Skip to main content
SpringerLink
Log in

Clinical Use of Bone Turnover Markers to Monitor Pharmacologic Fracture Prevention Therapy

  • Current Therapeutics (SL Silverman, Section Editor)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Monitoring of drug therapies to prevent fractures is controversial. Measurement of bone turnover markers has the potential to identify those with a suboptimal response to fracture prevention medication within a few months of its commencement. However, given the imprecision of currently commercially available assays of bone turnover markers, many individual persons who are “suboptimal medication responders” are likely to be misclassified as “adequate responders” or vice versa, depending on the cut point chosen to define suboptimal and adequate response. Before bone turnover markers can be recommended for routine use in clinical practice to monitor fracture prevention therapies, three advances are needed: 1) bone marker assays with better precision; 2) research establishing optimal cut points of bone marker levels to distinguish “suboptimal responders” from “adequate responders”; and 3) research establishing the incremental fracture reduction benefit from clinical interventions for “suboptimal responders” identified from bone marker measurements.

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

Abbreviations

FIT:

Fracture Intervention Trial

HORIZON:

Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly

IMPACT:

Improving Measurements of Persistence on Actonel Treatment

MOBILE:

Monthly Oral Ibandronate in Ladies

MORE:

Multiple Outcomes of Raloxifene Evaluation

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Nguyen ND, Ahlborg HG, Center JR, Eisman JA, Nguyen TV. Residual lifetime risk of fractures in women and men. J Bone Miner Res. 2007;22(6):781–8.

    Article  PubMed  Google Scholar 

  2. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465–75.

    Article  PubMed  Google Scholar 

  3. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.

  4. Wells G, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.

  5. MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008;148(3):197–213.

    PubMed  Google Scholar 

  6. Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess. 2005;9(22):1–160.

    PubMed  CAS  Google Scholar 

  7. International Society for Clinical D. 2007 Official Positions. International Society for Clinical Densitometry; 2008.

  8. National OF. Clinician’s guide to prevention and treatment of osteoporosis. National Osteoporosis Foundation; 2008.

  9. Bell KJ, Hayen A, Macaskill P, Irwig L, Craig JC, Ensrud K, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ. 2009;338:b2266.

    Article  PubMed  Google Scholar 

  10. Chapurlat RD, Palermo L, Ramsay P, Cummings SR. Risk of fracture among women who lose bone density during treatment with alendronate. The fracture intervention trial. Osteoporos Int. 2005;16(7):842–8.

    Article  PubMed  CAS  Google Scholar 

  11. Watts NB, Cooper C, Lindsay R, Eastell R, Manhart MD, Barton IP, et al. 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. 2004;7(3):255–61.

    Article  PubMed  Google Scholar 

  12. Watts NB, Geusens P, Barton IP, Felsenberg D. Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res. 2005;20(12):2097–104.

    Article  PubMed  Google Scholar 

  13. Watts NB, Miller PD, Kohlmeier LA, Sebba A, Chen P, Wong M, et al. Vertebral fracture risk is reduced in women who lose femoral neck BMD with teriparatide treatment. J Bone Miner Res. 2009;24(6):1125–31.

    Article  PubMed  CAS  Google Scholar 

  14. Johnston Jr CC, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak BH, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000;160(22):3444–50.

    Article  PubMed  CAS  Google Scholar 

  15. Watts NB, Lewiecki EM, Bonnick SL, Laster AJ, Binkley N, Blank RD, et al. Clinical value of monitoring BMD in patients treated with bisphosphonates for osteoporosis. J Bone Miner Res. 2009;24(10):1643–6.

    Article  PubMed  CAS  Google Scholar 

  16. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420. This is the most comprehensive review to date of the use of bone metabolism markers in the clinical management of osteoporosis from a joint committee of the IOF and the IFCC.

    Article  PubMed  CAS  Google Scholar 

  17. Bergmann P, Body JJ, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, et al. 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. 2009;63(1):19–26. This is a review articulating the arguments in favor of using bone turnover markers to monitor fracture prevention therapies.

    Article  PubMed  CAS  Google Scholar 

  18. Lewiecki EM. Monitoring pharmacological therapy for osteoporosis. Rev Endocr Metab Disord. 2010;11(4):261–73.

    Article  PubMed  CAS  Google Scholar 

  19. Vasikaran SD, Vasikaran SD. Utility of biochemical markers of bone turnover and bone mineral density in management of osteoporosis. Crit Rev Clin Lab Sci. 2008;45(2):221–58.

    Article  PubMed  CAS  Google Scholar 

  20. Civitelli R, Armamento-Villareal R, Napoli N. Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int. 2009;20(6):843–51.

    Article  PubMed  CAS  Google Scholar 

  21. Compston J, Compston J. Monitoring osteoporosis treatment. Best Pract Res Clin Rheumatol. 2009;23(6):781–8. This is a recent review articulating the arguments against use of bone turnover markers to monitor fracture prevention therapies.

    Article  PubMed  Google Scholar 

  22. Bell KJ, Hayen A, Irwig L, Hochberg MC, Ensrud KE, Cummings S, et al. The potential value of monitoring bone turnover markers among women on alendronate. J Bone Miner Res. 2011. This paper re-analyzes data from the FIT trial to make the point that in-person variability of serum bone markers (albeit with older assays for P1NP) is greater than the differences in bone marker change in those on alendronate versus placebo; thus, there is the potential for significant misclassification of “suboptimal responders” as “robust responders” and vice versa.

  23. Robins SP, Brady JD. Collagen cross-linking and metabolism. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. San Diego: Academic; 2002. p. 211–24.

    Chapter  Google Scholar 

  24. Wichers M, Schmidt E, Bidlingmaier F, Klingmuller D. Diurnal rhythm of CrossLaps in human serum. Clin Chem. 1999;45(10):1858–60.

    PubMed  CAS  Google Scholar 

  25. Clowes JA, Allen HC, Prentis DM, Eastell R, Blumsohn A. Octreotide abolishes the acute decrease in bone turnover in response to oral glucose. J Clin Endocrinol Metab. 2003;88(10):4867–73.

    Article  PubMed  CAS  Google Scholar 

  26. Claudon A, Vergnaud P, Valverde C, Mayr A, Klause U, Garnero P, et al. New automated multiplex assay for bone turnover markers in osteoporosis. Clin Chem. 2008;54(9):1554–63.

    Article  PubMed  CAS  Google Scholar 

  27. Greenspan SL, Dresner-Pollak R, Parker RA, London D, Ferguson L. Diurnal variation of bone mineral turnover in elderly men and women. Calcif Tissue Int. 1997;60(5):419–23.

    Article  PubMed  CAS  Google Scholar 

  28. Clowes JA, Khosla S, Eastell R. Potential role of pancreatic and enteric hormones in regulating bone turnover. J Bone Miner Res. 2005;20(9):1497–506.

    Article  PubMed  CAS  Google Scholar 

  29. Obrant KJ, Ivaska KK, Gerdhem P, Alatalo SL, Pettersson K, Vaananen HK. Biochemical markers of bone turnover are influenced by recently sustained fracture. Bone. 2005;36(5):786–92.

    Article  PubMed  CAS  Google Scholar 

  30. Ardissone P, Rota E, Durelli L, Limone P, Isaia GC. Effects of high doses of corticosteroids on bone metabolism. J Endocrinol Invest. 2002;25(2):129–33.

    PubMed  CAS  Google Scholar 

  31. Ebeling PR, Erbas B, Hopper JL, Wark JD, Rubinfeld AR. Bone mineral density and bone turnover in asthmatics treated with long-term inhaled or oral glucocorticoids. J Bone Miner Res. 1998;13(8):1283–9.

    Article  PubMed  CAS  Google Scholar 

  32. Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff J, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004;19(8):1250–8.

    Article  PubMed  Google Scholar 

  33. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. 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. 2000;11(1):83–91.

    Article  PubMed  CAS  Google Scholar 

  34. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. 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. 1999;282(14):1344–52.

    Article  PubMed  CAS  Google Scholar 

  35. Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;18(6):1051–6.

    Article  PubMed  CAS  Google Scholar 

  36. Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res. 2007;22(11):1656–60.

    Article  PubMed  Google Scholar 

  37. Eastell R, Vrijens B, Cahall DL, Ringe JD, Garnero P, Watts NB. Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence. J Bone Miner Res. 2011;26(7):1662–9. This is a detailed analysis of using bone turnover markers to identify “suboptimal responders” from “robust responders” on risedronate therapy.

    Article  PubMed  CAS  Google Scholar 

  38. Delmas PD, Munoz F, Black DM, Cosman F, Boonen S, Watts NB, et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res. 2009;24(9):1544–51.

    Article  PubMed  CAS  Google Scholar 

  39. Hochberg MC, Silverman SL, Barr CE, Miller PD. The utility of changes in serum levels of C-terminal telopeptide of type I collagen in predicting patient response to oral monthly ibandronate therapy. J Clin Densitom. 2010;13(2):181–9.

    Article  PubMed  Google Scholar 

  40. Chen P, Satterwhite JH, Licata AA, Lewiecki EM, Sipos AA, Misurski DM, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res. 2005;20(6):962–70.

    Article  PubMed  CAS  Google Scholar 

  41. Tsujimoto M, Chen P, Miyauchi A, Sowa H, Krege JH, Tsujimoto M, et al. PINP as an aid for monitoring patients treated with teriparatide. Bone. 2011;48(4):798–803.

    Article  PubMed  CAS  Google Scholar 

  42. Bauer DC, Garnero P, Bilezikian JP, Greenspan SL, Ensrud KE, Rosen CJ, et al. Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2006;91(4):1370–5.

    Article  PubMed  CAS  Google Scholar 

  43. Eastell R, Chen P, Saag KG, Burshell AL, Wong M, Warner MR, et al. Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate. Bone. 2010;46(4):929–34.

    Article  PubMed  CAS  Google Scholar 

  44. Saag KG, Shane E, Boonen S, Marin F, Donley DW, Taylor KA, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028–39.

    Article  PubMed  CAS  Google Scholar 

  45. Middleton ET, Steel SA, Doherty SM. The effect of prior bisphosphonate exposure on the treatment response to teriparatide in clinical practice. Calcif Tissue Int. 2007;81(5):335–40.

    Article  PubMed  CAS  Google Scholar 

  46. Eastell R, Krege JH, Chen P, Glass EV, Reginster JY, Eastell R, et al. Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin. 2006;22(1):61–6.

    Article  PubMed  CAS  Google Scholar 

  47. Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):530–7. This is a recent study showing universal reduction of bone turnover markers on denosumab therapy.

    Article  PubMed  CAS  Google Scholar 

  48. Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas PD, Christiansen C. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int. 2001;12(11):922–30.

    Article  PubMed  CAS  Google Scholar 

  49. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89(3):1117–23.

    Article  PubMed  CAS  Google Scholar 

  50. Delmas PD, Vrijens B, Eastell R, Roux C, Pols HA, Ringe JD, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007;92(4):1296–304.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of interest: J.T. Schousboe: is Vice President of the International Society of Clinical Densitometry (ISCD), a scientific and advocacy professional society; D.C. Bauer: has received grant support from Novartis and Amgen.

Author information

Authors and Affiliations

  1. Park Nicollet Health Services, Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA

    John T. Schousboe

  2. Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, CA, USA

    Douglas C. Bauer

Authors
  1. John T. Schousboe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas C. Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John T. Schousboe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schousboe, J.T., Bauer, D.C. Clinical Use of Bone Turnover Markers to Monitor Pharmacologic Fracture Prevention Therapy. Curr Osteoporos Rep 10, 56–63 (2012). https://doi.org/10.1007/s11914-011-0091-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-011-0091-y

Keywords

Search

Navigation