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PEDIATRICS Vol. 110 No. 1 July 2002, pp. 105-109

Urinary Excretion of Cross-Linked N-Telopeptides of Type 1 Collagen to Assess Bone Resorption in Infants From Birth to 1 Year of Age

Alexandre Lapillonne, MD, PhD*,{ddagger},§, Rose Travers||, Massimo DiMaio, MD*, Bernard L. Salle, MD*,{ddagger} and Francis H. Glorieux, MD, PhD||

* Department of Neonatology
{ddagger} Human Nutrition Research Center
§ INSERM U 403, Hôpital Edouard Herriot, Lyon, France
|| Genetics Unit, Shriners Hospital for Children, and McGill University, Montreal, Quebec, Canada


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objectives. To evaluate noninvasively bone resorption in infants and more specifically, to assess the accuracy of urinary collagen type 1 cross-linked N-telopeptide (NTX) excretion normalized to creatinine (NTX/Cr) in a spot urine sample as a reflection of daily NTX production in infants and to compute normative values for NTX excretion from birth to 1 year of age.

Methods. NTX/Cr values obtained from a single spot urine sample were compared with daily urinary NTX excretion and NTX/Cr obtained in 24-hour urine collected from 8 hospitalized infants. Normative values for NTX excretion were collated with a cross-sectional study in 70 healthy French infants (42 boys, 28 girls) aged 0 to 374 days (weight: 2700–11 340 g; length: 46–76.5 cm) and free of diseases or treatments that could influence growth, bone mineralization, or renal function.

Results. NTX/Cr values from single spot urine sample were significantly and linearly correlated with both daily NTX excretion (r = 0.783) and daily NTX/Cr (r = 0.952). In healthy infants, NTX excretion is low at birth, increases dramatically and significantly during the first 10 days of life, remains significantly elevated for approximately 3 months, and then decreases progressively to return to values similar to that observed at birth by 1 year of age.

Conclusions. These data provide new insights regarding the use of spot urine analysis for assessing NTX excretion during the first year of life. The normative data demonstrate significant age-related variations in this marker, which probably reflect adaptation to extrauterine life and accelerated bone turnover in infancy and which should be considered for the interpretation of this noninvasive bone resorption marker in the clinical setting.

Key Words: newborns • bone turnover • biochemical marker • bone remodeling • type 1 collagen

Abbreviations: NTX, cross-linked N-telopeptides of type 1 collagen • NTX/Cr, NTX to creatinine ratio • BCE, bone collagen equivalents • SD, standard deviation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human bone is continuously remodeled through a coupled process of bone resorption by osteoclasts followed by bone formation by osteoblasts. This process is necessary for normal development and bone growth as well as skeletal integrity. Measurement of specific degradation products of bone matrix allows analysis of the rate of bone remodeling. Approximately 90% of the bone organic matrix is made of type 1 collagen. This helical protein is stabilized by cross-links at its N-terminal and C-terminal ends and forms the basic fabric of bone tissue. Hydroxylysylpyridinoline and lysylpyridinoline are the predominant cross-linking amino acids of bone collagen. Total pyridinoline cross-links are excreted in free and peptide-bound forms in the urine, where they can be assessed by high-performance liquid chromatography techniques as indices of bone resorption.1

Rapid progress is being made in the development of easily performed and reliable assays for bone markers.2 The identification of urinary collagen type 1 cross-linked N-telopeptides (NTX) has provided a specific biochemical marker of bone resorption.3 The NTX molecule is, indeed, specific to bone as a result of the unique amino acid sequence and orientation of the cross-linked {alpha}-2 (I) N-telopeptide. The NTX peptide is a direct product of osteoclastic proteolysis and is found in the urine as a stable end product of degradation.1 The quantification of NTX in urine, therefore, has been proposed as a marker of bone resorption. It is easily and rapidly assessed by a convenient immunoassay that requires only a single spot urine sample; the results, therefore, are expressed normalized to creatinine.

This marker has been widely used in adults and provides probably one of the most responsive and specific indicators of the bone resorption process of all currently known markers.4–8 However, only a few studies have been conducted in children and infants. Particularly, the accuracy of spot urine analysis as a reflection of daily NTX excretion rate in infants has not been studied, and precise normative data during the first year of life are not available. We therefore undertook a validation study to assess the accuracy and day-to-day variation of spot urine NTX to creatinine ratio (NTX/Cr) in the evaluation of bone resorption in infants and a cross-sectional study in healthy infants to compute normative values for NTX excretion from birth to 1 year of age.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Accuracy and Day-to-Day Variation of Spot Urine NTX/Cr Measurements
To assess the accuracy of NTX/Cr in a spot urine sample as a reflection of total NTX production, we compared NTX/Cr values obtained from a single spot urine sample with daily urinary NTX excretion and NTX/Cr obtained in 24-hour urine collection. Therefore, 24-hour urine samples were collected from 8 hospitalized infants (weight: 1010–3500 g; postnatal age: 2–46 days) by using adhesive bags. All infants were in stable condition and were free of pulmonary, renal, and metabolic diseases. The 24-hour collection was immediately followed by the collection of the first void after the 24-hour collection (spot specimen).

To assess the day-to-day variation of spot NTX/Cr measurements, we collected a spot urine sample on each of 5 consecutive days in 10 hospitalized infants (weight: 1060–5240 g) who were free of any pulmonary, renal, or metabolic disease. The urine collection was performed between day 0 and day 10 of life for 4 patients to assess the magnitude of the change in NTX excretion during this period. The urine collection was performed between days 30 and 50 of life for 6 patients to assess the intra-individual coefficient of variation as a reflection of the reproducibility of the method.

Healthy Infants: Cross-Sectional Study
Spot urine samples from healthy infants were obtained to gather reference values during the first year of life. Over 1 year, infants who attended the Edouard Herriot Hospital for a routine health examination were evaluated for participating in this study. The study population consisted of 70 healthy infants (42 boys, 28 girls) aged 0 to 374 days (weight: 2700–11 340 g; length: 46–76.5 cm). All were born appropriate for gestational age after an uneventful pregnancy; had normal growth parameters; were free of diseases that could influence growth, mineralization, or renal function; and did not receive treatments that might affect bone metabolism (diuretics or steroids). No infants were studied sequentially. For all subjects, gender, age, weight, diet, vitamin D intake, and pathology were recorded. Two thirds of the infants aged 0 to 30 days of life were breastfed at time of study; all the infants aged 1 to 4 months were formula fed. After 4 months of age, all infants were fed a diet that met the criteria recommended for the French population;9 they were fed at least 0.5 L/d follow-up milk, and solids were added to the diet progressively between 4 and 6 months of age; all infants received an oral supplement of 800 to 1000 IU/d vitamin D.

Collection of Urine Samples and Assessment of NTX
All parents were informed of the details of the study, and informed consent was obtained in all cases. Spot urine samples were collected between 8:00 and 11:00 AM as bag catch and underwent standard urine analysis to avoid samples with detectable levels of blood, protein, nitrite, or leukocytes. Samples were stored at –20°C without preservatives until analysis.

Levels of NTX were assessed using a specific competitive-inhibition enzyme-linked immunosorbent assay (Osteomark; Ostex International Inc, Seattle, WA). Before analysis, we diluted samples appropriately to achieve concentrations within the calibration curve (1 in 2, 1 in 5, or 1 in 10). Creatinine concentration was measured by colorimetric assay (IL Monarch 2000, Lexington, MA). Results were expressed as nanomoles of bone collagen equivalents per day (nmol BCE/d) for the 24-hour urine collections and normalized to creatinine (nmol BCE/mmol Cr) for all other samples.

Statistical Analysis
Data are expressed as mean ± standard deviation (SD). Statistical comparisons between 2 groups were made by using unpaired Student’s t test, and intra-individual changes were assessed by paired t test. One-way analysis of variance was used for statistical comparisons among 3 or more groups, and the Tukey test was used for all pairwise comparisons of the mean values of the different groups. Correlation coefficients were determined by linear regression between continuous variables. Blind use of the data obtained from regression analysis has some limitations in clinical practice: a high correlation coefficient does not mean that the 2 methods agree in absolute terms. Therefore, we used the Bland and Altman method to compare spot NTX/Cr ratio with 24-hour NTX/Cr ratio.10 The relationship between urinary NTX levels and age was assessed using a polynomial procedure. P ≥ .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Accuracy and Day-to-Day Variation of Spot Urine NTX/Cr Measurements
Table 1 shows individual daily urine output, creatinine excretion, NTX excretion, and NTX/Cr as well as spot urine NTX/Cr of the infants from whom 24-hour urine samples were collected. Spot urine NTX/Cr was significantly and linearly correlated with 24-hour NTX excretion (r = 0.783; P = .013) and 24-hour NTX/Cr (r = 0.952; P < .0001). If 24-hour NTX/Cr ratio is considered as the reference method, then the accuracy of using a spot urine sample for assessing NTX excretion, instead of a 24-hour urine collection, seems to be excellent for the whole group of infants because the mean error between the 2 measurements, calculated according to the Bland and Altman method, is null (Table 1).


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  		TABLE 1. Comparison Between NTX Concentration Corrected for Creatinine in 24-Hour Urine Collection (24-h NTX/Cr) and That of a Spot Urine After the 24-Hour Urine Collection (Spot NTX/Cr) in 8 Infants

 
The NTX excretion of the 4 infants who underwent a urine collection for 5 consecutive days from 0 to 10 days of life exhibited a significant increase between the first and the fifth measurement (653 ± 306 vs 1192 ± 617 nmol BCE/mmol Cr, respectively; P < .05), illustrating the significant increase of this marker during this period. The NTX excretion values of the 6 infants who underwent a urine collection for 5 consecutive days between 30 and 50 days of age were used to assess the reproducibility of the method during a stable period. There was no significant difference between the first and the fifth measurements (2549 ± 594 vs 2873 ± 853 nmol BCE/mmol Cr, respectively) and the mean ± SD intra-individual coefficient of variation was 12 ± 9% (Table 2).


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  		TABLE 2. Reproducibility of NTX/Cr as Assessed by 5 Consecutive Days of Spot Urine Samples in 6 Infants

 
Age-Related Changes in Urinary NTX/Cr in Healthy Infants From Birth to 1 Year of Age
The mean ± SD NTX/Cr of the 70 infants was 2027 ± 999 nmol BCE/mmol Cr. For each 2-month period, there was no significant difference between boys and girls. Individual values of NTX/Cr are reported in Fig 1 as a function of age; a significant nonlinear relationship between age and NTX/Cr was found from birth to 1 year of age (r = 0.789, P = .0001). Significant changes of NTX/Cr were found over time (Fig 1, Table 3). The most rapid change in NTX/Cr ratio occurred during the first 10 days of life; meanwhile, a significant and linear increase occurred (r = 0.775, P = .001). NTX/Cr increased significantly from a mean value ± SD of 693 ± 286 nmol BCE/mmol Cr during the first 2 days of life to a mean value of 2942 ± 623 nmol BCE/mmol Cr between 10 and 39 days of life (Table 3). NTX/Cr remained elevated for approximately 3 months and then decreased progressively over time to reach a mean value of 1179 ± 303 nmol BCE/mmol Cr after 200 days of life (Table 3). Except for the first 10 days of life during which dramatic changes occurred, the interindividual variation for each period of time varied from 18 to 35% (24.8 ± 5.8%).


Figure 1
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  		Fig 1. Individual values of urinary NTX/Cr in 70 healthy infants from birth to 1 year of age. A significant nonlinear relationship (polynomial, sixth degree) between age and NTX/Cr was found from birth to 1 year of age (y = – E – 10 x 6 + 3E – 07 x 5 – 0.0001 x 4 + 0.0284 x 3 – 3.1792 x 2 + 146.79 x + 777.51; r = 0.789, P = .0001). The solid line represents the relationship between NTX/Cr and postnatal age and was obtained by combining a polynomial relationship (from birth to day 175 of age) and a linear relationship (from day 130 of age and 1 year of age).

 

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  		TABLE 3. Concentration NTX/Cr in Spot Urine Samples of 70 Healthy Infants Aged 0 to 375 Days

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was designed primarily to evaluate the use of NTX excretion as a noninvasive marker of bone resorption in infants. Like most of the bone resorption markers, NTX are measured in urine. To calculate the total amount of bone that is being resorbed in an individual patient, a 24-hour urine collection would be necessary. It is difficult to obtain and verify 24-hour urine collections in infants; spot urine samples, therefore, are far more convenient and have been used in previous studies in term or preterm infants.8,11,12 When using a spot urine sample, values of bone resorption markers must be normalized to urinary creatinine excretion. Because the rate of elimination of creatinine from the body has been shown not to fluctuate much in infants, children, and adults, the urinary solute/creatinine ratio is considered to be a useful and reliable tool in both infants and adults.13–16 There is still some debate on the proper use of the urinary solute/creatinine ratio during the first 5 days of life, however, because the urinary creatinine excretion as assessed in a spot urine could to be higher and more variable during this period than after 5 days of life.17,18

We demonstrate in this study that values of spot urine NTX/Cr correlate significantly with 24-hour NTX/Cr as well as daily NTX excretion rate. Despite that it could lead to a 25% over- or underestimation in some individuals, we also demonstrate that, on average, using a spot urine sample instead of a 24-hour collection does not lead to a significant error. We also show that the day-to-day variation of the measurement in infants during a stable period is small, as illustrated by a mean coefficient of variation of approximately 12%. If the use of a single value in 1 patient should be done with caution because of a relatively high interindividual variation of NTX excretion (approximately 25%), these results show that NTX excretion assessed in a spot urine sample is an index of bone resorption that can be used with confidence in infancy particularly for studying a patient longitudinally or comparing groups of patients.

In this study, we also describe on a cross-sectional basis the excretion rates of NTX in term infants from birth to 1 year of age. One previous study reported reference values of NTX/Cr in spot urine samples obtained from normal subjects from birth to 20 years of age.19 Infants who were younger than 1 year were described as a whole group in that report. The mean value of NTX/Cr that we report in this study is similar to that previously reported. However, we report here that significant postnatal age-related changes in NTX excretion occur during the first year of life. Indeed, NTX/Cr values are low at birth, dramatically increase during the first 10 days of life to reach a peak at 1 to 2 months of age, and then decrease progressively to return to values similar to that observed at birth. We postulate that the dramatic increase observed during the first 10 days of life is indicative of rapid matrix resorption that may reflect adaptation to extrauterine life. This is in agreement with previous results demonstrating a rapid increase in serum osteocalcin, parathyroid hormone, 1–25 hydroxyvitamin D, and calcium kinetics during the first 10 days of life, and we postulate that the whole process to maintain normal serum calcium during the first 10 days of life includes an increase of bone resorption.20–23 Vitamin D deficiency is known to increase markers of bone resorption, including NTX excretion.2 Despite that none of the infants had a bone radiograph, the increase of NTX excretion observed in our study is very unlikely to be related to vitamin D deficiency because all infants received from birth an exogenous vitamin D supplement. The accelerated growth and, presumably, bone turnover that take place during the first months of life probably explain the high values of NTX/Cr that we observed at 1 to 3 months of age. The progressive decrease afterward is also synchronous with the decrease of growth velocity after 3 to 6 months of life. These observations are not surprising, because the biology underlying bone growth requires an increase in bone resorption (and hence in collagen cross-link urinary excretion) during periods of increased growth. Studies in children have demonstrated that changes in the cross-link excretion rate correlates highly with age-related changes in bone growth rates.19 This finding is also in agreement with elevated values of other markers of bone turnover during this period (eg, osteocalcin,24 pyridinoline,25 cross-linked C-terminal telopeptide of type 1 collagen26). Finally, these results are perfectly in agreement with the intense bone remodeling that is known to occur during the first 6 months of life and that is mainly characterized by a redistribution of bone tissue from the endocortical to the periosteal surface.27

In conclusion, these data, obtained in a French population, provide new insights regarding the use of spot urine analysis for assessing NTX excretion during the first year of life. They demonstrate significant age-related variations in this marker, which probably reflect adaptation to extrauterine life and accelerated bone turnover in infancy. The age-related changes should be considered for the interpretation of this bone resorption marker in the clinical setting. Because the use of urinary NTX measurements in pediatrics is likely to continue to increase because this measurement is noninvasive, relatively inexpensive, and capable of determining changes in bone turnover over short intervals,2 these normative data are of importance for investigators who want to study, noninvasively, bone turnover in infants.


   ACKNOWLEDGMENTS
 
This work was supported by the Shriners of North America.

Dr Lapillonne was funded in part by the Institut Candia, France. We thank Ostex International Inc (Seattle, WA) for the generous gift of Osteomark.

We also acknowledge the contributions of William C. Heird and Steve A. Abrams for reviewing the manuscript; E. O’Brian Smith for statistical advice; Adam Gillum for graphic assistance; and Leslie A. Loddeke for editorial advice (USDA/ARS Children’s Nutrition Research Center, Houston, TX).


   FOOTNOTES
 
Received for publication Aug 20, 2001; Accepted Dec 27, 2001.

Reprint requests to (A.L.) USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030-2600. Email: alapillo{at}bcm.tmc.edu


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 INTRODUCTION
 METHODS
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 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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