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Rheumatology 2009 48(Supplement 4):iv1-iv2; doi:10.1093/rheumatology/kep277
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

This article appears in the following Rheumatology issue: Improvement of bone microarchitecture: the foundation for a better protection against osteoporotic fractures [View the issue table of contents]

Editorial

Strontium ranelate: new perspectives for the management of osteoporosis

Bernard Cortet1

1Department of Rheumatology, University-Hospital of Lille, University of Lille II, Lille cedex, France

Correspondence to: Bernard Cortet, Department of Rheumatology, University-Hospital of Lille, University of Lille II, 59045 Lille cedex, France. E-mail: bcortet{at}chru-lille.fr

Osteoporosis is a complex disease characterized by low bone mass and also alterations of bone quality leading to an increased fracture risk. The increasing worldwide incidence of osteoporosis requires the use of effective treatments.

Several classes of drugs are used in the prevention of osteoporosis-related fractures with proven clinical efficacy, mostly on vertebral fractures and more rarely on non-vertebral and hip fractures. Anti-resorptive agents are the most represented. The most numerous among them are bisphosphonates. They act by reducing not only bone resorption, but also bone formation due to the coupling between bone formation and resorption. Due to the mechanism of action, they do not have any effect on bone mass (although they increase BMD due to their effect on bone remodelling). Anabolic agents, such as teriparatide, not only increase bone formation but also bone resorption for the same reason.

Strontium ranelate (SR), a new oral treatment, has a major role for several reasons.

  1. Firstly, by its unique mode action: increasing bone formation and reducing bone resorption leading to rebalancing of bone remodelling in favour of bone formation. This unique and original mechanism of action was investigated in non-clinical and clinical studies. SR was shown to increase the recruitment and activity of osteoblastic cells using [3H]thymidine and [3H]proline-labelled calvariae of newborn rats [1]. Recent studies have shown that the activation of osteoblast replication is partly mediated by the calcium-sensing receptor (CaR). Indeed, SR enhances osteoblast replication obtained from rat calvariae [2]. Furthermore, SR is able to inhibit the recruitment and activity of osteoclasts in a dose-dependent manner, through an increase in osteoprotegerin (OPG) and a decrease in RANK ligand (RANKL) by osteoblasts [3]. SR may act by increasing apoptosis of osteoclasts, as shown in rabbit models [4]. CaR has also been shown to be involved in the SR-induced osteoclast apoptosis [5]. The increase in bone formation parameters has also been demonstrated in human bone biopsy studies, showing significant increases in osteoblastic surfaces by 38% and in mineral apposition rates for both cancellous and cortical bone by, respectively, 9 and 10% [6]. These biopsies were obtained after 3 years of treatment, suggesting a sustained effect over time. Moreover, the linear increase of BMD over an 8-year period also indicates a sustained effect on bone. In contrast, bisphosphonates do not have any effect on bone formation.
  2. Secondly, by its long-term efficacy proven in a wide range of patients: SR was thoroughly investigated by two major randomized, double-blind, placebo-controlled Phase III studies. The first one: Spinal Osteoporosis Therapeutic Intervention (SOTI) [7] demonstrated over a 4-year period a strong reduction of vertebral fracture risk by 33% and also a reduction of symptomatic vertebral fracture risk by 36% with an improvement in quality of life. The second one, TReatment Of Peripheral Osteoporosis Study (TROPOS) [8], demonstrated over a 5-year period that SR reduced any osteoporotic fracture risk by 20% and the risk of non-vertebral fractures by 15%. SR also decreased the risk of hip fracture by 43% for patients at high risk. SR is the only osteoporosis drug, which also benefits the elderly (aged >=80 years) by reducing the risk of both vertebral and major non-vertebral fractures by 32 and 37%, respectively.
  3. Thirdly, the efficacy of SR is independent of key risk factors at baseline and has also been proven for both young and elderly patients.
SR is effective for preventing vertebral fractures not only in young (50–65 years) [9] osteoporotic women but also in elderly patients, aged > 80 years [10]. Clinical efficacy has been demonstrated whatever the severity of disease, from patients with osteopenia (with and without prevalent vertebral fracture) to those with multiple prevalent fractures.

Due to its mechanism of action, SR dramatically increases BMD from baseline by 12.7% at the lumbar spine, 7.2% at the femoral neck and 8.6% at the total hip in the SOTI study. Nevertheless, strontium is an agent with a heavier atomic number than calcium, thus influencing BMD measurements. This effect accounts for ~50% of the changes in BMD. The relationship between BMD increases with SR and reduction in fracture rates has been assessed [11]. Thus, each 1% increase in femoral neck BMD after the first year of treatment by SR was associated with a 3% reduction in new clinical vertebral fracture at 3 years. Findings were similar for the risk of hip fracture: 1% increase in femoral neck BMD after 3 years of treatment by SR was associated with a 7% decline in the risk of hip fracture [12]. Overall BMD changes for patients on SR account for 75% of the fracture risk reduction. These data have a strong clinical implication in terms of follow-up in patients on SR. On the contrary, such a correlation is highly controversial for anti-resorptive agents. Indeed, the increase of BMD at lumbar spine and femoral neck sites has been shown to account for only 18 and 11%, respectively, of the effects of risedronate on vertebral fracture incidence [13]. The percentage reduction in vertebral fracture related to BMD increase is 16% with alendronate and 4% with raloxifene [14, 15].

Besides these relevant clinical data, SR has also been shown to improve bone quality. Bone biopsies obtained from both SOTI and TROPOS studies were analysed by three-dimensional micro-CT. After 3 years, patients treated by SR, compared with placebo, showed a significant increase in the number of trabeculae (+14%), a significant decrease of trabecular separation (–16%) and a significant increase in cortical thickness (+18%). Also, a significant decrease (–22%) of the model index structure was in favour of a shift in trabecular structure from rod-like to plate-like configuration resulting in stronger bone in SR-treated patients compared with untreated patients [6]. Obviously, these changes both for trabecular and cortical structure help explain the anti-fracture efficacy of SR.

These biopsy data differ from those obtained with some other osteoporosis drugs. Although all of them increase mean bone volume, treatment with anti-resorptive agents, such as bisphosphonates, preserves trabecular microarchitecture, but has no effect on cortical bone. Bone-forming agents, such as SR and teriparatide, improve trabecular micro-architecture and increase cortical thickness. The effects of SR occur without affecting the actual mineralization of bone.

Clinical data from the SOTI and TROPOS trials have demonstrated the long-term clinical efficacy of SR over 5 years on vertebral, non-vertebral and hip fractures, with good tolerability, similar to that of placebo in the two trials. This effect is demonstrated on a wide range of patients, whatever the baseline risk factors, the severity of the disease and the age. No other osteoporosis drug has demonstrated a reduction in the risk of fractures over 5 years, except risedronate on vertebral fractures in a small group of patients [16]. This clinical efficacy is also demonstrated in young patients aged 50–65 years, in elderly patients aged >=80 years, and in patients with osteopenia [17]. In these groups of patients, the data available with other drugs are particularly scarce.

All data considered make SR a first-choice treatment in the prevention of osteoporotic fractures in a wide range of patients, as recently acknowledged by the ESCEO (European Society for Clinical and Economic aspects of Osteoporosis and Osteoarthritis) European guidance.

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: B.C. has received consultancy fees from Servier, Amgen, MSD, GSK Roche and Novartis and speakers' fees from Servier, MSD, GSK Roche, Novartis, Eli-Lilly, Proctor & Gamble and Sanofi-Aventis.

References

  1. Brennan TC, Rybchyn MS, Halbout P, et al. Strontium ranelate effects in human osteoblasts support its uncoupling effect on bone formation and bone resorption. Calcif Tissue Int (2007) 80(5 Suppl. 1):S72.
  2. 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) 74:438–47.[CrossRef][Web of Science][Medline]
  3. Marie PJ. Strontium ranelate: new insights into its dual mode of action. Bone (2007) 40:S5–8.
  4. Mentaverri R, Hurtel AS, Kamel S, Robin B, Brazier M. Extracellular concentrations of strontium directly stimulates osteoclast apoptosis. J Bone Min Res (2003) 18:M237.[CrossRef]
  5. Mentaverri R, Hurtel AS, Wattel A, et al. Calcium-sensing receptor mediates ranelate-induced osteoclast apoptosis. Bone (2005) 36(Suppl. 2):S403.
  6. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res (2008) 23:215–22.[CrossRef][Web of Science][Medline]
  7. Meunier PJ, Roux C, Ortolani S, et al. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int. Advance access published January 20, 2009, doi: 10.1007/s00198-008-0825-6.
  8. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of non vertebral fractures and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum (2008) 58:1687–95.[CrossRef][Web of Science][Medline]
  9. Roux C, Fechtenbaum J, Kolta S, et al. Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis (2008) 67:1736–8.[Abstract/Free Full Text]
  10. Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and non-vertebral fractures in women eighty years of age and older. J Bone Miner Res (2006) 21:1113–20.[CrossRef][Web of Science][Medline]
  11. 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) 92:3076–81.[Abstract/Free Full Text]
  12. Bruyere 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) 12:3041–5.
  13. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med (2002) 112:281–9.[CrossRef][Web of Science][Medline]
  14. Kanis JA, Burlet N, Cooper C, et al. European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis Int (2008) 19:399–428.[CrossRef][Web of Science][Medline]
  15. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner res (2002) 17:1–10.[CrossRef][Web of Science][Medline]
  16. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone (2003) 32:120–6.[CrossRef][Web of Science][Medline]
  17. Seeman E, Devogelaer J-P, Lorenc R, et al. Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia. J Bone Miner Res (2008) 23:433–38.[CrossRef][Web of Science][Medline]
Accepted 31 July 2009


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