Osteoporosis International

, Volume 19, Issue 3, pp 365–372 | Cite as

Fracture risk remains reduced one year after discontinuation of risedronate

  • N. B. Watts
  • A. Chines
  • W. P. Olszynski
  • C. D. McKeever
  • M. R. McClung
  • X. Zhou
  • A. Grauer
Original Article

Abstract

Summary

One year after discontinuation of three year’s treatment with risedronate, BMD decreased at the lumbar spine and femoral neck and bone turnover markers returned to control group levels. Despite these changes, the risk of new morphometric vertebral fractures remained lower in previous risedronate patients compared with previous control patients.

Introduction

Differences in bisphosphonate pharmacology and pharmacokinetics could influence persistence or resolution of the effects once treatment is stopped. We investigated changes in intermediate markers—bone mineral density (BMD) and bone turnover markers (BTM)—and fracture risk after discontinuation of treatment with risedronate.

Methods

Patients who received risedronate 5 mg daily (N = 398) or placebo (N = 361) during the VERT-NA study stopped therapy per protocol after 3 years but continued taking vitamin D (if levels at study entry were low) and calcium and were reassessed one year later.

Results

In the year off treatment, spine BMD decreased significantly, but remained higher than baseline (p ≤ 0.001) and placebo (p < 0.001), with similar findings at the femoral neck and trochanter. Urinary NTX and bone-specific alkaline phosphatase, which decreased significantly with treatment, were not significantly different from placebo after 1 year off treatment. Despite the changes in intermediate markers, the incidence of new morphometric vertebral fractures was 46% lower in the former risedronate group compared with the former placebo group (RR 0.54 [95% CI, 0.34, 0.86, p = 0.009]).

Conclusions

Despite the apparent resolution of effect on BMD and BTM, the risk reduction of new vertebral fractures remained in the year after treatment with risedronate was stopped.

Keywords

Bone mineral density Bone turnover Osteoporotic fracture Postmenopausal osteoporosis Risedronate Vertebral fractures 

Notes

Acknowledgments

We would like to acknowledge Rosemary Hannon, Ph.D. for performing the NTX measurements reported in this study, Ruby Xia and John Banner, M.S. for performing part of the statistical analyses reported in this study as well as all the investigators and staff at the study centers.

Conflict of interest statements

Dr. Watts receives honoraria for lectures from Amgen, Novartis, Procter & Gamble and sanofi-aventis; consulting fees from Amgen, Eli Lilly, Kyphon, Novartis, Procter & Gamble, Roche and sanofi-aventis; and research support through Amgen, Eli Lilly, Novartis, Procter & Gamble and Solvay.

Dr. Chines is a former employee of Procter & Gamble and owns Procter & Gamble shares. He is currently an employee of Wyeth.

Dr. McKeever is a consultant for Procter & Gamble, Merck and Roche and receives research grants from Procter & Gamble, Merck, Lilly and Roche.

Dr. McClung receives research grants from Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, and Roche. He receives consulting fees from Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, Roche and sanofi-aventis. He is a member of speaker’s bureaus for Eli Lilly, Merck, Procter & Gamble, and sanofi-aventis.

Dr. Zhou and Dr. Grauer are full time employees of Procter & Gamble and own stocks of the company.

References

  1. 1.
    NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795Google Scholar
  2. 2.
    Felsenberg D, Boonen S (2005) The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 27:1–11PubMedCrossRefGoogle Scholar
  3. 3.
    Lindsay R, Boonen S, Burgio D et al (2004) Significant reduction of bone resorption with risedronate treatment in as soon as one week. J Bone Miner Res 19(Suppl. 1):SU434Google Scholar
  4. 4.
    Borah B, Ritman EL, Dufresne TE et al (2005) The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover. Bone 37:1–9PubMedCrossRefGoogle Scholar
  5. 5.
    Dufresne TE, Chmielewski PA, Manhart MD et al (2003) Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three-dimensional microcomputed tomography. Calcif Tissue Int 73:423–432PubMedCrossRefGoogle Scholar
  6. 6.
    Watts NB, Cooper C, Lindsay R et al (2004) Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 7:255–261PubMedCrossRefGoogle Scholar
  7. 7.
    Watts NB, Geusens P, Barton I et al (2005) The relationship between changes in bone mineral density and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in bone mineral density. J Bone Miner Res 20:2097–2104PubMedCrossRefGoogle Scholar
  8. 8.
    Eastell R, Barton I, Hannon RA et al (2003) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 18:1051–1056PubMedCrossRefGoogle Scholar
  9. 9.
    Chapurlat RD, Palermo L, Ramsay P et al (2005) Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial. Osteoporos Int 16:842–848PubMedCrossRefGoogle Scholar
  10. 10.
    Watts NB, Magowan S, Brown JP et al (2005) Risedronate demonstrates efficacy to reduce fragility fractures independent of treatment-related BMD changes. J Bone Miner Res 20(Suppl. 1):SA407Google Scholar
  11. 11.
    Bauer DC, Black DM, Garnero P et al (2004) Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res 19:1250–1258PubMedCrossRefGoogle Scholar
  12. 12.
    Roux C, Seeman E, Eastell R et al (2004) Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin 20:433–439PubMedCrossRefGoogle Scholar
  13. 13.
    Harrington JT, Ste-Marie LG, Brandi ML et al (2004) Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tiss Int 74:129–135CrossRefGoogle Scholar
  14. 14.
    Sorensen OH, Crawford GM, Mulder H et al (2003) Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 32:120–126PubMedCrossRefGoogle Scholar
  15. 15.
    Reid IR, Brown JP, Burckhardt P et al (2002) Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653–661PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Borah B, Dufresne TE, Chmielewski PA et al (2004) Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone 34:736–746PubMedCrossRefGoogle Scholar
  18. 18.
    Sarkar S, Reginster JY, Crans GG et al (2004) Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 19:394–401PubMedCrossRefGoogle Scholar
  19. 19.
    Cummings SR, Karpf DB, Harris F et al (2002) Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112:281–289PubMedCrossRefGoogle Scholar
  20. 20.
    Mellstrom DD, Sorensen OH, Goemaere S et al (2004) Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 75:462–468PubMedCrossRefGoogle Scholar
  21. 21.
    Bone HG, Hosking D, Devogelaer J-P et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199PubMedCrossRefGoogle Scholar
  22. 22.
    Ensrud KE, Barrett-Connor EL, Schwartz A et al (2004) Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 19:1259–1269PubMedCrossRefGoogle Scholar
  23. 23.
    Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938PubMedCrossRefGoogle Scholar
  24. 24.
    Ruggiero SL, Mehrotra B, Rosenberg TJ et al (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534PubMedCrossRefGoogle Scholar
  25. 25.
    Woo SB, Hellstein JW, Kalmar JR (2006) Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761PubMedGoogle Scholar
  26. 26.
    Odvina CV, Zerwekh JE, Rao DS et al (2005) Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301PubMedCrossRefGoogle Scholar
  27. 27.
    Greenspan SL, Emkey RD, Bone HG et al (2002) Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 137:875–883PubMedGoogle Scholar
  28. 28.
    Stock JL, Bell NH, Chesnut CH et al (1997) Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med 103:291–297PubMedCrossRefGoogle Scholar
  29. 29.
    Colon-Emeric CS (2006) Ten vs. five years of bisphosphonate treatment for postmenopausal osteoporosis: enough of a good thing. JAMA 296:2968–2969PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Authors and Affiliations

  • N. B. Watts
    • 1
  • A. Chines
    • 2
  • W. P. Olszynski
    • 3
  • C. D. McKeever
    • 4
  • M. R. McClung
    • 5
  • X. Zhou
    • 2
  • A. Grauer
    • 2
  1. 1.University of Cincinnati Bone Health and Osteoporosis CenterCincinnatiUSA
  2. 2.Procter & Gamble PharmaceuticalsCincinnatiUSA
  3. 3.Midtown Medical CenterSaskatoonCanada
  4. 4.McKeever Orthopedic ClinicHoustonUSA
  5. 5.Oregon Osteoporosis CenterPortlandUSA

Personalised recommendations