Introduction
Commonly used markers of bone turnover
Bone marker (Abbreviation) | Source | Action | Advantages | Disadvantages | Analysis and sample type |
---|---|---|---|---|---|
Formation markers
| |||||
Bone Alkaline Phosphatase (BAP) | Enzyme present in osteoblast plasma membranes | Enzymatic degradation of the mineralisation inhibitor pyrophosphate at alkaline pH | Automated and manual immunoassays Serum, EDTA plasma | ||
Osteocalcin (OC) | Major non-collagen bone Gla protein. Produced by osteoblasts during bone formation and bound to hydroxyapatite | Influences osteoid mineralisation Provides negative feedback during remodelling process | Intact molecule unstable [15] Large inter-lab variation [20] Released during formation and resorption [17] Short half-life of a few minutes [22, 23] Influenced by Vit K status, renal function and circadian variability [15, 17] OC gene regulated at transcriptional level by 1,25-OH2 Vit D Vit K essential co-factor for γ-carboxylation of OC resulting in ↑ affinity for Ca and hydroxyapatite [14] | Automated and manual immunoassays Multiplex microarray Serum, EDTA plasma | |
Procollagen type 1 Carboxy-terminal Propeptide (P1CP) | Specific product of proliferating osteoblasts and fibroblasts. | Cleaved from type 1 pro-collagen by proteases during type 1 collagen formation | Quantitative measure of newly formed type 1 collagen Thermostability [14] | Automated and manual immunoassays Serum, EDTA plasma | |
*Procollagen type 1 amiNo-terminal Propeptide (P1NP)
|
Specific product of proliferating osteoblasts and fibroblasts.
|
Cleaved from type 1 pro-collagen by proteases during type 1 collagen formation
| Total assay affected by delayed clearance of monomeric fraction e.g. in renal failure or metastatic bone disease[24] Expensive |
Automated and manual immunoassays Multiplex microarray Total or Intact fractions Serum, EDTA plasma
| |
Resorption markers
Collagen derived
| |||||
*Carboxy-Terminal cross-linked telopeptides of type 1 collagen (CTX)
|
Type 1 collagen mainly bone Isomerisation to β aspartyl occurs in mature collagen
|
Cleaved from type 1 collagen by cathepsin-K during bone resorption
| Large circadian variation – highest 01:30 – 04:30 approx 2x nadir 11:00–15:00[27] |
Automated and manual immunoassays Multiplex microarray Urine, serum, EDTA plasma
| |
Carboxy-Terminal cross-linked telopeptides of type 1 collagen (ICTP or CTX-MMP) | Newly synthesised type 1 collagen predominantly bone | Cleaved from type 1 collagen by MMP during bone resorption | Manual immunoassay | ||
amiNo-Terminal cross-linked telopeptides of type 1 collagen (NTX) | Type 1 collagen mainly bone | Cleaved from type 1 collagen by cathepsin-K during bone resorption | Automated and manual immunoassays Urine, serum, EDTA plasma | ||
Type 1 collagen alpha 1 helicoidal peptide (HELP) | Type 1 collagen Amino acid 620–633 sequence of the α chain | Cleaved from helical region of type 1 collagen by cathepsin-K during bone resorption | High correlation to other markers of collagen degradation [14] | 24 hr collection – hard to collect 2nd morning void with creatinine correction – additional analytical variability Clinical validity needs further investigation | Manual immunoassay Urinary marker |
Deoxypyridinoline (DPD) | Mature type 1 collagen | Cross link released when mature type 1 collagen breaks down Mechanically stabilise the molecule | 24 hr collection – hard to collect 2nd morning void with creatinine correction – additional analytical variability Circadian variation [20] | Automated and manual immunoassays Urinary marker | |
Pyridinoline (PYD) | Mature type 1 and 11 collagen | Cross link released when mature collagen type 1 and 11 breaks down Mechanically stabilise the molecule | Reflect degradation of mature collagen only Independent of dietary sources [20] | Automated and manual immunoassays Urinary marker | |
Resorption markers
Osteoclastic Enzymes
| |||||
Tartrate Resistant Acid Phosphatase –isoform 5b (TRAP5b) | Isoform of acid phosphatase, resistant to tartrate, cleaved by proteases into 5b, present in ruffled border of osteoclasts | Cleaves type 1 collagen into fragments | Characteristic of osteoclastic activity [14] | Automated and manual immunoassays Serum | |
Cathepsin K | Cysteine protease present in ruffled border of actively resorbing osteoclasts | Cleaves telopeptide and helical regions of type 1 collagen | Specific biomarker of osteoclastic activity [14] | Unstable at room temp Clinical validity needs further investigation | Manual immunoassay Serum, EDTA plasma |
Osteocyte activity markers
| |||||
Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) | Produced by osteoblasts, activated by B and T cells | Binds to RANK, which is expressed on osteoclasts and their precursors, stimulating their differentiation and activity | Novel biomarker Provide safety, efficacy and pharmacokinetics data to confirm drug mechanisms and mode of action for future use | Manual research –grade immunoassay Total or soluble forms in serum | |
Osteoprotegerin (OPG) | Secreted by osteoblasts | Decoy receptor to RANKL reduces bone resorption by binding to RANK and preventing osteoclastogenesis | Novel biomarker Provide safety, efficacy and pharmacokinetics data to confirm drug mechanisms and mode of action for future use | Affected by thyroid function [32] Research method only Clinical and analytical validity needs further investigation | Manual research-grade immunoassay Serum |
Dickkopf-related protein 1 (DKK1) | Produced by osteocytes | Inhibition of Wnt signalling pathway through binding to LRP5/6, blocking the Wnt effects on osteoblasts and decreasing bone formation | Key role in regulation of bone turnover | Research method only Clinical and analytical validity needs further investigation | Manual research –grade immunoassay Serum |
Sclerostin (SCL) | Secreted by osteocytes | Inhibition of Wnt signalling pathway through binding to LRP5/6, blocking the Wnt effects on osteoblasts and decreasing bone formation | Significant ↓ with PTH therapy [33] | Manual research-grade immunoassaySerum |