Clinical Chemistry 51:12
2312–2317 (2005)
Endocrinology and
Metabolism
Serum Concentrations of Cross-Linked
N-Telopeptides of Type I Collagen: New Marker
for Bone Resorption in Hemodialysis Patients
Yoshifumi Maeno,2 Masaaki Inaba,1* Senji Okuno,2 Tomoyuki Yamakawa,2
Eiji Ishimura,1 and Yoshiki Nishizawa1
Background: Urinary cross-linked N-telopeptide of
type I collagen (NTX) is a reliable bone resorption
marker in patients with metabolic bone disease. We
assessed a clinically available serum NTX assay suitable
for anuric patients on hemodialysis (HD).
Methods: Serum concentrations of NTX, C-terminal
telopeptide of type I collagen (␤-CTX), pyridinoline
(PYD), and deoxypyridinoline (DPD) were determined
as bone resorption markers, and those of bone alkaline
phosphatase (BAP) and intact osteocalcin (OC) as bone
formation markers, in 113 male HD patients (mean age,
59.3 years; mean HD duration, 67.7 months). Each patient’s bone mineral density (BMD) in the distal third of
the radius was measured twice, with a 2-year interval
between measurements, by dual-energy x-ray absorptiometry.
Results: Serum NTX correlated significantly with
␤-CTX, PYD, DPD, BAP, and intact OC. NTX, as well as
␤-CTX, PYD, DPD, BAP, and intact OC, correlated
significantly with BMD at the time of measurement.
NTX, ␤-CTX, and DPD correlated significantly with the
annual change in BMD during the 2-year period thereafter, in contrast to PYD, BAP, and intact OC. Patients in
the highest quartile of serum NTX concentrations
showed the fastest rate of bone loss. The sensitivity and
specificity for detecting rapid bone loss were 48% and
83%, respectively, for serum NTX.
1
Department of Metabolism, Endocrinology and Molecular Medicine,
Osaka City University Graduate School of Medicine, Osaka, Japan.
2
Shirasagi Hospital, Osaka, Japan.
*Address correspondence to this author at: Department of Metabolism,
Endocrinology and Molecular Medicine, Osaka City University Graduate
School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Fax
81-6-6645-3808; e-mail inaba-m@med.osaka-cu.ac.jp.
Received March 28, 2005; accepted September 23, 2005.
Previously published online at DOI: 10.1373/clinchem.2005.051524
Conclusion: Serum NTX may provide a clinically relevant serum assay to estimate bone turnover in HD
patients.
© 2005 American Association for Clinical Chemistry
Renal osteodystrophy is one of the major complications in
hemodialysis (HD)3 patients, leading to a substantial
increase in fracture rate and increased morbidity and
mortality (1 ). Bone mineral density (BMD) is widely used
to estimate bone fracture risk. In addition, evaluation of
bone turnover rate is established as an independent
predictor for bone fracture (2, 3 ) and future bone loss (4 ),
and measurements of bone metabolic markers are increasingly used to complement BMD measurements (5, 6 ).
Bone resorption markers are assumed to be superior to
bone formation markers for predicting future changes in
bone mass, well in advance of detection of BMD reductions (7 ). Measurement of cross-linked N-telopeptide of
type I collagen (NTX) in serum was recently approved in
Japan for clinical use as a bone resorption marker. Impaired urinary excretion precludes urinary measurement
of bone resorption markers in HD patients, but measurement of serum NTX may provide a good marker for the
bone resorption state in these patients. We recently reported (8 ) that the ␤-CrossLaps assay for serum Cterminal telopeptide of type I collagen (␤-CTX) (9 –11 )
provides values that are no less significant than those for
pyridinoline (PYD) and deoxypyridinoline (DPD), 2 commonly used serum bone resorption markers, in assessing
bone metabolism in HD patients. Because NTX is derived
from a different part of the same type I collagen as ␤-CTX
3
Nonstandard abbreviations: HD, hemodialysis; BMD, bone mineral density; NTX, cross-linked N-telopeptide of type I collagen; ␤-CTX, C-terminal
telopeptide of type I collagen; PYD, pyridinoline; DPD, deoxypyridinoline;
BAP, bone alkaline phosphatase; OC, osteocalcin; PTH, parathyroid hormone;
and BCE, bone collagen equivalent(s).
2312
Clinical Chemistry 51, No. 12, 2005
(the NH2 and COOH termini for NTX and ␤-CTX, respectively), it is important to determine the significance of
serum NTX as a bone resorption marker in HD patients.
We assessed the performance of serum NTX as a bone
resorption marker in HD patients, compared with other
established markers of bone resorption (␤-CTX, PYD, and
DPD) and bone formation [bone alkaline phosphatase
(BAP) and intact osteocalcin (OC)], by examining the
correlation of NTX with other markers and with the rate
of bone loss over a subsequent 2-year period.
Patients and Methods
patients
A total of 113 patients maintained on HD at Shirasagi
Hospital were enrolled. Informed consent to the study
protocol was obtained from each patient. Participation
was restricted to male patients to avoid the influence of
the menstrual cycle and menopause on bone metabolism.
Underlying kidney diseases were as follows: diabetic
nephropathy (n ⫽ 31), chronic glomerulonephritis (n ⫽
52), nephrosclerosis (n ⫽ 8), polycystic kidney disease
(n ⫽ 3), other diseases (n ⫽ 5), and unknown diseases
(n ⫽ 14). None of the patients had a past history of
parathyroidectomy or renal transplantation, and all patients were free of significant acute illness during the
protocol period of 2 years. They also had neither a past
history of fracture nor radiographic evidence of vertebral
or rib fracture, and the possibility of past exposure to
aluminum was negated in all of the participants. Because
bone biopsy was not performed, adynamic bone disease
could not be ruled out in the study patients. The active
vitamin D derivatives calcitriol or alfacalcidiol were given
orally to 55 patients, with the daily dose unchanged
during the study period. None of the patients received
any other medication that might affect calcium metabolism, such as ipriflavone, vitamin K, or aluminum hydroxide. Patients underwent HD 3 times a week in sessions of
4 h each, performed with a hollow-fiber dialyzer and
dialysate containing 3.0 mEq/L calcium. BMD was measured twice for all patients, and measurement of serum
markers for bone metabolism was performed at the time
of the first BMD measurement.
biochemical markers for calcium and bone
metabolism
A blood sample collected from the arteriovenous fistula
immediately before a morning dialysis session on March
18 and 19, 2002, was kept on ice for 1 h and then
centrifuged at 1000g for 10 min. The serum obtained was
stored in aliquots at ⫺20 °C until assayed, with measurements made immediately after thawing. NTX and other
biochemical bone markers were measured in the same
assay run ⬃1 year after sample collection. Although blood
collection in the early morning after overnight fasting is
important in persons with normal kidney function, the
influence of diurnal variation seems less in HD patients
whose serum NTX concentration exceeds the normal
2313
value by 6.2-fold (as found in the current study), because
impaired urinary excretion leads to NTX accumulation in
serum. Furthermore, because the effect of dietary collagen
intake on serum NTX is negligible (12 ), blood samples for
determination of serum NTX were collected between 0800
and 1000 in the morning, after the patients had eaten
breakfast.
Biochemical markers for calcium metabolism were
measured as described previously (13–15 ). Serum parathyroid hormone (PTH) was measured by an IRMA
(Allegro Intact PTH; Nichols Institute) (16, 17 ) with an
intraassay CV for PTH of 4.8% (13 ). Serum NTX was
measured by ELISA (Osteomark NTX serum; Ostex International) (18, 19 ) with an intraassay CV of 4.6%. Serum
␤-CTX was determined by an Elecsys ␤-CrossLapsTM
serum assay (Roche Diagnostics) (9 ) with an intraassay
CV of 2.6% (9 ). Serum PYD and DPD were measured by
HPLC (20 ) with intraassay CVs of 1.3% for serum PYD
and 6.8% for serum DPD (21 ). Serum BAP and intact OC
were measured with an enzyme immunoassay (ALKPHASE-B; Metra Biosystems) (22 ) and with a 2-site IRMA
(Mitsubishi Kagaku Bioclinical Laboratories), respectively. The intraassay CVs for BAP and intact OC were
2.2% (13 ) and 6.3%, respectively (23 ).
bmd measurement
Measurement of BMD in the distal third of the radius by
dual-energy x-ray absorptiometry (QDR-4500; Hologic
Inc.) was performed 21–24 h after completion of an HD
session. Serum measurements of bone markers were performed within 6 months of the first BMD measurement.
The second BMD measurement was performed ⬃2 years
after the first measurement, and the BMD change is
expressed as the mean annual change in BMD over the
2-year period.
statistical analysis
Data were analyzed with use of the StatView 5.0 J
program (Abacus Concepts, Inc.). Correlation coefficients
were calculated by simple regression analysis after logarithmic transformation of bone marker data. Comparisons
of the change in BMD in the distal third of the radius
between marker concentration quartiles were performed
by one-way ANOVA with the Fisher protected leastsignificant difference multiple comparison test as a post
hoc test. To determine the sensitivity, specificity, and
positive and negative predictive values of serum bone
markers for prediction of rapid bone loss, the patients
were grouped into quartiles according to the rate of BMD
change, and the correlation of increased bone marker
values (the highest quartile) with the highest bone loss
quartile was examined. The highest bone loss quartile was
chosen for this comparison because there is no generally
accepted clinical cutoff point that defines excessive bone
loss in male HD patients. The Youden index was calculated by combination of the sensitivity and specificity
2314
Maeno et al.: Serum NTX in HD Patients
(sensitivity ⫹ specificity ⫺ 1). P values ⬍0.05 were
considered statistically significant.
Table 2. Serum biochemical markers of bone turnover.
Mean (SD)
Results
clinical characteristics of hd patients
The baseline characteristics of the male HD patients are
shown in Table 1. The mean (SD) age of the participants
was 59.3 (11.1) years (range, 26 –79 years) and the HD
duration was 67.7 (32.2) months (range, 17–142 months).
NTX, nmol/L BCE 112.1 (105.3)
␤-CTX, ␮g/L
1.62 (1.04)
PYD, nmol/L
51.5 (28.9)
DPD, nmol/L
9.6 (6.5)
BAP, U/L
23.7 (13.0)
Intact OC, ␮g/L
44.2 (47.1)
Intact PTH, ng/L 225.3 (226.7)
Range
15.0–675.0
0.31–5.69
14.2–191.8
2.3–50.0
10.5–101.0
2.1–319.0
9.3–1148.0
Highest
quartile
Reference
interval
ⱖ151.0 9.3–18.0
ⱖ2.29 0.05–0.65
ⱖ58.1
2.0–3.6
ⱖ12.3
1.5–2.3
ⱖ27.7 10.2–24.6
ⱖ61.9
3.1–12.7
ⱖ298.1 15.4–60.0
serum ntx and other bone markers in hd patients
The mean serum NTX value in the HD patients was 112.1
nmol of bone collagen equivalents (BCE) per liter (range,
15.0 – 675.0 nmol/L BCE), 6.2-fold higher than the upper
reference value of 18.0 nmol/L BCE, as we reported
previously in a study of 192 healthy men (24 ). Serum NTX
concentrations were above the upper reference limit in
112 (99.1%) of 113 patients. The mean concentration of
serum ␤-CTX was 1.62 ␮g/L, 4.4-fold higher than the
value of 0.37 ␮g/L reported in 25 apparently healthy men
(25 ). The mean concentrations of serum PYD and DPD
were 51.5 and 9.6 nmol/L, 18.4- and 5.1-fold higher than
the respective reference values of 2.8 (0.8) and 1.9 (0.4)
nmol/L reported for healthy individuals (20 ). The mean
serum BAP was 23.7 U/L, close to the reference value of
24.9 (7.0) U/L reported in healthy individuals (22 ). The
mean serum intact OC was 44.2 ␮g/L, 6.5-fold higher
than the value of 6.8 (2.4) ␮g/L reported in healthy
individuals. Serum BAP and intact OC concentrations
were above the respective upper reference limits in
37 (32.7%) and 87 (77.0%) of the 113 patients, respectively.
The mean (SD), range, and highest quartile values for
each marker are listed in Table 2.
correlation of serum ntx with other bone markers
As shown in Fig. 1 of the Data Supplement that accompanies the online version of this article at http://www.
clinchem.org/content/vol51/issue12/, serum NTX correlated significantly with serum ␤-CTX (r ⫽ 0.929; P
⬍0.0001) and the 2 other bone resorption markers, PYD
(r ⫽ 0.793; P ⬍0.0001) and DPD (r ⫽ 0.919; P ⬍0.0001).
Serum NTX also showed significant correlations with
intact PTH (r ⫽ 0.735; P ⬍0.0001) and the bone formation
markers BAP (r ⫽ 0.697; P ⬍0.0001) and intact OC (r ⫽
0.776; P ⬍0.0001).
Table 1. Clinical characteristics of 113 male HD patients.
Age, years
HD duration, months
Body weight, kg
Height, cm
BMI,a kg/m2
Calcium, mg/L
Phosphorus, mg/L
a
BMI, body mass index.
Mean (SD)
Range
59.3 (11.1)
67.7 (32.2)
58.2 (9.0)
165 (6)
21.4 (2.7)
90 (7)
57 (16)
26–79
17–142
38.8–82.7
148–183
15.2–32.3
72–110
23–102
correlation of serum ntx and other bone
markers with bmd in distal third of the radius
During the 2 years of the study period, the patients
suffered significant bone loss in the distal third of the
radius, with BMD decreasing from 0.696 (0.081) to
0.685 (0.085) g/cm2 (P ⬍0.0001) with a mean annual rate
of bone loss of 0.74 (1.77)%. Lumbar spine BMD did not
change appreciably, from 0.709 (0.138) to 0.677 (0.169)
g/cm2 (P ⫽ 0.126). Serum NTX correlated significantly in
a negative manner with the first measurement of BMD in
the distal third of the radius (r ⫽ ⫺0.372; P ⬍0.0001) when
serum bone markers were determined (Fig. 2 in the online
Data Supplement). BMD in the distal third of the radius
was also significantly and negatively correlated with
serum intact PTH (r ⫽ ⫺0.270; P ⫽ 0.0038), ␤-CTX (r ⫽
⫺0.340; P ⫽ 0.0002), PYD (r ⫽ ⫺0.286; P ⫽ 0.0022), DPD
(r ⫽ ⫺0.371; P ⬍0.0001), BAP (r ⫽ ⫺0.334; P ⫽ 0.0003),
and intact OC (r ⫽ ⫺0.300; P ⫽ 0.0013). Lumbar spine
BMD did not correlate with either PTH or any of the bone
markers (data not shown).
Of particular interest, serum NTX (r ⫽ ⫺0.236; P ⫽
0.0118), ␤-CTX (r ⫽ ⫺0.285; P ⫽ 0.0022), and DPD (r ⫽
⫺0.188; P ⫽ 0.0465) showed a significant correlation with
annual BMD change in the distal third of the radius
during the 2-year study period, in contrast to the lack of
significant correlation with any of the other markers:
serum intact PTH (r ⫽ ⫺0.087), PYD (r ⫽ ⫺0.175), BAP
(r ⫽ ⫺0.181), and intact OC (r ⫽ ⫺0.020; see Fig. 3 in the
online Data Supplement).
annual bmd change in distal third of the
radius in quartiles based on serum
concentrations of ntx and other bone markers
Patients were divided into quartiles on the basis of serum
NTX concentrations and other bone markers, and the
annual rate of BMD reduction in the distal third of the
radius was compared among these quartiles (see Fig. 4 in
the online Data Supplement). The quartiles for a given
bone marker are referred to as Q1, Q2, Q3, and Q4, with
Q1 representing the 25% of patients with the lowest
concentration of that particular marker. The mean BMD
change in each serum NTX quartile (P ⫽ 0.033) and each
␤-CTX quartile (P ⫽ 0.038) were statistically different,
whereas quartiles based on the serum intact PTH concentration and on other bone markers showed no statistically
2315
Clinical Chemistry 51, No. 12, 2005
significant differences in BMD change. The percentage
reduction in BMD in the distal third of the radius was
0.37 (1.44)% per year in the lowest serum NTX quartile
(Q1), but was 1.59 (2.21)% per year in the highest NTX
quartile (Q4), with statistically significant differences between Q4 and all other NTX quartiles (Q1 vs Q4, P ⬍0.01;
Q2 vs Q4, P ⬍0.05; Q3 vs Q4, P ⬍0.05).
serum concentrations of ntx and other bone
markers in quartiles based on annual bmd
change in distal third of the radius
Patients were divided into quartiles on the basis of annual
BMD change in the distal third of the radius over a 2-year
period. The 25% of patients showing the highest BMD
reduction (Q4) was defined as the fast bone loss group,
and the remaining patients were defined as the slow bone
loss group (Q1–Q3). We compared the mean concentrations of bone markers in the fast bone loss group and the
slow bone loss group (see Fig. 5 in the online Data
Supplement). The serum NTX concentrations were
151.1 (23.7) and 98.7 (10.2) nmol/L BCE in the fast and
slow bone loss groups, respectively. Both serum NTX
(P ⫽ 0.0201) and ␤-CTX (P ⫽ 0.0021) were significantly
different between the 2 groups of patients, in contrast to
intact PTH and the other bone markers.
sensitivity and specificity of the serum ntx assay
Shown in Table 3 are the sensitivity, specificity, and
positive and negative predictive values of the highest
quartile concentration of each marker for identification of
HD patients in the highest quartile of BMD reduction in
the distal third of the radius (loss ⱖ1.66%/year). The
sensitivities of the highest quartiles as cutoff points for
identification of those HD patients who had lost bone
mass in the distal third of the radius at a rate of more than
1.66%/year during the preceding 2 years were 48% for
NTX, 45% for ␤-CTX, 41% for PYD, and 38% for DPD. The
specificities for identification of those HD patients who
had lost bone mass at no more than 1.66%/year were
high: 83% for NTX, 82% for ␤-CTX, 81% for PYD, and 80%
for DPD. The Youden index obtained for NTX (0.31) was
greater than the indexes for ␤-CTX (0.27), PYD (0.22), and
DPD (0.18). The positive predictive values of serum bone
marker concentrations in the highest quartile were 50%
for NTX, 46% for ␤-CTX, 43% for PYD, and 39% for DPD,
and the positive predictive values for increased bone
formation markers were 39% for BAP and 32% for intact
OC. The negative predictive values for serum marker
concentrations below the highest quartile were 82% for
NTX, 81% for ␤-CTX, 80% for PYD, 79% for DPD, 79% for
BAP, and 76% for intact OC.
Discussion
We compared serum NTX, a newly identified biochemical
marker for bone resorption, with established biochemical
markers of bone resorption (PYD, DPD, and ␤-CTX) and
bone formation (BAP and intact OC) as indicators for
Table 3. Sensitivity, specificity, Youden index, and positive
and negative predictive values of highest quartile marker
concentrations for identification of male HD patients with
BMD loss >1.66% per year in the distal third of the radius
(highest quartile for rate of BMD loss).
NTX
␤-CTX
PYD
DPD
BAP
Intact OC
Intact PTH
Sensitivity,a %
Specificity,b %
Youden
indexc
PPV,d,e %
NPV,f %
48
45
41
38
38
38
31
83
82
81
80
80
77
75
0.31
0.27
0.22
0.18
0.18
0.08
0.03
50
46
43
39
39
32
28
82
81
80
79
79
76
75
a
Proportion of male HD patients with rapid bone loss (ⱖ1.66% per year in the
distal third of the radius) with marker concentrations in the highest quartiles of
bone marker concentrations.
b
Proportion of male HD patients with slow bone loss (⬍1.66% per year) with
marker concentrations below the highest quartiles of bone marker concentrations.
c
Sensitivity ⫹ specificity ⫺ 1.
d
PPV, positive predictive value; NPV, negative predictive value.
e
Incidence of rapid bone loss among male HD patients with marker concentrations in the highest quartiles of bone marker concentrations.
f
Incidence of slow bone loss among male HD patients with marker concentrations below the highest quartiles of bone marker concentrations.
BMD loss in male HD patients. We observed a good
correlation of serum NTX with serum concentrations of
intact PTH and other bone markers (Fig. 1 in the online
Data Supplement) and a significant and negative correlation of serum NTX with BMD in the distal third of the
radius, as with other bone markers (Fig. 2 in the online
Data Supplement). Of interest, only serum NTX, ␤-CTX,
and DPD exhibited a significant correlation with annual
BMD reduction in the distal third of the radius over a
2-year period. Because serum bone markers theoretically
reflect systemic bone metabolism and the bone surface at
the distal radius is quite small because of the preferential
distribution of cortical bone at the indicated site, the
correlation of serum markers with BMD or its annual
change at the distal third of the radius should be weak.
Furthermore, when the patients were divided into 4
groups on the basis of serum concentrations of bone
markers, increased concentrations of serum NTX and
␤-CTX, but not other bone markers, were significantly
associated with a faster rate of bone loss in the distal third
of the radius during the 2-year period (Fig. 4 in the online
Data Supplement). Serum NTX and ␤-CTX differed significantly between the groups of patients with fast and
slow bone loss, whereas other bone markers did not (Fig.
5 in the online Data Supplement), suggesting that serum
NTX, in addition to serum ␤-CTX, is the best marker for
assessing the bone metabolic state and thus is the best
predictor for the rate of bone loss or fracture risk.
It is recommended that BMD be measured at the
forearm in patients with uremic hyperparathyroidism
because of the preferential effect of PTH on cortical bone
2316
Maeno et al.: Serum NTX in HD Patients
(26, 27 ). Although lumbar spine BMD is usually measured in anterior–posterior projection in osteoporotic patients because of superior precision and reproducibility, it
may be complicated by the frequent occurrence of vascular calcification of the abdominal aorta in HD patients
(28 ). Indeed, the patients in the present study showed a
significant annual bone loss of 0.74% at the forearm but
not at the lumbar spine BMD (data not shown), as
described previously (29, 30 ).
Type I collagen is degraded during the bone resorption
process, liberating small fragments, such as NTX, ␤-CTX,
PYD, and DPD, into the blood and then into the urine
(5, 31 ) and making serum and urinary concentrations of
these fragments available as biochemical markers of bone
resorption. In patients with anuria, fragments derived
from cleavage of type I collagen accumulate in serum
because of impaired urinary excretion. Indeed, the mean
serum NTX concentration in male HD patients was 6.2fold higher than the upper reference limit for healthy
individuals. Some bone formation markers, such as BAP,
remained within the reference intervals (32 ), but serum
N-terminal propeptide of type I collagen, another bone
formation marker, showed a 1.34-fold increase (33 ). Although bone markers accumulate in serum, except for
serum BAP, because of impaired secretion into urine, a
significant correlation persists between bone markers and
histomorphometric indexes in HD patients (34, 35 ),
clearly indicating that the rate-limiting step in determining serum concentrations of bone markers is the release of
these molecules from bone, supporting the clinical utility
of these molecule as bone markers in hemodialyzed
patients.
The results of the current study indicate that only
serum NTX, ␤-CTX, and DPD are correlated significantly
with the annual change in BMD in the distal third of the
radius. The NTX and ␤-CTX epitopes, which are preferentially liberated from type I collagen in bone by osteoclastic hydrolysis (36 ), suggest bone specificity. PYD
occurs in many tissues outside bone, and DPD is also
found in other tissues, such as dentine, skeletal muscle,
and the aorta. Furthermore, assaying of serum PYD and
DPD is problematic with regard to sample preparation
and the stability of internal standards. Because NTX can
be measured by ELISA with much smaller assay CVs, the
stable assay method may also improve the precision of
NTX measurements. Indeed, in clinical practice in osteoporosis, serum NTX is reported to be superior to other
markers because of its small assay CV and greater suppression rate after treatment with bone antiresorptive
drugs (37 ).
Few studies have examined the clinical usefulness of
serum NTX compared with other bone metabolic markers
in HD patients. Because serum BAP is unaffected by renal
dysfunction and is thus useful in HD patients, serum BAP
in HD patients remained within the reference interval
(Table 2). However, the significant correlations of serum
NTX with serum intact PTH and other bone markers (see
Fig. 1 in the online Data Supplement) indicate that the
increase in serum NTX is also related to enhanced bone
turnover attributable to secondary hyperparathyroidism.
Biochemical markers of bone turnover are used to
predict future bone loss in osteoporotic patients
(4, 38, 39 ). We found that serum NTX and ␤-CTX, but not
intact PTH or other bone markers such as PYD, DPD,
BAP, and intact OC, correlated significantly with the rate
of forearm bone loss during a subsequent 2-year period in
HD patients (see Fig. 3 in the online Data Supplement).
Furthermore, we found a strong relationship between the
quartile distribution of serum NTX concentrations and
faster rates of cortical bone loss, with patients in the
highest quartile of NTX concentrations showing a significantly faster cortical bone loss than those in the lowest
quartile (see Fig. 4 in the online Data Supplement).
The sensitivity, specificity, and positive and negative
predictive values of serum NTX were as high as those of
serum intact PTH and other bone markers (Table 3). These
data indicate that serum NTX might provide a more
relevant prediction of the rate of cortical bone loss in HD
patients. For all bone markers, including NTX, the sensitivity and positive predictive value were relatively lower
but the specificity and the negative predictive value were
good. The Youden index for NTX was 1.5-fold better than
the indexes for PYD, DPD, and BAP, and more than 4-fold
better than the indexes for intact OC and intact PTH,
further suggesting that measurement of NTX might be
more useful than other bone resorption markers for
predicting cortical bone loss in HD patients.
In summary, we found that serum NTX, a newly identified biochemical marker of bone resorption, is equivalent
to or better than other established serum bone markers for
predicting the rate of forearm bone loss over a subsequent
2-year period in male HD patients. Use of serum NTX as
a bone resorption marker for detection of rapid cortical
bone loss may also be an improvement over use of intact
PTH.
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