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Vol. 10, 2705–2708, April 15, 2004
Clinical Cancer Research 2705
Contribution of Androgen Deprivation Therapy to Elevated
Osteoclast Activity in Men with Metastatic Prostate Cancer
M. Dror Michaelson, Rose M. Marujo, and
Matthew R. Smith
Division of Hematology/Oncology, Massachusetts General Hospital,
Boston, Massachusetts
ABSTRACT
Purpose: Biochemical markers of both osteoblast and
osteoclast activity are elevated in men with osteoblastic metastases from prostate cancer. Androgen deprivation therapy (ADT), the mainstay of therapy for advanced prostate
cancer, increases markers of osteoblast and osteoclast activity, even in the absence of bone metastases. Little is known
about the relative contributions of ADT and skeletal metastases to elevated bone turnover in men with prostate cancer.
Experimental Design: To evaluate the relative contributions of ADT and skeletal metastases to osteoblast and osteoclast activity, we performed a cross-sectional study in
three groups of men with advanced prostate cancer: (a)
hormone-naı̈ve men without bone metastases; (b) castrate
men without bone metastases; and (c) castrate men with
bone metastases. The primary study end points were serum
levels of bone-specific alkaline phosphatase (BSAP), a
marker of osteoblast activity, and N-telopeptide (NTX), a
marker of osteoclast activity.
Results: Serum levels of both BSAP and NTX were
significantly higher in groups of castrate men (groups 2 and
3) than in hormone-naı̈ve men (group 1; P < 0.01 for all
comparisons). Among castrate men, serum BSAP was significantly higher in men with bone metastases than in men
without bone metastases (P ⴝ 0.01). In contrast, serum levels
of NTX were similar in groups 2 and 3 (P ⴝ 0.33).
Conclusions: The unintended effects of ADT on the
skeleton are sufficient to explain increased osteoclast activity
in castrate men with bone metastases. These results may
have important implications for the optimal timing and
schedule of osteoclast-targeted therapy in men with advanced prostate cancer.
Received 12/15/03; accepted 12/18/03.
Grant support: Supported by the National Cancer Institute
(1K12CA87723-01) and CaPCURE.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
Note: This study has been presented in part at the 2003 Annual Meeting
of the American Society of Clinical Oncology, Chicago, Illinois.
Requests for reprints: M. Dror Michaelson, Department of Hematology/Oncology, Massachusetts General Hospital, 100 Blossom Street,
Cox 640, Boston, MA 02114. Phone: (617) 726-1594; Fax: (617) 7243166; E-mail: [email protected].
INTRODUCTION
Prostate cancer metastasizes primarily to the skeleton.
On radiographic evaluation, these bone metastases are described as “osteoblastic” based on excessive new bone formation. The biology of osteoblastic bone metastases may be
more complex, however, than suggested by their radiographic
appearance. Osteoclast number and activity are increased in
bone metastases, in bone adjacent to metastases, and in
distant uninvolved bone (1, 2). Additionally, biochemical
markers of both osteoblast and osteoclast activity are elevated in men with metastatic prostate cancer (3–7). In a small
prospective study of men with metastatic prostate cancer,
markers of osteoclast activity predicted independently the
risk of subsequent skeletal complications (8). These observations form the basis for evaluation of osteoclast-targeted
therapies in men with osteoblastic metastases.
Androgen deprivation therapy (ADT) by either bilateral
orchiectomy or treatment with gonadotropin-releasing hormone
agonist is the mainstay of therapy for advanced prostate cancer.
Medical or surgical castration adversely affects bone metabolism. ADT increases markers of osteoblast and osteoclast activity, decreases bone mineral density, and increases fracture risk
(9 –12). Thus, treatment-related osteoporosis may account for
some of the skeletal complications experienced in men with
advanced prostate cancer. This distinction may have important
implications in our understanding of bone complications in
prostate cancer, and in the timing and schedule of bone-targeted
therapy.
Little is known about the relative contributions of ADT and
skeletal metastases to increased bone turnover in men with bone
metastases from prostate cancer. To address this question, we
conducted a cross-sectional study in three groups of men with
prostate cancer: (a) hormone-naı̈ve men without bone metastases; (b) castrate men without bone metastases; and (c) castrate
men with bone metastases.
PATIENTS AND METHODS
Subjects were recruited from the Massachusetts General
Hospital Cancer Center. Three groups of men were analyzed.
The first group included men with rising prostate-specific
antigen (PSA) after radical prostatectomy or radiation therapy, no clinical or radiographic evidence of skeletal metastases, and no current ADT (group 1, hormone-naı̈ve nonmetastatic). The second group included men on ADT, no clinical
or radiographic evidence of skeletal metastases, and stable
disease by PSA Working Group criteria (Ref. 13; group 2,
castrate nonmetastatic). The third group included men with
radiographically proven skeletal metastases who were receiving ADT (group 3, castrate metastatic). Group 3 included
men with stable disease and men with progressive, androgenindependent disease, by PSA Working Group criteria (13).
Markers of osteoblast activity appear to plateau after 6
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2706 Osteoclast Activity in Metastatic Prostate Cancer
Table 1 Subject characteristics
Unless otherwise stated, values are given as mean ⫾ SE.
Hormone-naïve
nonmetastatic (group 1)
Castrate nonmetastatic
(group 2)
Castrate metastatic
(group 3)
Normal range
20
62.5 ⫾ 1.9
80
27.3 ⫾ 0.8
3.3
365 ⫾ 28d
79 ⫾ 5
14.4 ⫾ 0.3d
19
65.6 ⫾ 2.5
89
26.8 ⫾ 0.6
0.1
9⫾2
88 ⫾ 4
12.9 ⫾ 0.2
28
73.4 ⫾ 1.9a
93
28.8 ⫾ 0.8
15.0c
15 ⫾ 2
132 ⫾ 15a
13.2 ⫾ 0.3
270–1070
45–115
13.5–17.5
Subjects (n)
Age (yr)
Caucasian race (%)
Body mass index (kg/m2)
Median PSA (ng/ml)b
Testosterone (ng/dl)
Alkaline phosphatase (units/liter)
Hemoglobin (g/dl)
P ⬍ 0.05 versus other groups.
PSA, prostate-specific antigen.
c
P ⬍ 0.05 for group 3 versus group 2.
d
P ⬍ 0.05 for group 1 versus other groups.
a
b
months of ADT (10). Accordingly, men who had received
less than 6 months of ADT were excluded from groups 2
and 3.
Men with Paget’s disease, hyperthyroidism, Cushing’s
disease, hyperprolactinemia, chronic liver disease, or chronic
renal insufficiency (serum creatinine ⬎2.0 mg/dl) were excluded. Men were also excluded if they had received glucocorticoids, calcitonin, or suppressive doses of thyroxine
within 1 year, or had ever received any bisphosphonate
therapy. Subjects in groups 1 and 2 had never been treated for
prostate cancer with chemotherapy, palliative radiation therapy, radionuclides, estrogens, or PC-SPES. Men in group 3
had not received chemotherapy, palliative radiation therapy,
estrogens, or PC-SPES for a minimum of 6 weeks, and had
not received radionuclides for a minimum of 12 weeks,
before entry into the study.
The study was reviewed and approved by the institutional
review board, and all of the subjects gave written informed
consent.
Serum concentrations of bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTX) were measured in the
core laboratory for the Massachusetts General Hospital General
Clinical Research Center. Samples for all of the subjects were
analyzed at the same time. Serum BSAP concentrations were
measured by enzyme immunoassay with a sensitivity of 0.5
units/liter and intra- and interassay coefficients of variation of
3.5 and 6.5%, respectively (Metra Biosystems, Mountain View,
CA). Serum NTX concentrations were measured by enzyme
immunoassay with a sensitivity of 0.5 nM bone collagen equivalents and intra- and interassay coefficients of variation of 5.5
and 3.6%, respectively (Osteomark, Ostex International, Seattle,
WA). The normal ranges (mean ⫾2 SDs) for BSAP and NTX
were 15.0 – 41.3 units/liter and 5.4 –24.2 nM BCE, respectively.
Serum concentrations of testosterone, PSA, and alkaline phosphatase were measured in the Massachusetts General Hospital
clinical laboratory.
Values are reported as the mean ⫾ the SE, unless otherwise
indicated. Comparison between groups was calculated using
two-sided t tests, and Ps less than 0.05 were considered statistically significant.
RESULTS
Subject Characteristics. Sixty-seven subjects were included in the analyses. Men in the castrate metastatic group
were older than men in the other two groups (Table 1). Mean
testosterone concentrations were significantly lower in groups 2
and 3 than in group 1. Serum PSA was higher in group 3 than
in group 2. Consistent with the burden of metastatic disease to
bone, mean serum alkaline phosphatase was higher in group 3
than in the other groups.
Bone Turnover Markers. Serum concentrations of
BSAP, a marker of osteoblast activity, differed significantly
between the groups (Fig. 1). Mean serum BSAP was higher in
both groups of castrate men than in hormone-naı̈ve men (P ⬍
0.01 for each comparison). Additionally, mean serum BSAP
was significantly higher in the castrate metastatic group than in
the castrate nonmetastatic group (P ⫽ 0.01).
Serum concentrations of NTX, a marker of osteoclast activity, were significantly higher in castrate men, with or without
bone metastases, than in hormone-naı̈ve men (P ⬍ 0.001 for
each comparison). In contrast to the results with BSAP, however, mean serum NTX levels were similar between the castrate
metastatic and castrate nonmetastatic groups (P ⫽ 0.33).
We also compared men in the castrate nonmetastatic group
with the subset of men in group 3 with progressive, androgenindependent disease. In this subset of 17 men (median PSA,
44.7; mean alkaline phosphatase, 147 ⫾ 22), mean serum BSAP
was significantly higher than in the castrate, nonmetastatic
group (58.4 ⫾ 15.3 versus 33.3 ⫾ 2.2; P ⫽ 0.02). Even in this
subset of men with progressive disease, NTX did not differ
significantly from men in the castrate, nonmetastatic group
(25 ⫾ 3.8 versus 20.5 ⫾ 1.2; P ⫽ 0.27).
DISCUSSION
This study demonstrates that levels of serum NTX, a
marker of osteoclast activity, are significantly higher in castrate
men than in hormone-naı̈ve men but similar between castrate
men with bone metastases and castrate men without bone metastases. In contrast, serum BSAP levels, a marker of osteoblast
activity, are significantly higher in castrate men than in hormone-naı̈ve men and significantly higher in castrate men with
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Clinical Cancer Research 2707
Fig. 1 Serum markers of osteoblast and osteoclast activity in men with
prostate cancer. Serum bone-specific alkaline phosphatase (BSAP) and
N-telopeptide (NTX) in men with hormone-naı̈ve, nonmetastatic prostate
cancer (group 1, ), castrate nonmetastatic prostate cancer (group 2, ,
and castrate metastatic prostate cancer (group 3, ). ⴱ, P ⬍ 0.01 versus
group 1; †, P ⫽ 0.01 versus group 2; P ⫽ 0.33 for comparison of NTX
between Groups 2 and 3. BCE, bone collagen equivalents.
bone metastases than in castrate men without bone metastases.
These results suggest that the adverse effects of ADT on the
skeleton are sufficient to explain elevated osteoclast activity in
men with bone metastases.
Our observation that markers of osteoclast activity are
elevated in castrate men with metastatic disease is consistent
with earlier reports (3– 6, 14). These studies attributed elevated
osteoclast activity to tumor-mediated bone destruction. Although not specified in most studies, the majority of subjects
probably had castrate testosterone levels given that ADT is the
cornerstone of treatment for advanced prostate cancer. In the
one study that specified current treatment, 30 of 32 men with
skeletal metastases received ADT (4).
This study may have important implications for the optimal
timing and schedule of bisphosphonates and other osteoclasttargeted therapy in men with prostate cancer. In a randomized
controlled trial of men with bone metastases and progressive
prostate cancer despite ADT, zoledronic acid (4 mg i.v. every 3
weeks) decreased significantly the risk of skeletal related events,
a composite end point consisting of radiation to bone, fractures,
spinal cord compression, change in antineoplastic therapy to
treat bone pain, and surgery to bone (14). Zoledronic acid
decreased urinary NTX by ⬃70%. In a 1-year randomized
controlled trial in postmenopausal women with osteoporosis,
zoledronic acid (4 mg i.v. once) decreased markers of osteoclast
activity by about 60% and increased bone mineral density (15).
In another 1-year randomized controlled trial, zoledronic acid (4
mg i.v. every 12 weeks) increased bone mineral density in
castrate men with nonmetastatic prostate cancer (16). Our results raise the possibility that a bisphosphonate dose/schedule
sufficient to increase bone mineral density in castrate men may
also be adequate to prevent skeletal-related events in castrate
men with bone metastases.
The study design was cross-sectional and prospective
studies are needed to confirm our observations. Of interest,
markers of osteoclast and osteoblast activity were prospectively evaluated in the randomized control trial of zoledronic
acid in men with bone metastases and disease progression
despite ADT (14). Mean bone alkaline phosphatase levels
increased progressively in the placebo group over 15 months.
In contrast, urinary NTX levels remained stable throughout
the study. The marked disparity between changes in markers
of osteoblast and osteoclast activity in a large group of men
with progressive metastatic disease supports the observations
of our cross-sectional study.
We excluded men receiving chemotherapy or palliative
radiation therapy from our castrate metastatic group to avoid the
confounding effects of these treatments on bone metabolism.
Despite these exclusions, PSA and alkaline phosphatase were
markedly elevated in this group, consistent with substantial bone
metastases. Nevertheless, different results may be observed in
men receiving chemotherapy or palliative radiation therapy because of either more extensive disease or the unintended effects
of these other treatments on bone metabolism.
In summary, serum levels of both BSAP and NTX are
significantly increased by ADT in men with nonmetastatic prostate cancer. In contrast, BSAP but not NTX increases further in
the presence of bone metastases. These findings have important
implications in our understanding of bone metabolism, and may
affect the manner in which bone-targeted therapy is studied and
used in men with prostate cancer.
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Contribution of Androgen Deprivation Therapy to Elevated
Osteoclast Activity in Men with Metastatic Prostate Cancer
M. Dror Michaelson, Rose M. Marujo and Matthew R. Smith
Clin Cancer Res 2004;10:2705-2708.
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