- Email: [email protected]
Strontium ranelate: A physiological approach for an improved bone quality
Bone 38 (2006) S15 – S18 www.elsevier.com/locate/bone
Strontium ranelate: A physiological approach for an improved bone quality Patrick Ammann ⁎ Division of Bone Diseases, WHO Collaborating Center for Osteoporosis and Bone Disease, Department of Rehabilitation and Geriatrics, University Hospital of Geneva, Geneva, CH-1211 Geneva 14, Switzerland Received 6 July 2005; accepted 19 September 2005
Abstract In vitro studies have suggested that strontium ranelate enhances osteoblastic cell replication leading to an increase in bone-forming activity. Simultaneously, strontium ranelate dose dependently decreases osteoclastic activity. In vivo studies indicate that strontium ranelate decreases bone resorption and maintains a high bone formation and prevents bone loss. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture in growing animals. In intact female rats, a 2-year period of exposure to strontium ranelate significantly increased bone mechanical properties of vertebrae and midshaft femur. All the determinants of bone strength were positively influenced by the treatment like bone mass, dimension, microarchitecture, and intrinsic bone tissue quality. The increment in bone mechanical properties was characterized by an increase in maximal load but also by a dramatic improvement in energy to failure, which was essentially due to an increment in plastic energy. Such modifications observed with strontium ranelate treatment are in good agreement with the improvement in intrinsic bone quality. These results strongly suggest that new bone formed following strontium ranelate treatment is able to withstand greater deformation before fracture. Furthermore, treatment with strontium ranelate prevents the deleterious effect of ovariectomy on bone strength. In this model, a 1-year period of exposure to strontium ranelate significantly prevents alteration of bone mechanical properties of vertebrae in association with a partial preservation of the trabecular microarchitecture: a dose-dependent effect on the bone volume/trabecular volume ratio and trabecular number and thickness. © 2005 Elsevier Inc. All rights reserved. Keywords: Strontium ranelate; Bone quality
Introduction Various bone resorption inhibitors have been shown to decrease the risk of osteoporotic fractures. However, there is still a need for agents promoting bone formation by inducing positive uncoupling between bone formation and bone resorption. Strontium ranelate (Protelos®), which has a dual effect on bone metabolism, has recently been demonstrated to reduce both vertebral and hip fracture risk and is a good candidate [1,2]. Action of strontium ranelate on bone turnover In vitro studies have suggested that strontium ranelate enhances osteoblastic cell replication and activity [3]. Simultaneously, strontium ranelate dose dependently decreases pre⁎ Fax: +41 22 38 29 973. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2005.09.023
osteoclast differentiation and osteoclastic activity [3–5]. Some recent studies suggest that interaction of strontium with the calcium-sensing receptor might be one of the explanations of the mechanism of action [6]. This potential mechanism of action and of other possible modulations of bone turnover remains to be fully elucidated. Strontium ranelate has been studied in various rodent models like intact animals, model of immobilization or ovariectomy-induced osteoporosis. All these in vivo studies suggest that strontium ranelate reduces bone resorption in mice and rats and increases markers of bone formation [7–13]. The increment in external diameter of the long bone on strontium ranelate treatment is an element in favor of a stimulation of periosteal bone apposition and thus of bone formation. Thus, there is no dynamic histomorphometry demonstrating a stimulation of bone formation. This modulation of bone turnover prevents bone loss and promotes bone gain, as investigated by histomorphometry, dual-energy X-ray absorptiometry (DXA), and biomechanics in preclinical
S16
P. Ammann / Bone 38 (2006) S15–S18
Fig. 1. Differences over time in biochemical markers (bone-specific alkaline phosphatase [bALP] and C-telopeptide cross-links (CTX) between treated and control groups. Data shown are mean (±SE) values in the strontium ranelate group minus mean values in the placebo group. Comparisons were performed with analyses of covariance in which baseline values were used as covariates. Reproduced from Reference [1].
studies [7–13]. Taken together, these results indicate that strontium ranelate administration induces positive uncoupling between bone formation and bone resorption. Furthermore, this stimulating effect on bone balance and increase in bone mass did not affect bone mineralization [14]. These observations in animals are in agreement with the observations in postmenopausal women. Strontium ranelate treatment in humans induces similar modulation of markers of bone turnover, increase in bone alkaline phosphatase activity (marker of bone formation) and a decrease in C-telopeptide cross-links (CTX) (marker of bone resorption) (Fig. 1), which results in a decrease in vertebral [1] and hip [2] fracture risks. Bone mechanical properties The aim of any antiosteoporotic treatment is to improve bone strength and thus to decrease the risk of fracture. In humans, the approach for evaluating bone strength is the recording of the fracture rate, which implies a large group of patients. A fracture is not only due to decreased bone mineral mass or alteration of the microarchitecture but is also related to falls, as a result of loss of balance, inappropriate protective responses, or muscle weakness [15–17]. Thus, careful and specific investigation on bone strength and its determinants in animal models of treatments against osteoporosis is of major importance. Only animal model could provide objective measurements of all these determinants and allow a better understanding of the mechanisms of action. This is particularly the case when anabolic agents are investigated, since they can potentially influence all these determinants. Bone strength is determined by bone geometry, cortical thickness and porosity, trabecular bone morphology, and intrinsic properties of bony tissue. Only the careful investigation of all these determinants of bone strength (including bone tissue quality)
should be considered to fully understand the mechanisms of action of antiosteoporotic drugs. Effects of strontium ranelate in intact rats Two series of studies were performed in intact male and female rats [13]. In intact female rats, a 2-year period of exposure to various strontium ranelate doses (225, 450, and 900 mg/kg/day) mixed in the diet was investigated. The animals were treated during their entire lifespan including their growing period. Since the treatment was started during the growth phase, the overall bone tissue was formed under the influence of strontium ranelate. This type of model allows an optimal investigation of potential deleterious effects of an antiosteoporotic treatment on bone mechanical properties and their determinants. The doses of strontium ranelate selected are much higher than the dose administered to humans in clinical studies, but the plasma level obtained in animals treated with 625 mg/ kg/day was close to the value observed in patients treated with 2 g/day. This difference between humans and rats is related to a reduced intestinal absorption of strontium in rats. Strontium ranelate treatment induces a dose-dependent increase in bone mechanical properties at the level of the vertebral body, which contains a large proportion of trabecular bone, as investigated by an axial compression test mimicking a vertebral fracture. The stiffness of the vertebra was not affected by the treatment. Using a 3-point bending test performed at the level of the midshaft femur, which mainly contains cortical bone, a dose-dependent increment in maximal load was observed but without significant effect on stiffness. These effects on bone mechanical properties were also observed in intact male rats. The increase in bone strength was related to positive influences on most of the determinants of bone strength such as bone mass, bone geometry, bone microarchitecture, and bone tissue quality.
P. Ammann / Bone 38 (2006) S15–S18
Bone static histomorphometry and bone microcomputed tomography demonstrated a dose-dependent increase in trabecular bone volume, trabeculae number, trabecular thickness, connectivity, and cortical thickness, as assessed at the level of the tibia (Fig. 2) and vertebra. These effects are in agreement with a net gain in bone mass resulting from the rebalancing of bone turnover in favor of bone formation by strontium ranelate treatment. Furthermore, these results underlined the major improvement in bone microarchitecture on treatment. Strontium ranelate also improved bone geometry by increasing the external diameter and cortical thickness of the long bone through periosteal and endosteal apposition, respectively. A slight increment in the outer diameter could contribute to major improvement in bone mechanical properties. At the level of the midshaft femur, 55% of the variance of the maximal load was predicted by the increment in the outer diameter. Part of these positive effects on bone geometry and trabecular number might be related to an influence of treatment during the growth phase, leading to optimal peak bone mass, architecture, and size. The increment in bone mechanical properties was characterized by an increase in maximal load but also by a dramatic improvement in energy to failure, which was essentially due to an increase in plastic energy (Fig. 3). The plastic energy corresponds to the energy absorbed during irreversible bone deformation, which is associated with microcracks and fissures. These results suggest that new bone formed following strontium ranelate treatment is able to withstand greater deformation before fracture while possessing similar elastic properties to normal bone. Such modifications observed on strontium ranelate treatment are in good agreement with an improvement in intrinsic bone tissue quality. This was confirmed by nanoindentation tests, which were performed at the level of the trabecular node and cortical shell of the vertebra. The results indicated a significant increase in intrinsic bone tissue quality (modulus, hardness, and dissipated energy) in trabecular bone [17]. At the level of the cortical bone, this effect was still significant but less pronounced. This difference between trabecular and cortical bone could be explained by the fact that strontium is heterogeneously distributed in bone with a higher concentration in trabecular
S17
Fig. 3. Load deflection curves obtain by axial compression of the vertebral body in intact rats treated during 2 years with strontium ranelate at a dose of 900 mg/ kg/day or placebo. The white area corresponds to the elastic energy (energy dissipated during the reversible deformation of the sample). The black area corresponds to the plastic energy (energy dissipated during the irreversible deformation of the sample). The increment in bone mechanical properties was characterized by an increase in ultimate strength but also by a dramatic improvement in energy to failure, which was essentially due to an increase in plastic energy.
bone than in cortical bone [14,18]. This effect could correspond to part of the mechanism of action of strontium ranelate on bone mechanical properties. Indeed, strontium is taken up in the hydroxyapatite crystal (1 atom Sr/10 atoms Ca at most, in animals receiving high doses) and mainly adsorbed around the crystal surface. Furthermore, strontium is distributed in calcified matrix and is easily exchangeable from bone mineral, being linked to mature crystals through ionic substitutions to only a small extent. Finally, a 2-year period of exposure to strontium ranelate did not cause any alteration of bone mineralization as assessed by histomorphometry (similar osteoid thickness in control and treated rats) or of bone stiffness (similar bone stiffness in control and treated rats). These results confirm the safety of strontium ranelate on bone tissue. Effects of strontium ranelate in ovariectomized rats To investigate the effect of strontium ranelate in an animal model more representative of the clinical situation, 6-month-old
Fig. 2. Static bone histomorphometry was performed in intact rats treated during 2 years with strontium ranelate at a dose of 900 mg/kg/day or placebo. Figures represent section of proximal tibia stained using von Kossa stain with McNeal counterstain (magnification 10×).
S18
P. Ammann / Bone 38 (2006) S15–S18
ovariectomized (OVX) rats were treated with various strontium ranelate daily doses (125, 250, and 625 mg/kg) mixed in the diet over a 1-year period [19]. As investigated by an axial compression test of the vertebra, dose-dependent prevention of bone strength alteration was observed. Ultimate strength and energy were not different from sham controls in animals treated with 625 mg/kg, indicating a prevention of the effect of ovariectomy on bone strength by strontium ranelate treatment. This was associated with significant positive effects on bone strength determinants. Treatment with strontium ranelate resulted in a partial prevention of microarchitecture alterations as evaluated by static histomorphometry [19]. The absence of osteoid accumulation and the maintained bone stiffness showed that strontium ranelate was safe in OVX animals. This apparent discrepancy between full prevention of bone strength alteration in OVX rats treated with strontium ranelate and the partial preservation of bone microarchitecture suggests that intrinsic bone tissue quality might represent an important contribution to improvement in bone strength in mature rats. These results confirm the positive effect of strontium ranelate in adult OVX rats, a model much closer to the human clinical condition. Effect of strontium ranelate in postmenopausal women To investigate bone safety of strontium ranelate treatment in humans, bone biopsies were performed at 24, 36, or 48 months in 20 consenting patients of the Spinal Osteoporosis Therapeutic Intervention (SOTI) study, resulting in 14 samples that could be assessed [1]. All biopsy specimens consisted of lamellar bone. None of the biopsies showed evidence of osteomalacia or any sign of a primary mineralization defect. Compared with the placebo group, the strontium ranelate group had no increase in osteoid thickness or in the mineralization lag time and no decrease in the mineral apposition rate. These results confirm in humans that treatment with strontium ranelate leading to a mean plasma level of strontium of 120 μmol/l is associated with the formation of normal bone, as has been observed in preclinical studies. Furthermore, strontium ranelate increases bone mineral density (BMD) at the different skeletal sites investigated. This increase in BMD is overestimated by the atomic size of strontium, by approximately 50%. These positive effects on bone mass and the presence of normal bone tissue were associated with a significant decrease in vertebral and hip fracture risks. Conclusion Strontium ranelate, a new treatment of postmenopausal osteoporosis, has a dual effect on bone metabolism, resulting in a rebalance of bone turnover in favor of bone formation.
These data show that strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in increased bone strength and bone intrinsic quality improvement. References [1] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [2] Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, 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;90:2816–22. [3] 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;18:517–23. [4] Baron R, Tsouderos Y. In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 2002;450:11–7. [5] Takahashi N, Sasaki T, Tsouderos Y, Suda T. S 12911-2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 2003;18:1082–7. [6] 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;323:1184–90. [7] Marie PJ, Hott M, Modrowski D, De Polak C, Guillemain J, Deloffre P, et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogendeficient rats. J Bone Miner Res 1993;8:607–15. [8] Marie PJ, Garba MT, Hott M, Miravet L. Effect of low doses of stable strontium on bone metabolism in rats. Miner Electrolyte Metab 1985;11:5–13. [9] Grynpas MD, Marie PJ. Effects of low doses of strontium on bone quality and quantity in rats. Bone 1990;11:313–9. [10] Delannoy P, Bazot D, Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism 2002;51:906–11. [11] Grynpas MD, Hamilton E, Cheung R, Tsouderos Y, Deloffre P, Hott M, et al. Strontium increases vertebral bone volume in rats at a low dose that does not induce detectable mineralization defect. Bone 1996;18:253–9. [12] Hott M, Deloffre P, Tsouderos Y, Marie PJ. S12911-2 reduces bone loss induced by short-term immobilization in rats. Bone 2003;33:115–23. [13] 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;19:2012–20. [14] Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res 1996;11:1302–11. [15] Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int 1999;9:379–93. [16] Ammann P, Rizzoli R, Bonjour JP. Preclinical evaluation of new therapeutic agents for osteoporosis. In: Meunier PJ, editor. Osteoporosis: Diagnosis and Management. London: Martin Dunitz Ltd; 1998. p. 257–73. [17] Ammann P, Barrauld S, Dayer R, Dupin-Roger I, Rizzoli R. Strontium ranelate increases bone quality in rats: improvement of the microarchitecture and preservation of the intrinsic bone quality. J Bone Miner Res 2004;19(Suppl 1):S178. [18] Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, et al. Incorporation and distribution of strontium in bone. Bone 2001;28:446–53. [19] Marie P, Ammann P, Shen V, Bain S, Robin B, Dupin-Roger I. Evidence that strontium ranelate increases bone quality in rats by improving bone strength and architecture. Bone 2003;32(5):S80(OR29W).
Strontium ranelate: A physiological approach for an improved bone quality Patrick Ammann ⁎ Division of Bone Diseases, WHO Collaborating Center for Osteoporosis and Bone Disease, Department of Rehabilitation and Geriatrics, University Hospital of Geneva, Geneva, CH-1211 Geneva 14, Switzerland Received 6 July 2005; accepted 19 September 2005
Abstract In vitro studies have suggested that strontium ranelate enhances osteoblastic cell replication leading to an increase in bone-forming activity. Simultaneously, strontium ranelate dose dependently decreases osteoclastic activity. In vivo studies indicate that strontium ranelate decreases bone resorption and maintains a high bone formation and prevents bone loss. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture in growing animals. In intact female rats, a 2-year period of exposure to strontium ranelate significantly increased bone mechanical properties of vertebrae and midshaft femur. All the determinants of bone strength were positively influenced by the treatment like bone mass, dimension, microarchitecture, and intrinsic bone tissue quality. The increment in bone mechanical properties was characterized by an increase in maximal load but also by a dramatic improvement in energy to failure, which was essentially due to an increment in plastic energy. Such modifications observed with strontium ranelate treatment are in good agreement with the improvement in intrinsic bone quality. These results strongly suggest that new bone formed following strontium ranelate treatment is able to withstand greater deformation before fracture. Furthermore, treatment with strontium ranelate prevents the deleterious effect of ovariectomy on bone strength. In this model, a 1-year period of exposure to strontium ranelate significantly prevents alteration of bone mechanical properties of vertebrae in association with a partial preservation of the trabecular microarchitecture: a dose-dependent effect on the bone volume/trabecular volume ratio and trabecular number and thickness. © 2005 Elsevier Inc. All rights reserved. Keywords: Strontium ranelate; Bone quality
Introduction Various bone resorption inhibitors have been shown to decrease the risk of osteoporotic fractures. However, there is still a need for agents promoting bone formation by inducing positive uncoupling between bone formation and bone resorption. Strontium ranelate (Protelos®), which has a dual effect on bone metabolism, has recently been demonstrated to reduce both vertebral and hip fracture risk and is a good candidate [1,2]. Action of strontium ranelate on bone turnover In vitro studies have suggested that strontium ranelate enhances osteoblastic cell replication and activity [3]. Simultaneously, strontium ranelate dose dependently decreases pre⁎ Fax: +41 22 38 29 973. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2005.09.023
osteoclast differentiation and osteoclastic activity [3–5]. Some recent studies suggest that interaction of strontium with the calcium-sensing receptor might be one of the explanations of the mechanism of action [6]. This potential mechanism of action and of other possible modulations of bone turnover remains to be fully elucidated. Strontium ranelate has been studied in various rodent models like intact animals, model of immobilization or ovariectomy-induced osteoporosis. All these in vivo studies suggest that strontium ranelate reduces bone resorption in mice and rats and increases markers of bone formation [7–13]. The increment in external diameter of the long bone on strontium ranelate treatment is an element in favor of a stimulation of periosteal bone apposition and thus of bone formation. Thus, there is no dynamic histomorphometry demonstrating a stimulation of bone formation. This modulation of bone turnover prevents bone loss and promotes bone gain, as investigated by histomorphometry, dual-energy X-ray absorptiometry (DXA), and biomechanics in preclinical
S16
P. Ammann / Bone 38 (2006) S15–S18
Fig. 1. Differences over time in biochemical markers (bone-specific alkaline phosphatase [bALP] and C-telopeptide cross-links (CTX) between treated and control groups. Data shown are mean (±SE) values in the strontium ranelate group minus mean values in the placebo group. Comparisons were performed with analyses of covariance in which baseline values were used as covariates. Reproduced from Reference [1].
studies [7–13]. Taken together, these results indicate that strontium ranelate administration induces positive uncoupling between bone formation and bone resorption. Furthermore, this stimulating effect on bone balance and increase in bone mass did not affect bone mineralization [14]. These observations in animals are in agreement with the observations in postmenopausal women. Strontium ranelate treatment in humans induces similar modulation of markers of bone turnover, increase in bone alkaline phosphatase activity (marker of bone formation) and a decrease in C-telopeptide cross-links (CTX) (marker of bone resorption) (Fig. 1), which results in a decrease in vertebral [1] and hip [2] fracture risks. Bone mechanical properties The aim of any antiosteoporotic treatment is to improve bone strength and thus to decrease the risk of fracture. In humans, the approach for evaluating bone strength is the recording of the fracture rate, which implies a large group of patients. A fracture is not only due to decreased bone mineral mass or alteration of the microarchitecture but is also related to falls, as a result of loss of balance, inappropriate protective responses, or muscle weakness [15–17]. Thus, careful and specific investigation on bone strength and its determinants in animal models of treatments against osteoporosis is of major importance. Only animal model could provide objective measurements of all these determinants and allow a better understanding of the mechanisms of action. This is particularly the case when anabolic agents are investigated, since they can potentially influence all these determinants. Bone strength is determined by bone geometry, cortical thickness and porosity, trabecular bone morphology, and intrinsic properties of bony tissue. Only the careful investigation of all these determinants of bone strength (including bone tissue quality)
should be considered to fully understand the mechanisms of action of antiosteoporotic drugs. Effects of strontium ranelate in intact rats Two series of studies were performed in intact male and female rats [13]. In intact female rats, a 2-year period of exposure to various strontium ranelate doses (225, 450, and 900 mg/kg/day) mixed in the diet was investigated. The animals were treated during their entire lifespan including their growing period. Since the treatment was started during the growth phase, the overall bone tissue was formed under the influence of strontium ranelate. This type of model allows an optimal investigation of potential deleterious effects of an antiosteoporotic treatment on bone mechanical properties and their determinants. The doses of strontium ranelate selected are much higher than the dose administered to humans in clinical studies, but the plasma level obtained in animals treated with 625 mg/ kg/day was close to the value observed in patients treated with 2 g/day. This difference between humans and rats is related to a reduced intestinal absorption of strontium in rats. Strontium ranelate treatment induces a dose-dependent increase in bone mechanical properties at the level of the vertebral body, which contains a large proportion of trabecular bone, as investigated by an axial compression test mimicking a vertebral fracture. The stiffness of the vertebra was not affected by the treatment. Using a 3-point bending test performed at the level of the midshaft femur, which mainly contains cortical bone, a dose-dependent increment in maximal load was observed but without significant effect on stiffness. These effects on bone mechanical properties were also observed in intact male rats. The increase in bone strength was related to positive influences on most of the determinants of bone strength such as bone mass, bone geometry, bone microarchitecture, and bone tissue quality.
P. Ammann / Bone 38 (2006) S15–S18
Bone static histomorphometry and bone microcomputed tomography demonstrated a dose-dependent increase in trabecular bone volume, trabeculae number, trabecular thickness, connectivity, and cortical thickness, as assessed at the level of the tibia (Fig. 2) and vertebra. These effects are in agreement with a net gain in bone mass resulting from the rebalancing of bone turnover in favor of bone formation by strontium ranelate treatment. Furthermore, these results underlined the major improvement in bone microarchitecture on treatment. Strontium ranelate also improved bone geometry by increasing the external diameter and cortical thickness of the long bone through periosteal and endosteal apposition, respectively. A slight increment in the outer diameter could contribute to major improvement in bone mechanical properties. At the level of the midshaft femur, 55% of the variance of the maximal load was predicted by the increment in the outer diameter. Part of these positive effects on bone geometry and trabecular number might be related to an influence of treatment during the growth phase, leading to optimal peak bone mass, architecture, and size. The increment in bone mechanical properties was characterized by an increase in maximal load but also by a dramatic improvement in energy to failure, which was essentially due to an increase in plastic energy (Fig. 3). The plastic energy corresponds to the energy absorbed during irreversible bone deformation, which is associated with microcracks and fissures. These results suggest that new bone formed following strontium ranelate treatment is able to withstand greater deformation before fracture while possessing similar elastic properties to normal bone. Such modifications observed on strontium ranelate treatment are in good agreement with an improvement in intrinsic bone tissue quality. This was confirmed by nanoindentation tests, which were performed at the level of the trabecular node and cortical shell of the vertebra. The results indicated a significant increase in intrinsic bone tissue quality (modulus, hardness, and dissipated energy) in trabecular bone [17]. At the level of the cortical bone, this effect was still significant but less pronounced. This difference between trabecular and cortical bone could be explained by the fact that strontium is heterogeneously distributed in bone with a higher concentration in trabecular
S17
Fig. 3. Load deflection curves obtain by axial compression of the vertebral body in intact rats treated during 2 years with strontium ranelate at a dose of 900 mg/ kg/day or placebo. The white area corresponds to the elastic energy (energy dissipated during the reversible deformation of the sample). The black area corresponds to the plastic energy (energy dissipated during the irreversible deformation of the sample). The increment in bone mechanical properties was characterized by an increase in ultimate strength but also by a dramatic improvement in energy to failure, which was essentially due to an increase in plastic energy.
bone than in cortical bone [14,18]. This effect could correspond to part of the mechanism of action of strontium ranelate on bone mechanical properties. Indeed, strontium is taken up in the hydroxyapatite crystal (1 atom Sr/10 atoms Ca at most, in animals receiving high doses) and mainly adsorbed around the crystal surface. Furthermore, strontium is distributed in calcified matrix and is easily exchangeable from bone mineral, being linked to mature crystals through ionic substitutions to only a small extent. Finally, a 2-year period of exposure to strontium ranelate did not cause any alteration of bone mineralization as assessed by histomorphometry (similar osteoid thickness in control and treated rats) or of bone stiffness (similar bone stiffness in control and treated rats). These results confirm the safety of strontium ranelate on bone tissue. Effects of strontium ranelate in ovariectomized rats To investigate the effect of strontium ranelate in an animal model more representative of the clinical situation, 6-month-old
Fig. 2. Static bone histomorphometry was performed in intact rats treated during 2 years with strontium ranelate at a dose of 900 mg/kg/day or placebo. Figures represent section of proximal tibia stained using von Kossa stain with McNeal counterstain (magnification 10×).
S18
P. Ammann / Bone 38 (2006) S15–S18
ovariectomized (OVX) rats were treated with various strontium ranelate daily doses (125, 250, and 625 mg/kg) mixed in the diet over a 1-year period [19]. As investigated by an axial compression test of the vertebra, dose-dependent prevention of bone strength alteration was observed. Ultimate strength and energy were not different from sham controls in animals treated with 625 mg/kg, indicating a prevention of the effect of ovariectomy on bone strength by strontium ranelate treatment. This was associated with significant positive effects on bone strength determinants. Treatment with strontium ranelate resulted in a partial prevention of microarchitecture alterations as evaluated by static histomorphometry [19]. The absence of osteoid accumulation and the maintained bone stiffness showed that strontium ranelate was safe in OVX animals. This apparent discrepancy between full prevention of bone strength alteration in OVX rats treated with strontium ranelate and the partial preservation of bone microarchitecture suggests that intrinsic bone tissue quality might represent an important contribution to improvement in bone strength in mature rats. These results confirm the positive effect of strontium ranelate in adult OVX rats, a model much closer to the human clinical condition. Effect of strontium ranelate in postmenopausal women To investigate bone safety of strontium ranelate treatment in humans, bone biopsies were performed at 24, 36, or 48 months in 20 consenting patients of the Spinal Osteoporosis Therapeutic Intervention (SOTI) study, resulting in 14 samples that could be assessed [1]. All biopsy specimens consisted of lamellar bone. None of the biopsies showed evidence of osteomalacia or any sign of a primary mineralization defect. Compared with the placebo group, the strontium ranelate group had no increase in osteoid thickness or in the mineralization lag time and no decrease in the mineral apposition rate. These results confirm in humans that treatment with strontium ranelate leading to a mean plasma level of strontium of 120 μmol/l is associated with the formation of normal bone, as has been observed in preclinical studies. Furthermore, strontium ranelate increases bone mineral density (BMD) at the different skeletal sites investigated. This increase in BMD is overestimated by the atomic size of strontium, by approximately 50%. These positive effects on bone mass and the presence of normal bone tissue were associated with a significant decrease in vertebral and hip fracture risks. Conclusion Strontium ranelate, a new treatment of postmenopausal osteoporosis, has a dual effect on bone metabolism, resulting in a rebalance of bone turnover in favor of bone formation.
These data show that strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in increased bone strength and bone intrinsic quality improvement. References [1] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [2] Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, 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;90:2816–22. [3] 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;18:517–23. [4] Baron R, Tsouderos Y. In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 2002;450:11–7. [5] Takahashi N, Sasaki T, Tsouderos Y, Suda T. S 12911-2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 2003;18:1082–7. [6] 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;323:1184–90. [7] Marie PJ, Hott M, Modrowski D, De Polak C, Guillemain J, Deloffre P, et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogendeficient rats. J Bone Miner Res 1993;8:607–15. [8] Marie PJ, Garba MT, Hott M, Miravet L. Effect of low doses of stable strontium on bone metabolism in rats. Miner Electrolyte Metab 1985;11:5–13. [9] Grynpas MD, Marie PJ. Effects of low doses of strontium on bone quality and quantity in rats. Bone 1990;11:313–9. [10] Delannoy P, Bazot D, Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism 2002;51:906–11. [11] Grynpas MD, Hamilton E, Cheung R, Tsouderos Y, Deloffre P, Hott M, et al. Strontium increases vertebral bone volume in rats at a low dose that does not induce detectable mineralization defect. Bone 1996;18:253–9. [12] Hott M, Deloffre P, Tsouderos Y, Marie PJ. S12911-2 reduces bone loss induced by short-term immobilization in rats. Bone 2003;33:115–23. [13] 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;19:2012–20. [14] Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res 1996;11:1302–11. [15] Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int 1999;9:379–93. [16] Ammann P, Rizzoli R, Bonjour JP. Preclinical evaluation of new therapeutic agents for osteoporosis. In: Meunier PJ, editor. Osteoporosis: Diagnosis and Management. London: Martin Dunitz Ltd; 1998. p. 257–73. [17] Ammann P, Barrauld S, Dayer R, Dupin-Roger I, Rizzoli R. Strontium ranelate increases bone quality in rats: improvement of the microarchitecture and preservation of the intrinsic bone quality. J Bone Miner Res 2004;19(Suppl 1):S178. [18] Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, et al. Incorporation and distribution of strontium in bone. Bone 2001;28:446–53. [19] Marie P, Ammann P, Shen V, Bain S, Robin B, Dupin-Roger I. Evidence that strontium ranelate increases bone quality in rats by improving bone strength and architecture. Bone 2003;32(5):S80(OR29W).