INTRODUCTION — In adults, bone is constantly being remodeled, first being torn down (bone resorption) and then being rebuilt (bone formation) [1,2]. The resorption and reformation of bone is important for repair of microfractures and to allow modification of structure in response to stress and other biomechanical forces. Bone formation is normally tightly coupled to bone resorption, so that bone mass does not change. Bone diseases occur when formation and resorption are uncoupled. (See "Normal skeletal development and regulation of bone formation and resorption".)
Changes in the rate of bone turnover are an important determinant of bone disease, and therefore, measurements that correlate with the rate of turnover provide important information in assessing patients with bone disease. In the past, the best way to measure bone turnover was to perform a bone biopsy after double-labeling with tetracycline [1,3]. This technique permits measurement of the rates of bone formation and bone resorption, and the fractions of bone surface at which active resorption and formation are ongoing. However, the complexity and expense of this procedure make it unsuitable for routine clinical practice.
As an alternative, several assays are currently available that measure bone turnover markers (BTMs) (table 1). These assays measure collagen breakdown products and other molecules released from osteoclasts and osteoblasts during the process of bone resorption and formation. Although the development of better assays has improved the ability of BTMs to reflect the rate of bone turnover, biologic and laboratory variability have confounded their widespread use in clinical practice.
This topic will review bone physiology and the measurement of BTMs. The clinical utility of BTMs is reviewed separately. (See "Use of biochemical markers of bone turnover in osteoporosis" and "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
BONE REMODELING — The steps involved in bone formation and resorption are described briefly here and in detail separately. (See "Normal skeletal development and regulation of bone formation and resorption".)
Bone resorption — Bone resorption is initiated by osteoclasts, which are derived from hematopoietic stem cells  and have acid phosphatase anchored to their cell membranes [2,5]. Although acid phosphatase activity is present in other tissues such as the prostate gland, the two forms of the enzyme can be distinguished by the insensitivity of osteoclastic acid phosphatase to inhibition by tartrate (tartrate-resistant acid phosphatase, TRAP).
The osteoclasts attach to the bone surface and secrete acid and hydrolytic enzymes that resorb bone, releasing bone minerals and fragments of collagen. Some of the collagen is completely digested to its smallest chemical units, resulting in formation of free pyridinoline and deoxypyridinoline residues that circulate in the blood and are excreted in the urine. Some, however, is incompletely digested, resulting in formation in pyridinoline crosslinks bound to fragments of the alpha-1 and alpha-2 chains; these peptide-bound crosslinks also circulate in the blood and are excreted in the urine [5-7].
Bone formation — Bone formation is initiated by osteoblasts, which synthesize type I collagen and other proteins, such as osteocalcin, that combine extracellularly to form osteoid, the organic substrate upon which mineralization occurs . The osteoblasts contain alkaline phosphatase anchored to their cell membranes. This alkaline phosphatase is functionally similar to but antigenically distinct from hepatic and placental alkaline phosphatases .
The synthesis of type I collagen in bone involves the intertwining of one alpha-2 and two alpha-1 polypeptide chains to form a helical structure known as procollagen, followed by cleavage of their amino-terminal and carboxy-terminal peptides to form tropocollagen (figure 1) . Tropocollagen is mainly helical; the nonhelical portions at the amino and carboxy terminals are known as the N-telopeptide and C-telopeptide regions, respectively.
The side chains of three hydroxylysine residues from different tropocollagen molecules condense to form a pyridinium ring, thereby forming the pyridinoline crosslinks (PYD) that connect three different tropocollagen molecules [1,9]. A deoxypyridinoline (D-PYR) crosslink is a variant form of the pyridinoline crosslink that is formed when two hydroxylysine side chains condense with one lysine side chain . Pyridinoline crosslinks also occur in many types of collagen outside of bone except for collagen in skin [10,11].
There are three types of pyridinoline crosslinks that are characteristic of bone collagen (figure 2):
●D-PYR is present in substantial amounts only in bone and in dentin [10-12].
●N-telopeptide (NTX) is the pyridinoline crosslink in the N-telopeptide region that joins alpha-1 chains to alpha-2 chains .
●C-telopeptide (CTX) is a fragment of the alpha-1 peptide with an isomerized bond between the aspartate and the glycine from the C-telopeptide region .
MARKERS OF BONE TURNOVER — Urinary N-telopeptide crosslink (NTX) and serum C-telopeptide crosslink (CTX) are widely regarded as the most clinically useful markers of bone resorption, while bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (PINP) are the most clinically useful markers of bone formation [14,15].
The normal process of bone resorption results in the liberation of bone mineral and osteoid (which is composed mostly of collagen). The latter is not completely digested to its amino acid constituents, but to peptides that can be measured in serum and urine (table 1). The total quantity of these peptides reflects the rate of bone resorption. Similarly, osteoid formation leads to the production of byproducts of collagen and other proteins as they mature and are rearranged to form osteoid. Some of these substances are released into the circulation. Thus, measurement of their serum concentrations can provide information about the rate of bone formation (table 1) [5,16].
The serum concentration of BSAP and osteocalcin reflect the cellular activity of osteoblasts [5,8,17,18]. The serum concentration of the carboxy-terminal and amino-terminal propeptides of type I procollagen (PICP and PINP, respectively) reflects changes in synthesis of new collagen. The PINP measurement appears to be more specific than PICP for synthesis of bone collagen .
Urinary and serum concentrations of collagen crosslinks reflect bone resorption but not dietary intake. As a result, these substances are better indicators of bone resorption than urinary calcium or hydroxyproline excretion . Furthermore, because deoxypyridinoline (D-PYR) and the peptide-bound alpha-1 to alpha-2 NTX and CTX are almost exclusively derived from collagen in bone, measurements of these substances are specific markers of bone resorption .
Assay variability — There are many different ways to measure these metabolites of collagen. Although the original assays for collagen crosslinks required high-performance liquid chromatography (HPLC), antibodies have been raised to various regions of the pyridinoline crosslinks, and these substances can now be measured in serum or urine by immunoassays [6,21-27]. Serum assays tend to have less intraindividual variability than urine assays (10 versus 20 percent) [1,28].
Assay variability and poor standardization have limited the use of bone turnover markers (BTMs) in clinical practice . However, several immunoassays have been automated, which improves reproducibility. In addition, normative values for premenopausal women are more rigorously established [25,30].
Biologic variability — In addition to assay variability, there are a number of physiologic conditions that increase or decrease bone turnover and, therefore, alter BTMs (table 2). These factors must be considered when interpreting laboratory results [31,32]. As examples:
●There is a diurnal variation in bone turnover and a strong circadian rhythm to several indices of bone remodeling. The serum concentration or urinary excretion of most markers peaks around 6 AM and nadirs around 6 PM [33-36]. The only marker that is not influenced by diurnal variation is serum BSAP .
●Lower body mass index (BMI) and smoking are associated with higher bone turnover and, therefore, higher BTMs .
●BTMs are increased around the time of ovulation [38-40].
●Recent food consumption suppresses BTMs .
●Exercise and physical activity may be associated with decreased bone turnover (lower BTMs) .
●Bone remodeling is important for fracture healing. BTMs remain elevated for up to four months after fracture [43,44].
Practical aspects of measurement — Because bone turnover and BTMs follow a circadian rhythm and are altered by food intake, urine measurements of BTMs should be collected as second morning fasting samples, and serum samples should be collected in the morning after an overnight fast [45-47]. Because BTM results vary with different laboratories, patients should have all of their measurements performed in the same laboratory.
VALIDATION OF MARKERS OF BONE TURNOVER — As noted above, many substances are released from bone during the processes of resorption and formation. However, several criteria must be fulfilled for a particular measurement to have value as a marker of bone turnover (BTMs):
●The serum concentration or urinary excretion of the substance must be high in conditions characterized by high bone turnover, such as hyperparathyroidism, hyperthyroidism, and Paget disease of bone [1,49].
●The serum concentration or urinary excretion of the substance must be low in conditions characterized by low bone turnover, as occurs after the administration of antiresorptive drugs.
Correlation of markers with histomorphometry and calcium kinetics — Bone biopsies are expensive and invasive, and there are few studies correlating bone histology with BTMs. The correlations were adequate in the studies performed. In one report, as an example, the correlation coefficients between the results of histomorphometric measurements of bone resorption and urinary excretion of hydroxyproline, pyridinoline, and deoxypyridinoline (D-PYR) were 0.22, 0.77, and 0.80, respectively . In other studies, correlation coefficients between the results of histomorphometric measurements of bone formation and serum cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), serum carboxy-terminal propeptide of type 1 collagen (PICP), and serum osteocalcin were 0.61 , 0.77 , and 0.79 , respectively.
Studies of calcium kinetics are tedious and cumbersome but provide very accurate measurements of bone formation. In one study, as an example, most markers were very highly correlated (r = 0.9) with calcium accretion .
Elevation of markers in conditions characterized by increased bone turnover — The available BTMs are high in conditions characterized by increased bone turnover, but the extent of the elevations varies considerably.
●The values for most markers are high in patients with hyperthyroidism [23,53,54], hyperparathyroidism [53,55,56], and in postmenopausal women [17,53,57]; serum C-telopeptide crosslink (CTX) and urinary N-telopeptide crosslink (NTX) values tend to increase more at menopause than the pyridinolines [15,46,58].
●Most patients with Paget disease [59-61] or osseous metastases [62-67] have high values for most tests, but serum osteocalcin concentrations are often normal [61,62]. Urinary NTX excretion and serum BSAP and (amino-terminal propeptide of type I procollagen) PINP are the most sensitive indicators of turnover in patients with Paget disease [59,65,68,69]. (See "Treatment of Paget disease of bone", section on 'Monitoring'.)
Decline in markers after antiresorptive therapy — The serum concentrations or urinary excretion of most BTMs fall during antiresorptive therapy. The extent of the reduction, however, depends upon both the therapy and the marker. As an example, in postmenopausal women treated with bisphosphonates or menopausal hormone therapy, urinary NTX decreased to a greater extent in the alendronate group compared with the hormone therapy group . However, BSAP decreased similarly in both groups, and the decrease in osteocalcin was greater in the hormone therapy group.
Several trials have shown an association between the decrease in BTMs after initiation of antiresorptive therapy and long-term antifracture efficacy. These trials are reviewed in detail elsewhere. (See "Use of biochemical markers of bone turnover in osteoporosis", section on 'Osteoporosis therapy'.)
SUMMARY AND RECOMMENDATIONS
●Measurement – BTMs are not widely used in clinical practice because of analytical and biological variability (table 2). When they are used in clinical practice, measurements should be made under standardized conditions using the same laboratory for a given patient. In addition, biological variability should be considered when interpreting BTM results. (See 'Markers of bone turnover' above.)
●Clinical utility – Urinary N-telopeptide crosslink (NTX) and serum C-telopeptide crosslink (CTX) are widely regarded as the most clinically useful markers of bone resorption, while bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (PINP) are the most clinically useful markers of bone formation. (See 'Markers of bone turnover' above.)
The clinical utility of BTMs in monitoring the response to osteoporosis therapy is reviewed separately. (See "Use of biochemical markers of bone turnover in osteoporosis".)
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