Skip to main content
SpringerLink
Log in

Preventing osteoporotic fractures with bisphosphonates: A review of the efficacy and tolerability

  • Review Article
  • Published:
Aging Clinical and Experimental Research Aims and scope Submit manuscript

Abstract

Although change in bone mineral density was the outcome most commonly measured in early clinical trials of osteoporosis therapies, it is now understood that the most clinically important outcome is reduction in the risk of fractures. Of currently available osteoporosis therapies, the bisphosphonates have been most thoroughly investigated in studies with fracture risk as the primary outcome. The most widely studied bisphosphonates include etidronate, alendronate and risedronate. Alendronate and risedronate have the most compelling evidence for vertebral and non-vertebral fracture reduction. This review provides a comprehensive overview of the anti-fracture efficacy of bisphosphonates at the spine, hip, and non-vertebral sites.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Consensus Development Conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993; 94: 646–50.

    Article  Google Scholar 

  2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285: 785–95.

    Article  Google Scholar 

  3. Ross PD. Clinical consequences of vertebral fractures. Am J Med 1997; 103: 30S–43S.

    Article  PubMed  CAS  Google Scholar 

  4. Gold DT. The clinical impact of vertebral fractures: quality of life in women with osteoporosis. Bone 1996; 18 (Suppl 3): 185S–9S.

    Article  PubMed  CAS  Google Scholar 

  5. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med 1991; 151: 2026–32.

    Article  PubMed  CAS  Google Scholar 

  6. Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992; 2: 285–9.

    Article  PubMed  CAS  Google Scholar 

  7. Cooper C, Atkinson EJ, O’Fallon WM, Melton LJ 3rd. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989. J Bone Miner Res 1992; 7: 221–7.

    Article  PubMed  CAS  Google Scholar 

  8. Riggs BL, Melton LJ 3rd. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 1995; 17 (Suppl): 505S–11S.

    Article  PubMed  CAS  Google Scholar 

  9. Ettinger B, Black DM, Nevitt MC, et al., and the Study of Osteoporotic Fractures Research Group. Contribution of vertebral deformities to chronic back pain and disability. J Bone Miner Res 1992; 7: 449–56.

    Article  PubMed  CAS  Google Scholar 

  10. Gehlbach SH, Bigelow C, Heimisdottir M, May S, Walker M, Kirkwood JR. Recognition of vertebral fracture in a clinical setting. Osteoporos Int 2000; 11: 577–82.

    Article  PubMed  CAS  Google Scholar 

  11. Black DM, Arden NK, Palermo L, Pearson J, Cummings SR, for the Study of Osteoporotic Fractures Research Group. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. J Bone Miner Res 1999; 14: 821–8.

    Article  PubMed  CAS  Google Scholar 

  12. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 2000; 15: 721–39.

    Article  PubMed  CAS  Google Scholar 

  13. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001; 285: 320–23.

    Article  PubMed  CAS  Google Scholar 

  14. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998; 19: 80–100.

    Article  PubMed  CAS  Google Scholar 

  15. Fleisch H, Russell RG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 1966; 212: 901–3.

    Article  PubMed  CAS  Google Scholar 

  16. Fleisch H, Russell RG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969; 165: 1262–4.

    Article  PubMed  CAS  Google Scholar 

  17. Francis MD, Russell RG, Fleisch H. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 1969; 165: 1264–6.

    Article  PubMed  CAS  Google Scholar 

  18. Geddes AD, D’Souza SM, Ebetino FH, Ibbotson KJ. Bisphosphonates: structure-activity relationships and therapeutic implications. In Heersche JNM, Kanis JA, Eds. Bone and mineral research. Amsterdam: Elsevier Science, 1994: 265–74.

    Google Scholar 

  19. Sietsema WK, Ebetino FH, Salvagno AM, Bevan JA. Antiresorptive dose-response relationships across three generations of bisphosphonates. Drugs Exp Clin Res 1989; 15: 389–96.

    PubMed  CAS  Google Scholar 

  20. van Beek ER, Lowik CW, Ebetino FH, Papapoulos SE. Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships. Bone 1998; 23: 437–42.

    Article  PubMed  Google Scholar 

  21. Fleisch H. Bisphosphonates—preclinical. In Bisphosphonates in bone disease: from the laboratory to the patient, 4th ed. New York: Parthenon, 2000.

    Google Scholar 

  22. Borah B, Dufresne TE, Chmielewski PA, Gross GJ, Prenger MC, Phipps RJ. Risedronate preserves trabecular architecture and increases bone strength in vertebra of ovariectomized minipigs as measured by three-dimensional microcomputed tomography. J Bone Miner Res 2002; 17: 1139–47.

    Article  PubMed  CAS  Google Scholar 

  23. Eriksen EF, Melsen F, Sod E, Barton I, Chines A. Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone 2002; 31: 620–5.

    Article  PubMed  CAS  Google Scholar 

  24. Delmas PD. How does antiresorptive therapy decrease the risk of fracture in women with osteoporosis? Bone 2000; 27: 1–3.

    Article  PubMed  CAS  Google Scholar 

  25. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 2000; 85: 231–6.

    Article  PubMed  CAS  Google Scholar 

  26. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285: 785–95.

    Article  Google Scholar 

  27. Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73–9.

    Article  PubMed  CAS  Google Scholar 

  28. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265–71.

    Article  PubMed  CAS  Google Scholar 

  29. Harris ST, Watts NB, Jackson RD, et al. Four-year study of intermittent cyclic etidronate treatment of post-menopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993; 95: 557–67.

    Article  PubMed  CAS  Google Scholar 

  30. Black DM, Cummings SR, Karpf DB, et al., for the Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–41.

    Article  PubMed  CAS  Google Scholar 

  31. Cummings SR, Black DM, Thompson DE, et al., for the Fracture Intervention Trial Research Group. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998; 280: 2077–82.

    Article  PubMed  CAS  Google Scholar 

  32. Liberman UA, Weiss SR, Bröll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333: 1437–43.

    Article  PubMed  CAS  Google Scholar 

  33. Harris ST, Watts NB, Genant HK, et al., for the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. A randomized controlled trial. JAMA 1999; 282: 1344–52.

    Article  PubMed  CAS  Google Scholar 

  34. Reginster J-Y, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11: 83–91.

    Article  PubMed  CAS  Google Scholar 

  35. Sorenson OH, Crawford GM, Mulder H, et al. Sustained effects of risedronate on vertebal and nonvertebral fracture: results of a 5-year placebo-controlled trial. Bone 2003; 32: 120–6.

    Article  Google Scholar 

  36. Heaney RP, Zizic TM, Fogelman I, et al. Risedronate reduces the risk of first vertebral fracture in osteoporotic women. Osteoporos Int 2002; 13: 501–5.

    Article  PubMed  CAS  Google Scholar 

  37. Chesnut CH. Tiludronate: development of an osteoporosis therapy. Bone 1995; 17: 517S–9S.

    Article  PubMed  CAS  Google Scholar 

  38. Reginster JY, Christiansen C, Roux C, Fechtenbaum J, Rouillon A, Tou KP. Intermittent cyclic tiludronate in the treatment of osteoporosis. Osteoporos Int 2001; 12: 169–77.

    Article  PubMed  CAS  Google Scholar 

  39. Black DM, Thompson DE, Bauer DC, et al., for the FIT Research Group. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000; 85: 4118–24.

    Article  PubMed  CAS  Google Scholar 

  40. Watts NB, Josse RG, Hamdy RC, et al. Risedronate prevents new vertebral fractures in postmenopausal women at high risk. J Clin Endocrinol Metab 2003; 88: 542–9.

    Article  PubMed  CAS  Google Scholar 

  41. McCloskey E, Selby P, de Takats D, et al. Effects of clodronate on vertebral fracture risk in osteoporosis: a 1-year interim analysis. Bone 2001; 28: 310–5.

    Article  PubMed  CAS  Google Scholar 

  42. Van Staa TP, Abenhaim L, Cooper C. Use of cyclical etidronate and prevention of non-vertebral fractures. Br J Rheumatol 1998; 37: 87–94.

    Article  PubMed  Google Scholar 

  43. McClung MR, Geusens P, Miller PD, et al., for the Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344: 333–40.

    Article  PubMed  CAS  Google Scholar 

  44. Pols HAP, Felsenberg D, Hanley DA, et al., for the Fosamax International Trial Study Group. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporos Int 1999; 9: 461–8.

    Article  PubMed  CAS  Google Scholar 

  45. Van Staa TP, Leufkens HGM, Abenhaim H, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993–1000.

    Article  PubMed  Google Scholar 

  46. Adachi JD, Bensen WG, Brown J, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382–8.

    Article  PubMed  CAS  Google Scholar 

  47. Saag KG, Emkey R, Schnitzer TJ, et al., for the Glucocorticoid-Induced Osteoporosis Intervention Study Group. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339: 292–9.

    Article  PubMed  CAS  Google Scholar 

  48. Adachi JD, Saag K, Delmas P, et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids. Arthritis Rheum 2001; 44: 202–11.

    Article  PubMed  CAS  Google Scholar 

  49. Reid DM, Hughes RA, Laan RFJM, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res 2000; 15: 1006–13.

    Article  PubMed  CAS  Google Scholar 

  50. Cohen S, Levy RM, Keller M, et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999; 42: 2309–18.

    Article  PubMed  CAS  Google Scholar 

  51. Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 2000; 67: 277–85.

    Article  PubMed  CAS  Google Scholar 

  52. O’Neill TW, Felsenberg D, Varlow J, et al. The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 1996; 11: 1010–8.

    Article  PubMed  Google Scholar 

  53. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000; 343: 604–10.

    Article  PubMed  CAS  Google Scholar 

  54. Reid DM, Adami S, Devogelaer J-P, Chines A.A. Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy. Calcif. Tissue Int. 2001; 69: 242–7.

    Article  PubMed  CAS  Google Scholar 

  55. Vega E, Mautalen C, Roldan EJ, Perez Lloret A. Preliminary study of multiple increasing oral doses of dimethyl-APD on bone metabolism dynamics and safety profile. Drugs Exp Clin Res 1994; 20: 103–8.

    PubMed  CAS  Google Scholar 

  56. Ettinger B, Pressman A, Schein J, Chan J, Silver P, Connolly N. Alendronate use among 812 women: prevalence of gastrointestinal complaints, noncompliance with patient instructions, and discontinuation. J Managed Care Pharm 1998; 4: 488–92.

    Google Scholar 

  57. de Groen PC, Lubbe DF, Hirsch L, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996; 335: 1016–21.

    Article  PubMed  Google Scholar 

  58. Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC 2nd. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996; 101: 488–501.

    Article  PubMed  CAS  Google Scholar 

  59. Devogelaer JP, Bröll H, Correa-Rotter R, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996; 18: 141–50.

    Article  PubMed  CAS  Google Scholar 

  60. Miller PD, Woodson G, Licata AA, et al. Rechallenge of patients who had discontinued aledronate therapy because of upper gastrointestinal symptoms. Clin Ther 2000; 22: 1433–42.

    Article  PubMed  CAS  Google Scholar 

  61. Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002; 77: 262–70.

    Article  PubMed  CAS  Google Scholar 

  62. Lanza FL, Hunt RH, Thomson ABR, Provenza JM, Blank MA, for the Risedronate Endoscopy Study Group. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 2000; 119: 631–8.

    Article  PubMed  CAS  Google Scholar 

  63. Lanza F, Rack MF, Simon TJ, Lombardi A, Reyes R, Suryawanshi S. Effects of alendronate on gastric and duodenal mucosa. Am J Gastroenterol 1998; 93: 753–7.

    Article  PubMed  CAS  Google Scholar 

  64. Herrera JA, Sarabia MO, Gonzalez MM. Effects of treatment with bisphosphonates on gastrointestinal and esophageal mucosa in patients with osteoporosis: pamidronate versus alendronate. Curr Ther Res 1999; 60: 307–13.

    Article  CAS  Google Scholar 

  65. Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med 2001; 161: 107–10.

    Article  PubMed  CAS  Google Scholar 

  66. Marshall JK, Rainsford KD, James C, Hunt RH. A randomized controlled trial to assess alendronate-associated injury of the upper gastrointestinal tract. Aliment Pharmacol Ther 2000; 14: 1451–7.

    Article  PubMed  CAS  Google Scholar 

  67. Graham DY, Malaty HM, Goodgame R. Primary amino-bisphosphonates: A new class of gastrotoxic drugs. Comparison of alendronate and aspirin. Am J Gastroenterol 1997; 92: 1322–5.

    PubMed  CAS  Google Scholar 

  68. Thomson ABR, Marshall JK, Hunt RH, et al., for the Risedronate Endoscopy Study Group. 14-Day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by helicobacter pylori status. J Rheumatol 2002; 29: 1965–74.

    PubMed  CAS  Google Scholar 

  69. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000; 12: 1–12.

    CAS  Google Scholar 

  70. Brown JP, Kendler DL, McClung MR, Emkey RD. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002; 71: 103–11.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Gerontology Research Unit and Department of Medicine, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

    Tahir Masud MA, MBBS, FRCP

  2. Department of Medical and Surgical Sciences, Clinica Medica I, University of Padova, Padova, Italy

    Sandro Giannini

Authors
  1. Tahir Masud MA, MBBS, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandro Giannini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tahir Masud MA, MBBS, FRCP.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Masud, T., Giannini, S. Preventing osteoporotic fractures with bisphosphonates: A review of the efficacy and tolerability. Aging Clin Exp Res 15, 89–98 (2003). https://doi.org/10.1007/BF03324485

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03324485

Key words

Search

Navigation