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A multicenter study to evaluate harmonization of assays for C‑terminal telopeptides of type I collagen (ß‑CTX): a report from the IFCC‑IOF Committee for Bone Metabolism (C‑BM)

A multicenter study to evaluate harmonization of assays for C‑terminal telopeptides of type I collagen (ß‑CTX): a report from the IFCC‑IOF Committee for Bone Metabolism (C‑BM)
A multicenter study to evaluate harmonization of assays for C‑terminal telopeptides of type I collagen (ß‑CTX): a report from the IFCC‑IOF Committee for Bone Metabolism (C‑BM)
Background: biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies.

Methods: we describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield 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 Concordance correlation coefficient for ß-CTX 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. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods.

Results: we identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum.

Conclusion: our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed.
Bone resorption, Bone turnover markers, C-terminal telopeptide of type I collagen, Harmonization, ß-CTX, ß-crosslaps
0171-967X
785-797
Cavalier, Etienne
bc312308-1b70-4434-ab15-28860479d2e9
Eastell, Richard
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Jorgensen, N.R.
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Makris, Konstantinos
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Tournis, Symeon
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Vasikaran, Samuel
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Kanis, J. A.
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Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Pottel, Hans
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Morris, Howard A.
cd727ba3-3bcc-44b5-b9be-34d95962b987
Cavalier, Etienne
bc312308-1b70-4434-ab15-28860479d2e9
Eastell, Richard
b19615e4-bc97-4ddf-b8d7-7f48b7220228
Jorgensen, N.R.
b5ac9720-c794-4851-86d6-e6e6ad019543
Makris, Konstantinos
1d7847d4-7ace-417c-8c5b-c0f892558d47
Tournis, Symeon
cdcbb48e-2fc1-499e-9eb8-f8e9611c7a8b
Vasikaran, Samuel
3ce2872a-4e12-4835-85a9-c48b734dfa28
Kanis, J. A.
ec5ad011-1ed5-43e9-acac-b0d4f535f5b1
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Pottel, Hans
80e23479-69ff-4682-9c54-c703eb0ea762
Morris, Howard A.
cd727ba3-3bcc-44b5-b9be-34d95962b987

Cavalier, Etienne, Eastell, Richard, Jorgensen, N.R., Makris, Konstantinos, Tournis, Symeon, Vasikaran, Samuel, Kanis, J. A., Cooper, Cyrus, Pottel, Hans and Morris, Howard A. (2021) A multicenter study to evaluate harmonization of assays for C‑terminal telopeptides of type I collagen (ß‑CTX): a report from the IFCC‑IOF Committee for Bone Metabolism (C‑BM). Calcified Tissue International, 108 (6), 785-797. (doi:10.1007/s00223-021-00816-5).

Record type: Article

Abstract

Background: biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies.

Methods: we describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield 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 Concordance correlation coefficient for ß-CTX 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. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods.

Results: we identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum.

Conclusion: our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed.

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Accepted/In Press date: 27 January 2021
e-pub ahead of print date: 4 March 2021
Keywords: Bone resorption, Bone turnover markers, C-terminal telopeptide of type I collagen, Harmonization, ß-CTX, ß-crosslaps

Identifiers

Local EPrints ID: 447756
URI: http://eprints.soton.ac.uk/id/eprint/447756
ISSN: 0171-967X
PURE UUID: 053e244a-d0af-4e0c-afdd-29ec484fcf39
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

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Date deposited: 19 Mar 2021 17:32
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Etienne Cavalier
Author: Richard Eastell
Author: N.R. Jorgensen
Author: Konstantinos Makris
Author: Symeon Tournis
Author: Samuel Vasikaran
Author: J. A. Kanis
Author: Cyrus Cooper ORCID iD
Author: Hans Pottel
Author: Howard A. Morris

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