Proposed common reference intervals for reference bone turnover markers in osteoporosis

In 2011, serum pro-collagen type I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type 1 collagen (β-CTX) were designated as reference bone turnover markers (BTMs) for inclusion in clinical studies of osteoporosis. Recently, bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase 5b (TRACP5b) were designated as reference BTMs for clinical studies in chronic kidney disease-associated osteoporosis. Following these developments, there is a requirement for authoritative common reference intervals for these BTMs for use in clinical care settings. The aim of this study was to develop candidate common reference intervals for P1NP, β-CTX, BALP and TRACP5b measured by automated methods, based on current literature. A systematic review of publications that reported reference intervals for the reference BTM in adults was conducted. For each BTM, method, age and sex category, reference interval limits and central values were pooled and used to estimate weighted means and confidence limits for pre- and post-menopausal females, and males. From this information, candidate common reference intervals for clinical use were developed. The systematic review yielded 31 studies. There were 20 studies for the Roche Cobas methods for P1NP and β-CTX, five for the IDS iSYS methods for P1NP and β-CTX and 10 for automated methods for BALP. No studies were found for automated methods of measuring TRACP5b, but data for the Nittobo enzyme-linked immunosorbent assay were analysed. There was strong evidence that the same reference intervals for P1NP by both iSYS and Cobas methods could be used. Different reference intervals are needed for iSYS and Cobas β-CTX assays, as well as for iSYS and Beckman Ostase BALP assays. The proposed reference intervals for BTMs in adults will contribute to the refinement of existing common reference intervals and focus research effort on those BTMs where more data are required.