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Collagen N-Telopeptide Excretion in Men: The Effects of Age and Intrasubject Variability¹

Bone and Mineral Unit, Oregon Health Sciences University and Veterans Administration Medical Center (E.S.O.), Portland, Oregon 97201; Veterans Administration Medical Center and Medical University of South Carolina (N.H.B.), Charleston, South Carolina 29401; Veterans Administration Medical Center and Emory University (M.S.N.), Atlanta, Georgia 30033; and Ostex International, Inc. (K.A.F., M.B.P., N.J.S.M., D.F.C.), Seattle, Washington 98134

Address all correspondence and requests for reprints to: Eric S. Orwoll, M.D., Bone and Mineral Unit (CR113), Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201.

	Abstract

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Biochemical markers of bone resorption are useful for evaluating metabolic bone diseases. A three-center study was performed in 253 men, 21–86 yr of age, to determine the normal range of urinary N-telopeptide of type I collagen (NTX/creatinine) in a nonfasting, second void, morning specimen, to define the biological variability and to examine the relationship between NTX/creatinine and age. Men with disorders or taking medications known to alter bone turnover, or with a serum creatinine level greater than 2 mg/dL were excluded. Results are expressed as nanomoles of bone collagen equivalents (BCE) per mmol creatinine. In a subset of individuals over age 30 yr, additional second void morning urine specimens were obtained at 2, 3, and 4 days (short term study) and at 2, 3, and 4 months (long term study) after the first specimen. After collection, samples were shipped to one laboratory for analysis. Multiple samples from the same subject were analyzed in separate assays. It was found that urinary NTX/creatinine was significantly higher in 45 men, aged 21–30 yr, than in 206 men, aged 31–86 yr (48 ± 22 vs. 33 ± 15 nmol/L BCE/mmol/L creatinine; P < 0.00001). Values did not otherwise change with age. The range of values in men aged 21–30 yr was 4–92 nmol/L BCE/mmol/L creatinine. The range for men over age 30 yr was 3–63 nmol/L BCE/mmol/L creatinine, essentially the same as that previously reported for premenopausal women. The coefficient of variation was determined in each individual for the short term (n = 36) and long term studies (n = 35) and averaged 18% and 19%, respectively. There was no correlation between short term and long term coefficient of variations. In summary, urinary NTX/creatinine is higher in men aged 21–30 yr than in men over age 30 yr and may reflect continued skeletal maturation. Intrasubject variability of urinary NTX/creatinine in short term and long term studies has been defined for clinical purposes.

	Introduction

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BIOCHEMICAL markers of bone remodeling provide information important for the management of metabolic bone disease. Urinary cross-linked N-telopeptide of type I bone collagen (NTX) is a marker of osteoclast work and has been used to indicate the level of bone resorption, predict skeletal response to hormonal antiresorptive therapy in postmenopausal women (1, 2), and monitor the effect of antiresorptive therapy in individuals with osteoporosis (3) and Paget’s disease of bone (4). Recently, it was proposed that the levels of NTX/creatinine excretion may predict current bone mineral density and subsequent risk for fracture (5, 6, 7).

Until recently, osteoporosis in men has been ignored as a public health concern. The incidence of fracture in men is less than that in women, but approximately 20–30% of all hip fractures in the United States occur in men, and it is estimated that 20% of the total health care expenditure for osteoporosis is a result of fractures in men (8). As in women, osteoporosis in men is primarily a disorder of the elderly, with the highest incidence of osteoporotic fractures occurring after age 70 yr. Whereas the etiology of osteoporotic fractures in men is certainly complex, the decline in bone mass that occurs in aging men is considered to be an important contributing factor (9, 10, 11, 12). There are few histomorphometric data concerning changes in remodeling with aging in men, and the few available studies concerning age-related changes in biochemical indexes of remodeling in men are inconsistent. Wishart et al. have shown that there appears to be a decline in markers of bone turnover with age (13). This relationship, however, was not linear, and the pattern of overall decrease was not consistent for the markers tested (serum bone alkaline phosphatase and osteocalcin for formation and urinary hydroxyproline, pyridinoline, and deoxypyridinoline for resorption). There did, however, appear to be a relative decrease in markers of bone formation compared to those of bone resorption. In contrast, Orwoll and Deftos found a gradual increase in serum midregion osteocalcin values with increasing age in normal men (14), whereas Resch et al. (15) reported that serum alkaline phosphatase and osteocalcin values remained unchanged with aging, perhaps suggesting no link between bone turnover, at least in terms of formation, and age. The inconsistency in these reports is contrary to studies of biochemical indices of bone turnover in women, which have shown a dramatic increase at the menopause (16, 17, 18).

This study was designed to expand the understanding of the relationship between NTX/creatinine excretion and age in men. To further lay the groundwork for the use of NTX/creatinine excretion in clinical disorders, we have also established the expected range for urinary NTX/creatinine values in healthy adult men and determined the short term and long term variabilities in urinary NTX/creatinine in the male population.

	Subjects and Methods

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For this study 253 men were recruited from 3 sites in the United States. The protocol was reviewed and approved by local institutional review boards, and informed consent was obtained from each subject before enrollment. Recruitment, limited to healthy adult men, was targeted to include an equal number of participants per decade for age groups 21–80+ yr. Volunteers with medical disorders known to be associated with metabolic bone disease, such as hyperparathyroidism, recent fracture, prolonged immobilization, malabsorption or gastrectomy, hypogonadism, and history of nondermatological malignancy, were excluded. In addition, subjects taking medications that affect bone metabolism or urinary creatinine excretion were excluded. Only subjects with serum creatinine levels less than 2.0 mg/dL were included. Demographic information, such as race, height, and weight, and self-reported smoking history, family history of osteoporosis, current medications, alcohol and caffeine consumption (number of drinks per day), and exercise (rarely, occasionally, and regularly), was obtained to determine their effects on NTX/creatinine excretion and its variability. Nonfasting, second void morning urine specimens (SMV) and serum were collected from each participant and tested by a commercial reference laboratory.

Urinary NTX was measured by an enzyme-linked immunosorbent assay that uses a specific monoclonal antibody directed against the N-telopeptide intermolecular cross-linking domain of type I collagen of bone (Osteomark, Ostex International, Inc., Seattle, WA). Urinary values are calculated from a standard curve of known NTX concentrations and expressed as bone collagen equivalents (BCE). Samples were determined in duplicate, and the final value was the mean of the duplicates. The assay values were then corrected for dilution by analysis of urinary creatinine and expressed as nanomoles per L BCE/millimoles per L creatinine (18, 19). The lower limit of detection for NTX (before creatinine correction) is 20 nmol/L BCE, with inter- and intraassay coefficients of variation of 4.0% and 7.6%, respectively (19). In this evaluation, two men had urinary NTX values less than the lower limit of detection and were therefore excluded from all analyses.

A subset of subjects at two of the three sites provided additional specimens to assess the short term and long term within-subject variability in NTX/creatinine excretion. In addition to the baseline SMV used to establish the reference range, an SMV was collected from these subjects for 3 more consecutive days (short term) and at three consecutive monthly intervals (long term). To reproduce standard clinical testing procedures for sequential collection and analysis of samples and to include intraassay variability, these specimens were analyzed soon after collection and were not stored frozen for later measurement in the same assay.

Statistical methods

For comparing NTX/creatinine values by categorical data, a Wilcoxon rank-sum or Kruskal-Wallis rank test was used. ² or Fisher’s exact test was used to test for an association between two categorical variables. Spearman rank correlation coefficients were computed to determine the degree of association between two continuous parameters. Partial correlation coefficients were calculated to take into account the effect of a third variable. Linear regression models allowed for examination of the association between two continuous variables while adjusting for possibly confounding factors. The relationship between age and urinary NTX/creatinine was analyzed with a split point regression model that allows for the slope of the regression line to change at a specified point. This model is expressed as follows: yi = ß₀ + ß₁x_i1 + ß₂ (x_i1 - 30) x_i2 + _i, where y_i is NTX/creatinine, x_i1 is age, and x_i2 = 1 if age is 30 or less and 0 otherwise. ß₁ and (ß₁ + ß₂) are the slopes of the two regression lines, and ß₀ and (ß₀-30ß₂) are the two y-intercepts.

The 90th percentiles were chosen as cut-off values for defining excessive alcohol and caffeine intake. Individual measures of within-subject variability were reported as coefficients of variation (CVs; SD x 100/mean). Data are presented as the mean ± SD. All P values are two-sided; P < 0.05 was considered to indicate statistical significance. All analyses were performed with the Statistical Analysis System (SAS Institute, Inc., Cary, NC).

	Results

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Demographic characteristics of the 251 study participants are presented in Table 1. Small, but significant, differences in mean age, race, smoking status, and daily alcohol intake existed among the clinical sites. However, the distribution of urinary NTX/creatinine values did not differ by site (P = 0.81), and no significant differences in the distribution of urinary NTX/creatinine values were found when compared by race, family history of osteoporosis, smoking status, exercise level, or caffeine intake. Because no ethnic differences in NTX/creatinine excretion were identified, the subjects were combined for subsequent analyses. Men with the highest level of alcohol consumption, as defined by the 90th percentile (>2 drinks/day), had significantly lower mean urinary NTX/creatinine values than men who drank less often (25 ± 7 vs. 36 ± 18 nmol/L BCE/mmol/L creatinine; P = 0.02). This relationship between urinary NTX/creatinine and alcohol consumption was no longer statistically significant after adjustment for age and site. The correlation coefficient between urinary NTX/creatinine and BMI was -0.29 (P = 0.0001); the partial correlation coefficient was -0.30 (P = 0.0001) when the age of the study participants was taken into account. The correlation between urinary creatinine concentration and BMI was not significant (r = 0.02; P = 0.77). The relationship between age and NTX/creatinine excretion was not altered when BMI was included in the model.

View larger version (16K): [in this window] [in a new window]   Figure 1. Urinary NTX/creatinine in normal men by age. Individual subject values are plotted as a function of age. Thesolid line is fit to the data using a cubic spline method.

The mean ± SD urinary NTX/creatinine in men aged 21–30 yr (n = 45) was 48 ± 22 nmol/L BCE/mmol/L creatinine, with a range of 4–92. Similarly, the mean urinary NTX/creatinine in men greater than age 30 yr (n = 206) was 33 ± 15 nmol/L BCE/mmol/L creatinine, resulting in a reference range of 3–63 nmol/L BCE/mmol/L creatinine. The reference range computed from log-transformed urinary NTX/creatinine values is 13–78 nmol/L BCE/mmol/L creatinine.

A subset of 37 men greater than age 30 yr participated in the variability study. Of this subset, 36 had complete data for the short term analysis of variability, and 35 had complete data for the long term analysis of variability. Their ages ranged from 33–86 yr, with a mean of 62.5 yr. For each subject, a CV was computed for both short term and long term urinary NTX/creatinine values. The mean CV for short term values was 18%, and that for long term values was 19% (Table 2). The mean baseline urinary NTX/creatinine in this subset was significantly lower than the mean urinary NTX/creatinine of the remaining 214 men (28 ± 13 vs. 38 ± 19 nmol/L BCE/mmol/L creatinine; P = 0.001). In addition to the average CV, the CV computed using the mean square method revealed a short term CV of 20% and a long term CV of 21%. No significant correlation was found between the baseline urinary NTX/creatinine and the short and long term CVs, and the mean CV did not differ by tertile of baseline urinary NTX/creatinine in either the short term or long term studies. To illustrate the precision of urinary NTX/creatinine values over time, data for all participating subjects are plotted in Figs. 2 and 3 (short term and long term variabilities, respectively), where each point represents a urinary NTX/creatinine value for that time point.

View larger version (33K): [in this window] [in a new window]   Figure 2. Evaluation of short term urinary NTX/creatinine in men. Individual subject values are plotted by time of specimen collection. Solid lines connect each subject’s values over the 4-day study.

View larger version (34K): [in this window] [in a new window]   Figure 3. Evaluation of long term urinary NTX/creatinine in men. Individual subject values are plotted by time of specimen collection. Solid lines connect each subject’s values over the 4-month study.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this population of normal men, urinary NTX excretion remained stable after age 30 yr. There was a tendency for excretion to be higher in the oldest subjects (>80 yr), but that trend did not reach significance, probably because of the limited number of older men studied. Although the number of studies is limited, several other reports describe similar findings. Schneider et al. (5) as well as Wishart et al. (13) reported that markers of bone resorption were stable in adult men until old age, when there was a trend toward increasing values for urinary NTX/creatinine and pyridinoline, respectively. Gallagher et al. (20) studied only men in the older age groups (65 yr) and reported an age-related increase in urinary NTX/creatinine excretion, a finding consistent with the trends noted above. Contrary to these data, Delmas et al. (21) noted a gradual increase in urinary free pyridinoline excretion with age in men between 30–90 yr of age. The findings reported here (as well as those of most of the other studies discussed above) are based on the NTX/creatinine ratio, and because creatinine excretion may change with age in parallel with a decline in lean body mass, the relationships we noted with age would be more confidently defined with 24-h urine specimens that could be used to assess total urinary NTX and creatinine outputs.

Our finding that mean urinary NTX/creatinine excretion was considerably higher in 20- to 30-yr-old men is interesting and useful. Wishart reported similar findings using a panel of 6 indexes of resorption and formation. It is well documented that biochemical indexes of remodeling are high during childhood and adolescence (18, 22), but it has not been appreciated that this skeletal phase may extend into the third decade (23, 24). Some investigators have reported a slower but persistent increase in bone mass into the third decade, and elevated urinary NTX/creatinine excretion supports the contention that accelerated remodeling activity continues in this period. From a clinical perspective, it is important to recognize that high urinary NTX/creatinine excretion should be expected in male patients until age 30 yr.

It is interesting to note that the range of urinary NTX/creatinine values seen in this normal male population is virtually identical to that seen in premenopausal women (16, 19, 25). In women, the decline in bone mass after the menopause is considered to be due in part to an absolute increase in bone resorption. Urinary NTX/creatinine values increase with the decline in estrogen production at the time of menopause and remain elevated thereafter. Studies have shown that bone mass also declines with age in men (26), and the lack of increase in urinary NTX/creatinine seen in this study suggests that the decrease in bone density is not attributable to major changes in bone resorption. It has been suggested that a reduction in bone formation may be the hallmark of bone loss in men (13), and these results are not inconsistent with that hypothesis. Because the subjects studied here were healthy, our observations may not be true in an unselected population of men.

For a metabolic marker such as urinary NTX/creatinine to be useful clinically, there must be a clear understanding of its analytical and its inherent biological variability. In urinary NTX/creatinine, the reported analytical variability is 8% (19). An evaluation of both short term and long term intrasubject variability in this study indicates that the day to day and month to month CV is 18–19%, respectively. This measure of variability includes the analytical CV because samples from the same individual were measured separately and not necessarily in the same assay. This variability is consistent with similar studies conducted with postmenopausal women (27). It is also comparable to the variability seen in other quantitative urine laboratory tests, such as free pyridinoline/creatinine ratio (12.9% and 16.3%) (28, 29), urinary hydroxyproline/creatinine ratio (18.7% CV), and urinary calcium/creatinine ratio (43.6% CV), as well as serum assays such as prostate-specific antigen (18.1% CV), cortisol (15.2% CV), and cholesterol (8.2% CV) (30). No association between age, lifestyle factors, or baseline urinary NTX/creatinine and either short term or long term urinary NTX/creatinine was observed.

To examine the clinical utility in individual patients, the least significant change was calculated (31). With this method, to achieve a 90% confidence level that the decrease between two sequential measurements is clinically relevant and not due to variability alone, decreases of 32% and 35% in the short and long term studies, respectively, were required. This is consistent with the degrees of change found in previous studies in men evaluating therapeutic outcome with hormone treatment of osteoporosis (32) and bisphosphonate treatment of Paget’s disease of bone (4).

In summary, we found mean urinary NTX/creatinine values to be stable in men after age 30 yr, at least until age 80 yr. In men aged 20–30 yr, values are higher (by 31%) than at subsequent ages. The range of urinary NTX/creatinine values seen in this study for men greater than age 30 yr was 33.0 ± 15.4 (mean ± SD). Short term (4 consecutive days) intrasubject variability was 18% CV, and long term (3 consecutive months) intrasubject variability was 19% CV. This information is essential for the interpretation of urinary NTX/creatinine values in the clinical evaluation and management of bone disease in men.

	Acknowledgments

 
The authors thank Virginia Chambers, Sandra Veith, Judith Shary, April Hamilton, and Farrukh Iqbal, M.D., for their assistance in conducting this study.

	Footnotes

 
¹ This work was supported by USPHS Grants 5-MO1-RR-00334 (Oregon Health Sciences University) and 5-MO1-RR-01770 (Medical University of South Carolina), V.A. Merit Review funds (Atlanta, GA), and Ostex International, Inc. (Seattle, WA).

Received April 27, 1998.

Revised July 14, 1998.

Accepted July 29, 1998.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Orwoll, E. S. Articles by Cain, D. F. Search for Related Content PubMed PubMed Citation Articles by Orwoll, E. S. Articles by Cain, D. F.