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's 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.
1. An adjunct in the diagnosis of medical conditions associated with increased bone turnover
2. The differential diagnosis of osteomalacia versus osteoporosis
3. Identifying individuals with osteoporosis with elevated bone turnover and consequent increased risk for rapid disease progression
4. Prediction of bone densitometry response to antiresorptive therapy of osteoporosis
5. Monitoring and assessing effectiveness of therapy in patients treated for osteopenia, osteoporosis, Paget disease, or other disorders treated with antiresorptive therapy
6. An adjunct in monitoring response to other therapeutic intervention in diseases with increased bone turnover (eg, rickets, osteomalacia, hyperthyroidism)
Indications 3 through 5 have been endorsed by the Negotiated Rulemaking Committee of HCFA and are therefore federally reimbursed.
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 50% 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."
Patients with diseases such as hyperthyroidism, which can be cured, should have a return of bone NTx levels to the reference range within 3 to 6 months after complete cure.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The intraindividual coefficient of variation of urine N-terminal telopeptide (NTx) measurements is approximately 30%. Part of this variation is due to diurnal fluctuations, and a 24-hour collection is preferred. However, a second-morning void and other random collections are acceptable. In the latter case, it is recommended that the measurement is repeated at least once in order to allow a more accurate estimation of the true average bone turnover in a patient.
Very dilute specimens may not allow measurement of a urine creatinine level and, therefore, reporting of 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.
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.
<6 years: 576-1,763
6-13 years: 307-1,367
14-17 years: 102-1,048
> or =18 years: 21-66
<6 years: 576-1,763
6-13 years: 307-1,367
14-17 years: 55-378
> or =18 years: 19-63
Values are based on Mayo in-house studies of 75 children and adolescents age 3.5 to 18.5 and >100 adults.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Harper KD, Weber TJ: Secondary osteoporosis. Diagnostic considerations. Endocrinol Metab Clin North Am 1998;27:325-348
2. 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
3. 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
4. Harris SS, Soteriades E, Dawson-Hughes B, et al: Secondary hyperparathyroidism and bone turnover in elderly blacks and whites. J Clin Endocrinol Metab 2001 August;86(8):3801-3804