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Strontium ranelate: A novel mode of action leading to renewed bone quality

Osteoporosis International volume 16, pages S11–S15 (2005)Cite this article

Abstract

Various bone resorption inhibitors and bone stimulators 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. In vitro studies have suggested that strontium ranelate enhances osteoblast cell replication and activity. Simultaneously, strontium ranelate dose-dependently inhibits osteoclast activity. In vivo studies indicate that strontium ranelate stimulates bone formation and inhibits bone resorption and prevents bone loss and/or promotes bone gain. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture, without affecting the intrinsic bone tissue quality. Thus, all the determinants of bone strength are positively influenced. In conclusion, strontium ranelate, a new treatment of postmenopausal osteoporosis, acts through an innovative mode of action, both stimulating bone formation and inhibiting bone resorption, resulting in the rebalancing of bone turnover in favor of bone formation. Strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in improvement in bone strength and bone quality.

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References

  1. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468

    Article  CAS  PubMed  Google Scholar 

  2. Rizzoli R, Reginster JY, Diaz-Curiel M et al (2004) Patients at high risk of hip fracture benefit from treatment with strontium ranelate. Osteoporos Int 15(S1):OC39

    Google Scholar 

  3. Ammann P, Rizzoli R, Bonjour JP (1998) Preclinical evaluation of new therapeutic agents for osteoporosis. In: Meunier PJ (ed) Osteoporosis: diagnosis and management. Martin Dunitz, London, pp 257–273

  4. Ammann P, Rizzoli R, Bonjour JP (1998) Protein malnutrition-induced bone loss is associated with alteration of growth hormone-IGF-I axis and with estrogen deficiency in adult rats. Osteoporos Int 8(S3):10

    Google Scholar 

  5. Bonjour JP, Ammann P, Rizzoli R (1999) Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int 9:379–293

    Article  CAS  PubMed  Google Scholar 

  6. Rho JY, Tsui YT, Pharr GM (1997) Elastic properties of human cortical and trabecular lamellar bone measured by nanoindentation. Biomaterials 18/20:1325–1330

    Google Scholar 

  7. Zysset PK, Guo XE, Hoffler CE, Moore KE, Goldstein SA (1999) Elastic modulus and hardness of cortical and trabecular bone lamellae measured by nanoindentation in the human femur. J Biomech 32:1005–1012

    Article  CAS  PubMed  Google Scholar 

  8. Roy ME, Rho JY, Tsui YT, Evans NS, Pharr GM (1999) Mechanical and morphological variation of the human lumbar vertebral cortical and trabecular bone. J Biomed Mater Res 44:191–199

    CAS  PubMed  Google Scholar 

  9. Hoffler CE, Moore KE, Kozloff K, Zysset PK, Brown MB, Goldstein SA (2000) Heterogeneity of bone lamellar-level elastic moduli. Bone 26:603–609

    Article  CAS  PubMed  Google Scholar 

  10. Hoffler CE, Moore KE, Kozloff K, Zysset PK, Goldstein SA (2000) Age, gender, and bone lamellae elastic moduli. J Orthop Res 18:432–437

    CAS  PubMed  Google Scholar 

  11. Hengsberger S, Boivin G, Zysset PK (2002) Morphological and mechanical properties of bone structural units: a two-case study. JSME Series C 45/4:936–43

    Google Scholar 

  12. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282:637–645

    Article  CAS  PubMed  Google Scholar 

  13. Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302

    Article  CAS  PubMed  Google Scholar 

  14. Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD (2002) Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 87:1586–1592

    Article  CAS  PubMed  Google Scholar 

  15. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443

    Article  CAS  PubMed  Google Scholar 

  16. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541

    Article  CAS  PubMed  Google Scholar 

  17. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647

    Article  CAS  PubMed  Google Scholar 

  18. Bourrin S, Ammann P, Bonjour JP, Rizzoli R (2002) Recovery of proximal tibia bone mineral density and strength, but not cancellous bone architecture, after long-term bisphosphonate or selective estrogen receptor modulator therapy in aged rats. Bone 30:195–200

    Article  CAS  PubMed  Google Scholar 

  19. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100:1475–1480

    CAS  PubMed  Google Scholar 

  20. Meunier PJ, Boivin G (1997) Bone mineral density reflects bone mass but also the degree of mineralization of bone: therapeutic implications. Bone 21:373–377

    Article  CAS  PubMed  Google Scholar 

  21. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27:687–694

    Article  CAS  PubMed  Google Scholar 

  22. Garnero P, Delmas PD (1996) New developments in biochemical markers for osteoporosis. Calcif Tissue Int 59 [Suppl 1]:S2–9

    Google Scholar 

  23. Pak CY, Sakhaee K, Zerwekh JE, Parcel C, Peterson R, Johnson K (1989) Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone mass and inhibition of fractures. J Clin Endocrinol Metab 68:150–159

    CAS  PubMed  Google Scholar 

  24. Hedlund LR, Gallagher JC (1989) Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Miner Res 4:223–225

    CAS  PubMed  Google Scholar 

  25. Schnitzler CM, Wing JR, Gear KA, Robson HJ (1990) Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis. Clin Orthop:268–275

    Google Scholar 

  26. Riggs BL, Hodgson SF, O’Fallon WM, Chao EY, Wahner HW, Muhs JM, Cedel SL, Melton LJ 3rd (1990) Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802–809

    CAS  PubMed  Google Scholar 

  27. Pouilles JM, Tremollieres F, Causse E, Louvet JP, Ribot C (1991) Fluoride therapy in postmenopausal osteopenic women: effect on vertebral and femoral bone density and prediction of bone response. Osteoporos Int 1:103–109

    CAS  PubMed  Google Scholar 

  28. Turner CH, Owan I, Brizendine EJ, Zhang W, Wilson ME, Dunipace AJ (1996) High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency. Bone 19:595–601

    Article  CAS  PubMed  Google Scholar 

  29. Meunier PJ, Sebert JL, Reginster JY, Briancon D, Appelboom T, Netter P, Loeb G, Rouillon A, Barry S, Evreux JC, Avouac B, Marchandise X (1998) Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOStudy. Osteoporos Int 8:4–12

    Article  CAS  PubMed  Google Scholar 

  30. Jorgensen PH, Bak B, Andreassen TT (1991) Mechanical properties and biochemical composition of rat cortical femur and tibia after long-term treatment with biosynthetic human growth hormone. Bone 12:353–359

    Article  CAS  PubMed  Google Scholar 

  31. Ammann P, Rizzoli R, Muller K, Slosman D, Bonjour JP (1993) IGF-I and pamidronate increase bone mineral density in ovariectomized adult rats. Am J Physiol 265:E770–E776

    CAS  PubMed  Google Scholar 

  32. Ammann P, Rizzoli R, Meyer JM, Bonjour JP (1996) Bone density and shape as determinants of bone strength in IGF-I and/or pamidronate-treated ovariectomized rats. Osteoporos Int 6:219–227

    CAS  PubMed  Google Scholar 

  33. Oxlund H, Ejersted C, Andreassen TT, Torring O, Nilsson MH (1993) Parathyroid hormone (1–34) and (1–84) stimulate cortical bone formation both from periosteum and endosteum. Calcif Tissue Int 53:394–399

    CAS  PubMed  Google Scholar 

  34. Ejersted C, Andreassen TT, Oxlund H, Jorgensen PH, Bak B, Haggblad J, Torring O, Nilsson MH (1993) Human parathyroid hormone (1–34) and (1–84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res 8:1097–1101

    CAS  PubMed  Google Scholar 

  35. Mosekilde L, Danielsen CC, Gasser J (1994) The effect on vertebral bone mass and strength of long-term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1–38), and combination therapy, assessed in aged ovariectomized rats. Endocrinology 134:2126–2134

    Article  CAS  PubMed  Google Scholar 

  36. Mosekilde L, Sogaard CH, McOsker JE, Wronski TJ (1994) PTH has a more pronounced effect on vertebral bone mass and biomechanical competence than antiresorptive agents (estrogen and bisphosphonate)—assessed in sexually mature, ovariectomized rats. Bone 15:401–408

    Article  CAS  PubMed  Google Scholar 

  37. Li M, Wronski TJ (1995) Response of femoral neck to estrogen depletion and parathyroid hormone in aged rats. Bone 16:551–557

    Article  CAS  PubMed  Google Scholar 

  38. Andreassen TT, Jorgensen PH, Flyvbjerg A, Orskov H, Oxlund H (1995) Growth hormone stimulates bone formation and strength of cortical bone in aged rats. J Bone Miner Res 10:1057–1067

    CAS  PubMed  Google Scholar 

  39. Andreassen TT, Oxlund H (2000) The influence of combined parathyroid hormone and growth hormone treatment on cortical bone in aged ovariectomized rats. J Bone Miner Res 15:2266–2275

    CAS  PubMed  Google Scholar 

  40. Toromanoff A, Ammann P, Riond JL (1998) Early effects of short-term parathyroid hormone administration on bone mass, mineral content, and strength in female rats. Bone 22:217–223

    Article  CAS  PubMed  Google Scholar 

  41. Bonjour JP, Chevalley T, Ammann P, Slosman D, Rizzoli R (2001) Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study. Lancet 358:1208–1212

    Article  CAS  PubMed  Google Scholar 

  42. Canalis E, Hott M, Deloffre P, Tsouderos Y, Marie PJ (1996) The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone 18:517–523

    Article  CAS  PubMed  Google Scholar 

  43. Baron R, Tsouderos Y (2002) In vitro effects of S12911–2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 450:11–17

    Article  CAS  PubMed  Google Scholar 

  44. Takahashi N, Sasaki T, Tsouderos Y, Suda T (2003) S 12911–2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 18:1082–1087

    CAS  PubMed  Google Scholar 

  45. Delannoy P, Bazot D, Marie PJ (2002) Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism 51:906–911

    Article  CAS  PubMed  Google Scholar 

  46. Grynpas MD, Hamilton E, Cheung R, Tsouderos Y, Deloffre P, Hott M, Marie PJ (1996) Strontium increases vertebral bone volume in rats at a low dose that does not induce detectable mineralization defect. Bone 18:253–259

    Article  CAS  PubMed  Google Scholar 

  47. Marie PJ, Hott M, Modrowski D, De Pollak C, Guillemain J, Deloffre P, Tsouderos Y (1993): An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res 8:607–615

    CAS  PubMed  Google Scholar 

  48. Bain S, Shen V, Hara P, Dupin-Roger I (2003) Long-term treatment with strontium ranelate increases histomorphometric indices of bone formation in ovariectomized rats. J Bone Miner Res 18 [suppl 2]:S277

  49. Hott M, Deloffre P, Tsouderos Y, Marie PJ (2003) S12911–2 reduces bone loss induced by short-term immobilization in rats. Bone 33:115–123

    Article  CAS  PubMed  Google Scholar 

  50. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R (2004) Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res 19(12):2012–2020

    PubMed  Google Scholar 

  51. Ammann P, Barrauld S, Dayer R, Dupin-Roger I, Rizzoli R (2004) Strontium ranelate increases bone quality in rats: improvement of the microarchitecture and preservation of the intrinsic bone quality. J Bone Miner Res 19 [Suppl 1]:S178

  52. Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, Tsouderos Y, Meunier PJ (1996), Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S12911) administration. J Bone Miner Res 11:1302–1311

    CAS  PubMed  Google Scholar 

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  1. Division of Bone Diseases, WHO Collaborating Center for Osteoporosis Prevention, Department of Rehabilitation and Geriatrics, University Hospital of Geneva, 1211 , Geneva 14, Switzerland

    Patrick Ammann

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  1. Patrick Ammann
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Correspondence to Patrick Ammann.

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Ammann, P. Strontium ranelate: A novel mode of action leading to renewed bone quality. Osteoporos Int 16, S11–S15 (2005). https://doi.org/10.1007/s00198-004-1809-9

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  • DOI: https://doi.org/10.1007/s00198-004-1809-9

Keywords

  • Bone quality
  • Strontium ranelate