Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis

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



Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment.


Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD).


We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > − 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value.


Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was − 2.98%, 95%CI − 4.75 to − 1.22, P < 0.001, PINP − 2.25%, 95% CI − 4.46 to − 0.032, P = 0.046).


The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.


Bisphosphonate Bone density Bone markers Osteoporosis 



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 study. We acknowledge the support of the NIHR Clinical Research Facility, Northern General Hospital, Sheffield. This work was supported by the South Yorkshire and North Derbyshire Musculoskeletal Biobank, which received ethics approval from NRES REC South Central Oxford C, (REC ref. 15/SC/0132) and is housed in the University of Sheffield Biorepository (HTA Licence no. 12182). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR.

Funding information

The TRIO 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 (Emeritus). The authors approved the manuscript for publication and vouched 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.

Compliance with ethical standards

Conflict of interest

NP has received speaker’s honoraria and funding to attend educational events from Warner-Chilcott, Eli Lilly, Amgen, GSK and Prostrakan and consultancy fees from Internis Pharma and Eli Lilly. JW has received speaker’s honoraria from Eli Lilly, grant funding from Alexion and Immunodiagnostic Systems, research drug and kits from Eli Lilly, Prostrakan (Kyowa Kirin), Consilient and Biomedica, consulting fees from Shire and Mereo Biopharma. EM has received speaker’s honoraria and/or research funding and/or advisory board funding from Warner-Chilcott, Merck, AgNovos, Amgen, GSK, Bayer, Consilient Healthcare, Hologic, Eli Lilly, Novartis, Pfizer, Radius Pharmaceuticals, Servier, Wyeth, UCB and Roche. RE 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. KN, RJ, MP and FG have nothing to disclose.

Supplementary material

198_2018_4823_MOESM1_ESM.pdf (60 kb)
Suppl Fig 2 The time course of changes in BTM during 2 years BP treatment then 2 years off treatment for individuals (top panels), mean value with SE (bottom panels) for CTX and PINP. BTM values at 48 weeks (labelled as year 3) after stopping treatment were used to identify a significant change. Lines shown in red: BTM Δ > LSC and BTM > mean, green: BTM Δ > LSC or BTM > mean, black: BTM Δ < LSC and < mean, black dash line: premenopausal mean. (PDF 59 kb)


  1. 1.
    Russell RG (2006) Bisphosphonates: from bench to bedside. Ann N Y Acad Sci 1068:367–401CrossRefGoogle Scholar
  2. 2.
    Compston J, Cooper A, Cooper C et al (2017) UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 12:43CrossRefGoogle Scholar
  3. 3.
    Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Torner JC, Lombardi A, Black DM, for the Fracture Intervention Trial Long-Term Extension Research Group (2004) Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the fracture intervention trial long-term extension. JBone MinerRes 19:1259–1269CrossRefGoogle Scholar
  4. 4.
    Papapoulos SE, Cremers SC (2007) Prolonged bisphosphonate release after treatment in children. N Engl J Med 356:1075–1076CrossRefGoogle Scholar
  5. 5.
    Adler RA, El-Hajj Fuleihan G, Bauer DC et al (2016) Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 31:16–35CrossRefGoogle Scholar
  6. 6.
    Chubb SAP, Vasikaran SD (2017) Measurement and clinical utility of betaCTX in serum and plasma. Adv Clin Chem 81:97–134CrossRefGoogle Scholar
  7. 7.
    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 22:391–420CrossRefGoogle Scholar
  8. 8.
    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. ClinChemLab Med 49:1271–1274Google Scholar
  9. 9.
    Diez-Perez A, Naylor KE, Abrahamsen B et al (2017) International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates. Osteoporos Int 28:767–774CrossRefGoogle Scholar
  10. 10.
    Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR, FLEX Research Group (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension (FLEX): a randomized trial. JAMA 296:2927–2938CrossRefGoogle Scholar
  11. 11.
    Eastell R, Hannon RA, Wenderoth D, Rodriguez-Moreno J, Sawicki A (2011) Effect of stopping risedronate after long-term treatment on bone turnover. J Clin Endocrinol Metab 96:3367–3373CrossRefGoogle Scholar
  12. 12.
    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 25:2729–2741CrossRefGoogle Scholar
  13. 13.
    Naylor KE, Jacques RM, Paggiosi M, Gossiel F, Peel NF, McCloskey EV, Walsh JS, Eastell R (2016) Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study. Osteoporos Int 27:21–31CrossRefGoogle Scholar
  14. 14.
    Naylor KE, Bradburn M, Paggiosi MA, Gossiel F, Peel NFA, McCloskey EV, Walsh JS, Eastell R (2018) Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density. Osteoporos Int 29:1407–1417CrossRefGoogle Scholar
  15. 15.
    Szulc P, Naylor K, Hoyle NR, Eastell R, Leary ET, National Bone Health Alliance Bone Turnover Marker P (2017) Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporos Int 28:2541–2556CrossRefGoogle Scholar
  16. 16.
    Morris HA, Eastell R, Jorgensen NR, Cavalier E, Vasikaran S, Chubb SAP, Kanis JA, Cooper C, Makris K, Assays I-IWGfSoBM (2017) Clinical usefulness of bone turnover marker concentrations in osteoporosis. Clin Chim Acta 467:34–41CrossRefGoogle Scholar
  17. 17.
    Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, Reid IR, Resch H, Siris E, Uebelhart D, Wang A, Weryha G, Cummings SR (2011) Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. JBone MinerRes 26:530–537CrossRefGoogle Scholar
  18. 18.
    Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San MJ (2008) Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43:222–229CrossRefGoogle Scholar
  19. 19.
    Jorgensen NR, Mollehave LT, Hansen YBL, Quardon N, Lylloff L, Linneberg A (2017) Comparison of two automated assays of BTM (CTX and P1NP) and reference intervals in a Danish population. Osteoporos Int 28:2103–2113CrossRefGoogle Scholar
  20. 20.
    Silverman SL, Schousboe JT, Gold DT (2011) Oral bisphosphonate compliance and persistence: a matter of choice? Osteoporos Int 22:21–26CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  1. 1.Academic Unit of Bone Metabolism, The Mellanby Centre for Bone ResearchUniversity of SheffieldSheffieldUK
  2. 2.Centre for Integrated Research into Musculoskeletal AgeingLiverpoolUK
  3. 3.School of Health and Related ResearchUniversity of SheffieldSheffieldUK
  4. 4.Metabolic Bone Centre, Sheffield Teaching Hospitals NHS Foundation TrustNorthern General Hospital SheffieldSheffieldUK

Personalised recommendations