Chapter 101Bone Biomarkers

Bone is a complex tissue that undergoes change throughout life by the processes of bone formation by osteoblasts and bone resorption by osteoclasts.¹ Modeling and subsequent remodeling of bone are required for bone health and allow the skeleton to respond rapidly to changes in its internal and external environment. Bone formation and resorption of bone are “coupled”²; the cycle of remodeling begins with the recruitment of osteoclasts, which attach to the bone surface and resorb the subjacent bone matrix. After osteoclasts evacuate a resorption pit, osteoblasts differentiate from mesenchymal precursors and fill in the lacuna with new bone matrix.³ In a healthy adult skeleton, formation and resorption are balanced. However, the balance is changed during growth, in response to altered exercise, by hormonal changes, during ageing, after therapeutic intervention, in metabolic bone disease, in neoplasia, and in response to injuries such as stress fractures.^4-6 Changes in subchondral bone metabolism are also potentially important in the pathogenesis of osteoarthritis (OA).^7,8 A challenge is to develop sensitive and specific noninvasive methods to detect changes in bone turnover in vivo. Abbreviations used in this chapter are summarized in Box 101-1.

Changes in bone mass and structure are assessed using techniques such as quantitative ultrasound (QUS), dual energy x-ray absorbiometry (DEXA), and quantitative computed tomography (QCT).^9-11 However, it may take several months for changes in bone mass and architecture to be of a sufficient magnitude to be detected with these methods. Furthermore, QCT and DEXA are not straightforward to use in a conscious horse, and use is restricted to ex vivo or in vivo research studies. Magnetic resonance imaging (MRI) is being used increasingly to study bone pathology in people,¹² but in a standing horse it can be used only for the distal aspect of the limb. It is expensive and not appropriate for screening potentially at-risk populations. In contrast, bone biomarkers measure dynamic changes in bone cell activity and can be measured in body fluids using relatively inexpensive straightforward methods. Biomarker measurements can be repeated at frequent intervals and so are convenient to use in the field. Although bone biomarkers remain predominantly research tools, considerable investigation has been undertaken on potential clinical applications. Soon it is highly likely that selected biomarkers will be used in conjunction with other tools to identify at-risk horses.^13,14

Ideally, a biomarker should be measurable in body fluids by a sensitive and specific technique and be specific to its tissue of origin. Detailed molecular characterization of bone has led to the development of biomarkers with increased specificity. Progress in equine bone biomarker research has been led by work in people—in particular, use of biomarkers to detect osteoporosis.^15-17 There are a number of equine-specific assays, but most assays in use were originally developed for people.

Bone biomarkers are generally classified as markers of bone formation or markers of bone resorption or degradation, although some reflect changes in both processes (Tables 101-1 and 101-2). In general, bone biomarkers are enzymes expressed by osteoblasts or osteoclasts or organic components released during the synthesis and resorption of bone matrix.^15-17 However, many bone biomarkers are present in tissues other than bone and may therefore be influenced by other physiological processes. Because each biomarker may reflect a different physiological process, it is preferable to assay for a combination of markers, as this will provide more information on bone (re)modeling. However, human studies have shown that in certain diseases individual markers give more useful information than others,¹⁵ and the same may be true in horses. Other criteria that determine the value of any biochemical marker are whether the factors that control its synthesis and metabolic pathway are understood and what factors influence its biological variability. For many biomarkers used in human clinical studies, surprisingly little is known about the regulation of synthesis and metabolism, and in horses even less is understood about these variables.

TABLE 101-1 Bone Formation Biomarkers

TABLE 101-2 Bone Resorption Biomarkers

Biomarkers That Measure Changes in Bone Resorption

The majority of bone biomarkers that reflect osteoclastic resorption of bone matrix are degradation products of type I collagen (see Table 101-2). Originally, collagen-related resorption biomarkers were measured in urine samples collected over a 24-hour period, but in practice this is difficult in the horse. More recently developed resorption markers can be measured in serum and synovial fluid.

Cross-Linked Collagen Telopeptides

Cross-links are located at the amino (N-) and carboxy (C-) termini in the type I collagen molecule, and a number of peptide assays have been developed for measuring telopeptides generated during osteoclastic resorption. The first of these was a RIA for the carboxy-terminal telopeptide of type I collagen (ICTP), which works well for serum of the horse. Because the enzyme cathepsin K cleaves the telopeptide, the assay is now abbreviated to CTX-MMP.¹⁶

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