N-Terminal Telopeptide 

N-Terminal Telopeptide 

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The biomarker N-terminal telopeptide (NTX) detected in urine, is reported in nmol of bone collagen equivalents/mmol creatinine. Therefore, detectable levels of creatinine in urine are needed to report normalized levels of NTX. [1]

In males, the reference ranges are as follows: [2]

Birth through age 5 years – 576-1763

Age 6-13 years – 307-1367

Age 14-17 years – 102-1048

Age 18 years or older – 21-66

For females, the reference range is as follows:

Birth to 5 years – 576-1763

Age 6-13 years – 307-1367

Age 14-17 years – 55-378

Age 18 years or older – 19-63

Elevated levels of NTX indicate increased bone turnover. Mild to moderate elevation in turnover markers characterize the unbalanced remodeling of osteoporosis while markedly elevated levels (>1.5–2 fold) may indicate the co-existence of alternative bone conditions like osteomalacia.

Elevated levels of NTX in osteoporosis/osteopenia patients without alternative causes suggest increased risk of accelerated progression of the disease. [3, 4]

NTX is also useful in assessing nonsurgical treatment response in patients with osteoporosis. A reduction of 50% or more in this level at 6 months of treatment indicates a satisfactory response to therapy. [5, 6]

NTX levels may vary spontaneously as much 30-50% for the same individual over 24 hours. Significant diurnal variations have been consistently reported, which is why 24-hour urine samples are preferred. A second-morning void or random collections of urine are acceptable as long as the measurement is repeated at least once to allow a more accurate estimation of the true average levels. [2]

Since urine creatinine levels are needed in order to report normalized levels of NTX, extremely diluted urine sample can make its determination impossible.

Collection details are as follows: [2]

Specimen type – 24-hour urine; second-morning voided or random specimen also acceptable

Container – Plastic, 10-mL urine tube (Do not use preservative.)

Specimen volume – 4 mL (minimum volume 2 mL)

Stability – 30 days frozen (preferred) or 5 days refrigerated (ambient sample not acceptable)

Refrigerate specimen after collection. Collection bottle with acidic preservatives (pH < 5) produce significant artifactual elevation of the NTX level, therefore these are unacceptable.

More than 90% of the protein in bone is composed of type 1 collagen. Degradation products that are derived from the enzymatic hydrolysis of type 1 collagen are therefore the most useful markers of bone resorption. Since the 1990s, multiple blood and urine markers have been used as surrogate markers of bone remodeling, but those peptides related to regions that cross-link with pyridinoline (PYD) have been proven to be the most sensitive and specific. The pyridinium compounds PYD and DPD, as well as hydroxypyridinium cross-link collagen, are among the more specific markers. These are formed during extracellular maturation of fibrillar collagens and are released when mature collagens degrade. Measurement of these markers does not depend on the degradation of newly synthesized collagens or dietary sources.

Several groups have developed tests based on specific antibodies that are raised against isolated collagen peptides that contain cross-links, as opposed to using the cross-links themselves.

These fragments detected by radioimmunoassay technique are available for C-telopeptide of type 1 collagen (CTX, CrossLaps) [7] and cross-linked N-terminal telopeptide (NTX) of type 1 collagen by enzyme-linked immunosorbent assay (ELISA) technique (NTX, Osteomark). [8] NTX assay uses a monoclonal antibody directed against a urinary pool of collagen cross-links that is derived from a patient with Paget disease.

Measurement of NTX levels can be useful in the following situations:

Assessment of antiresorptive therapy response in patients with osteoporosis, osteopenia, Paget disease, or other disorders

Assessment of therapy efficacy in patients who have increased bone turnover due to various conditions (eg, rickets, osteomalacia, hyperthyroidism)

Recommendations for assessing antiresorptive therapy efficacy in postmenopausal women using bone markers are summarized below.

For bone resorption, urine NTX, urine CTX, or serum CTX is used. To assess bone formation, bone-specific alkaline phosphatase or osteocalcin is used. In that setting, use either one marker or both one resorption and one formation marker.

Resorption markers should be obtained prior to treatment and 3 or 6 months after therapy initiation. Formation markers should be obtained prior to treatment and 6 months after the start of treatment.

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:

Bone resorption markers elevated more than +2 standard deviation/T score >2 above the premenopausal mean range is associated with approximately 2-fold increase in osteoporotic fracture risk. [9]

In selected patients whose clinical risk factors and none mineral density assessment are not sufficient to allow treatment decision, resorption markers can be used to assess fracture risk. [5]

A high level of bone turnover marker (T score >3) suggests other metabolic bone disease, including malignancy, in patients with osteoporosis. [9]

Normal values are reference values derived from the evaluation of healthy, premenopausal women aged 30-45 years.

Palacios S, Neyro JL, Ferrer J, et al. Reduction of urinary levels of N-telopeptide correlates with treatment compliance in women with postmenopausal osteoporosis receiving alendronate. Menopause. 2012 Jan. 19(1):67-74. [Medline].

Marquette General Health System. N-telopeptides urine. Available at http://www.mgh.org/lab/CATALOG/TESTS/5070.HTM. Accessed: 9/6/12.

Brown JP, Albert C, Nassar BA, Adachi JD, Cole D, Davison KS. Bone turnover markers in the management of postmenopausal osteoporosis. Clin Biochem. Jul 2009. 42(10-11):929-42. [Medline].

Bone HG, Downs RW Jr, Tucci JR, Harris ST, Weinstein RS, Licata AA, et al. Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab. Jan 1997. 82(1):265-74. [Medline].

Garnero P. Markers of bone turnover for the prediction of fracture risk. Osteoporos Int. 2000. 11 Suppl 6:S55-65.

Roy DK, O’Neill TW, Finn JD, Lunt M, Silman AJ,et al. Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int. Jan 2003. 14(1):19-26. [Medline].

Li M, Li Y, Deng W, Zhang Z, Deng Z, Hu Y, et al. Chinese bone turnover marker study: reference ranges for C-terminal telopeptide of type I collagen and procollagen I N-terminal Peptide by age and gender. PLoS One. 2014. 9(8):e103841. [Medline]. [Full Text].

Shin HJ, Lee HY, Cho HY, Park YJ, Moon HH, Lee SH, et al. Effects of new sports tennis type exercise on aerobic capacity, follicle stimulating hormone and N-terminal telopeptide in the postmenopausal women. J Exerc Rehabil. 2014 Apr. 10(2):89-91. [Medline]. [Full Text].

Bonde M, Fledelius C, Qvist P, Christiansen C. Coated-tube radioimmunoassay for C-telopeptides of type I collagen to assess bone resorption. Clin Chem. 1996 Oct. 42(10):1639-44. [Medline].

Garnero P, Borel O, Delmas PD. Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem. 2001 Apr. 47(4):694-702. [Medline].

Garnero P, Hausherr E, Chapuy MC, Marcelli C, Grandjean H, Muller C. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res. Oct 1996. 11(10):1531-8. [Medline].

Carlos Solano Loran, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Carlos Solano Loran, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

N-Terminal Telopeptide 

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