Strontium ranelate improves bone microarchitecture in osteoporosis

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1 Rheumatology 2009;48:iv9 iv13 doi: /rheumatology/kep274 Strontium ranelate improves bone microarchitecture in osteoporosis Neveen A. T. Hamdy 1 In osteoporosis disruption of bone remodelling leads to bone loss microarchitectural damage and increased fracture risk and the goal of any treatment for osteoporosis is to decrease this fracture risk. Available anti-resorptive and anabolic agents effectively achieve this goal by either suppressing or stimulating the activation frequency of bone remodelling units and by improving the biomechanical properties of bone by a number of different mechanisms. Strontium ranelate represents a novel approach in the management of osteoporosis with proven antifracture efficacy. Two putative mechanisms have been proposed for the unique dual mode of action of strontium ranelate rebalancing bone turnover in favour of bone formation: activation of the calcium- or other cation-sensing receptor and increase in the expression of osteoprotegerin (OPG) coupled with a decrease in RANK ligand expression by the osteoblasts. In addition to these cellular changes micro-ct analysis of bone biopsies from strontium ranelate-treated patients demonstrate improvement in intrinsic bone tissue quality as evidenced by increased trabecular number decreased trabecular separation lower structure model index and increased cortical thickness associated with a shift in trabecular structure from rod-to plate-like configuration compared with controls. This review examines the evidence for the ability of strontium ranelate to improve bone microarchitecture in osteoporosis and explores the cellular and microstructural changes by which its antifracture efficacy may be achieved. No attempt is made at comparing the effects of strontium ranelate on bone microarchitecture with that of other anti-resorptive or anabolic osteoporosis agents. KEY WORDS: Bone mineral density Bone quality Bone strength Bone biopsy Bone histomorphometry micro-ct analysis Dual mode of action Calcium-sensing receptor RANK/RANKL/OPG pathway. Introduction Bone is a unique living tissue with an infinite capacity for renewal and repair through the dynamic process of bone remodelling which maintains the material and architectural properties of bone which in turn determines bone strength and competence. The most important consequence of a disruption in the process of bone remodelling is bone loss and microarchitectural damage in the form of thinning and loss of trabeculae thinning of the cortex and accumulation of micro-damage. An imbalance in the finetuned process of bone resorption and formation represents the essence of the pathogenesis of bone loss in all forms of osteoporosis: postmenopausal age-related glucocorticoid-induced or due to other secondary causes [1 6]. Traditional approaches in the management of osteoporosis The goal of any treatment for osteoporosis is to improve bone strength thereby decreasing fracture risk. The last two decades have witnessed the development of a number of therapies effective in achieving this goal. These therapies have largely targeted bone remodelling increasing bone mass by either significantly suppressing bone resorption and also bone formation resulting in overall suppression of bone turnover using anti-resorptive agents such as bisphosphonates or significantly stimulating bone formation and also bone resorption resulting in overall stimulation of bone turnover using anabolic agents such as recombinant parathyroid hormone 1 34 and 1 84 [6 10]. Acting on bone remodelling in diametrically opposite ways both anti-resorptive and anabolic approaches to the treatment of osteoporosis have been shown to significantly decrease the risk of fracture by improving the biomechanical properties of bone by a number of different mechanisms [6 13]. The optimal level of bone turnover that would maintain the material and structural properties of bone 1 Department of Endocrinology and Metabolic Diseases Leiden University Medical Centre Leiden The Netherlands. Submitted 4 February 2009; revised version accepted 31 July Correspondence to: Neveen A. T. Hamdy Department of Endocrinology and Metabolic Diseases Leiden University Medical Center Albinusdreef ZA Leiden The Netherlands. n.a.t.hamdy@lumc.nl with ageing including its ability to respond to mechanical loading is however yet to be determined [4 5]. Strontium ranelate is a novel paradigm in the management of osteoporosis by its unique dual mode of action which rebalances bone turnover in favour of bone formation. The aim of this review is to examine the evidence for the ability of strontium ranelate to improve bone microarchitecture in osteoporosis as a potential significant component of its anti-fracture efficacy [14 21]. The cellular and microstructural changes by which this antifracture efficacy may be achieved are also explored. Evidence for the dual mode of action of strontium ranelate Evidence from clinical data Changes in bone markers: Spinal Osteoporosis Therapeutic Intervention and TReatment Of Peripheral OSteoporosis studies. Data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) study which evaluated the efficacy of strontium ranelate in reducing the incidence of vertebral fractures [14] demonstrated a simultaneous increase of 8.1% in serum bonespecific alkaline phosphatase a marker of bone formation and a decrease of 12.2% in serum C telopeptide cross-links of type I collagen a marker of bone resorption at the third month of treatment compared with placebo (P < 0.001). These changes were sustained from the third month of treatment onwards to 3 years of treatment. Similar changes were also observed in the TReatment Of Peripheral OSteoporosis (TROPOS) study which evaluated the efficacy of the agent in reducing the incidence of non-vertebral fractures [15 22]. The dissociate changes in markers of bone formation and resorption suggest an uncoupling effect of strontium ranelate on bone remodelling. Histomorphometric analysis of bone biopsies: SOTI TROPOS and STRontium Administration for the Treatment of OSteoporosis studies. Histomorphometric analysis of unpaired transiliac bone biopsies was conducted in a subset of postmenopausal women with osteoporosis participating in the SOTI TROPOS and STRontium Administration for the Treatment of OSteoporosis (STRATOS) studies the latter investigating the efficacy and safety of different doses of strontium ranelate in osteoporosis [23 24]. The bone biopsies were obtained iv9 ß The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions please journals.permissions@oxfordjournals.org

2 iv10 Neveen A. T. Hamdy from patients who were treated with strontium ranelate (n ¼ 49) or placebo (n ¼ 89) for a duration of 1 5 years before being biopsied [24]. In the strontium ranelate-treated group there was a significant increase in bone formation parameters as evidenced by a significant increase in osteoblastic surfaces (þ38%; P ¼ 0.047) and in mineral apposition rate in both cancellous and cortical bone (þ9%; P ¼ and þ10%; P ¼ respectively) in treated compared with untreated patients. There was no change in activation frequency and mineralization was preserved. Evidence from in vitro studies and animal models In vitro experiments provide the evidence that strontium ranelate is able to directly inhibit the recruitment and activity of osteoclasts. Strontium ranelate significantly and dose-dependently inhibited the expression of two osteoclast markers: carbonic anhydrase-ii and the v subunit of the vitronectin receptor in a chicken bone marrow culture system suggesting that this agent has an inhibitory effect on the differentiation of pre-osteoclasts into osteoclasts [25]. The dose-dependent inhibitory effect of strontium ranelate on the resorbing activity of osteoclasts was further demonstrated using a pit assay of isolated rat osteoclasts [25] the pit area resorbed by isolated mouse bone marrow osteoclasts in dentine slices and the 45 Ca release from organ cultures of mouse fetal long bones under basal or 125(OH) 2 D-stimulated conditions [26]. Strontium ranelate was also shown to decrease osteoclast resorbing activity increase apoptosis of isolated rabbit osteoclasts [27] and to reduce human peripheral blood monocyte differentiation into osteoclasts [28]. Strontium ranelate was shown to increase the recruitment and activity of osteoblastic cells using 3 H-thymidine- and 3 H-proline-labelled calvariae of newborn rats [29]. Treatment with strontium ranelate also significantly increased osteoblastic proliferation/replication 3- to 4-fold as evaluated by the measurement of DNA synthesis in cell populations enriched with fibroblasts or pre-osteoblastic cells [29]. In an osteogenic model of differentiating mouse calvaria-derived osteoblastic cells strontium ranelate increased alkaline phosphatase activity (a marker of osteoblast differentiation) and increased collagen synthesis without affecting matrix mineralization [30]. Strontium ranelate was shown to stimulate osteoblastic differentiation by the induction of gene expression of the master gene Runx2 and bone sialoprotein that was associated with a significant increase in the formation of colony-forming unit osteoblasts [31] and also significantly increased human primary osteoblast survival under oxidative stress conditions [32]. Studies in primary human osteoblasts suggest that strontium ranelate may also have the ability to promote the differentiation and survival of osteocytes an additional mechanism potentially contributing to its anti-fracture efficacy [33]. More recently in vitro assays on primary murine bone cells confirmed the dual mode of action of strontium ranelate by providing evidence for stimulation of bone formation through a positive action on osteoblast differentiation and action and a decrease in osteoclast differentiation and function by disrupting actin cytoskeleton organization [34]. Data from animal models Two models were used to investigate the effects of strontium ranelate in the prevention of bone loss in osteopenic animals. Administration of strontium ranelate for 2 months to rats immediately after ovariectomy prevented trabecular bone loss. The biochemical and histological changes observed showed that strontium ranelate acted as an uncoupling agent preventing the increased bone resorption associated with oestrogen deficiency while maintaining high levels of bone formation thus dissociating the two components of bone remodelling. A decrease in osteoclast surface and number was observed in treated animals and bone volume was 30% greater than in untreated controls [35]. Treatment with strontium ranelate was also associated with an improvement in bone microarchitecture and bone strength [36]. In rats with hind limb immobilization strontium ranelate increased alkaline phosphatase activity without altering bone mineralization was only partially able to prevent the bone loss induced by immobilization [37]. Potential molecular mechanisms by which strontium ranelate exerts its dual action At least two putative molecular targets have been suggested for the actions of strontium ranelate on bone cells: the calcium sensing receptor (CaSR) or another cation-sensing receptor and the RANK/RANK ligand (RANKL)/osteoprotegerin (OPG) signalling pathway [38] (Fig. 1). CaSR (or another cation-sensing receptor) The CaSR is a G protein-coupled receptor that was first cloned from parathyroid cells and subsequently found to be expressed in many other tissues including osteoblasts and osteoclasts [39]. Strontium a divalent cation closely resembling Ca 2þ in its atomic and ionic properties is an agonist of the extracellular CaSR [40]. Studies in rat primary osteoblasts obtained from calvarial cultures expressing the CaSR endogenously demonstrate that strontium is a full CaSR agonist and that strontium ranelate enhances osteoblast proliferation and bone formation via a CaSRmediated effect [41]. CaSR activation is thus at least in part responsible for mediating the anabolic actions of Sr 2þ on bone [41 42]. However studies in mice with targeted disruption of the CaSR gene (CaSR-null mice) support the additional involvement of another cation-sensing mechanism distinct from CaSR in activating osteoblast replication [43]. The CaSR has also been shown to be involved in strontium ranelate-induced osteoclast apoptosis [44]. The RANK/RANKL/OPG pathway The concerted actions of OPG RANK and its ligand RANKL play a central role in maintaining the delicate balance between bone resorption and formation and in the preservation of bone mass [45 47]. In vitro data suggest that after 24-h incubation strontium ranelate enhances OPG expression while simultaneously down-regulating RANKL expression in primary human osteoblastic cells the combined effect of which leads to decreased osteoclastogenesis [33]. These data suggest that the RANK/ RANKL/OPG pathway is a key molecular target for the dual mode of action of strontium ranelate on bone cells. Effects of strontium ranelate on bone strength Data from intact animal models In normal adult mice strontium ranelate increased trabecular bone volume dose-dependently as evaluated by histomorphometry of the vertebrae [48]. In normal rats treated with strontium ranelate an increase in the diameter of the humeral shaft was observed suggesting an effect on periosteal bone formation [49]. An increase in trabecular thickness and number and a decrease in trabecular separation were also observed in the axial and appendicular skeleton [49]. In monkeys treated with strontium ranelate for 52 weeks there was a dose-dependent uptake of the compound into cortical and cancellous bone with a 1.6-fold higher content in new than in old bone. Strontium uptake into bone decreased by 50% 10 weeks after treatment withdrawal and this was almost exclusively in new bone. Crystal characteristics of bone mineral were preserved at the end of treatment confirming that strontium ranelate was

3 Strontium ranelate improves microarchitecture iv11 FIG. 1. Putative mechanisms of action of strontium ranelate on bone cells. Adapted from [38] with permission from the International Bone and Mineral Society. only weakly linked to crystals and did not affect bone mineralization as mean degree of mineralization was preserved [50]. Beside its influence on determinants of bone strength such as geometry and microarchitecture which is likely to be related to a cellular effect strontium ranelate was also shown to increase elastic modulus hardness and dissipated energy in rat vertebrae using the technique of nanoindentation. These changes in intrinsic bone tissue quality may contribute to the increase in bone strength and decreased fracture risk observed in strontium ranelate-treated osteoporotic patients [51]. Studies on intact animals confirm that strontium ranelate improves bone microarchitecture at both trabecular and cortical levels and preserves the structure of bone matrix crystals without affecting the mineralization process. It is possible that these changes may be associated with an improvement in the biomechanical properties of bone. Data from an ovariectomized rat model In an ovariectomized rat model strontium ranelate was shown to improve bone strength by preventing ovariectomy-induced vertebral biomechanical degradation thereby positively influencing bone resistance determinants. Prevention of ovariectomy-induced bone loss and microarchitectural degradation was associated with a beneficial effect on intrinsic bone material quality [52]. Clinical evidence for the effects of strontium ranelate on bone strength Effects on BMD Strontium ranelate has been shown to significantly increase BMD at the lumbar spine femoral neck and total hip. Whereas overestimation of BMD should be taken into consideration due to skeletal accretion of strontium in strontium ranelate-treated patients [53 54] BMD changes have nevertheless been shown to be significantly related to fracture risk reduction. A post hoc analysis of pooled data from the SOTI and TROPOS studies thus demonstrated that changes of BMD at the femoral neck after 3 years of treatment were predictive of vertebral fracture risk reduction with each 1% increase in femoral neck BMD found to be associated with a 3% reduction in vertebral fracture risk. Changes in BMD thus explained 76% of the fracture risk reduction observed after 3 years of treatment [55]. An increase in femoral neck BMD after 1 year of treatment was also associated with a reduction in new vertebral fractures after 3 years of treatment (P ¼ 0.04). During 3 years of treatment femoral neck BMD changes were also associated with hip fracture risk reduction [56]. These data suggest that femoral neck BMD assessment may be a more appropriate monitoring tool than lumbar spine BMD measurements in strontium ranelate-treated patients. Effects on bone microarchitecture in patients treated with strontium ranelate Forty-one unpaired bone biopsies obtained from patients participating in the SOTI and TROPOS studies were examined using 3D micro-ct (mct) [24]. Compared with placebo (n ¼ 21) strontium ranelate-treated biopsies (n ¼ 20) demonstrated a significant increase in the number of trabeculae (þ14%; P ¼ 0.05) decrease in trabecular separation ( 16%; P ¼ 0.04) and increase in cortical thickness (þ18%; P ¼ 0.008). There was also a shift in trabecular structure from rod-like to plate-like configuration resulting in an improved trabecular structural model index and substantially stronger bone in strontium ranelate-treated compared with untreated patients ( 22%; P ¼ 0.01) [24] (Fig. 2). These changes in trabecular and cortical microstructure are likely to improve the biomechanical properties of bone and contribute to the antifracture efficacy observed with strontium ranelate. Conclusion Increasing knowledge about the cellular and molecular pathways involved in the maintenance of bone homeostasis and about the role of disturbances in these pathways in the pathogenesis of osteoporosis has paved the way for a better understanding of the putative mechanisms responsible for the beneficial effects of strontium ranelate on bone. A decade of extensive in vitro and in vivo pre-clinical evaluation followed by a comprehensive clinical

4 iv12 Neveen A. T. Hamdy SMI: 22% P = Rod-like structure Plate-like structure Placebo 36 M Trabecular number Trabecular separation programme in postmenopausal women has led to the realization that strontium ranelate represents a novel and unique approach in the management of osteoporosis by its ability to restore the imbalance between bone resorption and formation in favour of bone formation and by its beneficial effects on bone microarchitecture which improve the biomechanical properties of bone. Rheumatology key messages Strontium ranelate has a dual mode of action of rebalancing bone remodelling in favour of bone formation. Putative molecular targets for strontium ranelate include CaSR and the RANK/RANKL/OPG signalling pathway. Histomorphometry and mct of bone biopsies from osteoporotic patients show that strontium ranelate improves bone microarchitecture and strength. Acknowledgements Supplement: This paper forms part of the supplement entitled Improvement of bone microarchitecture: the foundation for a better protection against osteoporotic fractures. This supplement was supported by an unrestricted grant from Servier. Disclosure statement: N.A.T.H. has been the recipient of consultancy and/or lecture fees from Lilly Nycomed MSD Procter & Gamble Roche and Servier. References Cortical thickness: + 18% P = Strontium ranelate 36 M + 14% 16% P = 0.05 P = 0.04 FIG. 2. Micro-CT-derived 3D microstructure of transiliac bone biopsies obtained from postmenopausal osteoporotic women treated with strontium ranelate (2 g/day) or placebo for 3 years [24]. SMI: structural model index. Adapted from [24] with permission of the American Society for Bone and Mineral Research. 1 Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999;45: Seeman E Delmas PD. Bone quality - the material and structural basis of bone strength and fragility. N Engl J Med 2006;354: Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21: Recker RR. Skeletal fragility and bone quality. J Musculoskelet Neuronal Interact 2007;7: Weinstein RS. True strength. J Bone Miner Res 2000;15: Cheng Z Yao W Zimmermann EA Busse C Ritchie RO Lane NE. Prolonged treatments with anti-resorptive agents and PTH have different effects on bone strength and the degree of mineralization in old estrogen deficient osteoporotic rats. J Bone Miner Res 2009;24: Brennan TC Rizzoli R Ammann P. Selective modification of bone quality by PTH pamidronate or raloxifene. J Bone Miner Res 2009;24: Hernandez CJ. How can bone turnover modify bone strength independent of bone mass? Bone 2008;42: Martin TJ Seeman E. New mechanisms and targets in the treatment of bone fragility. Clin Sci 2007;112: Riggs BL Parfitt M. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005;20: Rodan GA Martin TJ. Therapeutic approaches to bone diseases. Science 2000;289: Kanis J Burlet N Cooper C et al. European guidance for the diagnosis and treatment of osteoporosis in postmenopausal women. Osteoporos Int 2008;19: NIH Consensus Development Panel on Osteoporosis Prevention Diagnosis & Therapy. Osteoporosis prevention diagnosis and therapy. J Am Med Assoc 2001; 285: Meunier PJ Roux C Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004; 350: Reginster JY Seeman E de Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90: Reginster JY Felsenberg D Boonen S et al. 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S inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 2003;18: Mentaverri R Chattopadhyay N Lemaire-Hurtel AS et al. The effects of strontium ranelate on osteoclasts are calcium-receptor dependent. J Bone Miner Res 2005;20: S Wattel A Lemaire-Hurtel AS Godin C et al. Strontium ranelate decreases in vitro osteoclastic differentiation and bone resorption. Osteoporos Int 2005;16:S Canalis E Hott M Deloffre P Tsouderos Y Marie PJ. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone 1996;18: Barbara A Delannoy P Denis BG et al. Normal matrix mineralization induced by strontium ranelate in MC3T3-E1 osteogenic cells. Metabolism 2004;53: Zhu LL Zaidi S Peng Y et al. Induction of a program gene expression during osteoblast differentiation with strontium ranelate. Biochem Biophys Res Commun 2007;355: Brennan TC Rybchyn MS Hallbout P et al. Strontium ranelate effects in human osteoblasts support its uncoupling effect on bone formation and bone resorption. Calcif Tissue Int 2007;80(Suppl. 1):S Atkins GJ Welldon KJ Halbout P Findlay DM. Strontium ranelate treatment of primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 2009;20: Bonnelye E Chabadel A Saltel F Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 2008;42: Marie PJ Hott M Modrowski D et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res 1993;8: Ammann P Badoud I Shen V et al. Strontium ranelate prevents alteration in bone strength in OVX rats by improving bone tissue quality. Calcif Tissue Int 2006;78: S Hott M Deloffre P Tsouderos Y Marie PJ. 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5 Strontium ranelate improves microarchitecture iv13 40 Coulombe J Faure H Robin B Ruat M. In vitro effects of strontium ranelate on the extracellular calcium-sensing receptor. Biochem Biophys Res Commun 2004;323: Chattopadhyay N Quinn SJ Kifor O Ye C Brown EM. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol 2007;74: Caverzasio J. Strontium ranelate promotes osteoblast cell replication through at least two different mechanisms. Bone 2008;42: Pi M Quarles LD. A novel cation-sensing mechanism in osteoblasts is a molecular target for strontium. J Bone Miner Res 2004;19: Hurtel-Lemaire AS Mentaverri R Caudrillier A et al. The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. J Biol Chem 2009;284: Boyle WJ Simonet WS Lacey DL. Osteoclast differentiation and activation. Nature 2003;423: Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001;142: Hofbauer LC Schoppet M. Clinical implications of the osteoprotegerin/ RANKL/RANK system for bone and vascular diseases. J Am Med Assoc 2004; 292: Delannoy P Bazot D Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism 2002;51: Ammann P Shen V Robin B Mauras Y Bonjour JP Rizzoli R. Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res 2004;19: Farlay D Boivin G Panczer G Lalande A Meunier PJ. Long-term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralization of bone. J Bone Miner Res 2005;20: Ammann P Badoud I Barraud S Dayer R Rizzoli R. Strontium ranelate treatment improves trabecular and cortical intrinsic bone quality a determinant of bone strength. J Bone Mineral Res 2007;22: Bain SD Jerome C Dupin-Roger I Amman P. Strontium ranelate improves bone strength in ovariectomized rat by positively influencing bone resistance determinants. Osteoporos Int 2009;20: Blake GM Lewiecki EM Kendler DL Fogelman I. A review of strontium ranelate and its effect on DXA scans. J Clin Densitom 2007;10: Blake GM Fogelman I. The correction of BMD measurements for bone strontium content. J Clin Densitom 2007;10: Bruyere O Roux C Detilleux J et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab 2007;92: Bruyère O Roux C Badurski J et al. Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate. Curr Med Res Opin 2007;23:

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