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Enzymes and Protein Markers |
1
Osteometer Biotech A/S, Osteopark, Herlev Hovedgade 207, 2730 Herlev, Denmark.
2
Center for Clinical and Basic Research, Ballerup Byvej
222, 2750 Ballerup, Denmark.
a Author for correspondence. Fax 45 4494 8940; e-mail Stephan_Christgau{at}osteobio.dk.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1-chain. Our objective was to
assess the clinical value of the Serum CrossLaps assay for monitoring
antiresorptive therapy in osteoporosis treatment. Samples obtained from
postmenopausal women treated with different doses of cyclic or
continuous hormone replacement therapy (HRT) with an estrogen analog
(tibolone) or with a bisphosphonate (ibandronate) were measured in the
Serum CrossLaps One Step ELISA at baseline and at various time points
during therapy. The corresponding urine samples were measured in the
urine CrossLapsTM ELISA and corrected for creatinine
excretion. The serum CrossLaps measurements and corresponding urinary
CrossLaps measurements were highly correlated (r >0.8
for all studies). The serum and urine CrossLaps measurements showed a
significant decrease among the women treated with clinically relevant
doses of either of the antiresorptive agents. Furthermore, the annual
percentage change in bone mineral density (BMD) correlated with the
measured changes in CrossLaps concentration. The serum CrossLaps assay
showed a specificity of 83–100% and a sensitivity of 59–83% for
assessing BMD changes. The corresponding values for the
creatinine-corrected urinary measurements were 83–92% specificity and
68–79% sensitivity. We conclude that performance of the convenient
Serum CrossLaps One Step ELISA is at least equivalent to that of the
urine text for follow up of antiresorptive treatment in osteoporosis.
Further studies are needed to optimize its use in this and other
clinical applications. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-
to the ß-carboxyl group (3)(4). The CrossLaps
assay has been shown to provide an index of bone resorption in women
undergoing therapy with antiresorptive agents
(5)(6). Several studies have shown that biochemical markers of bone resorption are of clinical value when used for monitoring the effect of antiresorptive therapy (2)(7). The effect of antiresorptive therapy can also be assessed by measurement of bone mineral density (BMD).1 However, the precision error for bone densitometry is ~1–5% (8); thus extended follow-up periods are generally necessary to assess a statistically significant effect of antiresorptive therapy by BMD measurements. In contrast, a clear response measured by biochemical markers of bone resorption has been demonstrated within a short period of time after initiation of the therapy (2)(5)(7). Hence, it has been suggested that biochemical markers such as CrossLaps are valuable in monitoring the effect of antiresorptive therapy (2)(5)(9)(10). We have developed an ELISA for measurement of CrossLaps molecules in serum (11); thus, the C-terminal degradation products of collagen type I measured in the CrossLaps assay can now be measured in both urine and serum. Assessments of the clinical value of the Serum CrossLaps One Step ELISA have not been published before.
Hormone replacement therapy (HRT) has been used for more than two decades to alleviate climacteric symptoms in postmenopausal women, and the ability of this therapy to reduce postmenopausal bone loss is well established (12). However, HRT often has adverse effects (13)(14), which have prompted the development of new therapeutic agents for prevention of bone loss associated with cessation of estrogen production at menopause and for treatment of osteoporosis (15)(16)(17).
The present study investigates the clinical utility of both the serum and urine CrossLaps markers for monitoring the effect of HRT and therapy with an estrogen analog (tibolone) or bisphosphonate (ibandronate) and compares these assays to state-of-the-art BMD measurements. Tibolone is a synthetic steroid with a combination of estrogenic, androgenic, and progestogenic properties (18)(19). Ibandronate is highly efficient for reducing bone resorption (7). We assess the ability of the CrossLaps markers to monitor the responses to therapy, and we compare the value of these markers of bone resorption with results obtained by spinal BMD measurements.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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tibolone study group
The study group comprised 91 healthy, postmenopausal women with
BMD values within health-related reference intervals. At baseline they
were at least 10 years past natural menopause and <76 years of age
(mean, 67 years). The women were randomly allocated to three groups for
assessment of the effect of tibolone
[(7,17)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one;
livial; Organon]. Thirteen women received only placebo (400 mg of
calcium daily), 29 women received 1.25 mg of tibolone in addition to
the calcium daily, and 28 women received 2.5 mg of tibolone in
addition to calcium daily. The women were followed during a 2-year
study period. All women were monitored for spinal BMD, and serum and
urine (fasting, second morning void) samples were taken at 3-month
intervals during the study period. The baseline demographic data
and inclusion criteria for the study-population are described in
more detail by Bjarnason et al. (18).
ibandronate study group
The study group originally comprised 180 healthy, postmenopausal
women, at least 10 years past natural menopause and <75 years of age
(mean, 65 years) who entered a double-blind placebo-controlled
dose-finding study of the bisphosphonate ibandronate (bondronate,
Boehringer Mannheim). The participants had a BMD in the distal forearm
at least 1.5 SD below the premenopausal mean for healthy white women.
One hundred and forty-one women completed the full 1-year study period,
and all samples and measurements were available for 131 women.
Twenty-three women received placebo; 23 women received 0.25 mg of
ibandronate; 21 women received 0.5 mg of ibandronate; 24 women received
1 mg of ibandronate; 23 women received 2.5 mg of ibandronate; and 17
women received 5 mg of ibandronate. All of these women received 1
g of calcium daily. All women were monitored for spinal BMD, and serum
and urine (fasting, second morning void) samples were taken at 3-month
intervals during the 12-month study period. The study group and
baseline demographic data are described by Ravn et al. (7).
hrt study group
The study group originally comprised 200 healthy, Caucasian
postmenopausal women, at least 12 months past natural menopause and
<65 years of age (mean, 59 years) with a BMD within health-related
reference intervals. Two hundred women were enrolled and randomly
allocated into one of four groups of 50 each. One hundred and fourteen
women completed the full 2-year study period and had samples available
for all measuring times. Thirty-four women received placebo treatment;
33 women received continuous HRT with 2 mg of estradiol and 1 mg of
norethisterone acetate daily (kliogest); 38 women received a cyclic
regimen of 0.75 mg/day piperazine estrone sulfate (EP) plus five
periods of 3 days/month with norethisterone (low EP); and 31 women
received 1.5 mg/day EP plus five periods of 3 days with 0.7 mg/day
norethisterone (high EP). All women were monitored for spinal BMD, and
serum and urine (fasting, second morning void) samples were taken at
6-month intervals (0, 6, 12, 18, and 24 months) during the 2-year study
period. The study group and baseline demographic data are described in
detail by Alexandersen et al. (manuscript submitted for
publication).
serum CrossLaps ONE-STEP ELISA
The Serum CrossLaps One Step ELISA is performed as a monoclonal
sandwich assay in a one-step procedure. Calibrators, controls, or
unknown serum samples are added into microtiter wells coated with
streptavidin, followed by a mixture of a biotinylated antibody and a
peroxidase-conjugated antibody. A complex between CrossLaps antigens,
biotinylated antibody, and peroxidase-conjugated antibody will be
generated, and this complex will bind to the streptavidin surface via
the biotinylated antibody. The amount of bound antigen is quantified by
the use of a chromogenic peroxidase substrate. A more thorough
description and characterization of the assay is presented by
Rosenquist et al. (11) in this issue.
urine CrossLaps ELISA
Urinary excreted degradation products of type I collagen were
measured by the CrossLaps ELISA (Osteometer Biotech). This assay uses a
polyclonal antiserum specific for the CrossLaps antigens in a
competitive ELISA format (20).
bmd measurements
BMD in the lumbar spine was measured at baseline and every 3 or 6
months thereafter. BMD was measured by dual energy x-ray absorptiometry
(Hologic, Inc., model QDR-2000 or QDR-1000) in the lumbar spine
anterior posterior projection (L1–L4) according to the manufacturer's
instructions (7)(18).
statistical analysis
The comparability of the study groups at baseline was assessed as
appropriate by one-way ANOVA. The serial measurements of the
biochemical markers were calculated as percentage of baseline values,
which were set at 100% for each woman and used as summary measures in
the response groups to account for individual differences at baseline
and to get a harmonized way of presentation. The individual responses
in BMD at the different regions were calculated as the slopes of the
lines estimated by linear regression, using serial BMD measurements and
used as a summary measure (percentage of change per year was designated
-BMD). Single and multiple regressions were used to examine the
relationship between the response in BMD and the change from baseline
in serum CrossLaps measurements. The diagnostic validity of the serum
CrossLaps marker was analyzed by ROC analysis. The number of "true
positives" were plotted against the number of "true negatives" at
different cutoff values for change in CrossLaps concentration. The
cutoff value used to calculate the sensitivity and specificity was a
spinal -BMD of -1% per year. This cutoff value was used to take
into account the precision error of the spinal BMD measurements (1%
per year).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the dose responses measured in each of the three groups
in the two CrossLaps assays, where the values for each woman are
expressed in percentage of change from the baseline values. The overall
correlation between serum and urinary CrossLaps measurements for all
samples measured in the study was 0.80.
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BMD measurements of the spine demonstrated a dose-dependent increase as
a result of tibolone treatment (19). The annual percentage
of change in spinal BMD (-BMD) showed an increase significantly
different from the placebo group among the women treated with any one
of the three tibolone regimens. In the placebo group no significant
change in spinal BMD was observed. When -BMD was correlated to the
change in serum CrossLaps concentration observed over 12 months,
r = -0.62 was obtained (Table 1
). The change over 3, 6, and 9 months correlated, with
r = -0.53, -0.48, and -0.59, respectively. Likewise
the changes in urinary CrossLaps concentration observed after 3, 6, 9,
and 12 months correlated to -BMD with r = -0.54,
-0.49, -0.59, and -0.56, respectively.
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The diagnostic sensitivity and specificity of changes in serum and
urinary CrossLaps concentration observed after 12 months for predicting
changes in spine BMD was calculated by ROC (Table 1
). Both assays
showed a specificity of 83%, whereas the sensitivity was 83% for the
serum assay and 79% for the urinary CrossLaps assay for prediction of
BMD response. The odds ratio for significant bone loss (-BMD
<-1%) was 24.0 for the serum and 7.7 for the urinary CrossLaps
measurements when the women showing an insignificant decrease or an
increase in CrossLaps concentration were compared with the women
showing a significant decrease (Table 2
). The odds ratio of significant bone gain (-BMD >1%) was
33.3 and 41.0, respectively, for serum and urinary measurements when
the women showing a larger change in the biochemical markers were
compared with women showing an insignificant decrease or an increase.
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effect of ibandronate treatment of postmenopausal women
The baseline demographic data and other data about the study
population have been reported previously (7). Urine and
serum samples, taken at 3-month intervals, were available for 131 women
who had completed a 1-year dose-finding study of the effect of
ibandronate. The measurements were expressed in percentage of change
from the baseline values for each woman, and the average responses
within each of the five treatment groups are shown in Fig. 2
. The effect of the treatment could be detected by serum
CrossLaps measurements after 3 months of treatment, where the women
receiving the clinically relevant doses of 1, 2.5, or 5 mg daily showed
an average decrease of 67.6%, 77.4%, and 79.4%, respectively, from
the baseline values. A similar effect was also seen in urinary
CrossLaps measurements, with decreases after 3 months of 52.7%,
76.3%, and 80.7%, respectively, in the groups receiving 1, 2.5, and 5
mg ibandronate. Measurements of urinary and serum CrossLaps
concentrations correlated well, with an overall r =
0.86 for all measurements in the ibandronate study.
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The changes observed over 6 and 12 months in serum CrossLaps
concentration as a result of ibandronate therapy correlated with the
changes observed in spinal BMD (r = -0.38 and -0.53,
respectively; Table 1
). In addition, the changes observed in urinary
CrossLaps correlated with -BMD (r = -0.36 and
-0.52 for changes observed over 6 and 12 months, respectively; Table 1
). The diagnostic sensitivity and specificity for the change in
CrossLaps concentration over 12 months for predicting the -BMD
response was calculated by ROC analysis (Table 1
). Odds ratios for the
risk of significant bone loss (-BMD <-1%) or gain (-BMD >1%)
were calculated for women in the two groups showing either a
significant decrease in CrossLaps concentration or an insignificant
decrease or an increase in the concentration (Table 2
).
effect of hrt
The effect of HRT on serum CrossLaps concentration was assessed by
measurements of samples from 136 women who had participated in a 2-year
study of the effect of cyclic and continuous HRT (Alexandersen et al.,
manuscript submitted for publication). Urine and serum samples
were measured in the urine CrossLaps ELISA and Serum CrossLaps One Step
ELISA, respectively (Fig. 3
). The correlation between serum and corresponding
creatinine-corrected urine CrossLaps measurements was 0.86. Both the
serum and creatinine-corrected urine CrossLaps measurements showed a
significant decrease among the three HRT-treated groups, whereas the
placebo group showed no overall change during the study period (Fig. 3
). Fig. 4
shows the response in serum and urine CrossLaps over the first
6 months of the study period in each individual in the four treatment
groups. The changes were significantly different in the three groups of
women receiving HRT compared with the placebo group (P
<0.001).
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Spine -BMD correlated with the change in serum CrossLaps
concentration over 6, 12, 18, and 24 months with the following
coefficients: r = -0.56, -0.54, -0.66, and -0.55
(Fig. 5
). The corresponding values for the creatinine-corrected urinary
measurements were r = -0.27, -0.43, -0.62, and
-0.44 (Table 1
and Fig. 5
).
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ROC analysis was used to calculate the sensitivity and specificity for
the changes measured over 12 months in the CrossLaps assays to predict
-BMD in individual patients (Table 1
). The change in serum CrossLaps
concentration observed after 12 months showed a sensitivity of 82% and
a specificity of 100% for predicting the BMD response using a cutoff
value of -BMD = -1%/year and a calculated cutoff value for
significant change in serum CrossLaps concentration of 27.8% decrease
from baseline (Fig. 6
, A and C). The diagnostic sensitivity and specificity of
changes in urine CrossLaps concentration to predict changes in spinal
BMD were 72% and 92%, respectively, at 12 months, using the same
cutoff value of -1% for the -BMD measurements and a calculated
cutoff value of significant change in the concentration of the urinary
CrossLaps of 41.2% (Fig. 6
, B and D).
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When the women were stratified in quartiles according average on-study
concentration of either urinary or serum CrossLaps concentration, a
correlation to -BMD was apparent as the highly significant
differences in average -BMD concentration between the first and the
last quartile (P <0.0001; data not shown).
Odds ratios for the risk of significant bone loss (-BMD <-1%) or
gain (-BMD >1%) were calculated for women in the two groups
showing either a significant decrease in CrossLaps concentration or an
insignificant decrease or an increase in the concentration (Table 2
).
We assessed whether baseline CrossLaps concentrations was also
associated with BMD changes, and whether this marker was predictive for
the outcome of antiresorptive therapy (Table 3
). The women in either the placebo group or the combined
HRT-treated group were stratified into quartiles according to baseline
serum CrossLaps concentration or according to creatinine-corrected
urine CrossLaps concentration. The average -BMD in each quartile was
calculated. In the placebo group the women in the lowest quartile of
serum CrossLaps had a net gain in spinal BMD of 0.66% per year,
whereas the women in the highest quartile of serum CrossLaps
concentration had an average annual BMD loss of 0.26%. When the
stratification was carried out according to the urinary CrossLaps
measurements, the lowest quartile among the placebo group was found to
have a net gain in spine BMD of 0.42% per year; the highest quartile
had an average annual loss of 0.23% spine BMD. Because of the small
number of individuals, these differences were not statistically
significant. Among the HRT-treated women, the lowest quartile showed a
significantly lower response to the therapy than the women in the
highest quartile (average -BMD, 2.5 for the lowest quartile and 4.53
for the highest quartile; P = 0.0051) when stratified
according to serum CrossLaps measurements, whereas the difference
between the highest and lowest quartile stratified according to urine
CrossLaps was statistically insignificant (average -BMD, 3.06 for
the lowest quartile and 3.95 for the highest quartile).
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The relative risk of losing bone if not treated with HRT was significantly larger among the women in the highest quartile of baseline serum CrossLaps concentration (2.7-fold relative risk; 95% confidence interval, 1.3–5.4) compared with the women in the lowest quartile (1.2-fold relative risk; 95% confidence interval, 0.7–2.0). Similarly, when the women were stratified according to baseline urine CrossLaps measurements, the women in the highest quartile had a significantly higher relative risk of losing bone if not treated with HRT compared with the women in the lowest quartile [relative risk, 2.5 (1.3–5.0) vs 1.5 (0.9–2.6)].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Serum CrossLaps One Step ELISA measures collagen type I
C-telopeptide fragments containing two cross-linked EKAHD-ß-GGR
epitopes. The serum assay exclusively measures molecules where the
peptide bond between the aspartate (D) and the glycine residue (G) has
undergone a spontaneous rearrangement from the - to the ß-carboxyl
group of the aspartate side chain (3), and the lysine
residue (K) participates in an intermolecular covalent cross-link
(21). The urinary CrossLaps assay is performed as a
competitive assay measuring both cross-linked and non-cross-linked
fragments containing the EKAHD-ß-GGR epitope (3). In spite
of this difference in assay formats, the correlation between the serum
and urine concentrations of the molecules measured in the two
CrossLaps assays was above r = 0.8 for all studies
reported here. This suggests that the serum and urinary CrossLaps
assays measure similar populations of antigens (11).
The restriction of the serum CrossLaps assay to measurement of fragments containing two posttranslational modifications (ß-isomerization and intermolecular cross-links) may be important for assuring that the majority of the molecules measured in the assay are derived from resorption of mature collagen and not generated during synthesis of new collagen during bone formation (4). Hence, the measurements are likely to represent a true indicator for the resorptive process, with no or very little contribution from bone formation. However, this will need to be established in future studies.
The C-telopeptide fragments of type I collagen measured in the Serum CrossLaps One Step ELISA may be generated by several tissues unrelated to bone because type I collagen is widespread throughout the body (22). However, the pronounced effects of all tested antiresorptive therapies suggest that the large majority of the molecules measured in the serum CrossLaps assay are bone-derived. The decreases of >50% in the serum CrossLaps concentration observed in all women as a result of treatment with the two highest doses of ibandronate are especially noteworthy. Ibandronate and other bisphosphonates have not been reported to have any effect on collagen metabolism in tissues other than bone (15).
Another serum assay for a C-telopeptide fragment of type I
collagen, the ICTP assay (23)(24), has been
described previously. This marker has shown only a very limited
response to antiresorptive bisphosphonate therapy
(25)(26). Furthermore, ICTP does not reflect the
decreased bone resorption obtained by HRT or other antiresorptive
therapies (10)(11). The epitope recognized by
the ICTP assay is believed to comprise a larger part of the
cross-linked telopeptide closer to the N terminus than the EKAHDGGR
epitope recognized in the CrossLaps assay, as well as parts of the
-helix (27). It has been demonstrated in vitro that
CrossLaps reactive fragments are generated by osteoclasts
(28). Whether the larger ICTP reactive fragments are
generated during osteoclastic bone resorption or during collagen
synthesis is not known. In fact, it has been suggested that the ICTP
marker predominantly reflects collagen type I synthesis in bone and
other tissues (29).
We evaluated the Serum CrossLaps One Step ELISA clinically in three
studies of the antiresorptive effects of conventional HRT, tibolone, or
ibandronate. The three investigated therapies have different methods of
action and efficacy for reducing bone turnover
(14)(15)(18). However, each drug
clearly reduced bone resorption in a dose-dependent manner, as shown by
the pronounced dose-dependent decreases in serum CrossLaps
concentration occurring in all three studies (
Figs. 1–3
). A similar
decrease was also observed in corresponding creatinine-corrected
urinary CrossLaps measurements in accordance with previous reports on
the clinical value of measurements of this biochemical marker of bone
resorption (2)(5)(6)(7)(18). It is also
noteworthy that in the tibolone and ibandronate studies, the
antiresorptive effect of treatment assessed by the CrossLaps
measurements could be demonstrated after the first 3 months (Figs. 1
and 2
). In the HRT study, the response measured in either of the two
CrossLaps assays over the first 6 months was significantly different in
all three treated groups compared with the placebo group (P
<0.001; Figs. 3
and 4
).
The antiresorptive effects could be monitored as an increase in spine
BMD. The correlation between the average changes in spinal BMD over 1
year (-BMD) and the change in serum concentration over 3 to 12
months varied from -0.53 to -0.62 in the three studies. Thus, the
measurement of changes in the CrossLaps concentration in serum
reflected the changes in BMD. The change in the urinary CrossLaps
correlated with -BMD in all studies, with correlation coefficients
of the same magnitude or slightly lower than the change in the serum
CrossLaps concentration (Fig. 5
and Table 1
).
The sensitivity and specificity of the serum CrossLaps measurements for
predicting BMD loss was calculated by ROC analysis using a cutoff value
of -BMD = -1% (Table 1
). This value was chosen to take into
account the precision error of the spine BMD measurements, which is
1%. Thus, only women with -BMD <-1% can be said to have
significant bone loss. The sensitivity varied from 59% to 83% in the
serum assay and from 68% to 79% in the urinary assay in the three
study populations, depending on the follow-up time. The specificity
varied from 83% to 100% in the serum and from 83% to 90% in the
urine CrossLaps ELISA. This suggests that both CrossLaps assays are of
high value for monitoring the response in individual patients, by
performing a measurement at baseline and after 3–12 months of therapy,
and that the change observed in the CrossLaps concentration may be used
as an indicator of BMD response. When the ROC analysis was performed
using other cutoff values for -BMD (0% or 1%), similar values for
specificity and sensitivity of the change in the marker for prediction
of BMD response were obtained (not shown).
The ROC analysis used for calculation of the assay sensitivity and
specificity also yields an assessment of the cutoff values of the
biochemical markers for evaluating a significant response to the
therapies (Table 1
). In both the HRT and tibolone studies, a change
from baseline after 12 months of ~25–30% in the serum and 35–40%
in the urinary CrossLaps measurements was calculated as giving the
optimal sensitivity and specificity of the test when -BMD =
-1% was used as a cutoff value. For the bisphosphonate study, a
change of 50–55% after 12 months therapy was found to give the best
sensitivity and specificity.
The odds ratio of significant bone loss (-BMD <-1%) for women
where no significant decrease in CrossLaps was observed after 12 months
compared with women showing a significant decrease was 6.3 to >100 for
the serum assay and 7.7–22.7 for the urine assay in the three studies
(Table 2
). The odds ratio for significant bone mass gain (-BMD
>1%) for women showing a substantial decrease in CrossLaps
concentration compared with women with a small decrease or an increase
in CrossLaps concentration was 3.8–33.3 for the serum measurements,
and 6.7–41.0 for the urinary CrossLaps measurements (Table 2
). All
odds ratios were calculated using cutoff values for significant changes
in CrossLaps concentration as determined by ROC analysis (Table 1
), and
all odds ratios were highly significant. This again supports the
observation that changes measured in the CrossLaps assays may be used
as a reliable measure of BMD response.
Stratification of women according to either change in serum CrossLaps
concentration or average on-study serum CrossLaps concentration
demonstrated a significant difference between average -BMD in the
quartiles (not shown) in accordance with the good correlation between
the change in serum CrossLaps concentration and -BMD (Table 1
and
Fig. 5
). Similar results were obtained when the stratification was
based on the response in urinary CrossLaps measurements. This is in
accordance with results reported for another urinary marker of
bone resorption measuring N-telopeptides of type I collagen
(30).
Baseline CrossLaps concentrations were also associated with BMD changes
and response to therapy. Among the HRT-treated women stratified
according to baseline serum CrossLaps concentration, the lowest
quartile showed a significantly lower response to the therapy than the
women in the highest quartile (Table 2
). When the stratification was
performed on the basis of the baseline urinary CrossLaps measurements,
the highest quartile did show a more pronounced effect of the therapy
compared with the lowest quartile, but the difference was not
statistically significant (Table 2
). When the relative risk of losing
bone if not treated with HRT was calculated for women in the highest
quartile of baseline CrossLaps concentration, stratification according
to both serum and urinary measurements showed a significantly increased
relative risk of bone loss (2.7- and 2.5-fold, respectively), compared
with the women in the lowest quartile of baseline CrossLaps
concentration, who had no significantly increased risk of losing bone
if left untreated.
A similar stratification was not possible for the tibolone and ibandronate studies because of the limited number of individuals in each group. However, the pronounced and highly significant response to therapy, the relatively high correlation to spine BMD measurements, and high sensitivity and specificity for predicting net gain or loss in spine BMD observed in all three studies with both urinary and serum CrossLaps measurements suggest that both these assays are suitable for monitoring antiresorptive therapy and that they may also be used for selecting individuals with high bone resorption who are at increased risk of developing osteoporosis.
In conclusion, the studies reported here suggest that follow up of therapy by measurement of CrossLaps concentration provides a rapid and equally predictive measure of the response in the individual patients to the antiresorptive therapy compared with traditional BMD measurements. The data demonstrate that serum CrossLaps measurements have a clinical value for assessment of the outcome of antiresorptive therapy of postmenopausal women.
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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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1 chain of type I collagen. J Biol Chem 1997;272:9755-9763.
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P. Szulc, F. Munoz, B. Claustrat, P. Garnero, F. Marchand, F. Duboeuf, and P. D. Delmas Bioavailable Estradiol May Be an Important Determinant of Osteoporosis in Men: The MINOS Study J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 192 - 199. [Abstract] [Full Text]
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S. L. Greenspan, H. N. Rosen, and R. A. Parker Early Changes in Serum N-Telopeptide and C-Telopeptide Cross-Linked Collagen Type 1 Predict Long-Term Response to Alendronate Therapy in Elderly Women J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3537 - 3540. [Abstract] [Full Text]
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F. Pagani and M. Panteghini Biological Variation in Serum Type I Collagen Carboxy-Terminal Telopeptide Concentrations Clin. Chem., September 1, 2000; 46(9): 1439 - 1440. [Full Text] [PDF]
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 E.-E. Baulieu, G. Thomas, S. Legrain, N. Lahlou, M. Roger, B. Debuire, V. Faucounau, L. Girard, M.-P. Hervy, F. Latour, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue PNAS, April 11, 2000; 97(8): 4279 - 4284. [Abstract] [Full Text] [PDF]
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S. Christgau Circadian Variation in Serum CrossLaps Concentration Is Reduced in Fasting Individuals Clin. Chem., March 1, 2000; 46(3): 431 - 431. [Full Text] [PDF]
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M. Wichers, E. Schmidt, F. Bidlingmaier, and D. Klingmuller Diurnal Rhythm of CrossLaps in Human Serum Clin. Chem., October 1, 1999; 45(10): 1858 - 1860. [Full Text] [PDF]
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N. B. Watts Clinical Utility of Biochemical Markers of Bone Remodeling Clin. Chem., August 1, 1999; 45(8): 1359 - 1368. [Abstract] [Full Text] [PDF]
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M. L. Traba, J. A. Calero, C. Mendez-Davila, C. Garcia-Moreno, and C. de la Piedra Different Behaviors of Serum and Urinary CrossLaps ELISA in the Assessment of Bone Resorption in Healthy Girls Clin. Chem., May 1, 1999; 45(5): 682 - 683. [Full Text] [PDF]
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, 0 mg/day; 
, 1.25
mg/day; 
, 2.5 mg/day.
, 1 mg/day; 
, 2.5 mg/day; 
, 5 mg/day.
-1%) over
the 24-month study period. The women were grouped according to their