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Irish Journal of Medical Science
ISSN 0021-1265
Volume 183
Number 1
Ir J Med Sci (2014) 183:47-52
DOI 10.1007/s11845-013-0970-6
Limited utility of tartrate-resistant acid
phosphatase isoform 5b in assessing
response to therapy in osteoporosis
J.J.Brady, R.K.Crowley, B.F.Murray,
M.T.Kilbane, M.O’Keane &
M.J.McKenna
1 23
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ORIGINAL ARTICLE
Limited utility of tartrate-resistant acid phosphatase isoform 5b
in assessing response to therapy in osteoporosis
J. J. Brady •R. K. Crowley •B. F. Murray •
M. T. Kilbane •M. O’Keane •M. J. McKenna
Received: 8 January 2013 / Accepted: 22 May 2013 / Published online: 5 June 2013
ÓRoyal Academy of Medicine in Ireland 2013
Abstract
Background Tartrate-resistant acid phosphatase isoform
5b (TRACP5b) is a serum bone resorption marker. Our aim
was to investigate its utility in monitoring metabolic bone
disease.
Methods Serum TRACP5b, C-terminal cross-linking tel-
opeptide of type I collagen, urine N-terminal cross-linking
telopeptide of type I collagen and free deoxypyridinoline
were measured pre- and post-treatment with a parathyroid
hormone analogue [PTH (1–34)] (n=14) or a bis-
phosphonate (N-BP) (n=8). TRACP5b, bone alkaline
phosphatase (bone ALP), 25-hydroxyvitamin D (25OHD)
and parathyroid hormone (PTH) were measured in 100
osteoporosis patients on prolonged bisphosphonate therapy.
Results Changes in TRACP5b were smaller in magnitude
but mimicked those of other bone resorption markers.
Absolute changes in TRACP5b and the other resorption
markers correlated significantly (p\0.001). In patients on
long-term bisphosphonates, TRACP5b and bone ALP
levels were not suppressed. Vitamin D status was consis-
tent with the level of supplementation.
Conclusion TRACP5b has limited utility as a single
marker of metabolic bone disease treatment.
Keywords TRACP5b Bisphosphonate Bone turnover
markers PTH Vitamin D
Introduction
In recent years, the safety and efficacy of bisphosphonates,
commonly used treatments for osteoporosis, have been
called into question [1,2]. An increased risk of atypical
femoral fractures, characterised as sub-trochanteric frac-
tures with breaking of the cortex, has been reported
in association with bisphosphonate use [3]. Amin-
obisphosphonates impair osteoclast cell function and
reduce bone remodelling rate. The explanation for this
fracture pattern is that bisphosphonates suppress bone
turnover and expose patients to the risk of fracture via
long-term accumulation of microdamage [4,5]. Measure-
ment of bone turnover markers (BTMs) is useful to track
suppression of bone turnover in patients on bisphospho-
nates [6].
Commonly used markers of bone resorption include
C-terminal cross-linking telopeptide of type 1 collagen
(CTX), free deoxypyridinoline (fDPD), and N-terminal
cross-linking telopeptide of type 1 collagen (NTX), the
latter two of which are measured in urine. These markers
are subject to significant pre-analytical variability includ-
ing diurnal variation and food intake that necessitates
standardised collection protocols [6]. Urine collection is
cumbersome for the patient and volume or sample timing
may be inaccurate. Intra-individual variation of urinary
resorption markers has been reported to be high, thus
impacting on clinical utility [6,7]. The reproducibility of
J. J. Brady and R. K. Crowley are joint first authors.
J. J. Brady (&)B. F. Murray M. T. Kilbane M. O’Keane
M. J. McKenna
Metabolism Laboratory, St. Vincent’s University Hospital,
Dublin, Ireland
e-mail: jbrady@mater.ie
R. K. Crowley M. J. McKenna
St. Michael’s Hospital, Du
´n Laoghaire, Dublin, Ireland
M. J. McKenna
School of Medicine and Medical Sciences, University College
Dublin, Dublin, Ireland
123
Ir J Med Sci (2014) 183:47–52
DOI 10.1007/s11845-013-0970-6
Author's personal copy
urine measurements is also significantly affected by the
variable ionic strength of samples and the need to correct
for creatinine excretion, which may introduce variability in
results [8].
The variability of bone resorption markers can be
reduced and their clinical utility improved by using a
marker unaffected by the limitations described. One such
serum marker is TRACP5b. This enzyme is present in the
osteoclast’s ruffled border membrane and in the resorptive
space [9]. Osteoclasts secrete TRACP5b into the circula-
tion as an active enzyme and serum levels act as a surro-
gate marker of osteoclast number [10]. TRACP5b is less
affected by feeding than CTX, NTX and fDPD. It has low
biological and analytical variability, and because it is
inactivated and degraded into fragments before it is
removed from the circulation, serum levels are not affected
by renal or hepatic failure [11].
Routine practice in our laboratory is to measure both
formation and resorption markers to monitor response or
adherence to treatment or identify non-responders in
patients on bone therapy. The purpose of this study was
twofold: firstly, to determine prospectively in a small
study of 22 patients, the clinical utility of TRACP5b in
comparison to other resorption markers (CTX, fDPD and
NTX) and formation markers (PINP and bone ALP) as a
tool for monitoring the response to either parathyroid
hormone [PTH (1–34)] or bisphosphonate therapy in
clinical practice; and secondly, to assess its utility as a
marker of bone turnover suppression in 100 patients on
prolonged bisphosphonate therapy. In the latter study,
TRACP5b, bone ALP, PTH and 25OHD levels were
determined; 25OHD served both as an estimate of vita-
min D status and as an indicator of compliance with
therapy.
Methods
The Ethics Committee of St Vincent’s University Hospital
approved the TRACP5b validation study. All patients
provided written informed consent. Two groups of patients
were recruited for the TRACP5b validation study; those
commencing PTH (1–34) for osteoporosis (n=14) and
those starting a bisphosphonate for either osteoporosis
(n=5) or Paget’s disease of bone (n=3). Patients pro-
vided fasting blood and second void urine samples for bone
biomarkers according to our laboratory protocol prior to
the treatment and approximately 16 weeks after com-
mencement of the treatment [12]. For the prolonged
bisphosphonate survey, 100 consecutive attendees on
prolonged bisphosphonate therapy for treatment of osteo-
porosis had blood drawn as part of their routine clinic visit;
so it was deemed that ethics approval was not required.
There were 89 women and 11 men. They were treated with
alendronate (n=41), risedronate (n=22), ibandronate
(n=21; intravenous form, n=10), etidronate (n=9),
zoledronic acid infusions (n=6), and pamidronate infu-
sions (n=1). Supplemental calcium and vitamin D intake
was as follows: none (n=9); vitamin D
3
only (n=2);
combined calcium and vitamin D
3
(n=89). Non-fasting
samples were drawn throughout the year for the estimation
of serum TRACP5b, bone ALP, 25OHD and PTH. In this
group, TRACP5b and bone ALP were compared with the
manufacturer’s reference range. Bone ALP and TRACP 5b
reference intervals were verified for use in-house in
accordance with IFCC and CLSI-C28 standard verification
protocols.
Samples were transported to the laboratory on ice
without delay, blood was centrifuged at 4 °C. Serum was
immediately separated and frozen at -80 °C until analysis.
Urine was stored at -30 °C prior to analysis. For the
TRACP5b validation study, serum TRACP5b, CTX, bone
ALP and PINP, and urine NTX, fDPD and creatinine were
measured. TRACP5b was measured by competitive
enzyme immunoassay (BoneTRAP
Ò
Assay, Immunodiag-
nostic Systems Ltd, Boldon, UK), on a Triturus automated
ELISA instrument. All patient samples were analysed in
duplicate and the mean of the results used; pre- and post-
treatment samples were measured in the same assay.
Within-run precision was \3.5 % (over TRACP5b con-
centration range 2.37–13.36 U/L); between-run precision
was \1.6 % (over range 1.46–4.18 U/L). Serum CTX,
bone ALP, PINP, 25OHD, PTH, and urine NTX and fDPD
were measured as previously described [12,13].
Descriptive statistics are presented as mean (standard
deviation) or median (interquartile range) as appropriate
for pattern of distribution. Analytical variability (CVa) of
TRACP5b was calculated as the mean CV of duplicate
measurements over two assays used in this study. The
intra-individual variability (CVi) was deduced from the
literature using a similar study group and time period [14].
The least significant change (LSC) was calculated from the
formula: 1.96H2H(CVa
2
?CVi
2
). Simple associations
were assessed by Pearson correlation coefficients or
Spearman rho coefficients, as appropriate. Results with
pvalues of \0.05 were considered statistically significant.
Statistical analysis was performed using IBM SPSS Stats
for Windows Version 20 (Armonk, New York).
Results
TRACP5b validation study
Following PTH (1–34) treatment, TRACP5b increased
from baseline in 12/14 (86 %) of patients (Table 1).
48 Ir J Med Sci
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The median (IQR) percentage increases were 25 % (7–78 %)
for TRACP5b, 84 % (33–140 %) for fDPD/Cr, 69 %
(35–317 %) for NTX/Cr, 125 % (66–635 %) for CTX,
37 % (13–99 %) for bone ALP, and 246 % (138–670 %)
for PINP. Using a CVa of 1.54 % and CVi of 5.4 %, the
LSC for TRACP5b was calculated as 15.6 %, indicating
that while the change was smaller in magnitude than the
other markers, it was methodologically significant. In the
two cases where TRACP5b did not increase, there were
rises in CTX (0.12 and 0.17 lg/L, respectively), but min-
imal changes in either of the urinary markers. PINP
increased in both cases, by 26.8 and 44.3 lg/L, respec-
tively, suggesting that compliance was not an issue.
Following bisphosphonate treatment, TRACP5b and all
the other resorption markers decreased in all patients
(Table 1). In the bisphosphonate-treated group, the median
(IQR) percentage decrease from baseline for TRACP5b
was 27 % (16–32 %), for CTX was 76 % (45–94 %), for
fDPD/Cr was 38 % (11–68 %), for NTX/Cr was 87 %
(36–92 %), for bone ALP was 54 % (13–75 %) and for
PINP was 73 % (37–91 %).
There were highly significant correlations between
TRACP5b and all three resorption markers at baseline as
follows: with NTX/Cr (r=0.610; p=0.003), with fDPD/
Cr (r=0.762; p\0.001), and with CTX (r=0.780;
p\0.001). Following treatment, the absolute change in
TRACP5b levels correlated significantly with: NTX/Cr
(r=0.786; p\0.001) (Fig. 1), fDPD/Cr (r=0.784;
p\0.001) and CTX (r=0.918; p\0.001). The Spear-
man rho correlations for percent changes were even
higher: for fDPD/Cr (r=0.855; p\0.001), for NTX/Cr
(r=0.877; p\0.001) and for CTX (r=0.921;
p\0.001).
Prolonged bisphosphonate survey
The mean ±SD age of subjects was 70.7±10.8 years, and
the mean ±SD duration of bisphosphonate therapy at the
time of the study was 5.8 ±4 years. Serum TRACP5b was
determined in 99/100 patients recruited. The mean ±SD
concentration of TRACP5b was 2.92 ±0.92 U/L, and for
bone ALP was 12.0 ±4.2 lg/L. No patient had a level of
TRACP5b or bone ALP suppressed below the respective
reference ranges quoted by the manufacturer. Bone ALP
correlated with TRACP5b (r=0.371, p\0.001).
Median (IQR) 25OHD was 77 (61–96) nmol/L; 54
subjects had levels [75 nmol/L and only 13 had levels
\50 nmol/L, of which 8 were taking vitamin D
3
\400
IU/day (Fig. 2). Significantly more subjects who under-
went 25OHD sampling during the summer achieved serum
levels greater than 50 nmol/L (100 %), compared to
spring/autumn (85 %) or winter (63 %, p\0.001). Nine
subjects were not taking a vitamin D supplement. In a
stepwise linear regression model with dependent variable
(serum 25OHD) and independent variables (age, duration
of treatment, season of study, and vitamin D intake),
vitamin D intake was the sole predictor of serum 25 OHD
(r
2
=0.296; p=0.003). Median PTH was 41.1 (14.5–
153.6) ng/L, and correlated with 25OHD level (r=-0.445,
p\0.001).
Discussion
We have demonstrated that the TRACP5b response to PTH
(1–34) and bisphosphonate parallels other bone resorption
markers as demonstrated by the correlation coefficients. In
the PTH (1–34) group, the tightest correlation was between
TRACP5b and CTX similar to a previous report [15]. The
BTM response to PTH (1–34) has been studied at different
time points following the commencement of treatment. In a
28-day study by Glover et al. [16], whilst formation
markers increased, markers of bone resorption showed an
unexpected pattern with serum CTX and NTX decreasing
until 19 days of treatment, and a nadir between days 9 and
13. A similar rapid decrease in bone resorption was
observed in a previous study after the daily administration
of a PTH-related peptide in postmenopausal women. In that
study, circulating TRACP5b did not change significantly
[17,18].
Table 1 Bone marker concentrations at baseline and post-treatment with either PTH (1–34) or bisphosphonate
PTH (1–34) Bisphosphonate
Pre-treatment Post-treatment Pre-treatment Post-treatment
TRACP5b (U/L) 2.91 (2.35–3.51) 4.25 (2.84–5.34) 4.15 (2.98–5.10) 3.18 (2.13–3.75)
CTX (lg/L) 0.278 (0.110–0.423) 0.782 (0.269–1.38) 0.526 (0.299–0.866) 0.166 (0.038–0.345)
NTX/Cr (nmol BCE/mmol) 23.6 (16.4–47.6) 73.9 (31.6–112.3) 135.5 (41.1–324.4) 23.6 (8.3–34.5)
fDPD/Cr (nmol/mmol) 5.0 (4.1–6.5) 8.45 (7.25–13.75) 10.4 (5.9–13.8) 5.5 (3.8–7.4)
Bone ALP (lg/L) 14.8 (12.8–23.0) 27.45 (16.3–46.4) 45.6 (12.6–85.8) 12.8 (6.0–24.9)
P1NP (lg/L) 31.7 (20.8–47.9) 120.9 (56.2–234.4) 118.2 (31.6–250.9) 22.7 (14.5–34.7)
All results are expressed as median (IQR)
Ir J Med Sci 49
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The major increases seen in BMD are thought to occur
early post-initiation of therapy, in ‘the anabolic window’.
In a review of the literature of the histomorphometric and
quantitative computed tomography (pQCT) changes
occurring in the first month of treatment, Compston [18]
found that modelling contributes up to one-third of the
bone formation, representing the laying down of new bone.
The observed lack of change of TRACP5b in two of the
patients following PTH (1–34) treatment, in contrast to a
rise in CTX was unlikely to be due to the lack of com-
pliance as PINP increased in both cases. It is possible that
there was a discrepancy between osteoclast number and
resorptive activity. Henriksen et al. [10] graphically
demonstrated discrepancies between the number of osteo-
clasts relative to the measured bone resorption where the
decrease in resorption was significantly greater than the
reduction in osteoclast number, highlighted particularly in
the case of several novel therapeutic compounds.
BTMs have been widely used in clinical practice to
assess patient adherence to bisphosphonates [6]. The
magnitude of change in serum TRACP5b in our study was
smaller than the other bone resorption markers; this
observation parallels findings in other studies [11,15].
However, these studies support the use of TRACP5b
measurement based on the finding that TRACP5b had
higher clinical sensitivity, and higher signal-to-noise ratio
than CTX. They conclude that the markers with the
greatest reduction are not necessarily the best markers for
monitoring the response to anti-resorptive treatment,
because of high analytical and biological variability.
TRACP5b, with its lower biological variation has a
number of theoretical advantages as a biochemical marker
of bone turnover, namely that it is less affected by feeding
and can be measured in a random blood sample, negating
the requirement for a urine collection. In addition, diurnal
variation of circulating TRACP5b is low and levels are not
affected by disorders of the kidney or liver [11]. The pri-
mary disadvantage of TRACP5b is its relative instability,
requiring serum samples to be stored at -20 °C initially
and at -80 °C if not assayed within 2 months of collection.
The facility of a -80 °C freezer may not be available in all
laboratories. The validation study demonstrated that
TRACP5b could be useful in an out-patient setting for
monitoring treatment of osteoporosis and Paget’s disease.
Fig. 1 Regression equation
between the change in
TRACP5b and change in NTX/
Cr: delta NTX/Cr =66.6 9
delta TRACP5b-39.4,
r=0.786, p\0.001
0
50
100
150
Serum 25OHD nmol/L
Fig. 2 Vitamin D status in osteoporosis patients indicating those
taking C400 IU/day (circles), those taking \400 IU/day (squares)
and those not on supplements (triangles). The horizontal lines
indicate different 25OHD thresholds according to the Institute of
Medicine report: 30–50 nmol/L indicates range of adequacy;
125 nmol/L indicates the limit above which harm is possible
50 Ir J Med Sci
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In the assessment of 100 patients on long-term bis-
phosphonates, bone ALP and TRACP5b levels drawn in
the non-fasting state were not suppressed below the normal
reference range in any patient. Bone remodelling units
appear to be mostly randomly distributed throughout the
skeleton and may be triggered by microcrack formation or
osteocyte apoptosis [19]. One of the concerns about pro-
longed bisphosphonate therapy is that over-suppression of
remodelling activity may impair microdamage repair. A
possible explanation for the lack of suppression below the
reference interval could be that bone turnover in these
patients was not over-suppressed. Bone ALP within the
normal reference range might suggest normal bone
remodelling activity and repair of microdamage. A com-
bination of a bone resorption marker (such as CTX), a
marker of osteoclast number (such as TRACP5b) and a
bone formation marker (such as PINP) may provide more
information about osteoclast activity and bone turnover in
the setting of anti-resorptive therapies as has been recom-
mended by other studies [15].
One limitation of this part of the study is that baseline
levels of the BTMs were not measured and therefore the
magnitude of change from baseline to after treatment could
not be ascertained. Another limitation of this study is that
CTX was not measured due to the fact the samples were
from non-fasting patients. CTX is particularly susceptible
to a decrease following intake of food, a fact that is well
documented in the literature [20]. Collection of fasting
samples can be impractical in the out-patient setting, and
our study confirms that non-fasting samples for TRACP5b
and bone ALP are difficult to interpret, particularly in the
absence of a baseline sample. Urine samples were not
collected from this patient cohort as part of routine prac-
tice, therefore we were not in a position to measure other
resorption markers such as NTX or fDPD. A further limi-
tation is that we did not have data on bone mineral density
changes in these patients, however, bone mineral density
can take up to 2 years to show significant changes fol-
lowing treatment, therefore may not have added any extra
information in this cohort.
The great majority (87 %) achieved 25OHD levels
greater than 50 nmol/L, which corresponds to the recom-
mended daily allowance as set by the IOM report.
According to the IOM, only 2.5 % of the population need
levels in excess of 50 nmol/L for bone health, and the
majority need a level between 30 and 50 nmol/L [21,22].
We have previously shown that vitamin D status in Irish
adults is suboptimal, particularly during the winter months
[13]. The vitamin D status of our cohort suggests that
appropriate supplements were prescribed and that adher-
ence was excellent. In fact, the finding of a result below
50 nmol/L probably suggests that a patient is either non-
compliant or has not been recommended supplements
given the known dose response to low dose oral vitamin D
supplementation [23].
In conclusion, while TRACP5b mimics other bone
resorption markers post-treatment, in the non-fasting state
it has limited utility in the monitoring of bone remodelling
and compliance with medication particularly when baseline
measurements have not been taken. It would appear that
TRACP5b is more suited to the investigation of the
mechanisms underlying the effects of treatment on the
bone microenvironment. As such its use is more suited to
drug trials and new therapies. Its routine use in more
complex metabolic bone diseases remains to be investi-
gated. Low-dose vitamin D supplementation in osteopo-
rosis is safe and effective in meeting the IOM
specifications regarding dietary reference intakes.
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