Biochemical markers of bone turnover

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Abstract

Background: Osteoporosis in many countries has reached epidemic proportions. This has stimulated the development of biochemical markers to assist in the assessment of osteoporotic risk and in monitoring the efficacy of treatment. Biochemical markers of bone turnover are products released from osteoblasts and osteoclasts or collagen breakdown products. Markers: Markers of bone formation include bone-specific alkaline phosphatase (BAP), osteocalcin (OC) and procollagen peptides. All of these can be measured easily by immunoassay techniques. Of these markers, OC has been extensively studied. However, OC undergoes in vitro degradation, thus, assay results are variable. BAP, on the other hand, is much more stable and shows less within-person biological variation. Bone resorption markers include tartrate-resistant acid phosphatase (TRAP) and collagen breakdown products, such as pyridinium cross-links, galactosyl hydroxylysine and cross-linked telopeptides, such as CTx and NTx. Of these, deoxypyridinium (DPD) has been extensively studied. DPD shows diurnal variation and the within-individual biological variation is large. Of the newer assays, NTx appear to show large differences at menopause. Conclusions: Thus, serum BAP and DPD or NTx are the current choice of bone markers.

Introduction

Bone, which is a metabolically active tissue, undergoes continuous remodelling, involving bone resorption and formation. In health, these two processes are tightly coupled through intricate mechanisms. Bone mass depends on the balance between resorption and formation. The cells responsible for resorption and formation are osteoclasts and osteoblasts, respectively. Numerous factors, systemic and local, regulate the function of these cells types.

Bone remodelling takes place on the surface of bone and in a typical remodelling cycle, resorption takes 7–10 days while formation takes 2–3 months. Cancellous bone makes up 20% of bone mass, accounts for 80% bone surface area and is, therefore, more metabolically active and undergoes more rapid remodelling. Every year, 25% of cancellous and 2–3% of compact bone undergoes remodelling.

Biochemical markers reflect the process involved in remodelling and are, therefore, useful in the management of metabolic bone diseases. Biochemical markers are noninvasive and can reveal acute changes in bone turnover. In order to be useful, an ideal biochemical marker of bone turnover should be specific for one of the metabolic processes in bone. Its mode of clearance, metabolism and plasma half-life should be known and it should be easily measurable and stable in serum or urine. No such ideal marker exists.

Section snippets

Biochemical markers of bone formation

Osteoblasts synthesize and secrete a number of proteins which can be measured in serum as markers of their activity and, therefore, of bone formation. The most commonly used markers of bone formation are alkaline phosphatase, osteocalcin and carboxy-terminal propeptide of type 1 procollagen (Table 1) [1], [2].

Acid phosphatase

Acid phosphatases are heterogeneous groups of enzymes. There are at least six isoforms. Two forms of acid phosphatases have been demonstrated in osteoclasts—a large isoenzyme, which is sensitive to tartrate, and a small 34-kDa isoenzyme, which is resistant to tartrate (tartrate-resistant acid phosphatase—TRACP EC 3.1.3.2). TRACP is encoded by a gene located on chromosome 19 [2], is present in large quantities in the ruffled border of osteoclasts and is released during bone resorption. TRACP is

Physiological factors affecting serum concentration and urinary excretion of bone markers

Some markers, such as OHP, are affected by diet, while others show a diurnal rhythm, such as OC PYD/DPD, NTx and CTx (Fig. 6) [37], [38], [39]. A diurnal rhythm for other markers of bone formation is less pronounced—probably because these markers have longer half-lives [40]. Serum OC is highest at 4 am and lowest at 5 pm with a 15% difference between the peak and trough values [21]. Urine excretion of DPD was 61% higher during the night than in the morning and correlated with nocturnal changes

Variability of biochemical markers

To be of value in the diagnosis and management of osteoporosis, biochemical markers should not show large variability within a person from month to month. Data available on the long-term within-person biological variation show that bone resorption markers vary more than formation markers. Serum assays are generally less variable than urine markers. (Table 2) Because of the biological variation, differences between two measurements have to vary by 54% for CTx and 108% for galactosyl

Potential uses of bone markers

Biochemical markers have only a minor role in the diagnosis of metabolic bone disease especially osteoporosis.

Conclusion

In conclusion, serum OC, bone AP and PICP are useful markers of bone formation and DPD and some of type 1 collagen breakdown products (NTx and CTx) are sensitive markers of bone resorption. The advantages and disadvantages of biochemical markers in the study of bone turnover are summarised in Table 3.

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