Professional Documents
Culture Documents
Volume 3, April 06
Immunodiagnostic Systems (IDS).
Jussi Halleen
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
Jussi Halleen
For Medical Educational Purposes Only.
TRACP ISOFORMS
TRACP 5a
YES
TRACP 5b
NO
5.2
Intact
5.8
Cleaved
Low
High
Macrophages,
dendritic cells
Inflammatory
conditions
Osteoclasts
Bone resorption
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
and shown to be an excellent method for determining
the bone resorption rate.
STABILITY OF TRACP 5B IN SERUM SAMPLES
Some time ago there was a common belief in the
scientific community that serum TRACP activity was
extremely labile, which causes problems in using it as a
marker. This belief was mostly due to a
misunderstanding that started in the early days when
kinetic assays were used. Later it was discovered that the
lability was actually due to an interfering non-type 5
tartrate-resistant acid phosphatase isoenzyme derived
from erythrocytes that the assays also measured.53 In
fact, with proper pre-incubation of serum samples, the
interfering enzyme was inactivated, which improved
clinical perform ance of the kinetic assay as a method for
determining bone resorption.53,54
Stability of serum TRACP 5b has been studied in detail
using the BoneTRAP assay, showing that serum
TRACP 5b is stable for routine laboratory
measurements. 52,55 TRACP 5b is stable for at least 2 days
at room temperature (+25C) and 3 days in the
refrigerator (+4C). However, care should be taken with
long-term storage of serum samples. To avoid problems
in long-term storage, freshly collected, separated serum
samples should be stored in aliquots at -70C
temperatures (or lower), where TRACP 5b is stable for
years. Serum samples can be stored at -20C for up to
one month, but after that the enzyme starts to inactivate.
Also, re-freezing of serum samples after thawing is not
recommended, as TRACP 5b looses activity rapidly
during the re-freezing period even at -70C.55 Table 2
summarizes stability of serum TRACP 5b in different
conditions.
Table 2: Stability of TRACP 5b in human serum
samples
Storage condition
Room temperature (+25C)
Refrigerator (+4C)
Frozen at -20C
Frozen at -70C
Re-freezing after thawing
Stability
2 days
3 days
1 month
Several years
Not recommended
Jussi Halleen
For Medical Educational Purposes Only.
TRACP 5B AS A MARKER OF BONE RESORPTION
Bone resorption starts when acid and proteolytic enzymes,
most importantly cathepsin K, are secreted from the
osteoclast into the space between the cell membrane and
bone surface, known as the resorption lacuna.56 Acid
dissolves the mineral phase of the bone matrix and provides
the optimal acidic environment for cathepsin K to initiate
degradation of the organic bone matrix. Initial organic matrix
degradation products are then endocytosed together with
cathepsin K into the osteoclast and transported through the
cell in transcytotic vesicles. 57,58 Vesicles containing TRACP
are fused into these vesicles, whose acidic pH allows
cathepsin K to cleave the loop-peptide, generating TRACP
5b with high specific activity. 24,59 When the vesicles move
away from the resorption lacuna their pH is changed to
neutral, providing an optimal environment for the ROS
generating activity of TRACP.15,24 TRACP then generates
ROS that are targeted to finalize degradation of the organic
matrix components during their transcytosis.23 Finally, the
matrix degradation products are released from the osteoclast
into the blood circulation together with TRACP 5b through
a functional secretory domain (FSD) in the basolateral
membrane. 60
As described previously, TRACP 5b is generated in
transcytotic vesicles of osteoclasts by cleavage of the
protease-sensitive loop-peptide by cathepsin K, and secreted
from the osteoclast through FSD at the end of the
transcytotic route. Based on this, it could be assumed that
secreted TRACP 5b would be a marker of osteoclast activity.
Surprisingly, this appears not to be the case. Instead, secreted
TRACP 5b has been shown in numerous studies to be an
accurate marker of osteoclast number. This concept was
introduced already in 1983 by Stepan and co-workers, who
observed that plasma TRACP activity was continuously
decreased after removal of parathyroid adenomas from
patients with primary hyperparathyroidism.36 Later, a strong
correlation of secreted TRACP 5b with osteoclast number
was observed in mouse osteoclast cultures where nonresorbing osteoclasts were cultured on plastic surface in the
absence of bone. 61 It was also noticed that serum TRACP 5b
had a strong correlation with histologically determined
number of osteoclasts in patients with renal bone disease, 62
and in orchidectomized rats.63 Secreted TRACP 5b has also
been shown to correlate with osteoclast number in patients
with autosomal dominant osteopetrosis type 2 (ADO2),64
various osteopetrotic rat strains and human osteoclast
cultures.65,66 These data together (summarized in table 3)
suggest that TRACP 5b could be secreted from osteoclasts at
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
a constant rate despite the resorbing activity of the cells.
A hypothesis of generation and secretion of TRACP 5b
in non-resorbing and resorbing osteoclasts is presented
in Figure 1.
Jussi Halleen
Reference
Stepan et al. 1983 (Ref. 36)
Alatalo et al. 2000 (Ref. 61)
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
Changes in bone resorption are usually associated with
changes in osteoclast number, suggesting that secreted
TRACP 5b may be a useful marker of bone resorption.
In fact, numerous clinical studies (summarized in table 4)
have demonstrated that TRACP 5b is elevated in bone
diseases such as postmenopausal osteoporosis,67- 69 breast
and prostate cancer bone metastases,67,70- 78 renal bone
disease,79-83 multiple myeloma,84-87 and Pagets disease of
bone.67 Additionally, it has been shown that TRACP 5b
values can predict future fracture risk. 88 Antiresorptive
treatment with estrogen and various bisphosphonates
resulted in decreased TRACP 5b levels (summarized in
table 5).52,68,70,71,73,77,84,86,87,89 - 94 Studies using human in vitro
osteoclast cultures have demonstrated that secreted
TRACP 5b activity correlates significantly with both
osteoclast number and bone resorption in the presence
of various antiresorptive agents, further demonstrating
that secreted TRACP 5b is a useful marker for
monitoring the efficacy of antiresorptive treatment.6 6 In
patients with ADO2 who have highly elevated number
of non-functional osteoclasts, serum TRACP 5b values
are exceptionally elevated, being much higher than in
any condition with increased bone resorption such as
osteoporosis and bone metastases. 64 In fact, the
exceptionally high TRACP 5b values can be used to help
diagnose ADO2. In this very rare disease, serum
TRACP 5b is a marker of osteoclast number, but
contrary to conditions of increased bone resorption such
as osteoporosis and bone metastases, it does not
demonstrate bone resorption.
Table 4: Summary of clinical studies showing that
TRACP 5b is elevated in bone diseases
Condition
Postmenopausal
osteoporosis
Breast cancer bone
metastases
Prostate cancer bone
metastases
Renal bone disease
Multiple myeloma
Pagets disease of bone
Fracture risk prediction
References
Jussi Halleen
References
Halleen et al. 2000 (Ref. 52), Halleen et al.
2002 (Ref. 68)
Hansdottir et al. 2004 (Ref. 91)
Hannon et al. 2004 (Ref. 90), Nenonen et al.
2005 (Ref. 92), Vlimki and Thtel 2005
(Ref. 94)
Vlimki and Thtel 2005 (Ref. 94)
Martinetti et al. 2002 (Ref. 70), Terpos et al.
2003a (Ref. 84), Terpos et al. 2003c (Ref.
86), Voskaridou et al. 2003 (Ref. 89)
Thtel et al. 2005 (Ref. 93)
Terpos et al. 2003c (Ref. 86),
Capeller et al. 2003 (Ref. 71), Koizumi et al.
2003b (Ref. 73), Lyubimova et al. 2004 (Ref.
77), Terpos et al. 2004 (Ref. 87)
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
4,0
3,5
S-TRACP5b (U/L)
3,0
2,5
***
***
***
2,0
1,5
1,0
0,5
0,0
0
12
Time (months)
Figure 2: Serum TRACP 5b values decrease to a new steadystate level at 3 months after start of alendronate treatment,
and stay at this new level thereafter (from Nenonen et al.
2005).92
Table 6: Comparison of the clinical use of serum TRACP 5b
(S-TRACP5b) and other commonly used bone turnover
markers S-CTX, U-DPD, S-PINP, S-OC and S-BAP for
m onitoring alendronate treatment.
Marker
Change
CVa
CVi
LSC
Jussi Halleen
SPEC
SENS
AUC
S-TRACP5b
S-CTX
U-DPD
- 40
- 64
- 34
2.1
2.6
4.3
12.5
22.4
13.8
29.5
52.5
33.7
89.0
98.6
95.9
82.7
78.7
56.0
0.88
0.87
0.78
3.17
2.82
2.31
S-PINP
- 54
3.6
17.9
42.5
93.2
73.3
0.86
2.95
S-OC
S-BAP
- 28
- 27
5.2
2.1
14.4
9.4
35.7
22.4
94.5
90.4
40.0
61.3
0.76
0.78
1.84
2.78
Change, change of marker level at 3 months after start of treatment (%); CVa,
Analytical variability (%); CVi, Biological variability (%); LSC, Least significant
change (%); SPEC, specificity (%); SENS, sensitivity (%); AUC, Area under
ROC curve; S/N, signal-to-noise ratio (from Nenonen et al. 2005).92
Method
Change
CVa
CVi
LSC
SPEC
SENS
AUC
S/N
BoneTRAP
- 42
2.1
12.7
29.9
91.4
80.0
0.93
3.19
ASBI
- 33
3.3
12.1
29.1
97.0
60.0
0.84
2.56
TRAP5
- 27
3.2
9.7
23.7
95.5
60.0
0.86
2.63
Sandwich
-7
1.8
7.3
17.5
86.6
12.9
0.55
0.97
Change, change of marker level at 3 months after start of treatment (%); CVa,
Analytical variability (%); CVi, Biological variability (%); LSC, Least significant
change (%); SPEC, specificity (%); SENS, sensitivity (%); AUC, Area under ROC
curve; S/N, signal-to-noise ratio (from Fagerlund et al. 2005).95
_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
must be collected at exactly the same time of day. The
effect of feeding requires that the serum samples must
be collected after overnight fasting. Recent studies have
demonstrated that the diurnal variability and the effect
of feeding are caused by the gastrointestinal hormone
glucagon-like peptide-2 (GLP-2) that modulates
osteoclast activity.99 Since GLP-2 has no effect on
osteoclast number, it should not affect serum TRACP
5b levels. Thus, serum TRACP 5b levels should not be
affected by feeding, and the diurnal variability of serum
TRACP 5b should be low. These assumptions have been
verified by Hannon and co-workers, who showed that
contrary to serum CTX, a marker of osteoclast activity,
serum TRACP 5b measured using the BoneTRAP
assay has a low diurnal variability and is not affected by
feeding.90
Renal function affects the marker values because the
markers are cleared from the circulation through the
kidneys, and when the kidneys do not work properly, the
markers can not be cleared from blood circulation,
leading to increased marker levels. This can lead to
elevated marker levels in conditions where bone
turnover is normal.97 This is a particularly serious
problem in renal osteodystrophy, a bone disease
affecting the majority of patients with chronic renal
failure, causing confusion in interpretation of bone
marker results. TRACP 5b is cleared from the blood
circulation through the liver,49 and the function of the
kidneys has no effect on serum TRACP 5b values.67,90
TRACP 5b is secreted from osteoclasts as an active
enzyme that is inactivated and degraded to fragments
before clearance from the blood circulation by the liver.
Thus, in hepatic failure, the inactive fragments
accumulate in the circulating blood, while the
enzymatically active TRACP 5b molecules measured in
the BoneTRAP assay do not accumulate. 67
CONCL USION
TRACP 5b is probably the most reliable marker of bone
resorption available. TRACP 5b is derived exclusively
from bone-resorbing osteoclasts. Contrary to most other
commonly used bone markers, TRACP 5b does not
accumulate in blood circulation during renal or hepatic
failure, has a low diurnal variability and is not affected by
feeding. TRACP 5b describes the number of osteoclasts
in addition to their activity, and appears to be a highly
specific and sensitive marker of bone resorption. Serum
TRACP 5b is elevated in bone diseases such as
Jussi Halleen
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*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
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_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
Jussi Halleen
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_________________________________________________________________________________________________________________________
*Dr. Jussi Halleen is a consultant to Immunodiagnostic Systems (IDS). All correspondence to
IDS Ltd, 10 Didcot Way, Boldon Business Park, Boldon, Tyne & Wear, NE35 9PD. UK
Review Series
Volume 3, April 06
Immunodiagnostic Systems (IDS).
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