Osteoporosis International

, Volume 20, Issue 5, pp 675–686 | Cite as

Comparing non-vertebral fracture risk reduction with osteoporosis therapies: looking beneath the surface




Data from pivotal trials of pharmacologic agents used to treat osteoporosis differ, suggesting that these agents vary in ability to reduce the risk of non-vertebral fractures (NVFs). However, variability among clinical trials in inclusion criteria, baseline characteristics, and definition of NVFs may account for many of these apparent differences.


Data from pivotal trials of individual pharmacologic agents for osteoporosis differ, and suggest that differences may exist between anti-resorptive agents in their ability to reduce the risk of NVFs. Careful examination of these trials’ inclusion criteria and patient characteristics indicates substantial differences between patient populations with respect to the baseline risk of NVFs. When baseline fracture risk is lower, the ability to produce a statistically significant reduction in fracture risk over the course of a clinical trial is reduced.


Analysis of clinical trials reveals that the number and type of baseline vertebral fractures and also baseline bone mineral density, all associated with the risk of vertebral fracture, vary.

Discussion and conclusion

The propensity to fall and patient frailty are additional factors associated with fracture risk that may influence study outcomes. One of the most significant variables, which also often differs considerably between trials, is the definition of an NVF. Variability between clinical trials in inclusion criteria, patients’ baseline characteristics, and how NVFs are defined may account for much of the apparent difference between agents in their ability to reduce NVF risk.


Alendronate Bisphosphonate Ibandronate Non-vertebral fractures Risedronate 


  1. 1.
    Empana JP, Dargent-Molina P, Breart G (2004) Effect of hip fracture on mortality in elderly women: the EPIDOS prospective study. J Am Geriatr Soc 52:685–690PubMedCrossRefGoogle Scholar
  2. 2.
    Kado DM, Browner WS, Palermo L et al (1999) Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med 159:1215–1220PubMedCrossRefGoogle Scholar
  3. 3.
    Division of Metabolic and Endocrine Drug Products (1994) Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Available at: http://www.fda.gov/cder/guidance/osteo.pdf. Accessed January 24, 2008
  4. 4.
    Klotzbuecher CM, Ross PD, Landsman PB et al (2000) Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 15:721–739PubMedCrossRefGoogle Scholar
  5. 5.
    Wasnich RD (1996) Vertebral fracture epidemiology. Bone 18(3 Suppl):179S–183SPubMedCrossRefGoogle Scholar
  6. 6.
    Riggs BL, Melton LJ 3rd, O’Fallon WM (1996) Drug therapy for vertebral fractures in osteoporosis: evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone 18(3 Suppl):197S–201SPubMedCrossRefGoogle Scholar
  7. 7.
    National Osteoporosis Foundation. Fast Facts (2008) NOF Web site. Available at: www.nof.org/osteoporosis/diseasefacts.htm. Accessed August 8, 2008
  8. 8.
    Eastell R, Reid DM, Compston J et al (2001) Secondary prevention of osteoporosis: when should a non-vertebral fracture be a trigger for action? Q J Med 94:575–597Google Scholar
  9. 9.
    Melton LJ, Chrischilles EA, Cooper C et al (1992) How many women have osteoporosis. J Bone Miner Res 7:1005–1010PubMedGoogle Scholar
  10. 10.
    U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Executive Summary (2004) USHHS Web site. Available at: http://www.surgeongeneral.gov/library/bonehealth. Accessed January 26, 2008
  11. 11.
    Black DM, Cummings SR, Karpf DB et al (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541PubMedCrossRefGoogle Scholar
  12. 12.
    Bone HG, Greenspan SL, McKeever C et al (2000) Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 85:720–726PubMedCrossRefGoogle Scholar
  13. 13.
    Bonnick S, Hochberg M, Broy S, et al (2005) Comparison of once-weekly alendronate and once-weekly risedronate in the osteoporotic subgroup from the FACT study. Presented at The Sixth International Symposium on Osteoporosis: Current Status and Future Directions: April 6–10; Washington, DCGoogle Scholar
  14. 14.
    Sebba AI, Bonnick SL, Kagan R et al (2004) Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis. Curr Med Res Opin 20:2031–2041PubMedCrossRefGoogle Scholar
  15. 15.
    Silverman SL, Watts NB, Delmas PD et al (2007) Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int 18:25–34PubMedCrossRefGoogle Scholar
  16. 16.
    Reginster J, Minne HW, Sorensen OH et al (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83–91PubMedCrossRefGoogle Scholar
  17. 17.
    Harris ST, Watts NB, Genant HK et al (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352PubMedCrossRefGoogle Scholar
  18. 18.
    McClung MR, Geusens P, Miller PD et al (2001) Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 344:333–340PubMedCrossRefGoogle Scholar
  19. 19.
    Liberman UA, Weiss SR, Bröll J et al (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 333:1437–1443PubMedCrossRefGoogle Scholar
  20. 20.
    Cummings SR, Black DM, Thompson DE et al (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082PubMedCrossRefGoogle Scholar
  21. 21.
    Chesnut CH III, Skag A, Christiansen C et al (2004) Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19:1241–1249CrossRefGoogle Scholar
  22. 22.
    Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  23. 23.
    Neer RM, Arnaud CD, Zanchetta JR et al (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441PubMedCrossRefGoogle Scholar
  24. 24.
    Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 282:637–645PubMedCrossRefGoogle Scholar
  25. 25.
    Chesnut CH 3rd, Silverman S, Andriano K et al (2000) A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 109:267–276PubMedCrossRefGoogle Scholar
  26. 26.
    Gallagher JC, Genant HK, Crans GG et al (2005) Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab 90:1583–1587PubMedCrossRefGoogle Scholar
  27. 27.
    Black DM, Thompson DE, Bauer DC et al (2000) Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. J Clin Endocrinol Metab 85:4118–4124PubMedCrossRefGoogle Scholar
  28. 28.
    Russell RG (2007) Bisphosphonates: mode of action and pharmacology. Pediatrics 119(Suppl 2):S150–S156PubMedCrossRefGoogle Scholar
  29. 29.
    Boniva Tablets [package insert] (2006) Roche Pharmaceuticals, Nutley, NJGoogle Scholar
  30. 30.
    Bone HG, Downs RW Jr, Tucci JR et al (1997) Dose–response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab 82:265–274PubMedCrossRefGoogle Scholar
  31. 31.
    Lindsay R, Silverman SL, Cooper C et al (2001) Risk of new vertebral fracture in the year following a fracture. JAMA 285:320–323PubMedCrossRefGoogle Scholar
  32. 32.
    Torgerson DJ, Campbell MK, Thomas RE (1996) Prediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res 11:293–297PubMedCrossRefGoogle Scholar
  33. 33.
    World Health Organization. WHO scientific group on the assessment of osteoporosis at primary health care level. Summary meeting report. Brussels, Belgium, May 5–7, 2004. Available at: www.who.int/entity/chp/topics/Osteoporosis.pdf. Accessed January 28, 2008
  34. 34.
    Lewiecki EM, Watts NB, McClung MR et al (2004) Official positions of the international society for clinical densitometry. J Clin Endocrinol Metab 89:3651–3655PubMedCrossRefGoogle Scholar
  35. 35.
    Leslie WD, Tsang JF, Caetano PA, for the Manitoba Bone Density Program (2007) Number of osteoporotic sites and fracture risk assessment: a cohort study from the Manitoba Bone Density Program. J Bone Miner Res 22:476–483PubMedCrossRefGoogle Scholar
  36. 36.
    Papaioannou A, Joseph L, Ioannidis G et al (2005) Risk factors associated with incident clinical vertebral and nonvertebral fractures in postmenopausal women: the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int 16:568–578PubMedCrossRefGoogle Scholar
  37. 37.
    Pols HA, Felsenberg D, Hanley DA et al (1999) 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. Fosamax International Trial Study Group. Osteoporos Int 9:461–468PubMedCrossRefGoogle Scholar
  38. 38.
    Black D, Palermo L, Pols H (2002) Reductions in non-vertebral fracture with alendronate depend on baseline BMD: The FOSIT Study. Osteoporos Int 13(Suppl 1):S22, Abstract P60SUGoogle Scholar
  39. 39.
    Bauer DC, Garnero P, Hochberg MC et al (2006) Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 21:292–299PubMedCrossRefGoogle Scholar
  40. 40.
    Lyles KW, Colón-Emeric CS, Magaziner JS et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809PubMedCrossRefGoogle Scholar
  41. 41.
    Dontas IA, Yiannakopoulos CK (2007) Risk factors and prevention of osteoporosis-related fractures. J Musculoskelet Neuronal Interact 7:268–272PubMedGoogle Scholar
  42. 42.
    Díez-Pérez A, González-Macías J, Marín F et al (2007) Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound. Osteoporos Int 18:629–639PubMedCrossRefGoogle Scholar
  43. 43.
    Ensrud KE, Ewing SK, Taylor BC et al (2007) Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci 62:744–751PubMedGoogle Scholar
  44. 44.
    Bonnick SL (2004) Bone densitometry in clinical practice: application and interpretation, 2nd edn. Humana Press, Totowa, NJ, p 282Google Scholar
  45. 45.
    Liberman UA, Hochberg MC, Geusens P et al (2006) Hip and non-spine fracture risk reductions differ among antiresorptive agents: Evidence from randomised controlled trials. Int J Clin Pract 60:1394–1400PubMedCrossRefGoogle Scholar
  46. 46.
    Boonen S, Laan RF, Barton IP et al (2005) Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int 16:1291–1298PubMedCrossRefGoogle Scholar
  47. 47.
    Cranney A, Wells G, Willan A et al (2002) Meta-analyses of alendronate for the treatment of postmenopausal women. Endocr Rev 23:508–516PubMedCrossRefGoogle Scholar
  48. 48.
    Cranney A, Guyatt G, Griffith L et al (2002) Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 23:570–578PubMedCrossRefGoogle Scholar
  49. 49.
    Harris ST, Blumentals WA, Miller PD (2008) Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of phase III studies. Curr Med Res Opin 24:237–245PubMedCrossRefGoogle Scholar
  50. 50.
    Roux C, Briot K, Horlait S et al (2007) Assessment of non-vertebral fracture risk in postmenopausal women. Ann Rheum Dis 66:931–935PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2008

Authors and Affiliations

  1. 1.Palm HarborUSA

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