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

P. Szulc, K. Naylor, N. R. Hoyle, R. Eastell, E. T. Leary, for the National Bone Health Alliance Bone Turnover Marker Project

N-terminal propeptide of type I procollagen and C-terminal telopeptide of type I collagen are the reference standards for bone turnover markers for monitoring osteoporosis treatment. We provide recommendations for standardized sample handling and encompassing aspects of preanalytical variability to improve the reproductibility of their measurements, their reliability, and clinical interpretation. The International Osteoporosis Foundation and International Federation of Clinical Chemistry bone turnover marker standards working group have identified N-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX-I) in the blood to be the international reference standards for bone turnover markers for the prediction of fracture risk and monitoring of osteoporosis treatment. The National Bone Health Alliance (NBHA) Bone Turnover Marker Project team set up a writing group to describe sources of pre-analytical variability that may influence the measurements of bone markers, and in particular PINP and CTX-I. Published data has been reviewed to provide a basis for recommendations for standardized sample handling, taking into account pre-analytical variability in order to decrease the variability for measurements of CTX and PINP so as to improve their reliability and interpretation. The International Osteoporosis Foundation and International Federation of Clinical Chemistry Bone Turnover Marker Standards Working Group have identified N-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX-I) in the blood to be the international reference standards for bone turnover markers for the prediction of fracture risk and monitoring of osteoporosis treatment. The National Bone Health Alliance (NBHA) Bone Turnover Marker Project team set up a writing group to describe sources of pre-analytical variability that may influence the measurements of PINP and CTX-I. Data were collected through literature review on PINP and CTX-I conducted in PubMed, references of available publications, and inserts of diagnostic kits. Published data has been reviewed to provide a basis for recommendations for standardized sample handling, taking into account pre-analytical variability in order to decrease the variability for measurements of CTX and PINP so as to improve their reliability and interpretation. Several key aspects of patient and sample management must be considered and adhered to in order to control and limit the impact of pre-analytical variability. The controllable aspects include, e.g., time of blood collection, food intake, and season. The uncontrollable aspects include age, sex, pregnancy, immobility, recent fracture, co-morbidities (renal function, multiple myeloma, primary hyperparathyroidism, HIV infection), anti-osteoporotic drugs, and other medications (e.g., hormonal contraceptives, corticosteroids, aromatase inhibitors). The successful adoption of standardized sample handling and patient preparation recommendations necessitates the close collaboration of various stakeholders at the global stage, including the reagent manufacturers, the laboratories, the medical community, and the regulatory agencies.