Bone Turnover Markers (CTX, P1NP)

Bone turnover comprises two processes, the removal of old bone (resorption) and the laying down of new bone (formation), and N-terminal propeptide of type I procollagen (PINP) and C-telopeptide of type I collagen (CTX-I) are the formation and resorption markers, respectively, recommended for clinical use. ^[1] The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) proposed PINP and beta-isomerized CTX-I as the reference bone turnover markers for osteoporosis in a 2011 position paper. ^[2] A consensus paper from ESCEO, IOF and IFCC re-affirmed serum or plasma total PINP and plasma beta-CTX-I as the reference markers for monitoring osteoporosis treatment in clinical practice when renal function is normal. ^[2] Bone turnover markers are not used for the diagnosis of osteoporosis. ^[1]

Adult bone is continuously remodeled through a balance between resorption by osteoclasts and subsequent formation by osteoblasts. ^[3] Bisphosphonates, the most widely used anti-resorptives, reduce bone turnover markers to low premenopausal concentrations. ^[4] Denosumab, a monoclonal antibody against RANKL, potently inhibits osteoclast development and activity, but unlike bisphosphonates it does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. ^{[4] [5]} During the menopause transition, the onset of the rapid bone loss phase is preceded by changes in sex steroid hormones and increases in markers of bone resorption, which may help identify the women who will lose the most bone strength. ^[6] In juvenile Paget disease, loss of osteoprotegerin action causes extremely rapid bone turnover, with very high alkaline phosphatase activity and elevation of other bone turnover markers. ^[7]

The ESCEO, IOF and IFCC consensus specifies that the reference markers be used with appropriate patient preparation and sample handling and measured by standardized or harmonized assays. ^[2] Bone turnover markers can be measured on several occasions in one individual with good precision, but they are subject to several sources of variability, including feeding (which decreases resorption) and recent fracture (which increases all markers for several months). ^[1] Serum and urine levels of bone turnover markers, such as collagen fragments and bone alkaline phosphatase, show circadian fluctuations. ^[3] Some bone turnover markers are retained by the kidneys, and total PINP and beta-CTX-I may be elevated in chronic kidney disease because of renal retention. ^{[8] [2]} In CKD-associated osteoporosis, bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase 5b (TRACP5b), measured by standardized assays, are recommended as the reference markers instead.