Description
Degradation products derived from the enzymatic hydrolysis of type 1 collagen, particularly peptides related to regions of cross-linking with PYD, are the best markers of bone resorption. Released collagen fragments are responsible for many bone markers, since more than 90% of protein in bone consists of collagen type 1.
Although urinary hydroxyproline was previously one of the primary bone resorption markers used, specificity and sensitivity were lacking in this assay. A component of bone collagen, hydroxyproline is released into the serum during degradation of bone, reaching the urine in free and bound forms. However, because it is derived from the degradation of newly synthesized collagens, from collagens of nonbone tissues, and from diet, serum hydroxyproline is now considered to be a nonspecific marker of bone turnover. Urinary hydroxyproline has consequently been replaced by more specific techniques.
The pyridinium compounds PYD and DPD, as well as hydroxypyridinium cross-links collagen, are among the more specific markers. Formed during the extracellular maturation of fibrillar collagens, PYD and DPD are released when mature collagens degrade. PYD and DPD measurement values do not change in association with the degradation of newly synthesized collagens and are not influenced by dietary sources.
Testing can also be performed without directly using cross-links as markers. Assays have been developed based on specific antibodies raised in an immune response against isolated collagen peptides containing cross-links. Detected by radioimmunoassay technique, fragments exist for C-telopeptide of type 1 collagen (CTX, CrossLaps) and cross-linked N-terminal telopeptide of type 1 collagen by ELISA technique (NTX, Osteomark). [2]
The NTX assay employs a monoclonal antibody directed against a urinary pool of collagen cross-links (originating from a patient with Paget disease). Serum CrossLaps assay measures only β-isomer of CTX, while the urine CrossLaps assay measures α- and β-isomers of CTX. Urine from healthy individuals has produced a detectable reaction from these assays, and elevated turnover has produced large increases.
The 2 categories of C-telopeptide methods are C-telopeptide of type 1 collagen (CTX) and type 1 collagen cross-linked C-telopeptide (ICTP). They differ with regard to which segment domains they recognize in the C-terminal telopeptide region of the α1 chain of type 1 collagen and also differ in their response to bone metabolic processes.
CTX shows remarkable response to antiresorptive therapies, while serum ICTP is insensitive to osteoporosis and other normal metabolic bone processes. However, in bone pathologic conditions such as bone metastasis and rheumatoid arthritis, serum ICTP may be a marker of bone degradation. [3]
Indications/Applications
In addition to the traditional evaluation of bone mineral density, biochemical markers of bone resorption provide additional predictive information on a patient’s fracture risk. Preventive therapy with antiresorptive agents is warranted for patients with low BMD or high marker values, because they would be at risk for osteoporosis.
Although results of prospective studies assessing the relationship between the rate of bone loss and biochemical markers of bone turnover have been conflicting, the following guidelines apply to the use of bone markers in prediction of fragility fractures:
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Bone resorption markers elevated more than +2 SD/T score more than 2 above the premenopausal normal range is associated with approximately 2-fold increase in osteoporotic fracture risk.
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In selected patients whose clinical risk factors and BMD assessment are not sufficient to allow treatment decision, resorption markers can be used to assess fracture risk. [4]
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A high level of bone turnover marker (T score >3) is highly suggestive of alternative metabolic bone diseases, including malignancy, in patients with osteoporosis.
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Normal values are reference values derived from the evaluation of healthy, premenopausal women aged 30-45 years.
A study by Massera et al indicated that to a limited degree, C-telopeptide of type I collagen (CTX) levels positively correspond to the risk of hip fracture in postmenopausal women. Linear spline analysis demonstrated the association, but only for CTX levels up to the middle-upper range. Levels beyond this, however, corresponded to marginally nonsignificant risk reductions. [5]
See also the Fracture Index WITH known Bone Mineral Density (BMD) calculator.
The lists below summarize recommendations for monitoring antiresorptive treatment in postmenopausal women with osteoporosis, using bone markers.
Types of marker include the following:
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Bone resorption - Urine NTX, serum CTX, or urine CTX
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Bone formation - Bone-specific alkaline phosphatase or osteocalcin (use 1 marker or 1 resorption and 1 formation marker.)
Intervals of measurement include the following:
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Resorption markers - Prior to starting treatment and 3 or 6 months after treatment initiation
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Formation markers - Prior to starting treatment and 6 months after treatment initiation
Considerations
Reduced urinary excretion of beta-CTX and a consequent rise in the apparent serum beta-CTX concentration may result from reduced renal function.
In patients undergoing treatment with high doses of biotin (ie, >5 mg/day), a specimen should not be drawn until at least 8 hours after the biotin was last administered, to avoid assay interference from the biotin.
Erroneous results may be derived from any test containing monoclonal mouse antibodies in a patient who has been treated with monoclonal mouse antibodies or has received them for diagnostic purposes.
