European Biological Variation Study (EuBIVAS):​ within- and between-subject biological variation estimates of β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin, intact fibroblast growth factor 23 and uncarboxylated-unphosphorylated matrix-Gla protein:​ a cooperation between the EFLM Working Group on Biological Variation and the International Osteoporosis Foundation-International Federation of Clinical Chemistry Committee on Bone Metabolism

Cavalier, E.; Lukas, P.; Bottani, M.; Aarsand, A. K.; Ceriotti, F.; Coşkun, A.; Díaz-Garzón, J.; Fernàndez-Calle, P.; Guerra, E.; Locatelli, M.; Sandberg, S.; Carobene, A.

Affiliations

¹Department of Clinical Chemistry, University of Liège, Liège, Belgium

²International Federation of Clinical Chemistry—International Osteoporosis Foundation Committee for Bone Markers, Milan, Italy

³IRCCS Istituto Ortopedico Galeazzi, Laboratory of Experimental Biochemistry & Molecular Biology, Milan, Italy

⁴Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway

⁵Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway

⁶Biological Variation Working Group, European Federation of Clinical Chemistry and Laboratory Medicine, Milan, Italy

⁷Clinical Laboratory, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

⁸School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

⁹Quality Analytical Commission of Spanish Society of Laboratory Medicine (SEQC-ML), Hospital Universitario La Paz, Madrid, Spain

¹⁰Laboratory Medicine, Ospedale San Raffaele, Milan, Italy

¹¹Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

Abstract and keywords

Summary: We have calculated the biological variation (BV) of different bone metabolism biomarkers on a large, well-described cohort of subjects. BV is important to calculate reference change value (or least significant change) which allows evaluating if the difference observed between two consecutive measurements in a patient is biologically significant or not.

Introduction: Within-subject (CVI) and between-subject (CVG) biological variation (BV) estimates are essential in determining both analytical performance specifications (APS) and reference change values (RCV). Previously published estimates of BV for bone metabolism biomarkers are generally not compliant with the most up-to-date quality criteria for BV studies. We calculated the BV and RCV for different bone metabolism markers, namely β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), osteocalcin (OC), intact fibroblast growth factor 23 (iFGF-23), and uncarboxylated-unphosphorylated Matrix-Gla Protein (uCuP-MGP) using samples from the European Biological Variation Study (EuBIVAS).

Methods: In the EuBIVAS, 91 subjects were recruited from six European laboratories. Fasting blood samples were obtained weekly for ten consecutive weeks. The samples were run in duplicate on IDS iSYS or DiaSorin Liaison instruments. The results were subjected to outlier and variance homogeneity analysis before CV-ANOVA was used to obtain the BV estimates.

Results: We found no effect of gender upon the CVI estimates. The following CVI estimates with 95% confidence intervals (95% CI) were obtained: β-CTX 15.1% (14.4–16.0%), PINP 8.8% (8.4–9.3%), OC 8.9% (8.5–9.4%), iFGF23 13.9% (13.2–14.7%), and uCuP-MGP 6.9% (6.1–7.3%).

Conclusions: The EuBIVAS has provided updated BV estimates for bone markers, including iFGF23, which have not been previously published, facilitating the improved follow-up of patients being treated for metabolic bone disease.

Keywords: Biological variation; Bone markers; CTX; FGF23; MGP; Osteocalcin; PINP; Reference change value

Links

DOI: 10.1007/s00198-020-05362-8

PubMed: 32270253

WoS: 000548231300005

History

Received: 2019-11-06

Accepted: 2020-02-19

Online: 2020-04-08

Cited Works (1)

Year	Entry
2020	Vasikaran SD, Bhattoa HP, Eastell R, Heijboer AC, Jørgensen NR, Makris K, Ulmer C, Kanis JA, Cooper C, Silverman S, Cavalier E. Harmonization of commercial assays for PINP: the way forward. Osteoporos Int. March 2020;31(3):409-412.

Cited By (1)

Year

Entry

2021

Cavalier E, Eastell R, Jørgensen NR, Makris K, Tournis S, Vasikaran S, Kanis JA, Cooper C, Pottel H, Morris HA; IFCC-IOF Committee for Bone Metabolism (C-BM). A multicenter study to evaluate harmonization of assays for -terminal telopeptides of type I collagen (ß-CTX): a report from the IFCC-IOF committee for bone metabolism (C-BM) [published correction appears in Calcif Tiss Int. June 2021;108(6):825-826]. Calcif Tiss Int. June 2021;108(6):785-797.