-time PCR for ALP and osteocalcin (OCN) mRNA expression, and alizarin red staining for mineralization. Medium PGE(2) was measured by radioimmunoassay or enzyme immunoassay. RESULTS AND CONCLUSIONS: In MSCs from COX-2 WT mice, strontium ranelate significantly increased ALP activity, ALP and OCN mRNA expression, and mineralization after 14 or 21 days of culture. A short treatment at the beginning of the culture (0-7 days) with strontium ranelate was as effective as continuous treatment. Strontium ranelate (1 and 3 mM Sr(+2)) dose-dependently increased PGE(2) production, with maximum PGE(2) production occurring during the first week of culture. NS-398, a selective COX-2 inhibitor, blocked the strontium ranelate stimulation of PGE(2) production and significantly inhibited the strontium ranelate stimulation of ALP activity. In MSCs from COX-2 KO mice, the strontium ranelate stimulation of ALP and OCN mRNA expression and mineralization were markedly reduced compared with COX-2 WT cultures. Similar effects of strontium ranelate on osteoblastic markers and on PGE(2) production were seen when MSCs were cultured with or without low-dose dexamethasone (10 nM). We conclude that PGE(2) produced by the strontium ranelate induction of COX-2 expression plays a role in strontium ranelate-induced osteoblastic differentiation in MSCs in vitro.     

Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats.

Strontium ranelate given to intact rats at doses up to 900 mg/kg/day increases bone resistance, cortical and trabecular bone volume, micro-architecture, bone mass, and total ALP activity, thus indicating a bone-forming activity and an improvement of overall bone tissue quality. INTRODUCTION: Various anti-osteoporotic agents are available for clinical use; however, there is still a need for drugs able to positively influence the coupling between bone formation and bone resorption to increase bone mass and bone strength. Strontium ranelate (PROTELOS), a new chemical entity containing stable strontium (Sr), was tested for its capacity to influence bone quality and quantity. MATERIALS AND METHODS: The long-term effects of strontium ranelate on bone were investigated in intact female rats treated with various doses of strontium ranelate (0, 225, 450, and 900 mg/kg/day) for 2 years. In a second series of experiments, the effects of 625 mg/kg/day were evaluated in intact male and female rats for the same period of time. Bone mineral mass and mechanical properties were evaluated at various skeletal sites (vertebra and femur), and bone tissue micro-architecture was evaluated by static histomorphometry at the tibio-fibular junction (cortical bone) and at the tibia metaphysis (trabecular bone). Plasma total alkaline phosphatase (ALP) activity and serum levels of insulin-like growth factor-I (IGF-I) were also assessed. RESULTS: In female rats treated with strontium ranelate over 2 years, dose-dependent increases of bone strength and bone mass of the vertebral body (containing a large proportion of trabecular bone) and of the midshaft femur (containing mainly cortical bone) were detected without change in bone stiffness. Similar effects were observed in males at the level of the vertebra. This increase in mechanical properties was associated with improvements of the micro-architecture as assessed by increases of trabecular and cortical bone volumes and trabecular number and thickness. Finally, plasma total ALP activity and IGF-I were also increased in treated animals, compatible with a bone-forming activity of strontium ranelate. CONCLUSION: A long-term treatment with strontium ranelate in intact rats is very safe for bone and improves bone resistance by increasing bone mass and improving architecture while maintaining bone stiffness.     

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.     

Incorporation and distribution of strontium in bone

The distribution and incorporation of strontium into bone has been examined in rats, monkeys, and humans after oral administration of strontium (either strontium chloride or strontium ranelate). After repeated administration for a sufficient period of time (at least 4 weeks in rats), strontium incorporation into bone reaches a plateau level. This plateau appears to be lower in females than in males due to a difference in the absorption process. Steady-state plasma strontium levels are reached more rapidly than in bones, and within 10 days in the rat. The strontium levels in bone vary according to the anatomical site. However, strontium levels at different skeletal sites are strongly correlated, and the strontium content of the lumbar vertebra may be estimated from iliac crest bone biopsies in monkeys. The strontium levels in bone also vary according to the bone structure and higher amounts of strontium are found in cancellous bone than in cortical bone. Furthermore, at the crystal level, higher concentrations of strontium are observed in newly formed bone than in old bone. After withdrawal of treatment, the bone strontium content rapidly decreases in monkeys. The relatively high clearance rate of strontium from bone can be explained by the mechanisms of its incorporation. Strontium is mainly incorporated by exchange onto the crystal surface. In new bone, only a few strontium atoms may be incorporated into the crystal by ionic substitution of calcium. After treatment withdrawal, strontium exchanged onto the crystal is rapidly eliminated, which leads to a rapid decrease in total bone strontium levels. In summary, incorporation of strontium into bone, mainly by exchange onto the crystal surface, is dependent on the duration of treatment, dose, gender, and skeletal site. Nevertheless, bone strontium content is highly correlated with plasma strontium levels and, in bone, between the different skeletal sites.     

Strontium Is Incorporated in Different Levels into Bones and Teeth of Rats Treated with Strontium Ranelate

The aim of this study was to evaluate the strontium incorporation into specific bones and teeth of rats treated with strontium ranelate. The relative strontium levels [Sr/(Ca?+?Sr) ratio] were obtained by synchrotron radiation micro X-ray fluorescence. The incisor teeth were further examined by energy dispersive X-ray spectroscopy (EDS) in a scanning electron microscope. The isolated mineral phase was investigated by EDS in a transmission electron microscope and X-ray diffraction. The strontium content was markedly increased in animals treated with strontium ranelate, with different incorporation levels found among specific bones, regions within the same bone and teeth. The highest strontium levels were observed in the iliac crest, mandible and calvaria, while the lowest were observed in the femoral diaphysis, lumbar vertebrae, rib and alveolar bone. The strontium content was higher in the femoral neck than in the diaphysis. The strontium levels also varied within the alveolar bone. High levels of strontium were found in the incisor tooth, with values similar to those in the iliac crest. Strontium was observed in both enamel and dentin. The strontium content of the molar tooth was negligible. Strontium was incorporated into the mineral substance, with up to one strontium replacing one out of 10 calcium ions within the apatite crystal lattice. The mineral from treated animals presented increased lattice parameters, which might be associated to their bone strontium contents. In conclusion, the incorporation of strontium occurred in different levels into distinct bones, regions within the same bone and teeth of rats treated with strontium ranelate.     

Strontium ranelate: New data on fracture prevention and mechanisms of action

Osteoporosis treatments need to combine an unequivocally demonstrated reduction of fractures, at various skeletal sites, long-term safety, and a user-friendly profile that optimizes therapeutic adherence. Strontium ranelate is the first compound to simultaneously decrease bone resorption and stimulate bone formation. Its anti-fracture efficacy at various skeletal sites has been established for as long as 5 years through studies of the highest methodological standards. Increases in bone mineral density observed after 1 year of treatment are predictive of the long-term fracture efficacy, suggesting for the first time in osteoporosis that bone densitometry can be used as a monitoring tool. Due to a positive risk/benefit ratio, strontium ranelate is now considered as a first-line treatment in the management of osteoporosis.     

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.     

How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis

Oestrogen deficiency increases the rate of bone remodelling which, in association with a negative remodelling balance (resorption exceeding formation), results in impaired bone architecture, mass and strength. Current anti-osteoporotic drugs act on bone remodelling by inhibiting bone resorption or by promoting its formation. An alternative therapeutic approach is based on the concept of inducing opposite effects on bone resorption and formation. One therapeutic agent, strontium ranelate, was shown to induce opposite effects on bone resorption and formation in pre-clinical studies and to reduce fracture risk in postmenopausal osteoporotic patients. How strontium ranelate acts to improve bone strength in humans remains a matter of debate, however. This review of the most recent pre-clinical and clinical studies is a critical analysis of strontium ranelate’s action on bone resorption and formation and how it increases bone mass, microarchitecture and strength in postmenopausal osteoporotic women.     

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.     

Histomorphometric and μCT Analysis of Bone Biopsies From Postmenopausal Osteoporotic Women Treated With Strontium Ranelate

Strontium ranelate is a new anti‐osteoporotic treatment. On bone biopsies collected from humans receiving long‐term treatment over 5 yr, it has been shown that strontium ranelate has good bone safety and better results than placebo on 3D microarchitecture. Hence, these effects may explain the decreased fracture rate. Introduction: Strontium ranelate's mode of action involving dissociation of bone formation and resorption was shown in preclinical studies and could explain its antifracture efficacy in humans. Materials and Methods: One hundred forty‐one transiliac bone biopsies were obtained from 133 postmenopausal osteoporotic women: 49 biopsies after 1–5 yr of 2 g/d strontium ranelate and 92 biopsies at baseline or after 1–5 yr of placebo. Results and Conclusions: Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3‐yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using μCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (?22%, p = 0.01) and trabecular separation (?16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.     

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.     

Accumulation of bone strontium measured by in vivo XRF in rats supplemented with strontium citrate and strontium ranelate

Strontium ranelate is an approved pharmacotherapy for osteoporosis in Europe and Australia, but not in Canada or the United States. Strontium citrate, an alternative strontium salt, however, is available for purchase over-the-counter as a nutritional supplement. The effects of strontium citrate on bone are largely unknown. The study's objectives were 1) to quantify bone strontium accumulation in female Sprague Dawley rats administered strontium citrate (N = 7) and compare these levels to rats administered strontium ranelate (N = 6) and vehicle (N = 6) over 8 weeks, and 2) to verify an in vivo X-ray fluorescence spectroscopy (XRF) system for measurement of bone strontium in the rat. Daily doses of strontium citrate and strontium ranelate were determined with the intention to achieve equivalent amounts of elemental strontium. However, post-hoc analyses of each strontium compound conducted using energy dispersive spectrometry microanalysis revealed a higher elemental strontium concentration in strontium citrate than strontium ranelate. Bone strontium levels were measured at baseline and 8 weeks follow-up using a unique in vivo XRF technique previously used in humans. XRF measurements were validated against ex vivo measurements of bone strontium using inductively coupled plasma mass spectrometry. Weight gain in rats in all three groups was equivalent over the study duration. A two-way ANOVA was conducted to compare bone strontium levels amongst the three groups. Bone strontium levels in rats administered strontium citrate were significantly greater (p < 0.05) than rats administered strontium ranelate and vehicle. ANCOVA analyses were performed with Sr dose as a covariate to account for differences in strontium dosing. The ANCOVA revealed differences in bone strontium levels between the strontium groups were not significant, but that bone strontium levels were still very significantly greater than vehicle.     

Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment

Strontium ranelate has been shown to increase bone mass in postmenopausal osteoporosis patients and to reduce fracture risk. The aim of this study was to investigate the potential influence of strontium ranelate (Protelos) treatment on human bone tissue characteristics and quality at the micro‐ and nanostructural levels. We investigated transiliac biopsies from patients treated for 36 months with strontium ranelate or placebo (n = 5 per group) using synchrotron radiation with a microbeam combining scanning small‐angle scattering, X‐ray diffraction, and fluorescence spectroscopy (SAXS/XRD/XRF) for a detailed characterization of the mineral crystals within the collagenous bone matrix. A scanning procedure allowed the simultaneous determination of maps of the chemical composition together with thickness, length, and lattice spacing of these mineral crystals within each of the 15‐ or 25‐µm‐wide pixels in a thin bone section. The fluorescence results show that only bone packets or osteons formed during the strontium ranelate treatment contain significant amounts of strontium and that up to 0.5 of 10 calcium atoms in the mineral crystals are replaced by strontium, as revealed by a corresponding shift in apatite lattice spacing. The thickness and length of the plate‐shaped bone mineral crystals were not affected by the strontium ranelate treatment. As a consequence, there was no indication for a change in human bone tissue quality at the nanoscale after a 36‐month treatment of postmenopausal osteoporotic women with strontium ranelate, except for a partial replacement of calcium by strontium ions in the hydroxyapatite crystals, only in newly formed bone. © 2010 American Society for Bone and Mineral Research     

Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength.

Beside its influence on determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality as evaluated by nanoindentation, increasing elastic modulus, hardness, and dissipated energy in vertebrae of rats treated for 104 wk with daily dose from 0 to 900 mg/kg. INTRODUCTION: We previously showed that strontium ranelate treatment improves the mechanical properties of the vertebral body and long bone midshaft in intact rats. The increased energy to failure obtained with strontium ranelate is essentially caused by an increase in plastic energy, suggesting that bone formed during treatment can withstand greater deformation before fracture. In the bone mineral phase, strontium is mainly located in the hydrated shell and could thus potentially influence intrinsic bone tissue quality. MATERIALS AND METHODS: To study whether strontium ranelate treatment could positively influence intrinsic bone tissue quality (elastic modulus, hardness, and dissipated energy), nanoindentation tests were performed at the level of trabecular nodes and cortex under physiological or dry conditions in vertebrae of rats treated for 104 wk with strontium ranelate at a daily dose of 0, 225, 450, or 900 mg/kg (n = 12 per group). Ex vivo microCT measurements and axial compression tests of adjacent vertebral bodies were also performed. Significance of difference was evaluated using ANOVA. RESULTS: In agreement with previous results, strontium ranelate (900 mg/kg/d) [corrected] increased versus controls in maximal load (+23%), total energy (+71%), and plastic energy (+143%). At the level of trabecular bone, strontium ranelate treatment resulted in a significant increase in elastic modulus (+15.1%, p < 0.01), hardness (+11.5%, p < 0.05), and dissipated energy (+16.2%, p < 0.001) versus controls in physiological, but not in dry, conditions. The effect was less pronounced in cortex. CONCLUSIONS: These results show for the first time a direct action of strontium ranelate on bone tissue quality. Beside its shown influence on classical determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality. This could contribute to the increase in bone strength and thus be involved in the reduction of fracture risk in postmenopausal osteoporotic patients treated with strontium ranelate.     

Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover

Summary  

Osteoporotic post-menopausal women patients in two randomised trials comparing the anti-fracture efficacy of strontium ranelate with placebo were separated into tertiles according to their baseline levels of biochemical markers of bone formation and resorption. The vertebral anti-fracture efficacy of strontium ranelate was shown to be independent of baseline bone turnover levels.     

Impact of Treatments for Postmenopausal Osteoporosis (Bisphosphonates, Parathyroid Hormone, Strontium Ranelate, and Denosumab) on Bone Quality: A Systematic Review

The objective of this systematic review was to examine the influence of treatments for postmenopausal osteoporosis (parathyroid hormone [PTH], bisphosphonates, strontium ranelate, and denosumab) on bone quality and discuss the clinical implications. Most bone-quality data for PTH is from teriparatide. Teriparatide results in a rapid increase in bone-formation markers, followed by increases in bone-resorption markers, opening an “anabolic window,” a period of time when PTH is maximally anabolic. Teriparatide reverses the structural damage seen in osteoporosis and restores the structure of trabecular bone. It has a positive effect on cortical bone, and any early increases in cortical porosity appear to be offset by increases in cortical thickness and diameter. Bisphosphonates are antiresorptive agents which reduce bone turnover, improve trabecular microarchitecture, and mineralization. Concerns have been raised that the prolonged antiresorptive action of bisphosphonates may lead to failure to repair microdamage, resulting in microcracks and atypical fragility. Strontium ranelate is thought to have a mixed mode of action, increasing bone formation and decreasing bone resorption. Strontium ranelate improves cortical thickness, trabecular number, and connectivity, with no change in cortical porosity. Denosumab exerts rapid, marked, and sustained effects on bone resorption, resulting in falls in the markers of bone turnover. Evidence from bone-quality studies suggests that treatment-naive women, aged 60–65 years, with very low BMD T scores may benefit from PTH as primary therapy to improve bone substrate and build bone. Post-PTH treatment with bisphosphonates will maintain improvements in bone quality and reduce the risk of fracture.