Sie sind auf Seite 1von 9

J Orthop Sci (2007) 12:219226

DOI 10.1007/s00776-007-1113-6
Original article
Change of cross-linked telopeptide of type I collagen (ICTP) and
other bone resorption markers in patients with bone fragility fractures
Kenji Takahara
1
, Mikio Kamimura
2
, Hiroyuki Hashidate
1
, Shigeharu Uchiyama
1
, and Hiroyuki Nakagawa
1
1
Department of Orthopedic Surgery, Suwa Red Cross Hospital, Suwa, Japan
2
Center of Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Nagano, Japan
Abstract
Background. The serum concentration of cross-linked telo-
peptide of type I collagen (ICTP) has been reported to be a
useful marker and for both diagnosis and monitoring of bone
metastasis. This study was performed to clarify the changes in
various bone turnover markers, including ICTP, after bone
fragility fracture.
Methods. Seventy-six bone fragility fracture patients (14 men
and 62 postmenopausal women; mean age, 77.0 years) were
evaluated for bone resorption markers, including serum ICTP.
We measured urinary N-terminal telopeptides of type I colla-
gen (NTX) several times after fracture. Furthermore, serum
ICTP, serum NTX, urinary deoxypyridinoline (DPD), and
urinary C-telopeptide-cross-linked type I collagen (CTX)
were measured at the times of both minimum and maximum
urinary NTX.
Results. Urinary NTX was increased signicantly from 86.4
57.9 to 214.3 137.2 nmol BCE/mmol Cr following fracture.
Serum ICTP showed a similar signicant increase from 7.6
4.7 to 10.4 5.5 ng/ml in bone fragility fracture patients. Fur-
thermore, other markers also showed similar increases. The
level of increase in urinary NTX (148.0%) was especially high
compared with other bone resorption markers. On the other
hand, the level of increase in serum ICTP (36.8%) was similar
to that in serum NTX (39.8%). Serum ICTP levels were sig-
nicantly correlated with other bone resorption markers, with
an especially strong correlation between serum ICTP and
serum NTX (r = 0.647, P < 0.001). The percentage of cases in
which ICTP exceeded the cutoff value for suspected bone
metastasis in postmenopausal women was 73.6%.
Conclusions. The value of ICTP increases with bone fragility
fracture and is correlated with other bone resorption markers,
and ICTP obviously exceeded the reference value as com-
pared with other bone resorption markers.
Introduction
The differential diagnosis of bone metastases usually
involves initial bone scintigraphy screening, and bone
X-ray computed tomography (CT) and/or magnetic
resonance imaging (MRI) are used for further evalua-
tion.
13
Although the sensitivity of bone scintigraphy is
high, its specicity is not satisfactory because of the
occurrence of false positives caused by insufciency
fracture (IF).
4
Several biochemical markers of bone formation and
bone resorption have been developed recently. Break-
down products of type I collagen are usually used as
sensitive bone resorption markers for evaluation of
bone metastasis, osteoporosis, and bone metabolic dis-
ease. We used urinary N-terminal telopeptides of type
I collagen (NTX) to monitor bone resorption because
urinary NTX was reported to be a sensitive and specic
marker of bone resorption.
5,6
We reported previously
that serum bone-specic alkaline phosphatase (BAP)
and urinary NTX levels were signicantly increased in
IF. Furthermore, we attempted differential diagnosis of
IF and bone metastasis using these markers of bone
turnover, but this proved quite difcult.
7
The serum concentration of the cross-linked carboxy-
terminal telopeptide of type I collagen (ICTP), a deg-
radation product of type I collagen, has been reported
to be a useful marker for predicting survival and for the
diagnosis and monitoring of bone metastasis in patients
with malignant tumors.
811
Breakdown of collagen in
vivo is thought to occur through two biochemical path-
ways, i.e., metabolism by phagocytes and enzymolysis.
Bone resorption in physiological remodeling is achieved
by phagocytes, and cathepsin K plays an important role
in this pathway. On the other hand, enzymolysis by
proteases is seen under conditions of excessive meta-
bolic turnover in bone metastasis.
1214
Serum ICTP lev-
els are increased in osteoclastic disorders, such as bone
metastasis of malignant tumors, multiple myeloma, and
Offprint requests to: K. Takahara, Department of Orthopedic
Surgery, Ina Central Hospital, Ina, Nagano 396-8555, Japan
Received: September 14, 2006 / Accepted: January 10, 2007
220 K. Takahara et al.: ICTP in patients with fractures
rheumatoid arthritis.
10,15,16
Generally, ICTP does not in-
crease under conditions of high turnover in osteoporo-
sis through cathepsin K.
1214
Recently, many authors have reported changes
in bone turnover markers in cases of various frac-
tures.
7,1727
However, there have been few reports de-
scribing the changes in ICTP in patients with bone
fracture.
20,28
Furthermore, there have been no reports
regarding the changes in ICTP and various other bone
turnover markers with bone fragility fracture.
The present study was performed to determine the
inuence of bone fragility fractures on changes in levels
of various bone resorption markers, including ICTP, in
elderly patients with osteoporosis.
Materials and methods
The initial study population consisted of 82 consecutive
patients with bone fragility fracture admitted to our
hospital between January 2002 and January 2004 in
whom bone turnover markers were measured at least
twice. Patients with rheumatoid arthritis, corticosteroid
therapy, other disorders affecting bone turnover, and
renal function disorder were excluded from the study.
The nal diagnosis of bone fragility fracture was made
retrospectively based on the clinical course. When pain
decreased over time, and such a state lasted for over 6
months, we diagnosed the patients as having had a frac-
ture. Finally, 76 patients (14 men and 62 postmeno-
pausal women; mean age, 77.0 years; range, 5696 years)
were included in this study. Twenty-one femoral neck
fractures and 23 trochanteric fractures were treated sur-
gically, and the remaining 28 vertebral, 2 sacral, and 2
pelvic fractures were treated conservatively by bed
rest.
Urinary NTX was measured at the time of consulta-
tion and several times after fracture (average, 6.9 times;
range, 415 times) as a marker of bone resorption in
each patient. Furthermore, the levels of serum ICTP,
serum NTX, urinary deoxypyridinoline (DPD), and uri-
nary C-telopeptide-cross-linked type I collagen (CTX)
were measured in stored samples when urinary NTX
was at the minimum and maximum levels. We dened
and calculated the increase rate (IR) of each bone re-
sorption marker associated with the changes in urinary
NTX.
IR
B A
A
% % ( ) =

( ) 100
where A is the value of bone resorption marker at mini-
mum urinary NTX and B is the value of bone resorption
marker at maximum urinary NTX.
Further, we divided these cases into those with in-
creasing urinary NTX and those with decreasing urinary
NTX, and examined the duration of measurement after
fracture.
Blood and urine samples were stored at 20C until
analysis. All samples were obtained after receiving for-
mal written consent from the patients, and the research
was carried out in accordance with the stipulations of
the Declaration of Helsinki. The levels of NTx (OSTE-
OMARK; Osteox International, Seattle, WA, USA),
DPD (METRAR DPD EIA Kit; Quidel Corporation,
San Diego, CA, USA), and CTX (FRELISA Cross-
Laps; Nordic Bioscience Diagnostics A/S, Herlev,
Denmark) levels were measured by enzyme-linked
immunosorbent assay (ELISA). ICTP was assessed in
serum, which was collected at the same time as the urine
sample, using a radioimmunoassay (RIA) kit. The
immunoassay was performed by SRL Inc. (Tokyo,
Japan).
The data are shown as the mean standard devia
-
tion. Differences in serum ICTP and other bone turn-
over markers in all patients between minimum and
maximum values were evaluated using paired t test or
Wilcoxons t test. The correlation of each marker was
evaluated using the Spearman rank test. The rates to
exceed the cutoff values of bone resorption markers and
serum ICTP were compared using the
2
test. Statistical
evaluation was performed using StatView version 5.0
(SAS, Cary, NC). P < 0.05 was considered statistically
signicant.
Results
The characteristics and backgrounds of patients and
mean values of principal laboratory studies are listed in
Table 1. Overall results of bone turnover markers and
reference values
29,30
are given in Table 2.
Urinary NTX levels increased signicantly (P <
0.001), from 86.4 57.9 nmol BCE/mmol Cr to 214.3
137.2 nmol BCE/mmol Cr (Table 2, Fig. 1), and ICTP
levels measured at the same time increased signicantly
(P < 0.001), from 7.6 4.7 ng/ml to 10.4 5.5 ng/ml
associated with increases in urinary NTX in patients
with bone fragility fractures (Fig. 2). Other bone
resorption markers, such as serum NTX (23.6 11.6
to 33.0 14.2), urinary DPD (9.8 5.9 to 15.6 7.6),
and urinary CTX (416.5 300.5 to 850.7 611.2) also
increased signicantly (P < 0.001) associated with in-
creasing urinary NTX in bone fragility fracture patients
(Fig. 2).
IR of urinary NTX was 148.0%. In patients with bone
fragility fractures, urinary NTX clearly had high IR
in comparison with other bone turnover markers
(Table 2). However, among the serum bone resorption
markers, IR caused by the inuence of a fracture was
not remarkably high compared with urinary markers.
K. Takahara et al.: ICTP in patients with fractures 221
Table 1. Patient characteristics
No. of patients 76 Reference value
(FNF : TF : VF : SCF : PF) (21 : 23 : 28 : 2 : 2)
Male : female 14 : 62
Age (years) 77 8.4
Ca (mg/dl) 9.4 0.3 8.310.0
P (mg/dl) 3.6 0.3 2.54.7
BUN (mg/dl) 15.3 3.7 7.023.0
Cr (mg/dl) 0.6 0.1 0.50.9
Intact PTH (pg/ml) 39.0 20.1 1050
1,25(OH)
2
D
3

(pg/ml) 20.5 6.6 2060
Values are means SD
FNF, femoral neck fracture; TF, trochanteric fracture; VF, vertebral fracture; SCF, sacral frac-
ture; PF, pelvic fracture; PTH, parathyroid hormone
Table 2. Bone turnover marker in patients with bone fragility fracture
Sex Minimum Maximum IR (%) Reference value
Urinary NTX F 91.5 59.1 225.6 139.4 146.6 9.354.3
(nmol BCE/mmol Cr) M 64.1 48.1 164.5 118.8 156.6
F + M 86.4 57.9 214.3 137.2 148.0
Serum NTX F 24.2 12.9 32.6 13.0 34.7 7.516.5
(nmol BCE/l) M 23.6 9.3 34.8 19.1 47.5
F + M 23.6 11.6 33.0 14.2 39.8
Urinary DPD F 10.4 6.2 16.1 7.5 54.8 2.87.6
(nmol/mmol Cr) M 7.2 4.0 12.7 7.9 76.4
F + M 9.8 5.9 15.6 7.6 59.2
Urinary CTX F 441.5 299.6 887.8 633.9 101.1 40.3301.4
(g/mmol Cr) M 311.1 291.1 671.2 467.3 115.8
F + M 416.5 300.5 850.7 611.2 104.2
Serum ICTP F 7.4 4.8 9.8 4.9 32.4
(ng/ml) M 8.3 4.7 12.9 7.4 55.4
F + M 7.6 4.7 10.4 5.5 36.8 4.5
a
Values are means SD
NTX, N-terminal telopeptides of type I collagen; DPD, deoxypyridinoline; CTX, C-telopeptide cross-links type I collagen; ICTP, carboxy-
terminal telopeptide of type I collagen; IR, increase rate
a
Cutoff value
Furthermore, serum NTX IR (39.8%) was very small
and approximately similar to serum ICTP IR (36.8%).
With regard to urinary NTX maximum, 92.1% (71/76)
of patients were above the cutoff value for suspected
bone metastasis in postmenopausal women, suggesting
that these cases had bone metastasis or other bone dis-
eases. In serum ICTP, similar to urinary NTX, 90.8%
(69/76) of patients were above the cutoff value. How-
ever, there were few cases in which the values for other
bone resorption markers (serum NTX, urinary DPD,
urinary CTX) exceeded the cutoff values for suspected
bone metastasis in postmenopausal women (Table 3).
At minimum urinary NTX, the ratios exceeding the
cutoff value of bone resorption markers other than
ICTP were lower than 40%. On the other hand, serum
ICTP was 73.7% (56/76), which was signicantly high in
comparison with other bone resorption markers (P <
0.001) (Table 3).
We divided the cases into two groups showing an
increase or decrease in urinary NTX, and changes with
time after fracture are shown in Table 4. Urinary NTX
showed a peak increase from about 35 to 40 days after
fracture (Table 4).
Among the values measured, serum ICTP levels were
signicantly correlated with urinary NTX (r = 0.454,
P < 0.001). In the same way, serum NTX (r = 0.647, P <
0.001), urinary DPD (r = 0.405, P < 0.001), and urinary
CTX (r = 0.262, P = 0.0017) were signicantly correlated
with serum ICTP (Fig. 3). The strongest correlation
among all bone resorption markers examined was with
serum NTX. Other urinary bone resorption markers
were correlated with serum ICTP, but the correlation
coefcients were lower than that for serum NTX.
The foregoing ndings conrmed that bone resorp-
tion markers, including ICTP levels, were signicantly
correlated with other markers of bone resorption asso-
222 K. Takahara et al.: ICTP in patients with fractures
Fig. 1. Urinary N-terminal telopeptides of type I collagen
(NTX) levels in patients with bone fragility fracture at the
time of minimum and maximum values
Table 3. Rate to exceed cutoff value
F (n = 62) Minimum Maximum
M (n = 14) REC (No. of Pt.) REC (No. of Pt.) Cutoff value
Urinary NTX 38.2% (29/76) 92.1% (71/76)
F 40.3% (25) 96.8% (60) 89.0
M 28.6% (4) 78.6% (11) 66.2
Serum NTX 39.5% (33/76) 73.7% (57/76)
F 37.1% (23) 71.0% (44) 24.0
M 71.4% (10) 92.9% (13) 17.7
Urinary DPD 23.3% (22/76) 58.6% (45/76)
F 22.6% (14) 58.1% (36) 13.1
M 57.1% (8) 64.3% (9) 5.6
Urinary CTX 26.0% (20/76) 68.6% (49/76)
F 25.8% (16) 67.7% (42) 564.8
M 28.6% (4) 50.0% (7) 346.1
Serum ICTP F + M 73.7% (56/76) 90.8% (69/76) 4.5
REC, rate to exceed cutoff value; No. of Pt., number of patients that exceeded the cutoff value;
cutoff value, value suggesting bone metastasis in postmenopausal women or men; NTX, N-
terminal telopeptides of type I collagen; DPD, deoxypyridinoline; CTX, C-telopeptide cross-links
type I collagen; ICTP, carboxy-terminal telopeptide of type I collagen
many patients with bone fragility fractures, the serum
ICTP level exceeded the reference values, suggesting
bone metastasis even at the time of minimum urinary
NTX level.
Discussion
IF is a type of stress fracture that results from normal
stress occurring in bone with reduced elastic resistance
due to structural alterations of the bone, such as osteo-
penia, osteoporosis, or disorders of bone metabolism.
4

IF occurs frequent and silently in patients with osteo-
porosis.
31
Imaging techniques, especially bone scintig-
raphy, can be used for differential diagnosis of IF and
bone metastasis. However, discriminating between
bone metastases and IF is often difcult. Furthermore,
IF are often discovered when searching for bone
metastasis.
It has been reported that there are pyridinium-based,
cross-linking amino acids at the ends of the molecules
of the C-telopeptide-to-helix site or the N-telopeptide-
to-helix site in different types of collagen (type I,
type II, and type III).
6,32
Among these, type I collagen
is the major collagen species in the extracellular
matrix of most soft connective tissues and represents
more than 90% of the organic matrix of mineralized
bone.
33
Many authors reported that elevation of bone turn-
over markers, such as DPD, CTX, and NTX levels, are
useful for monitoring in patients with bone metastases
originating from prostate carcinoma, breast carcinoma,
and lung carcinoma.
8,9,16,3437
Recent studies suggested
that NTX is a more specic indicator of bone resorption
ciated with bone fragility fractures. The increase in se-
rum NTX caused by fracture was mild compared with
urinary NTX. In addition, the increase in serum ICTP
was similar to that of serum NTX. Furthermore, in
K. Takahara et al.: ICTP in patients with fractures 223
Fig. 2. Levels of other bone resorption
markers in patients with bone fragility
fractures at the time corresponding to the
minimum urinary NTX value. Serum
cross-linked telopeptide of type I colla-
gen (ICTP), serum NTX, urinary deoxy-
pyridinoline (DPD), and urinary
C-telopeptide-cross-linked type I colla-
gen (CTX) levels increased signicantly
associated with increases in urinary NTX.
The data are shown as the median and
percentile
than pyridinoline and DPD. Furthermore, many au-
thors have reported that as a bone resorption marker
NTX is the most sensitive predictor of bone meta-
stasis.
35,38
Therefore, we used urinary NTX to monitor
bone resorption for evaluation of osteoporosis, bone
metastasis, and other bone disorders. Previously, we
reported that these bone formation (BAP) and resorp-
tion markers (urinary NTX) are signicantly increased
in IF.
7
In addition, we attempted differential diagnosis
of IF and bone metastasis using serum BAP and urinary
NTX, but this proved very difcult.
7
Furthermore, we reported recently that bone turn-
over markers frequently exceeded the cutoff value
associated with back pain in elderly women.
17
We
speculated that bone turnover markers are affected
by unrecognized vertebral fractures. High values of
bone turnover markers do not usually indicate the pres-
ence of bone metastasis in elderly women with osteo-
porosis.
17
Therefore, in elderly patients with high levels
of bone turnover markers, differential diagnosis of
bone metastasis is both very important and quite
difcult.
Table 4. Measurement times of groups showing increases and decreases in urinary NTX
Urinary NTX increase Urinary NTX (nmol BCE/mmol Cr) 83.0 43.1 206.7 130.1
group (n = 43) Serum ICTP (ng/ml) 7.3 3.9 10.9 5.6
Days after fracture (day) 7.7 9.7 34.5 21.6
Urinary NTX decrease Urinary NTX (nmol BCE/mmol Cr) 214.1 138.8 101.0 102.2
group (n = 33) Serum ICTP (ng/ml) 9.6 5.4 8.1 5.7
Days after fracture (day) 40.6 38.3 172.3 112.8
Values are means SD
NTX, N-terminal telopeptides of type I collagen; ICTP, carboxy-terminal telopeptide of type I collagen
224 K. Takahara et al.: ICTP in patients with fractures
Fig. 3. Relationship between levels of
each serum and urinary bone resorption
marker and serum ICTP level in patients
with bone fragility fracture
Recently, a bone resorption assay has been devel-
oped based on the cross-linked peptides liberated dur-
ing type I collagen degradation.
8
Breakdown of collagen
is mediated by proteases in patients with bone meta-
stases, although bone resorption is usually achieved via
cathepsin K in normal bone with osteoporosis. The
amino acid sequence of ICTP is not cleaved by pro-
teases,
33
although those of NTX or CTX are sensitive to
protease degradation.
12
Therefore, ICTP is considered
the most specic bone turnover marker for evaluation
of bone metastasis.
10,15,16
Many authors described ICTP as a sensitive marker
for bone metastasis. On the other hand, Sato et al.
28

reported changes in serum ICTP under the inuence of
hip fracture in elderly patients. They reported that mean
serum concentrations of ICTP were elevated 1 week
after fracture, decreasing at 2 months. Akesson et al.
20

reported that bone metabolic markers changed under
the inuence of clinical fracture using a proximal tibial
osteotomy model. They reported that serum ICTP was
increased 73% from 6 to 9 weeks after osteotomy.
However, they did not mention the correlations be-
tween ICTP and various other available bone resorp-
tion markers. We reported that bone resorption markers,
such as urinary NTX, serum NTX, urinary DPD, and
urinary CTX, showed a peak increase 3 to 5 weeks after
hip fracture and 3 weeks after vertebral fracture.
18,39
The
peaks of increases were different for each bone turn-
over marker according to the type of bone fracture and
the kind of marker.
In the present study, serum levels of ICTP were
signicantly increased in patients with bone fragility
fractures. Furthermore, IR of serum ICTP was
36.8%, which resembled that of serum NTX and was
about a quarter of IR of urinary NTX (see Table 2).
Urinary markers are affected by bone fractures
more easily than serum markers. Kamimura et al.
18

reported changes in various bone turnover markers
after hip fracture, and showed that changes in the
amount of each marker had a characteristic pattern,
even for urinary and serum NTX. Kamimuras report
supported the results of the present study, in which
each bone turnover marker had different IR associated
with urinary NTX.
18
The percentage of cases exceeding the cutoff value
for suspected bone metastasis at the time correspond-
ing to the urinary NTX minimum varied from 39.5%
(serum NTX) to 73.7% (serum ICTP) (see Table 3). In
serum markers, the false-positive rate was higher for
ICTP than NTX. It is clear that ICTP is altered by bone
fragility fractures as well as bone metastasis. In a previ-
ous study, bone turnover markers were shown to be
increased in elderly women with back pain,
17
and we
speculated that this may have been the result of unrec-
ognized fractures. Similar to BAP and urinary NTX, we
speculated that ICTP may increase in elderly patients,
K. Takahara et al.: ICTP in patients with fractures 225
especially those with back pain, and sometimes be above
the cutoff value indicating bone metastasis.
At the time point corresponding to the minimum uri-
nary NTX level, which is considered to show little inu-
ence of fracture, ICTP obviously exceeded the reference
value rather than other bone resorption markers. Fur-
thermore, in bone fragility fracture patients, serum
ICTP was signicantly correlated with urinary NTX and
other bone resorption markers. Overall, these observa-
tions suggest that the value of ICTP increases with bone
fragility fracture and is correlated with other bone re-
sorption markers. Furthermore, differential diagnosis
of bone fragility fracture and bone metastasis using
ICTP at the same time may be difcult, as for other
bone turnover markers. However, differential diagnosis
will be possible by measuring these markers repeatedly,
as values of bone resorption markers would be de-
creased by repetitive measurement in cases of bone
fragility fracture.
7
Our results indicated that urinary NTX increased
markedly under the inuence of bone fragility fracture.
Serum ICTP and other bone resorption markers were
also increased under the inuence of such fractures.
Furthermore, the rate of increase in serum ICTP that
resembled that of serum NTX was not high compared
with that of urinary NTX.
In conclusion, the results of the present study sug-
gested that the serum ICTP level showed similar chang-
es to other bone resorption markers in patients with
bone fragility fracture and the rate of change associated
with urinary NTX was most similar to those of ICTP
and serum NTX. In patients with bone fragility frac-
tures, ICTP obviously exceeded the reference value
rather than other bone resorption markers. However,
further studies are required to evaluate the utility of
these markers and may be useful in differential diagno-
sis of patients with fractures and bone metastases.
References
1. Brahme SK, Cervilla V, Vint V, Cooper K, Kortman K, Resnick
D. Magnetic resonance appearance of sacral insufciency frac-
tures. Skeletal Radiol 1990;9:48993.
2. Stafford SA, Rosenthal DI, Gebhardt MC, Brady TJ, Scott JA.
MRI in stress fracture. AJR Am J Roentgenol 1986;147:5536.
3. Seo GS, Aoki J, Karakida O, Sone S, Ishii K. Ischiopubic insuf-
ciency fractures: MRI appearances. Skeletal Radiol 1997;26:
70510.
4. Pentecost RL, Murray RA, Brindley HH. Fatigue, insufciency,
and pathologic fractures. JAMA 1964;187:10014.
5. Apone S, Lee MY, Eyre DR. Osteoclasts generate cross-linked
collagen N-telopeptides (NTx) but not free pyridinolines when
cultured on human bone. Bone (NY) 1997;21:12936.
6. Hanson DA, Weis MAE, Bollen AM, Maslan SL, Singer FR,
Eyre DR. A specic immunoassay for monitoring human bone
resorption: quantitation of type I collagen cross-linked N-
telopeptides in urine. J Bone Miner Res 1992;7:12518.
7. Takahara K, Kamimura M, Nakagawa H, Uchiyama S. Changes
in biochemical markers of bone in patients with insufciency frac-
tures. J Bone Miner Metab 2004;22:61825.
8. Tahtela R, Tholix E. Serum concentrations of type I collagen
carboxyterminal telopeptide (ICTP) and type I procollagen
carboxy-and aminoterminal propeptides (PICP, PINP) as mark-
ers of metastatic bone disease in breast cancer. Anticancer Res
1996;16:228993.
9. Miyamoto KK, McSherry SA, Robins SP, Besterman JM, Mohler
JL. Collagen cross-link metabolites in urine as markers of bone
metastases in prostatic carcinoma. J Urol 1994;151:90913.
10. Elomaa I, Virkkunen P, Risteli L, Risteli J. Serum concentration
of the cross-linked carboxyterminal telopeptide of type I collagen
(ICTP) is a useful prognostic indicator in multiple myeloma. Br
J Cancer 1992;66:33741.
11. Napoli LD, Hansen HH, Muggia FM, Twigg HL. The incidence
of osseous involvement in lung cancer, with special reference to
the development of osteoblastic changes. Radiology 1973;108:
1721.
12. Atley LM, Mort JS, Lalumiere M, Eyre DR. Proteolysis of human
bone collagen by cathepsin K: characterization of the cleavage
sites generating the cross-linked N-telopeptide neoepitope. Bone
(NY) 2000;26:2417.
13. Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda
T, et al. Determination of bone markers in pycnodysostosis:
effects of cathepsin K deciency on bone matrix degradation.
J Bone Miner Res 1999;14:19028.
14. Sassi ML, Eriksen H, Risteli L, Niemi S, Mansell J, Gowen M,
et al. Immunochemical characterization of assay for carboxyter-
minal telopeptide of human type I collagen: loss of antigenicity
by treatment with cathepsin K. Bone (NY) 2000;26:36773.
15. Koizumi M, Yamada Y, Takiguchi T, Nomura E, Furukawa M,
Kitahara T, et al. Bone metabolic markers in bone metastases.
J Cancer Res Clin Oncol 1995;121:5428.
16. Aruga A, Koizumi M, Hotta R, Takahashi S, Ogata E. Usefulness
of bone metabolic markers in the diagnosis and follow-up of bone
metastasis from lung cancer. Br J Cancer 1997;76:7604.
17. Kamimura M, Uchiyama S, Takahara K, Hashidate H, Kawagu-
chi A, Nakagawa H. Urinary excretion of type I collagen cross-
linked N-telopeptide and serum bone-specic alkaline phosphatase.
Age and back pain-related changes in elderly women. J Bone
Miner Metab 2005;23:495500.
18. Kamimura M, Nakagawa H, Takahara K, Hashidate H,
Uchiyama S. Change in bone specic turnover markers after
femoral neck fractures. Osteoporosis Jpn 2005;13:35560 (in
Japanese).
19. Nakagawa H, Kamimura M, Takahara K, Hashidate H, Kawagu-
chi A, Uchiyama S, et al. Changes in total alkaline phosphatase
level after hip fracture: comparison between femoral neck and
trochanter fracture. J Orthop Sci 2006;11:1359.
20. Akesson K, Kknen SM, Josefsson PO, Karlsson MK, Obrant
KJ, Pettersson K. Fracture-induced changes in bone turnover: a
potential confounder in the use of biochemical markers in osteo-
porosis. J Bone Miner Metab 2005;23:305.
21. Oni OOA, Mahabir JP, Iqbal SJ, Gregg PJ. Serum osteocalcin
and total alkaline phosphatase levels as prognostic indicators in
tibial shaft fractures. Injury 1989;20:378.
22. Joerring S, Jensen LT, Andersen GR, Johansen JS. Types I and
III procollagen extension peptides in serum respond to fracture
in humans. Arch Orthop Trauma Surg 1992;111:2657.
23. Joerring S, Krogsgaard M, Wilbek H, Jensen LT. Collagen turn-
over after tibial fractures. Arch Orthop Trauma Surg 1994;113:
3346.
24. Ingle BM, Hay SM, Bottjer HM, Eastell R. Changes in bone mass
and bone turnover following distal forearm fracture. Osteoporos
Int 1999;10:399407.
25. Ingle BM, Hay SM, Bottjer HM, Eastell R. Changes in bone mass
and bone turnover following ankle fracture. Osteoporos Int 1999;
10:40815.
226 K. Takahara et al.: ICTP in patients with fractures
26. Bowles SA, Kurdy N, Davis AM, France MW, Marsh DR. Serum
osteocalcin, total and bone-specic alkaline phosphatase follow-
ing isolated tibial shaft fracture. Ann Clin Biochem 1996;33:
196200.
27. Mallmin H, Ljunghall S, Larsson K. Biochemical markers of bone
metabolism in patients with fracture of the distal forearm. Clin
Orthop 1993;295:25963.
28. Sato Y, Kaji M, Higuchi F, Yanagida I, Oishi K, Oizumi K.
Changes in bone and calcium metabolism following hip fracture
in elderly patients. Osteoporos Int 2001;12:4459.
29. Nishizawa Y, Nakamura T, Ohta H, Kushida K, Gorai I, Shiraki
M, et al. Guidelines for the use of biochemical markers of bone
turnover in osteoporosis (2004). J Bone Miner Metab 2005;23:
97104.
30. Koizumi M, Takahashi S, Ogata E. Bone metabolic markers in
bone metastasis of breast cancer. Int J Clin Oncol 1999;4:3317.
31. Cook GJR, Hannaford E, See M, Clarke SEM, Fogelman I. The
value of bone scintigraphy in the evaluation of osteoporotic pa-
tients with back pain. Scand J Rheumatol 2002;31:2458.
32. Eyre DR, Paz MA, Gallop PM. Cross-linking in collagen and
elastin. Annu Rev Biochem 1984;53:71748.
33. Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L. Radioimmu-
noassay for the pyridinoline cross-linked carboxy-terminal telo-
peptide of type I collagen: a new serum marker of bone collagen
degradation. Clin Chem 1993;39:63540.
34. Koga H, Naito S, Koto S, Sakamoto N, Nakashima M, Yamasaki
T, et al. Use of bone turnover marker, pyridinoline cross-linked
carboxyterminal telopeptide of type I collagen (ICTP), in the as-
sessment and monitoring of bone metastasis in prostate cancer.
Prostate 1999;39:17.
35. Dermers LM, Costa L, Chinchilli VM, Gaydos L, Curley E,
Lipton A. Biochemical markers of bone turnover in patients
with metastatic bone disease. Clin Chem 1995;41:148994.
36. Sano M, Kushida K, Takahashi M, Ohishi T, Kawana K, Okada
M, et al. Urinary pyridinoline and deoxypyridinoline in prostate
carcinoma patients with bone metastasis. Br J Cancer 1994;70:
7013.
37. Miura H, Yamamoto I, Takada M, Kigami Y, Ohta T, Yuu I, et
al. Diagnostic validity of bone metabolic markers for bone metas-
tasis. Endocrine J 1997;44:7517.
38. Izumi M, Nakanishi Y, Takayama K, Kimotsuki K, Inoue K,
Wataya H, et al. Diagnostic value of bone-turnover metabolites
in the diagnosis of bone metastases in patients with lung carcino-
ma. Cancer (Phila) 2001;91:148793.
39. Hashidate H, Kamimura M, Nakagawa H, Takahara K,
Uchiyama S. Changes in bone specic turnover marker after
vertebral compression fracture. Osteoporosis Jpn 2006;14:28690
(in Japanese).
Reproducedwith permission of thecopyright owner. Further reproductionprohibited without permission.