Analytical and Preanalytical Issues in Measurement of Biochemical Bone Markers

Hubert W. Vesper, PhD


Lab Med. 2005;36(7):424-429. 

In This Article

Biochemical Bone Markers

Bone is a composite material made of approximately 70% mineral matter (mainly hydroxyapatite), 5% to 8% water and 22% to 25% organic matrix (mainly type I collagen). These components form a 3-dimensional network that provides mechanical integrity for locomotion and is associated in mineral homeostasis.[8] Throughout life, bone is constantly renewed with old bone being removed and new bone being formed. This bone remodeling process comprises of distinct stages in which bone resorption is followed by bone formation (Figure 1). Bone markers are products derived from the bone remodeling process. During this process, compounds are released either from bone or from the cells involved in the bone remodeling process (osteoblasts and osteoclasts, Figure 2). Depending on their involvement in the bone remodeling process, they are categorized into bone formation and resorption markers.

Bone remodeling cycle.[17]

Bone markers associated with bone formation and bone resorption.

A variety of bone markers have been described, and research is ongoing for new markers and assays.[9,10] Characteristics and biochemical properties of certain bone markers have been described and summarized elsewhere[10,11,12,13,14,15] and efforts have been made to standardize the nomenclature of these markers[16] ( Table 2 ). Currently available bone marker assays and assay characteristics are described by the Clinical and Laboratory Standards Institute in document C48-A.[17]

Bone resorption markers are degradation products of type I collagen, the collagen mainly found in bone, and the enzyme tartrate resistant acid phosphatase. For the collagen degradation products, assays have been developed to measure peptides from the crosslinking telopeptide region (C-telopeptides to helix [CTX] and N-telopeptides to helix [NTX]).[14,18] The compounds acting as crosslinks are formed during bone maturation. The 2 best-characterized collagen crosslinks are pyridinoline (PYD) and deoxypyridinoline (DPD).[19,20] Both compounds are used as markers for bone resorption, and methods have been developed to measure them in free, non peptide bound form or as total crosslinks after acidic hydrolysis.[20] Within the group of C-terminal telopeptides of type I collagen, peptides have been identified that underwent isomerisation and racemisation at the aspartyl residues. This isomerisation reaction is a time-dependent process, and accumulation of the resulting β-isomer is indicative for protein age. Assays, specific for this peptide, have been developed (β-CTx).[21,22,23,24] Tartrate-resistant acid phosphatase is produced by the osteoblasts during bone resorption, and the 5b isoform is a marker for bone resorption.

The group of bone formation markers comprises bone-specific alkaline phosphatase (boneALP) and peptides released from type I procollagen. Both procollagen peptides and boneALP are released from bone-forming cells. Immunoassays were developed towards the N- or C-terminal collagen propeptides (PINP, ICTP) as well as boneALP. Osteocalcin is the most abundant noncollagenous protein in the bone matrix. It is released by the osteoblast during bone formation and embedded into the bone matrix. Osteocalcin is normally considered a bone formation marker. However, because it is released during bone formation from bone-forming cells and during bone resorption from bone matrix, it reflects the overall turnover of bone and is considered a bone turnover marker. Assays have been developed to detect the intact protein and/or the main breakdown product called N-mid fragment.[25]


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