PURPOSE: The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) have proposed procollagen type I N propeptide (PINP) and β isomerized C-terminal telopeptide of type I collagen (β-CTX-I) as reference bone turnover markers (BTMs) for osteoporosis. This report examines the published literature since the 2011 IOF-IFCC position paper in order to determine the clinical potential of the reference BTMs and newer markers for the prediction of fracture risk and monitoring the treatment of osteoporosis. METHODS: Evidence for the relationship between BTMs and subsequent fractures was gathered from prospective studies through literature review of the Medline database from years 2011 to May 2024. The impact of treatment on BTMs was also studied by examining publications in that period. Studies of the accuracy of BTMs in the assessment of bone turnover in the setting of advanced chronic kidney disease were also examined. RESULTS: Increased BTM concentrations are associated with higher fracture risk in postmenopausal women. PINP and β-CTX-I measured in blood are associated with fracture risk but their interaction with other risk factors has not been sufficiently studied limiting their incorporation into fracture risk algorithms. Treatment-induced changes in PINP and β-CTX-I account for a substantial proportion of fracture risk reduction and are useful for improving adherence; they are recommended for inclusion in studies to examine adherence in individual patients. However, total PINP (tPINP) and β-CTX-I may be elevated in CKD due to renal retention. Bone alkaline phosphatase (BALP), intact PINP (iPINP), and tartrate resistant acid phosphatase 5b (TRACP5b) show the most promise in discriminating high and low turnover bone diseases in patients with advanced CKD and for predicting fracture risk, monitoring treatment response, and assessing the risk of treatment-related complications. CONCLUSION: We re-affirm the use of serum/plasma tPINP and plasma β-CTX-I as reference BTMs with appropriate patient preparation and sample handling and measurement by standardized/harmonized assays in clinical studies to accumulate further data, and for monitoring treatment of osteoporosis in the setting of normal renal function in clinical practice. BALP and TRACP5b, measured by standardized assays, are recommended as reference BTMs for CKD-associated osteoporosis and should be included in observational and intervention studies to ascertain their utility for risk-evaluation, treatment initiation, and assessment of treatment response in CKD-associated osteoporosis.

• Keywords
• BALP, Bone status indices, Bone turnover markers, PINP, TRACP5b, β-CTX-I,
• MeSH
• Biomarkers blood   MeSH
• Risk Assessment methods   MeSH
• Bone Density Conservation Agents therapeutic use   MeSH
• Collagen Type I blood   MeSH
• Consensus MeSH
• Humans MeSH
• Osteoporotic Fractures prevention & control   etiology   MeSH
• Osteoporosis * diagnosis   physiopathology   drug therapy   blood   therapy   MeSH
• Peptide Fragments blood   MeSH
• Peptides blood   MeSH
• Procollagen blood   MeSH
• Bone Remodeling * physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• collagen type I trimeric cross-linked peptide MeSH Browser
• Bone Density Conservation Agents MeSH
• Collagen Type I MeSH
• Peptide Fragments MeSH
• Peptides MeSH
• procollagen Type I N-terminal peptide MeSH Browser
• Procollagen MeSH