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1
INSERM Research Unit 403, Hôpital E Herriot, Pavillon F, 69437 Lyon Cedex 03, France.
2
Synarc, 69003 Lyon, France.
a Author for correspondence. Fax 33-4-72-68-65-09; e-mail
patrick.garnero{at}synarc.com.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Serum CTX was measured on the Elecsys 2010 automated analyzer (Roche). Results were compared with those of the manual ELISA. We measured serum CTX concentrations in 728 healthy women, ages 31–89 years. We investigated the ability of this assay to predict the rate of postmenopausal forearm bone loss evaluated by four repeated bone mineral density measurements using dual-x-ray absorptiometry in 305 women followed prospectively for 4 years. Finally, in a cohort of healthy, untreated, postmenopausal women, we compared baseline serum CTX in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with values in the 380 women who did not fracture during a mean 5 years of follow-up.
Results: The within- (n = 21) and between-run (n = 21) CVs were <4.1% and 5.7%, respectively. In 728 healthy women, serum CTX concentrations (automated) correlated with those of the manual ELISA (r = 0.82; P <0.0001). The median long-term within-person variability assessed by four repeated measurements over 3 months in 18 postmenopausal women was 9.4%. Compared with 254 premenopausal women, serum CTX was 39% (P <0.0001) higher in 45 perimenopausal women and 86% (P <0.0001) higher in 429 postmenopausal women (mean age, 64 years). Baseline serum CTX correlated negatively with changes of bone mass measured at the mid (r = -0.23; P <0.0001) and distal (r = -0.27; P <0001) radius. Postmenopausal women with serum CTX greater than the mean + 2 SD values in premenopausal women accounted for 42% of the population, lost bone at the mid radius on average eightfold more rapidly than the other women (-0.27% ± 2.92% vs -2.25% ± 3.95%; P <0.0001), and had increased risk of fracture with a relative risk (95% confidence interval) of 1.8 (1.01–3.1) after adjustment for physical activity.
Conclusions: The automated assay for serum CTX is precise and predicts rate of bone loss and fracture risk in postmenopausal women. Because it is convenient to use and has high throughput, this serum bone resorption marker may be useful for the investigation of patients with osteoporosis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An important issue for the clinical use of biochemical markers relates to their intraindividual reproducibility. This variation has been reported to be relatively high for urinary resorption markers (9)(10). One way to reduce the precision error of bone markers and hence improve their clinical utility is to use a serum-based assay. Indeed, measuring a marker in serum rather than in urine provides better reproducibility because the variable ionic strength of urine samples and the need to correct for creatinine excretion may introduce some variability in the results. This partly explains the recent development of a serum-based immunoassay for bone resorption markers including the C-terminal (11) and N-terminal (12) cross-linking telopeptides of type I collagen (CTX1 and NTX, respectively) and more recently the osteoclast-specific 5b isoenzyme of tartrate resistant acid phosphate (13). Recent data indicated an approximately twofold lower intrapatient variability of serum CTX and NTX compared with urinary measurements (14)(15). Another way to reduce variability is to use fully automated analyzers that are suitable for routine use in clinical chemistry. The aim of this study was to evaluate the technical and clinical performances of a new automated analyzer for serum CTX using a cohort of 728 healthy women followed prospectively.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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age- and menopause-related changes in serum ctx
Women were separated in three groups according to their menopausal
status.
Premenopausal women.
This group included 254 women, ages
31–58 years (mean age, 39 years), with regular menses and human
follicle-stimulating hormone (FSH) concentrations <16.7 IU/L. Serum
FSH was measured with a two-site immunochemiluminometric assay (Magic
Lite FSHTM; Ciba
Corning®).
Perimenopausal women.
This group included 45 women, ages
39–56 years (mean, 50.4 years), with irregular menses and serum FSH
>16.7 IU/L, which corresponds to the mean + 1 SD of the premenopausal
population.
Postmenopausal women.
This group included 429 women, ages
45–89 years (mean, 64 years), with no menses for at least 12 months.
The longest time period since last menses was 40 years (mean
time since menopause, 14 years).
serum ctx and rate of postmenopausal bone loss
To analyze the relationship between baseline serum CTX
concentrations and the rate of forearm bone loss, we investigated 305
postmenopausal women (mean age, 64 years; range, 50–88 years) who had
a completed 4-year follow-up and who did not receive any treatments,
including hormone replacement therapy, that could interfere with bone
metabolism during the 4 years of follow-up as described previously
(17).
serum ctx and fracture risk
The relationship between baseline serum CTX concentrations and the
risk of incident fracture was analyzed in 429 healthy untreated
postmenopausal women as described previously (18). At
baseline, women responded to a detailed questionnaire that included
questions on history of fragility fractures, physical activity, calcium
intake, and smoking habits (18). Subsequently, each woman
was seen every year for a maximum of 6 years. At each visit the
occurrence of fractures within the previous year was registered. For
women who did not continue, mail was sent every year to identify the
occurrence of fracture. All peripheral fractures were confirmed by
radiographs. Lateral x-ray films of the thoracic and lumbar spine were
obtained at baseline for all women and at follow-up for 79% of the
women after an average of 3.8 years. All vertebral prevalent and
incident fractures were identified by semiquantitative morphometry by
two individuals who were unaware of the baseline results. A vertebra
was classified as having a prevalent fracture on the baseline
radiograph if any of the vertical height (anterior, middle, and/or
posterior) was reduced by >20%. A new fracture was defined by a
decrease 
20% and at least 4 mm in any vertebral height of one or
more thoracic or lumbar vertebrae between follow-up and baseline x-ray
films (20). During a mean 5.0 ± 1.3 years of
follow-up, 21 vertebral fractures and 37 peripheral osteoporotic
fractures (12 wrist, 5 hip, 5 rib, 5 ankle, 3 patella, 3 humerus, 1
sacrum, 1 pelvis, and 2 metatarsi) were recorded in 55 women
(18).
intraindividual variability of serum ctx
To study intraindividual variations of serum CTX, we investigated
18 healthy untreated postmenopausal women, ages 56–72 years. Fasting
serum samples collected between 0730 and 0930 were obtained at
baseline, day 2, day 3, month 2, and month 3 and stored at -80 °C
until measurement.
serum ctx assays
ELISA for serum CTX (serum ELISA-CTX).
Serum CTX was measured
by a two-site ELISA (Serum Crosslaps one step; Osteometer Biotech),
which uses two monoclonal antibodies raised against an amino acid
sequence specific to part of the ß-isomerized C-telopeptide of type I
collagen (Glu-Lys-Ala-His-ßAsp-Gly-Gly-Arg; Crosslaps antigen)
(11). Briefly, calibrators, controls, or unknown
serum samples are added to microtiter wells coated with streptavidin,
followed by a mixture of a biotinylated antibody and a
peroxidase-conjugated antibody. A complex of CTX antigens, biotinylated
antibody, and peroxidase-conjugated antibody is generated, and the
complex binds to the streptavidin surface via the biotinylated
antibody. The amount of antigen is quantified by the use of a
chromogenic peroxidase substrate. The intra- and interassay CVs
are <8%.
Automated assay for serum CTX (serum automated-CTX).
Serum CTX
was measured on the Elecsys 2010 automated analyzer (Roche Diagnostics
GmbH, Mannheim, Germany) using the ß-Crosslaps/serum reagents. This
assay is specific for cross-linked ß-isomerized type I collagen
C-telopeptide fragments and uses two monoclonal antibodies, each
recognizing the Glu-Lys-Ala-His-ßAsp-Gly-Gly-Arg peptide (Crosslaps
antigen). Briefly, 50 µL of serum and a biotinylated monoclonal
antibody against the Crosslaps antigen are incubated together. A second
antibody labeled with a ruthenium complex is then added together with
streptavidin-coated microparticles. A sandwich complex is formed that
binds to the solid phase (the microparticles) via biotin-streptavidin
interactions. These microparticles are then magnetically captured onto
the surface of an electrode. Application of the voltage on this
electrode then induces a chemiluminescent emission, which is measured
by a photomultiplier and compared to a calibration curve, which is
instrument-specific and is generated by two-point calibration, and a
master curve provided via the bar code of the reagent. In total, the
duration of this automatic process is 18 min.
bone densitometry
Bone mineral density (BMD) of the mid and distal radius was
measured by dual x-ray absorptiometry on a QDR 2000 device
(Hologic, Inc). The mid area of the radius is composed mainly of
cortical (>95%) bone, and the distal area comprises both cortical
(
75%) and trabecular (25%) bone. The short-term in vivo
imprecision (CV) of dual x-ray absorptiometry was 1.2% and
0.6% for the mid and distal radius, respectively.
statistical analyses
As shown on Fig. 1
and as expected in postmenopausal women, CTX concentrations
measured either by ELISA or automated analyzer were not normally
distributed with a frequency distribution skewed to the left.
Consequently, CTX data were log-transformed before statistical
analysis. Correlations between the different variables were assessed by
linear regression analysis. The least significant change (LSC) at a
significance of P <0.05 was calculated by a two-tailed test
according the formula: LSC = 1.96 x 
2 x CVi
(9), where CVi is the intraindividual variability
assessed over 3 months. The effect of menopausal status on serum CTX
concentrations was determined by ANOVA. Comparisons between pre- and
postmenopausal women were also assessed using the t-score,
which is the number of SD from the premenopausal mean. The formula for
the t-score is: (xi -
M)/SD, where xi is the CTX
concentration of an individual postmenopausal woman, M is
the mean of the premenopausal reference population, and SD is the
standard deviation of the reference group.
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To analyze the relationship between baseline concentrations of serum CTX and the rate of postmenopausal bone loss, individual rates of change in BMD were calculated. It was assumed that the expected change in BMD was linear over the 4-year follow-up period. BMD values at baseline, year 2, year 3, and year 4 were regressed on time to yield a rate of change in BMD for each subject. The relationship between baseline concentrations of serum CTX and the rate of change was assessed by linear regression analyses. The mean + 2 SD of serum CTX concentrations of the premenopausal women was defined as the upper limit of the premenopausal range and was used as a cutoff limit between low and high bone turnover in postmenopausal women, as suggested previously (17)(18). Differences in the rate of BMD loss between women with low and high bone turnover at baseline were assessed by the Student t-test.
The relationships between baseline serum CTX concentrations and the risk of incident fracture were analyzed by logistic-regression analysis before and after adjustment for potential confounding factors.
All analyses were performed using the Statistical Analysis Software (SAS).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dilution test.
Three serum samples were diluted 1:2, 1:4, 1:8,
and 1:16 with assay buffer. As shown on Table 1
, the dilution recovery was 86–119% (mean, 104%).
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Recovery test.
Know amounts of ß-Crosslaps antigen
calibrator were added to three serum samples. The recovery was
91–101% (Table 2
).
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correlation of the automated serum ctx assay with the manual elisa
Serum CTX concentrations were measured in the 728 healthy women
using both the manual ELISA and the automated analyzer, and a highly
significant correlation was obtained (r = 0.82;
P <0.0001) between the two assays (Fig. 2
). The intercept of the regression line was significantly
different from 0 (P <0.001).
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long-term intraindividual variation of automated serum-ctx
Intraindividual variability of serum automated-CTX was assessed in
18 untreated postmenopausal women over 3 months. At baseline, the women
had an average serum CTX concentration of 0.516 ± 0.217 µg/L.
The median intraindividual CV (CVi) for serum CTX values was 9.4%
(range, 4.1–27%). On the basis of this CVi, the LSC was
determined to be 27%, meaning that an individual should display a
27% decrease of serum CTX concentrations when receiving
antiresorptive therapy to have a <5% chance of the decrease being the
result of random variation in marker concentration.
changes in serum ctx concentrations with age and menopause
In premenopausal women, there was no significant correlation
between serum automated-CTX and age (Fig. 3
and Table 3
). Serum automated-CTX was 39% (P <0.0001) higher
in perimenopausal women and 86% (P <0.0001) higher in
postmenopausal women than in premenopausal women (Fig. 3
and Table 3
).
When expressed as a t-score, serum automated-CTX
discriminated postmenopausal from premenopausal controls with a mean
t-score of 1.88. No significant change of serum
automated-CTX with age was observed in postmenopausal women (Fig. 3
and
Table 3
).
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serum ctx concentrations to predict rate of postmenopausal bone
loss
At baseline, serum automated-CTX correlated negatively with both
mid and distal radius BMD: r = -0.24 (P
<0.0001) and r = -0.18 (P = 0.0017)
for mid and distal radius, respectively.
In the whole population, baseline serum automated-CTX correlated significantly with changes of bone mass assessed prospectively over 4 years at both the mid (r = -0.23; P <0.0001) and the distal (r = -0.27; P <0.0001) radius. Results obtained for serum CTX measured by ELISA were similar: r = -0.20 and -0.24 (P <0.0001) for the mid and distal radius, respectively. In 51 women within 5 years of menopause, the rate of BMD loss was faster than in the whole population: -0.62% vs -0.22% per year for mid radius and -0.78% vs -0.59% per year for distal radius in the early and whole postmenopausal populations, respectively. When the analysis was restricted to these early postmenopausal women, the negative correlation between baseline serum automated-CTX concentrations and rate of bone loss was higher: r = -0.47 and -0.49 (P <0.001) for mid and distal radius, respectively.
Postmenopausal women with high turnover at baseline, i.e., with serum
automated-CTX greater than the mean + 2 SD values in premenopausal
women, accounted for 42% of the population and over 4 years lost bone
at the distal (-3.87% ± 4.36%) and mid radius (-2.25% ± 3.94%)
more rapidly (P <0.001) than women with low bone turnover
(-1.64% ± 3.2% and -0.27% ± 2.90% for distal and mid radius,
respectively; Fig. 4
). When we used serum CTX measured by ELISA, the difference in
bone loss over 4 years between high and low turnover was of a magnitude
similar to the results obtained by serum automated-CTX [-4.49% ±
4.65% vs -2.04% ± 3.47% and -2.78% ± 4.22% vs -0.63% ±
3.15% (P <0.0001) for distal and mid radius,
respectively].
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serum ctx concentrations to predict osteoporotic fractures in
postmenopausal women
At baseline, women who had osteoporotic fractures during the study
were older (67 vs 64 years; P = 0.004), had slightly
lower physical activity (physical activity score, 12.1 vs 13.8;
P = 0.004), and had a lower BMD at the femoral neck,
spine, and radius (P <0.0001 for all sites) than controls
but did not differ in body weight, height, and body mass index. An
increased physical activity score was associated with decreased
fracture risk with a relative risk (RR) of 0.61 [95% confidence
interval (95% CI), 0.45–0.84] for each SD increase in the score. As
expected, the proportion of women with prevalent osteoporotic fractures
was also higher among women who had fractures during the study (31% vs
13%; P = 0.002). Serum automated-CTX did not correlate
with age and was not different between women with and without prevalent
fractures (data not shown), but was moderately correlated with physical
activity score (r = 0.13; P = 0.006).
Women with serum automated-CTX greater than the mean + 2 SD values in
premenopausal women had an increased, although not statistically
significant, risk of fracture compared with the other groups, with a RR
of 1.6 (95% CI, 0.95–2.7). After adjustment for physical activity,
the RR of fracture associated with high serum automated-CTX increased
slightly and was significant [RR (95% CI), 1.8 (1.01–3.1)]. The
corresponding RR (95% CI) values obtained with serum CTX (ELISA) were
1.6 (0.92–2.9) and 2.0 (1.1–3.6) before and after adjustment for
physical activity, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The automated assay for serum CTX is fast, and the intra- and interassay CVs are <4% and 6%, respectively, which compare favorably with the CVs for the manual ELISA (11). We observed a high correlation between serum CTX concentrations measured with this automated assay and those obtained with the manual ELISA (r = 0.82). The manual ELISA uses SI units, whereas serum CTX values in the automated system are expressed in µg/L. It was not possible, however, to correlate the units used in the two assay systems because each assay may detect several differing molecular entities, precluding the determination of a specific molecular weight. Indeed, the enzymatic degradation of type I collagen by the osteoclasts generates several fragments of different molecular sizes, which would be measured by the immunoassays provided that they contain the 8-amino acid sequence used to raise the antibodies.
The long-term intraindividual variation of serum automated-CTX values in postmenopausal women was 9.4%, which is comparable to that of serum CTX by ELISA (11.5%) (14) and serum NTX (7.5%) (15). These data indicate that serum CTX measurements obtained in fasting subjects demonstrate lower intraindividual variability and consequently a lower LSC than the corresponding urinary measurements (9)(10).
As reported previously in other studies and in the same population with other markers of bone formation and bone resorption (16), we found no significant changes with age in serum automated-CTX concentrations in premenopausal women, ages 30–58 years. We believe that values obtained in this large population of well-characterized estrogen-replete women taken from the general population could represent an adequate reference range for this new marker. In women characterized by irregular bleeding and increased FSH concentrations, a pattern that is frequent in perimenopausal women (21), we found a significant increase of serum automated-CTX. This suggests that bone resorption increases before cessation of menses in women with estrogen deficiency and is consistent with data obtained for other biochemical markers in the same cohort (16). This increase in bone turnover that can be detected by serum CTX is likely to be responsible for the loss of trabecular and cortical bone observed in some of these women (22). The 39% increase of serum automated-CTX observed in perimenopausal women was larger than that reported previously in the same population for serum bone alkaline phosphatase (17%) and in the same order of magnitude as that of urinary CTX and NTX (30–40%). Thus, serum automated-CTX could be a sensitive index to identify perimenopausal women with high bone resorption who would be at risk for bone loss.
At the time of menopause, serum automated-CTX increased by 86%, a pattern consistent with the accelerated bone loss occurring within the first years following menopause (23). After this marked increased, we found no age-related decline. Such a sustained bone turnover has been found previously in this study with other bone formation and urinary resorption markers (16) and also in other populations (24)(25). In most previous studies, however, the bone resorption rate was assessed by urinary markers corrected for urinary creatinine. Because decreased muscle mass, and therefore low urinary creatinine value, is common in elderly women, one could speculate that increased bone resorption markers in advanced age may result from lower urinary creatinine. Our study, performed in a large cohort of healthy postmenopausal women using a serum assay, suggests that the rate of bone resorption remains high up to 40 years after menopause. However, we cannot exclude that increased serum CTX in elderly women could result in part from decreased clearance of this marker because of alterations in renal function.
In osteoporosis, the main cause for concern is increased risk of fractures. Several prospective studies have found that a decrease by 1 SD in BMD values measured by dual x-ray absorptiometry was associated with a two- to fourfold increase in the risk of fractures of the hip, wrist, or spine. In that context, an important issue is whether combined use of bone remodeling markers and BMD measurements could improve the accuracy of fracture risk evaluation. Increased bone turnover can be related to decreased bone strength as a result of two mechanisms. Several studies have shown that increased concentrations of bone markers are associated with increased rate of bone loss at the spine, forearm, and calcaneus in the subsequent years and thus a lower bone mass later in life (17)(26)(27)(28). In addition, recent data obtained in large prospective studies have shown that increased concentrations of bone resorption markers are associated with increased risk of hip, vertebral, and non-hip and non-vertebral fractures over follow-up periods ranging from 1.8 to 5 years (18)(29)(30)(31), independent of bone mass. Indeed, increased bone resorption may induce microarchitectural deterioration of bone tissue, such as perforation of trabeculae, a major component of bone strength (32). Consequently, use of a combination of BMD assessment and bone resorption markers has been suggested for improving risk assessment (33).
In this study, we found that higher physical activity was slightly
associated with increased serum CTX concentrations, suggesting that
increased physical activity may be associated with increased bone
resorption. However, the association was modest, the physical activity
score explaining <2% of the interindividual variability in serum CTX
concentrations. The relationship between physical activity and bone
resorption is actually unclear. Exercise has indeed been reported to be
associated with increased (34)(35), decreased
(36), or unchanged (37)(38) bone
resorption. This discrepancy could be related to the type of exercise
(anaerobic vs aerobic) (36) and/or its duration and
intensity. Women with serum automated-CTX greater than the mean + 2 SD
values in premenopausal women lost bone at the mid radius 8 times more
rapidly over the subsequent 4 years and had an 1.8-fold higher risk
of fracture than individuals with CTX concentrations below the mean + 2
SD cutoff after adjustment for physical activity. The
predictive value of bone loss and fracture risk is similar to that of
serum CTX by ELISA and to that reported previously in the same
population for urinary CTX (17)(18). Timing of
sample collection and fasting status of the subjects, however, seem to
be important for the clinical value of serum CTX measurements. In
nonfasting conditions, the maximum concentration of serum CTX is
reached during the night, followed by a marked decrease during the
morning until 1100, then by a nadir stable from 1100 to 1500, after
which serum CTX increases (14). Interestingly, this
circadian rhythm is markedly decreased when women are fasting
throughout the day, producing a day-to-day variation that is smaller in
fasting than nonfasting women (7% vs 14%) (14). In the
EPIDOS cohort, a large prospective study of elderly women, we found
that serum automated-CTX measured in the morning in nonfasting subjects
was not predictive of hip fracture risk (39). However, when
the analysis was restricted to the patients for whom serum samples had
been collected during the afternoon (1300–1500) after lunch, a
significant relationship between increased concentrations of serum CTX
and the risk of hip fracture was found (39). In nonfasting
women from the EPIDOS study, when samples were taken at different times
during the morning, variability of the measurement was high, which
probably explains the absence of a predictive value. In the afternoon,
women were at the nadir of the rhythm with stable concentrations. The
data we obtained in this study lend support to that hypothesis because
we found that when sampling is performed in the morning, but at a
standardized time (between 0730 and 0930) and in a fasting state, serum
automated-CTX is predictive of fracture risk.
In conclusion, we have validated a new automated assay for serum CTX. This assay is fast, convenient to use, precise, and was able to detect the increase of bone resorption in perimenopausal and postmenopausal women. Serum automated-CTX predicted rapid bone loss and fracture risk in a large population of postmenopausal women with a value similar to those of serum and urinary resorption markers measured by manual ELISA. This serum-based resorption marker is likely to be useful for the investigation of patients with osteoporosis.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-carboxyglutamic acid protein with aging in women. J Clin Invest 1983;71:1316-1321.
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, premenopausal women (r = 0.04;
P = 0.94 vs age); 
, perimenopausal women; 
,
postmenopausal women (r = -0.026;
P = 0.94 vs years since menopause).
Horizontal lines indicate the means. M,
menopause.