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Osteoporosis International

, Volume 27, Issue 1, pp 21–31 | Cite as

Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study

  • K. E. NaylorEmail author
  • R. M. Jacques
  • M. Paggiosi
  • F. Gossiel
  • N. F. A. Peel
  • E. V. McCloskey
  • J. S. Walsh
  • R. Eastell
Original Article

Abstract

Summary

We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication.

Introduction

Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers.

Methods

Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53–84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35–40 years).

Results

Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI −63 % (difference 13 %, 95 % CI 0 to 27.1, P = 0.049) and good compliance −67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate.

Conclusions

Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

Keywords

Bisphosphonate Bone turnover markers Postmenopausal osteoporosis Variability 

Notes

Acknowledgments

This study was funded by Warner Chilcott, the bone turnover marker measurements were funded by Immunodiagnostics Systems. Professor Richard Eastell (Academic Unit of Bone Metabolism, The University of Sheffield) is a National Institute for Health Research (NIHR) Senior Investigator. The authors approved the manuscript for publication and vouch for the completeness and accuracy of the data. The funder was involved in the design, but not in the conduct, analysis or reporting of the study.

We are grateful to the data safety monitoring board, the Clinical Trials Research Unit, School of Health and Related Research, for data management and statistical support and the staff of the Academic Unit of Bone Metabolism for conducting the study. We would also like to acknowledge the Lay Advisory Panel for Bone Research and the participants of the TRIO study. We acknowledge the support of the NIHR Clinical Research Facility. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research.

Conflicts of interest

Dr Naylor, Dr Paggiosi, Dr Jacques and Miss Gossiel have no disclosures. Dr N Peel has received speaker’s honoraria and funding to attend educational events from Warner Chilcott, Lilly, Servier, Merck, Roche, GSK and Prostrakan and consultancy fees from Internis Pharma and Lilly. Dr Walsh has received speaker’s honoraria from Lilly and the donation of drug and placebo from Prostrakan. Professor McCloskey has received speaker’s honoraria and/or research funding and/or advisory board funding from Warner Chilcott, Merck, Amgen, GSK, Bayer, Consilient Healthcare, Hologic, Lilly, Novartis, Pfizer, Servier, Wyeth and Roche. Professor Eastell has received grant funding from Warner Chilcott and the National Institute for Health research (NIHR) and consultancy funding from Warner Chilcott, Roche, Immunodiagnostic Systems and Merck.

References

  1. 1.
    Russell RG (2006) Bisphosphonates: from bench to bedside. Ann NY Acad Sci 1068:367–401PubMedCrossRefGoogle Scholar
  2. 2.
    Adachi JD, Rizzoli R, Boonen S, Li Z, Meredith MP, Chesnut CH 3rd (2005) Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data. Aging Clin Exp Res 17:150–156PubMedCrossRefGoogle Scholar
  3. 3.
    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 333:1437–1443PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    Bone HG, Hosking D, Devogelaer JP et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199PubMedCrossRefGoogle Scholar
  6. 6.
    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
  7. 7.
    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
  8. 8.
    Chesnut IC, 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 19:1241–1249PubMedCrossRefGoogle Scholar
  9. 9.
    Vasikaran S, Eastell R, Bruyere O et al (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420PubMedCrossRefGoogle Scholar
  10. 10.
    Riggs BL, Parfitt AM (2005) Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 20:177–184PubMedCrossRefGoogle Scholar
  11. 11.
    Arlot M, Meunier PJ, Boivin G et al (2005) Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res 20:1244–1253PubMedCrossRefGoogle Scholar
  12. 12.
    Rosen CJ, Hochberg MC, Bonnick SL et al (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151PubMedCrossRefGoogle Scholar
  13. 13.
    Emkey R, Delmas PD, Bolognese M et al (2009) Efficacy and tolerability of once-monthly oral ibandronate (150 mg) and once-weekly oral alendronate (70 mg): additional results from the Monthly Oral Therapy With Ibandronate For Osteoporosis Intervention (MOTION) study. Clin Ther 31:751–761PubMedCrossRefGoogle Scholar
  14. 14.
    Bauer DC, Garnero P, Hochberg MC, Santora A, Delmas P, Ewing SK, Black DM (2006) Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 21:292–299PubMedCrossRefGoogle Scholar
  15. 15.
    Greenspan SL, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey L, Karpf DB (1998) Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res 13:1431–1438PubMedCrossRefGoogle Scholar
  16. 16.
    Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff J, Thompson DE, Ewing SK, Delmas PD (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
  17. 17.
    Jacques RM, Boonen S, Cosman F, Reid IR, Bauer DC, Black DM, Eastell R (2012) Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:1627–1634PubMedCrossRefGoogle Scholar
  18. 18.
    Naylor K, Eastell R (2012) Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol 8:379–389PubMedCrossRefGoogle Scholar
  19. 19.
    Diez-Perez A, Adachi JD, Agnusdei D et al (2012) Treatment failure in osteoporosis. Osteoporos Int 23:2769–2774PubMedCrossRefGoogle Scholar
  20. 20.
    Hannon RA, Blumsohn A, Naylor KE, Eastell R (1998) Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Miner Res 13:1124–1133PubMedCrossRefGoogle Scholar
  21. 21.
    Rogers A, Glover SJ, Eastell R (2009) A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy. Bone 45:1044–1052PubMedCrossRefGoogle Scholar
  22. 22.
    Eastell R, Krege JH, Chen P, Glass EV, Reginster JY (2006) Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin 22:61–66PubMedCrossRefGoogle Scholar
  23. 23.
    Bergmann P, Body JJ, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, Kaufman JM, Reginster JY, Gangji V (2009) Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract 63:19–26PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Paggiosi MA, Peel N, McCloskey E, Walsh JS, Eastell R (2014) Comparison of the effects of three oral bisphosphonate therapies on the peripheral skeleton in postmenopausal osteoporosis: the TRIO study. Osteoporos Int 25:2729–2741PubMedCrossRefGoogle Scholar
  25. 25.
    CLSI (2008) Defining, establishing, and verifying reference intervals in the clinical laboratory; Clinical and Laboratory Standards Institute;, CLSI document C28-A3. Wayne, PA:Google Scholar
  26. 26.
    Ingle BM, Hay SM, Bottjer HM, Eastell R (1999) Changes in bone mass and bone turnover following ankle fracture. Osteoporos Int 10:408–415PubMedCrossRefGoogle Scholar
  27. 27.
    Hannon R, Eastell R (2000) Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 11(Suppl 6):S30–S44PubMedCrossRefGoogle Scholar
  28. 28.
    Vasikaran S, Cooper C, Eastell R, Griesmacher A, Morris HA, Trenti T, Kanis JA (2011) International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis. Clin Chem Lab Med 49:1271–1274PubMedCrossRefGoogle Scholar
  29. 29.
    Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C (2004) The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 15:1003–1008PubMedCrossRefGoogle Scholar
  30. 30.
    Finigan J, Naylor K, Paggiosi MA, Peel NF, Eastell R (2013) Adherence to raloxifene therapy: assessment methods and relationship with efficacy. Osteoporos Int 24:2879–2886PubMedCrossRefGoogle Scholar
  31. 31.
    Miller PD, Epstein S, Sedarati F, Reginster JY (2008) Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. Curr Med Res Opin 24:207–213PubMedCrossRefGoogle Scholar
  32. 32.
    Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759PubMedCrossRefGoogle Scholar
  33. 33.
    Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122PubMedPubMedCentralGoogle Scholar
  34. 34.
    Fink E, Cormier C, Steinmetz P, Kindermans C, Le Bouc Y, Souberbielle JC (2000) Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporos Int 11:295–303PubMedCrossRefGoogle Scholar
  35. 35.
    Vasikaran SD (2008) Utility of biochemical markers of bone turnover and bone mineral density in management of osteoporosis. Crit Rev Clin Lab Sci 45:221–258PubMedCrossRefGoogle Scholar
  36. 36.
    Eastell R, Vrijens B, Cahall DL, Ringe JD, Garnero P, Watts NB (2011) Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence. J Bone Miner Res 26:1662–1669PubMedCrossRefGoogle Scholar
  37. 37.
    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 137:875–883PubMedCrossRefGoogle Scholar
  38. 38.
    Baxter I, Rogers A, Eastell R, Peel N (2013) Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice. Osteoporos Int 24:941–947PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2015

Authors and Affiliations

  • K. E. Naylor
    • 1
    Email author
  • R. M. Jacques
    • 2
  • M. Paggiosi
    • 1
  • F. Gossiel
    • 1
  • N. F. A. Peel
    • 3
  • E. V. McCloskey
    • 1
  • J. S. Walsh
    • 1
  • R. Eastell
    • 1
  1. 1.Academic Unit of Bone Metabolism, The Mellanby Centre for Bone ResearchUniversity of SheffieldSheffieldUK
  2. 2.School of Health and Related ResearchUniversity of SheffieldSheffieldUK
  3. 3.Metabolic Bone Centre, Sheffield Teaching Hospitals NHS Foundation TrustNorthern General HospitalSheffieldUK

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