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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

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Volume 57, Issue 10


A multicenter study to evaluate harmonization of assays for N-terminal propeptide of type I procollagen (PINP): a report from the IFCC-IOF Joint Committee for Bone Metabolism

Etienne Cavalier
  • Corresponding author
  • Department of Clinical Chemistry, University of Liège, CHU Sart-Tilman, Domaine du Sart-Tilman, B-4000 Liège, Belgium
  • Email
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/ Richard Eastell / Niklas Rye Jørgensen
  • Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark
  • OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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/ Konstantinos Makris
  • Clinical Biochemistry Department, KAT General Hospital, Athens, Greece
  • Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, Medical School, University of Athens, Athens, Greece
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/ Symeon Tournis
  • Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, Medical School, University of Athens, Athens, Greece
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/ Samuel Vasikaran / John A. Kanis / Cyrus Cooper
  • The MRC Epidemiology Resource Centre, Southampton General Hospital, University of Southampton, Southampton, UK
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/ Hans Pottel
  • Department of Public Health and Primary Care, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
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/ Howard A. Morris
  • School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
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Published Online: 2019-05-14 | DOI: https://doi.org/10.1515/cclm-2019-0174



Biochemical bone turnover markers (BTM) are useful tools to assess bone remodeling at the cellular level. N-terminal propeptide of type I procollagen (PINP) has been recommended as a reference marker for bone formation in research studies.


We describe the results of a multicenter study for routine clinical laboratory assays for PINP in serum and plasma. Four centers (Athens, Greece [GR], Copenhagen, Denmark [DK], Liege, Belgium [BE] and Sheffield, United Kingdom [UK]) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers’ instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method and the concordance correlation coefficient for PINP values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods.


We showed that both EDTA plasma and serum were suitable for PINP determination. We observed a significant proportional bias between Orion radioimmunoassay and the automated methods for PINP (Roche Cobas and IDS iSYS), which both gave very similar results. The multivariate model did not improve the excellent correlation that was observed between the methods.


Harmonization of PINP assays is possible by applying a correction factor or correctly assigning the values of the calibrators. This work will benefit from further collaboration between assays manufacturers and clinical laboratory professionals.

Keywords: bone marker; bone turnover; bone turnover markers; harmonization; N-terminal propeptide of type I procollagene; propeptide of type I procollagen (PINP)


  • 1.

    Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8:136.CrossrefGoogle Scholar

  • 2.

    Vasikaran S, Cooper C, Eastell R, Griesmacher A, Morris HA, Trenti T, et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis. Clin Chem Lab Med 2011;49:1271–4.Web of ScienceGoogle Scholar

  • 3.

    Diez-Perez A, Naylor KE, Abrahamsen B, Agnusdei D, Brandi ML, Cooper C, et al. International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates. Osteoporos Int 2017;28:767–74.CrossrefGoogle Scholar

  • 4.

    Koivula MK, Risteli L, Risteli J. Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 2012;45:920–7.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 5.

    Szulc P, Naylor K, Hoyle NR, Eastell R, Leary ET. Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliancerecommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. Osteoporos Int 2017;28:2541–56.CrossrefPubMedGoogle Scholar

  • 6.

    Cavalier E, Lukas P, Carlisi A, Gadisseur R, Delanaye P. Aminoterminal propeptide of type I procollagen (PINP) in chronic kidney disease patients: the assay matters. Clin Chim Acta 2013;425:117–8.Web of SciencePubMedCrossrefGoogle Scholar

  • 7.

    Koivula MK, Ruotsalainen V, Björkman M, Nurmenniemi S, Ikäheimo R, Savolainen K, et al. Difference between total and intact assays for N-terminal propeptide of type I procollagen reflects degradation of pN-collagen rather than denaturation of intact propeptide. Ann Clin Biochem 2010;47:67–71.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 8.

    Marin L, Koivula MK, Jukkola-Vuorinen A, Leino A, Risteli J. Comparison of total and intact aminoterminal propeptide of type I procollagen assays in patients with breast cancer with or without bone metastases. Ann Clin Biochem 2011;48:447–51.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 9.

    Wheater G, Goodrum C, Tuck SP, Datta HK, van Laar JM. Method-specific differences in β-isomerised carboxy-terminal cross-linking telopeptide of type I collagen and procollagen type I amino-terminal propeptide using two fully automated immunoassays. Clin Chem Lab Med 2014;52:135–8.Web of ScienceGoogle Scholar

  • 10.

    Koivula MK, Richardson J, Leino A, Valleala H, Griffiths K, Barnes A, et al. Validation of an automated intact N-terminal propeptide of type I procollagen (PINP) assay. Clin Biochem 2010;43:1453–7.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 11.

    Jørgensen NR, Møllehave LT, Hansen YB, Quardon N, Lylloff L, Linneberg A. Comparison of two automated assays of BTM (CTX and P1NP) and reference intervals in a Danish population. Osteoporos Int 2017;28:2103–13.CrossrefGoogle Scholar

  • 12.

    Morovat A, Catchpole A, Meurisse A, Carlisi A, Bekaert A-C, Rousselle O, et al. IDS iSYS automated intact procollagen-1-N-terminus pro-peptide assay: method evaluation and reference intervals in adults and children. Clin Chem Lab Med 2013;51:2009–18.PubMedWeb of ScienceGoogle Scholar

  • 13.

    Garnero P, Vergnaud P, Hoyle N. Evaluation of a fully automated serum assay for total N-terminal propeptide of type I collagen in postmenopausal osteoporosis. Clin Chem 2008;54:188–96.PubMedWeb of ScienceGoogle Scholar

  • 14.

    Genant HK, Grampp S, Glüer CC, Faulkner KG, Jergas M, Engelke K, et al. Universal standardization for dual X-ray absorptiometry: patient and phantom cross-calibration results. J Bone Miner Res 1994;9:1503–14.PubMedGoogle Scholar

  • 15.

    CLSI. EP15-A3 User Verification of Precision and Estimation of Bias. 2014.Google Scholar

  • 16.

    Alvarez L, RicOs C, Peris P, GuaNabens N, Monegal A, Pons F, et al. Components of biological variation of biochemical markers of bone turnover in Paget’s bone disease. Bone 2000;26:571–6.CrossrefPubMedGoogle Scholar

  • 17.

    Hannon R, Blumsohn A, Naylor K, Eastell R. Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Min Res 1998;13:1124–33.CrossrefGoogle Scholar

  • 18.

    Clowes JA, Hannon RA, Yap TS, Hoyle NR, Blumsohn A, Eastell R. Effect of feeding on bone turnover markers and its impact on biological variability of measurements. Bone 2002;30:886–90.CrossrefGoogle Scholar

  • 19.

    Rogers A, Glover SJ, Eastell R. A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy. Bone 2009;45:1044–52.Web of ScienceCrossrefPubMedGoogle Scholar

  • 20.

    Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics 1989;45:255–68.CrossrefPubMedGoogle Scholar

  • 21.

    McBride GB. A proposal for strength-of-agreement criteria for Lin’s Concordance Correlation Coefficient. NIWA Client Rep 2005;HAM2005-06:14.Google Scholar

  • 22.

    Morris HA, Eastell R, Jorgesen NR, Cavalier E, Vasikaran S, Chubb SA, et al. Clinical usefulness of bone turnover marker concentrations in osteoporosis. Clin Chim Acta 2017;467:34–41.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 23.

    Redmond J, Fulford AJ, Jarjou L, Zhou B, Prentice A, Schoenmakers I. Diurnal rhythms of bone turnover markers in three ethnic groups. J Clin Endocrinol Metab 2016;101:3222–30.Web of SciencePubMedCrossrefGoogle Scholar

About the article

Received: 2019-02-13

Accepted: 2019-04-08

Published Online: 2019-05-14

Published in Print: 2019-09-25

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 10, Pages 1546–1555, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2019-0174.

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