Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Human bone is continuously remodeled through a process of osteoclast-mediated bone formation and resorption. This process can be monitored by measuring serum and urine markers of bone formation and resorption. Approximately 90% of the organic matrix of bone is type I collagen, a helical protein that is cross-linked at the N- and C-terminal ends of the molecule. The amino acid sequences and orientation of the cross-linked alpha 2 N-telopeptide of type 1 collagen make it a specific marker of human bone resorption. N-terminal telopeptide (NTx) molecules are mobilized from bone by osteoclasts and subsequently excreted in the urine. Elevated levels of NTx indicate increased bone resorption.
Bone turnover markers are physiologically elevated during childhood, growth, and during fracture healing. The elevations in bone resorption markers and bone formation markers are typically balanced in these circumstances and of no diagnostic value. By contrast, abnormalities in the process of bone remodeling can result in changes in skeletal mass and shape. Many diseases, in particular hyperthyroidism, all forms of hyperparathyroidism, most forms of osteomalacia and rickets (even if not associated with hyperparathyroidism), hypercalcemia of malignancy, Paget disease, multiple myeloma, and bony metastases, as well as various congenital diseases of bone formation and remodeling can result in accelerated and unbalanced bone turnover. Unbalanced bone turnover, usually without increase in bone turnover, is also found in age-related and postmenopausal osteopenia and osteoporosis.
Disease-associated bone turnover abnormalities should normalize in response to effective therapeutic interventions, which can be monitored by measurement of serum and urine bone resorption and formation markers.
As an adjunct in the diagnosis of medical conditions associated with increased bone turnover
Monitoring effectiveness of antiresorptive therapy in patients treated for osteopenia, osteoporosis, Paget disease, or other metabolic bone disorders
Elevated levels of N-terminal telopeptide (NTx) indicate increased bone resorption.
Most patients with osteopenia or osteoporosis have low, but unbalanced, bone turnover, with bone resorption dominating over bone formation. While this may result in mild elevations in bone turnover markers in these patients, finding significantly elevated urine NTx levels is atypical. Therefore, if levels are substantially elevated above the young adult reference range (>1.5- to 2-fold), the likelihood of coexisting osteomalacia, or of an alternative diagnosis as described in the Clinical Information section, should be considered.
When alternative causes for elevated NTx have been excluded in an osteopenia/osteoporosis patient, the patient must be considered at increased risk for accelerated progression of osteopenia/osteoporosis.
A 30% or greater reduction in this resorption marker 3 to 6 months after initiation of therapy indicates a probably adequate therapeutic response.
The Negotiated Rulemaking Committee of HCFA also recommends:
"Because of significant specimen to specimen collagen crosslink physiologic variability (15%-20%), current recommendations for appropriate utilization include: 1 or 2 baseline assays from specified urine collections on separate days; followed by a repeat assay about 3 months after starting antiresorptive therapy; followed by a repeat assay in 12 months; thereafter not more than annually, if medically necessary."
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Very dilute specimens may not allow measurement of a urine creatinine level and, therefore, reporting of N-terminal telopeptide (NTx) values normalized to creatinine becomes impossible.
Inadvertent collection of urine for NTx measurements in a collection bottle that contains an acidic preservative results in substantial artifactual elevations of apparent NTx concentrations; such specimens are unacceptable and will be rejected.
Hemolysis and turbidity in samples may affect test results.
While the VITROS NTx test is used as an indicator of bone resorption, use of this test has not been established to predict development of osteoporosis or future fracture risk. A single NTx value cannot provide the rate of bone resorption as reported results do not contain a measure of time.
Use of this test has not been established in primary hyperparathyroidism or hyperthyroidism.
Biotin levels in urine remain elevated for up to 24 hours after oral or intravenous biotin administration.
For 24 hours before urine collection, patient should not take multivitamins or dietary supplements containing biotin or vitamin B7 that are commonly found in hair, skin, and nail supplements and multivitamins.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
All units are reported in nmol Bone Collagen Equivalents/mmol creatinine.
Adult (> or =18 years of age)
21-83 nmol BCE/mmol creatinine
Premenopausal: 17-94 nmol BCE/mmol creatinine
Postmenopausal: 26-124 nmol BCE/mmol creatinine
Tanner Stage I: 55-508 nmol BCE/mmol creatinine
Tanner Stage II: 21-423 nmol BCE/mmol creatinine
Tanner Stage III: 27-462 nmol BCE/mmol creatinine
Tanner Stage IV: <609 nmol BCE/mmol creatinine
Tanner Stage V: <240 nmol BCE/mmol creatinine
Tanner Stage I: 6-662 nmol BCE/mmol creatinine
Tanner Stage II: 193-514 nmol BCE/mmol creatinine
Tanner Stage III: 13-632 nmol BCE/mmol creatinine
Tanner Stage IV: <389 nmol BCE/mmol creatinine
Tanner Stage V: <132 nmol BCE/mmol creatinine
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Miller PD, Baran DT, Bilezikian JP, et al: Practical clinical application of biochemical markers of bone turnover: Consensus of an expert panel. J Clin Densitom 1999;2(3):323-342
2. Delmas PD, Eastell R, Garnero P, et al: The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000;11(6):S2-S17
3. Mora S, Prinster C, Proverbio MC, et al: Urinary markers of bone turnover in healthy children and adolescents: age-related changes and effect of puberty. Calcif Tissue Int 1998;63:369-374