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Strontium as therapy for osteoporosis
Strontium as therapy for osteoporosis Pierre J Marie Osteoporosis is characterized by low bone mass and increased susceptibility to fracture. Recent in vitro studies showed that strontium ranelate, a novel agent containing two strontium atoms, acts as an effective anti-osteoporotic drug by inhibiting bone resorption by osteoclasts and promoting osteoblast replication and bone formation. Studies in animals demonstrated that strontium ranelate increases bone mass, microarchitecture and strength in intact rodents and prevents bone loss in osteopenic animals. Clinical studies show that strontium ranelate reduces the risk of vertebral and nonvertebral fractures in postmenopausal osteoporosis. Together, these recent advances point to unique effects of strontium ranelate on bone cells and show that strontium ranelate has significant clinical benefits in the treatment of postmenopausal osteoporosis. Addresses INSERM U606 and University Paris 7, Lariboisie`re Hospital, 2 Rue Ambroise Pare´, 75475 Paris cedex 10, France Corresponding author: Marie, Pierre J ([email protected])
resorptive and bone-forming effects, which represents an important new advance in the therapy of osteoporosis. Strontium, a trace element originally detected in lead mines near Strontian (Scotland) in the late 1700s, is a bone-seeking agent. In contrast to radioactive strontium, which induces toxic effects on bone cells, stable strontium was found to induce beneficial effects on bone [3,4]. Pionner experiments in animals showed that strontium salts can decrease bone resorption and increase bone formation and bone mass without affecting bone mineralization [5–8], raising the possibility that strontium may be of potential benefit for treatment of osteoporosis. This led to the development of a unique molecule called strontium ranelate (Protelos1; Servier Laboratories, France) that is composed of an organic moiety which binds two stable strontium atoms, resulting in increased strontium bioavailability. This review summarizes the available data on the mechanisms of action of strontium ranelate on bone cells, and its pharmacological and clinical effects on bone mass in animals and in postmenopausal subjects.
Current Opinion in Pharmacology 2005, 5:633–636 This review comes from a themed issue on Endocrine and metabolic diseases Edited by Cary Cooper and Gordon Klein Available online 23rd September 2005 1471-4892/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2005.05.005
Introduction Osteoporosis is characterized by low bone mass and deteriorated bone microarchitecture, resulting in increased bone fragility and susceptibility to fracture. A common cause of osteoporosis in women is estrogen deficiency at menopause which induces increased bone turnover, with an imbalance between bone resorption and formation. Most anti-osteoporotic therapies are therefore based on anti-catabolic drugs that inhibit excessive bone turnover, resulting in preservation of bone mass and strength and decreased occurrence of fractures in postmenopausal women [1,2]. By contrast, anabolic drugs increase bone remodeling with a greater effect on bone formation than bone resorption, resulting in increased bone mass and microarchitecture and a greater reduction of fractures [2]. A new compound — strontium ranelate — was recently shown to act as an effective anti-osteoporotic drug through a mechanism combining both antiwww.sciencedirect.com
How does strontium act on bone cells? Several studies indicate that strontium ranelate acts as an anti-resorbing and bone-forming agent [9]. In mouse calvaria cultures, strontium ranelate inhibits bone resorption by approximately 30% as assessed by calcium release [10]. Additionally, strontium ranelate decreases osteoclast activity by about 30%, as measured by the pit assay in isolated rat cells [11], and inhibits the bone-resorbing activity of mouse osteoclasts cultured on dentine slices in long bone culture, also measured in a pit assay [10]. These effects are specific to strontium ranelate and are not reproduced with calcium ranelate, suggesting a distinct effect of the two cations. Strontium ranelate was also shown to decrease the number of osteoclasts expressing two functional osteoclast markers, carbonic anhydrase II and vitronectin receptor, in chicken bone-marrow cultures induced to differentiate into osteoclasts by 1,25dihydroxyvitamin D3 treatment [10]. Although it is unknown whether the concentrations effective at inhibiting osteoclast activity in vitro are found in bone in vivo, it is likely that high concentrations of strontium that bind hydroxyapatite are found on bone crystal surfaces [12]. This indicates that inhibition of bone resorption in vitro by strontium may, in part, result from inhibition of osteoclast activity, which is, however, not completely abolished. Further studies indicate that strontium ranelate also has positive effects on bone formation in vitro. In rat calvaria Current Opinion in Pharmacology 2005, 5:633–636
634 Endocrine and metabolic diseases
organ culture and rat calvaria cell cultures, strontium ranelate was initially shown to enhance the replication of preosteoblastic cells and, consequently, the activity of functional cells and bone matrix synthesis, effects that were specific as calcium ranelate had no effect [13]. In a more recent in vitro osteogenic model of differentiating mouse calvaria-derived MC3T3-E1 osteoblastic cells, stontium ranelate was found to increase alkaline phosphatase activity, a marker of osteoblast differentiation, and to increase collagen synthesis in this system without affecting matrix mineralization, confirming the boneforming activity of strontium ranelate in vitro [14]. What are the mechanisms of action of strontium in bone cells? Although the cellular actions of strontium have not been fully identified, several mechanisms of action can be postulated [15]. For example, strontium was found to activate the calcium-sensing receptor in some cell types, resulting in activation of inositol trisphosphate production and mitogen-activated protein kinase signaling [16,17]. Other receptors sensitive to strontium, yet to be identified, might also be effective in bone cells [18]. Additionally, strontium was found to induce cyclooxygenase-2 expression and prostaglandin E2 production through activation of the extracellular signal-regulated kinase pathway in osteoblasts, which might be involved in the boneforming effect of strontium ranelate [19]. It is expected that future studies will provide more information on the cellular and molecular mechanisms by which strontium acts on bone cells to inhibit bone resorption and promote bone formation in vitro. The mechanisms by which strontium ranelate increases cartilage formation in vitro [20] also remain to be determined.
Effects of strontium ranelate on bone mass and strength Are the in vitro beneficial effects of strontium ranelate on bone cells also observed in vivo? Several studies indicate that the anti-resorbing and bone-forming effects of strontium ranelate do apply in intact animal models. In normal adult mice, administration of strontium ranelate increased vertebral bone formation and decreased bone resorption, resulting in increased bone mass [21]. In adult rats, strontium ranelate increased bone mass in the lumbar vertebra and femur, which was confirmed by histological assessment of trabecular bone volume [22]. This effect was associated with increased trabecular thickness and number, and decreased trabecular separation in the tibial metaphysis, indicating that strontium ranelate improved bone microarchitecture [22]. This resulted in improved bone strength, as shown by mechanical properties of the axial (lumbar vertebrae) and appendicular bone (midshaft humerus and midshaft femur) [22]. Interestingly, plasma alkaline phosphatase activity increased in treated animals, compatible with the bone-forming activity of strontium ranelate [22]. In normal adult monkeys (Macaca fascicularis), which exhibit mostly bone remodeling as in Current Opinion in Pharmacology 2005, 5:633–636
humans, strontium ranelate was found to decrease bone resorption and to increase mineralizing surfaces in alveolar bone [23]. The available pharmacological data therefore indicate that strontium ranelate induces antiresorbing and bone-forming effects in vivo, resulting in increased bone mass and bone strength in the vertebral and appendicular skeleton.
Does strontium affect bone mineral? Because strontium is a bone-seeking agent, it is important to determine whether strontium incorporation into bone interacts with bone mineralization; however, several studies indicate that this is not the case. First, strontium is mainly adsorbed on the crystal surface in bone, and only one in ten calcium cations in the apatite crystal was found to be replaced by strontium in vivo [24]. Second, analysis of hydroxyapatite crystals formed under treatment with strontium ranelate showed no alteration in the degree of mineralization or mineral properties in vitro [25]. Third, analysis in intact rats treated with high doses of strontium ranelate for two years showed no alteration of bone mineralization [22]. Although it has been suggested that strontium may be involved in delayed mineralization in dialyzed patients with end-stage renal failure exposed to elevated strontium content in dialyzed fluids [26], bone strontium content in dialyzed patients does not always correlate with defective bone mineralization [27].
Strontium ranelate prevents bone loss in osteopenic animals On the basis of the pharmacological data from intact animals, it was expected that strontium ranelate would be effective in preventing bone loss in animal models of osteoporosis. This has now been demonstrated in two studies. In ovariectomized rats, strontium ranelate prevented trabecular bone loss induced by estrogen deficiency, as shown by densitometric analysis, bone ash, bone mineral content and histomorphometrical analysis in the tibial metaphysis. This effect resulted from decreased bone resorption, while bone formation was maintained [28]. In another model of trabecular bone loss induced by hindlimb immobilization, strontium ranelate was found to prevent the increased bone resorption and trabecular bone loss induced by immobilization [29]. In this model, strontium ranelate increased plasmatic bone-specific alkaline phosphatase levels and decreased urinary hydroxyproline excretion, further indicating that it induces opposite effects on bone resorption and bone formation in vivo. These pharmacological data in osteopenic animals predicted that strontium ranelate may have anti-osteoporotic effects in clinical studies.
Anti-osteoporotic effects of strontium ranelate in postmenopausal osteoporosis Several clinical trials were performed to assess the efficacy of strontium ranelate in postmenopausal women with established osteoporosis. In a prospective, doublewww.sciencedirect.com
Strontium as therapy for osteoporosis Marie 635
blind, randomized, placebo-controlled trial, three doses of strontium ranelate (500 mg, 1 g, 2 g) or placebo were given to 353 osteoporotic women also receiving calcium (500 mg) and vitamin D. A significant 7.3% annual increase in lumbar bone mineral density was observed in the group receiving 2 g of strontium [30]. Although about half of this increase might be a result of the bone mineral density being overestimated when measured by dual X-ray absorptiometry [31], the number of patients receiving 2 g of strontium ranelate who experienced new vertebral fracture in the second year of treatment was reduced by 44% compared with those receiving placebo, which pointed to the potential anti-osteoporotic effects of strontium ranelate [30]. Because of these data, the anti-fracture efficacy of strontium ranelate was assessed in two large, randomized, double-blind, placebo-controlled clinical studies: the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial and the Treatment Of Peripheral Osteoporosis Study (TROPOS), including more than 6700 postmenopausal women. In the SOTI trial, strontium ranelate significantly reduced the incidence of new vertebral and clinical vertebral fractures by 40–50% after one and three years of treatment [32]. This was accompanied by decreased back pain and body height loss. In this trial, bone alkaline phosphatase levels (a marker of bone formation) increased by 8.1%, whereas telopeptide crosslink levels (a marker of bone resorption) decreased concomitantly by 12.2% in patients treated with strontium ranelate compared with the placebo group at all time-points (3–36 months), indicating that strontium ranelate induced opposite and concomitant changes in markers of bone resorption and formation. No delayed mineralization at the histological level was observed after treatment for three years with strontium ranelate, which further emphasizes the safety of the compound on bone mineralization in osteoporotic subjects [32]. The TROPOS trial included 5091 osteoporotic postmenopausal women aged 74 years (or 70 years with one risk factor for osteoporotic fracture) [33]. In this trial, strontium ranelate reduced by 16% the risk of non-vertebral fractures throughout the three year study compared with placebo. The compound also reduced by 19% the relative risk for major fragility fractures (i.e. hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus). In a subgroup of 1977 patients at high risk of hip fracture, strontium ranelate reduced the risk of hip fracture by 36% over three years [33]. Overall, strontium ranelate was well tolerated, especially in the upper gastrointestinal area. In both SOTI and TROPOS studies, the most common adverse effects consisted of nausea and diarrhea, which disappeared after the first three months [32,33]. These clinical data indicate that strontium ranelate has significant clinical benefits in the treatment of postmenopausal osteoporosis. Strontium ranelate is now cliniwww.sciencedirect.com
cally available in a number of countries for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.
Conclusions The available pharmacological and clinical data indicate that strontium ranelate is a unique anti-osteoporotic drug that reduces the risk of vertebral and non-vertebral fractures in potmenopausal women with good tolerability in patients, and which represents an important advance in the therapy of osteoporosis. Unlike the available antiosteoporotic drugs, the compound induces anti-resorbing and bone-forming effects on bone remodeling, resulting in improvement of bone mass and strength. Putative mechanisms of action of strontium ranelate on bone cells have recently been postulated; however, future studies are needed to establish the exact cellular and molecular mechanisms by which strontium ranelate exerts its antiosteoporotic effects in bone.
Acknowledgements I thank the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS) for the support of our work, and my colleagues and collaborators for their help.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
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10. Baron R, Tsouderos Y: In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 2002, 450:11-17. Current Opinion in Pharmacology 2005, 5:633–636
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11. Takahashi N, Sasaki T, Tsouderos Y, Suda T: S12911-2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 2003, 18:1082-1087. 12. Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, Tsouderos Y, Delmas PD, Christiansen C: Incorporation and distribution of strontium in bone. Bone 2001, 28:446-453. 13. 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, 18:517-523. 14. Barbara A, Delannoy P, Denis BG, Marie PJ: Normal matrix mineralization induced by strontium ranelate in MC3T3-E1 osteogenic cells. Metabolism 2004, 53:532-537. 15. Marie PJ: Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int 2005, 16(Suppl 1):s7-s10. A recent review updating the mechanisms of action of strontium in bone cells. 16. Brown EM: Is the calcium receptor a molecular target for the actions of strontium on bone? Osteoporos Int 2003, 14(Suppl 3):S25-S34. 17. 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, 323:1184-1190. 18. Pi M, Quarles LD: A novel cation-sensing mechanism in osteoblasts is a molecular target for strontium. J Bone Miner Res 2004, 19:862-869. 19. Choudhary S, Wadhwa S, Raisz LG, Alander C, Pilbeam CC: Extracellular calcium is a potent inducer of cyclo-oxygenase-2 in murine osteoblasts through an ERK signaling pathway. J Bone Miner Res 2003, 18:1813-1824. 20. Henrotin Y, Labasse A, Zheng SX, Galais P, Tsouderos Y, Crielaard JM, Reginster JY: Strontium ranelate increases cartilage matrix formation. J Bone Miner Res 2001, 16:299-308. 21. Delannoy Ph, Bazot D, Marie P: J. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism 2002, 51:906-911. 22. 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, 19:2012-2020. This article reports the beneficial effects of strontium on bone microarchitecture associated with increased bone mass without alteration of bone mineralization. 23. Buehler J, Chappuis P, Saffar JL, Tsouderos Y, Vignery A: Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis). Bone 2001, 29:176-179. 24. Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, Allain P, Tsouderos Y, Meunier PJ: Strontium distribution and
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interactions with bone mineral in monkey iliac bone after strontium salt (S12911) administration. J Bone Miner Res 1996, 11:1302-1311. 25. Farlay D, Boivin G, Panczer G, Lalande L, Meunier PJ: Long-term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralisation of bone. J Bone Miner Res 2005, 20:1569-1578. 26. D’Haese PC, Schrooten I, Goodman WG, Cabrera WE, Lamberts LV, Elseviers MM, Couttenye MM, De Broe ME: Increased bone strontium levels in hemodialysis patients with osteomalacia. Kidney Int 2000, 57:1107-1114. 27. Cohen-Solal ME, Augry F, Mauras Y, Morieux C, Allain P, de Vernejoul MC: Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients. Nephrol Dial Transplant 2002, 17:449-454. 28. Marie PJ, Hott M, Modrowski D, de Pollak C, Guillemain J, Deloffre P, Tsouderos Y: 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, 8:607-615. 29. Hott M, Deloffre P, Tsouderos Y, Marie PJ: S12911-2 reduces bone loss induced by short-term immobilization in rats. Bone 2003, 33:115-123. 30. Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Albanese C, Lorenc R, Pors-Nielsen S, De Vernejoul MC, Roces A, Reginster JY: Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis-a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002, 87:2060-2066. 31. Nielsen SP, Slosman D, Sorensen OH, Basse-Cathalinat B, De Cassin P, Roux CR, Meunier PJ: Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. J Clin Densitom 1999, 2:371-379. 32. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S et al.: The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004, 350:459-468. The first demonstration that strontium ranelate reduces the incidence of vertebral fractures in postmenopausal osteoporosis. 33. Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S 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, 90:2816-2822. This paper demonstrates that strontium ranelate reduces the incidence of non-vertebral fractures in postmenopausal osteoporosis.
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resorptive and bone-forming effects, which represents an important new advance in the therapy of osteoporosis. Strontium, a trace element originally detected in lead mines near Strontian (Scotland) in the late 1700s, is a bone-seeking agent. In contrast to radioactive strontium, which induces toxic effects on bone cells, stable strontium was found to induce beneficial effects on bone [3,4]. Pionner experiments in animals showed that strontium salts can decrease bone resorption and increase bone formation and bone mass without affecting bone mineralization [5–8], raising the possibility that strontium may be of potential benefit for treatment of osteoporosis. This led to the development of a unique molecule called strontium ranelate (Protelos1; Servier Laboratories, France) that is composed of an organic moiety which binds two stable strontium atoms, resulting in increased strontium bioavailability. This review summarizes the available data on the mechanisms of action of strontium ranelate on bone cells, and its pharmacological and clinical effects on bone mass in animals and in postmenopausal subjects.
Current Opinion in Pharmacology 2005, 5:633–636 This review comes from a themed issue on Endocrine and metabolic diseases Edited by Cary Cooper and Gordon Klein Available online 23rd September 2005 1471-4892/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2005.05.005
Introduction Osteoporosis is characterized by low bone mass and deteriorated bone microarchitecture, resulting in increased bone fragility and susceptibility to fracture. A common cause of osteoporosis in women is estrogen deficiency at menopause which induces increased bone turnover, with an imbalance between bone resorption and formation. Most anti-osteoporotic therapies are therefore based on anti-catabolic drugs that inhibit excessive bone turnover, resulting in preservation of bone mass and strength and decreased occurrence of fractures in postmenopausal women [1,2]. By contrast, anabolic drugs increase bone remodeling with a greater effect on bone formation than bone resorption, resulting in increased bone mass and microarchitecture and a greater reduction of fractures [2]. A new compound — strontium ranelate — was recently shown to act as an effective anti-osteoporotic drug through a mechanism combining both antiwww.sciencedirect.com
How does strontium act on bone cells? Several studies indicate that strontium ranelate acts as an anti-resorbing and bone-forming agent [9]. In mouse calvaria cultures, strontium ranelate inhibits bone resorption by approximately 30% as assessed by calcium release [10]. Additionally, strontium ranelate decreases osteoclast activity by about 30%, as measured by the pit assay in isolated rat cells [11], and inhibits the bone-resorbing activity of mouse osteoclasts cultured on dentine slices in long bone culture, also measured in a pit assay [10]. These effects are specific to strontium ranelate and are not reproduced with calcium ranelate, suggesting a distinct effect of the two cations. Strontium ranelate was also shown to decrease the number of osteoclasts expressing two functional osteoclast markers, carbonic anhydrase II and vitronectin receptor, in chicken bone-marrow cultures induced to differentiate into osteoclasts by 1,25dihydroxyvitamin D3 treatment [10]. Although it is unknown whether the concentrations effective at inhibiting osteoclast activity in vitro are found in bone in vivo, it is likely that high concentrations of strontium that bind hydroxyapatite are found on bone crystal surfaces [12]. This indicates that inhibition of bone resorption in vitro by strontium may, in part, result from inhibition of osteoclast activity, which is, however, not completely abolished. Further studies indicate that strontium ranelate also has positive effects on bone formation in vitro. In rat calvaria Current Opinion in Pharmacology 2005, 5:633–636
634 Endocrine and metabolic diseases
organ culture and rat calvaria cell cultures, strontium ranelate was initially shown to enhance the replication of preosteoblastic cells and, consequently, the activity of functional cells and bone matrix synthesis, effects that were specific as calcium ranelate had no effect [13]. In a more recent in vitro osteogenic model of differentiating mouse calvaria-derived MC3T3-E1 osteoblastic cells, stontium ranelate was found to increase alkaline phosphatase activity, a marker of osteoblast differentiation, and to increase collagen synthesis in this system without affecting matrix mineralization, confirming the boneforming activity of strontium ranelate in vitro [14]. What are the mechanisms of action of strontium in bone cells? Although the cellular actions of strontium have not been fully identified, several mechanisms of action can be postulated [15]. For example, strontium was found to activate the calcium-sensing receptor in some cell types, resulting in activation of inositol trisphosphate production and mitogen-activated protein kinase signaling [16,17]. Other receptors sensitive to strontium, yet to be identified, might also be effective in bone cells [18]. Additionally, strontium was found to induce cyclooxygenase-2 expression and prostaglandin E2 production through activation of the extracellular signal-regulated kinase pathway in osteoblasts, which might be involved in the boneforming effect of strontium ranelate [19]. It is expected that future studies will provide more information on the cellular and molecular mechanisms by which strontium acts on bone cells to inhibit bone resorption and promote bone formation in vitro. The mechanisms by which strontium ranelate increases cartilage formation in vitro [20] also remain to be determined.
Effects of strontium ranelate on bone mass and strength Are the in vitro beneficial effects of strontium ranelate on bone cells also observed in vivo? Several studies indicate that the anti-resorbing and bone-forming effects of strontium ranelate do apply in intact animal models. In normal adult mice, administration of strontium ranelate increased vertebral bone formation and decreased bone resorption, resulting in increased bone mass [21]. In adult rats, strontium ranelate increased bone mass in the lumbar vertebra and femur, which was confirmed by histological assessment of trabecular bone volume [22]. This effect was associated with increased trabecular thickness and number, and decreased trabecular separation in the tibial metaphysis, indicating that strontium ranelate improved bone microarchitecture [22]. This resulted in improved bone strength, as shown by mechanical properties of the axial (lumbar vertebrae) and appendicular bone (midshaft humerus and midshaft femur) [22]. Interestingly, plasma alkaline phosphatase activity increased in treated animals, compatible with the bone-forming activity of strontium ranelate [22]. In normal adult monkeys (Macaca fascicularis), which exhibit mostly bone remodeling as in Current Opinion in Pharmacology 2005, 5:633–636
humans, strontium ranelate was found to decrease bone resorption and to increase mineralizing surfaces in alveolar bone [23]. The available pharmacological data therefore indicate that strontium ranelate induces antiresorbing and bone-forming effects in vivo, resulting in increased bone mass and bone strength in the vertebral and appendicular skeleton.
Does strontium affect bone mineral? Because strontium is a bone-seeking agent, it is important to determine whether strontium incorporation into bone interacts with bone mineralization; however, several studies indicate that this is not the case. First, strontium is mainly adsorbed on the crystal surface in bone, and only one in ten calcium cations in the apatite crystal was found to be replaced by strontium in vivo [24]. Second, analysis of hydroxyapatite crystals formed under treatment with strontium ranelate showed no alteration in the degree of mineralization or mineral properties in vitro [25]. Third, analysis in intact rats treated with high doses of strontium ranelate for two years showed no alteration of bone mineralization [22]. Although it has been suggested that strontium may be involved in delayed mineralization in dialyzed patients with end-stage renal failure exposed to elevated strontium content in dialyzed fluids [26], bone strontium content in dialyzed patients does not always correlate with defective bone mineralization [27].
Strontium ranelate prevents bone loss in osteopenic animals On the basis of the pharmacological data from intact animals, it was expected that strontium ranelate would be effective in preventing bone loss in animal models of osteoporosis. This has now been demonstrated in two studies. In ovariectomized rats, strontium ranelate prevented trabecular bone loss induced by estrogen deficiency, as shown by densitometric analysis, bone ash, bone mineral content and histomorphometrical analysis in the tibial metaphysis. This effect resulted from decreased bone resorption, while bone formation was maintained [28]. In another model of trabecular bone loss induced by hindlimb immobilization, strontium ranelate was found to prevent the increased bone resorption and trabecular bone loss induced by immobilization [29]. In this model, strontium ranelate increased plasmatic bone-specific alkaline phosphatase levels and decreased urinary hydroxyproline excretion, further indicating that it induces opposite effects on bone resorption and bone formation in vivo. These pharmacological data in osteopenic animals predicted that strontium ranelate may have anti-osteoporotic effects in clinical studies.
Anti-osteoporotic effects of strontium ranelate in postmenopausal osteoporosis Several clinical trials were performed to assess the efficacy of strontium ranelate in postmenopausal women with established osteoporosis. In a prospective, doublewww.sciencedirect.com
Strontium as therapy for osteoporosis Marie 635
blind, randomized, placebo-controlled trial, three doses of strontium ranelate (500 mg, 1 g, 2 g) or placebo were given to 353 osteoporotic women also receiving calcium (500 mg) and vitamin D. A significant 7.3% annual increase in lumbar bone mineral density was observed in the group receiving 2 g of strontium [30]. Although about half of this increase might be a result of the bone mineral density being overestimated when measured by dual X-ray absorptiometry [31], the number of patients receiving 2 g of strontium ranelate who experienced new vertebral fracture in the second year of treatment was reduced by 44% compared with those receiving placebo, which pointed to the potential anti-osteoporotic effects of strontium ranelate [30]. Because of these data, the anti-fracture efficacy of strontium ranelate was assessed in two large, randomized, double-blind, placebo-controlled clinical studies: the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial and the Treatment Of Peripheral Osteoporosis Study (TROPOS), including more than 6700 postmenopausal women. In the SOTI trial, strontium ranelate significantly reduced the incidence of new vertebral and clinical vertebral fractures by 40–50% after one and three years of treatment [32]. This was accompanied by decreased back pain and body height loss. In this trial, bone alkaline phosphatase levels (a marker of bone formation) increased by 8.1%, whereas telopeptide crosslink levels (a marker of bone resorption) decreased concomitantly by 12.2% in patients treated with strontium ranelate compared with the placebo group at all time-points (3–36 months), indicating that strontium ranelate induced opposite and concomitant changes in markers of bone resorption and formation. No delayed mineralization at the histological level was observed after treatment for three years with strontium ranelate, which further emphasizes the safety of the compound on bone mineralization in osteoporotic subjects [32]. The TROPOS trial included 5091 osteoporotic postmenopausal women aged 74 years (or 70 years with one risk factor for osteoporotic fracture) [33]. In this trial, strontium ranelate reduced by 16% the risk of non-vertebral fractures throughout the three year study compared with placebo. The compound also reduced by 19% the relative risk for major fragility fractures (i.e. hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus). In a subgroup of 1977 patients at high risk of hip fracture, strontium ranelate reduced the risk of hip fracture by 36% over three years [33]. Overall, strontium ranelate was well tolerated, especially in the upper gastrointestinal area. In both SOTI and TROPOS studies, the most common adverse effects consisted of nausea and diarrhea, which disappeared after the first three months [32,33]. These clinical data indicate that strontium ranelate has significant clinical benefits in the treatment of postmenopausal osteoporosis. Strontium ranelate is now cliniwww.sciencedirect.com
cally available in a number of countries for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.
Conclusions The available pharmacological and clinical data indicate that strontium ranelate is a unique anti-osteoporotic drug that reduces the risk of vertebral and non-vertebral fractures in potmenopausal women with good tolerability in patients, and which represents an important advance in the therapy of osteoporosis. Unlike the available antiosteoporotic drugs, the compound induces anti-resorbing and bone-forming effects on bone remodeling, resulting in improvement of bone mass and strength. Putative mechanisms of action of strontium ranelate on bone cells have recently been postulated; however, future studies are needed to establish the exact cellular and molecular mechanisms by which strontium ranelate exerts its antiosteoporotic effects in bone.
Acknowledgements I thank the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS) for the support of our work, and my colleagues and collaborators for their help.
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