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european urology supplements 6 (2007) 677–682
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Risk Factors for the Development of Bone Metastases in
Prostate Cancer
Daniel P. Petrylak *
Columbia University College of Physicians and Surgeons, Division of Medical Oncology, 161 Fort Washington Avenue, Room 919,
Irving Pavilion, New York, NY 10032, USA
Article info
Abstract
Keywords:
Androgen-deprivation
therapy
Bone metastases
Prostate-specific antigen
Objectives: Bone health of men with prostate cancer is threatened
throughout the disease course. The majority of patients with advanced
prostate cancer will develop bone metastases that can undermine skeletal integrity and result in skeletal complications including pathologic
fractures, spinal cord compression, and palliative radiotherapy to bone.
The early identification of patients who are at a high risk for bone
metastases may enable earlier identification and treatment of bone
lesions, thereby preserving patients’ independence throughout the disease course.
Methods: Current guidelines for bone health maintenance were
reviewed and PubMed key word searches performed to identify risk
factors for the development of bone metastases in patients with prostate
cancer. Additionally, guidelines and consensus recommendations were
reviewed to identify bone health issues and their management in
patients with early prostate cancer.
Results: Current prostate cancer monitoring guidelines recommend
bone scans at initial diagnosis for patients with prostate-specific antigen
(PSA) levels >20 ng/ml and in patients with chronic bone pain or fractures. Multiple studies have concluded that high baseline PSA levels,
rising PSA despite androgen-deprivation therapy (ADT), and high PSA
velocity are risk factors for the development of bone metastasis in
patients with prostate cancer. In patients with early prostate cancer,
bone loss is an emerging concern, and bisphosphonates have been
demonstrated to prevent bone loss from ADT. Use of risk factors such
as PSA kinetics may optimize screening and enable earlier identification
of bone metastases.
Conclusions: Monitoring bone mineral density may allow for better preservation of skeletal health in patients undergoing ADT.
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# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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doi:10.1016/j.eursup.2007.03.005
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european urology supplements 6 (2007) 677–682
1.
Risk factors for the development of bone
metastases in prostate cancer
Although therapeutic advances have extended overall survival for patients with prostate cancer,
maintaining bone health may be challenging
throughout the course of the disease [1]. Patients
with prostate cancer are at high risk for bone loss
induced by cancer treatments, such as androgendeprivation therapy (ADT), and skeletal-related
events (SREs) from bone metastases including
pathologic fracture, spinal cord compression, surgery and palliative radiation to bone, and hypercalcemia of malignancy [2,3]. Therefore, maintaining
bone health in patients with prostate cancer
requires a multidisciplinary approach to provide
optimal clinical benefits to patients throughout the
course of their disease [4].
Prostate cancer metastasizes to bone in the
majority of patients with hormone-refractory disease [5]. Prostate cancer cells often secrete factors
that activate adjacent bone-forming osteoblasts to
produce aberrant bone matrix [6]. The resulting
osteoblastic bone lesions destabilize the structural
integrity of the bone [7]. Osteoclast-mediated osteolysis increases in response to the osteoblastic
lesions and can result in decreased bone integrity
[6]. This is the underlying cause for most SREs.
Moreover, unbalanced osteolysis and osteogenesis
during ADT can result in a net decrease in bone
mineral density (BMD), placing patients at increased
risk for fractures and potentially leaving bone
unprotected from invading tumor cells [8,9].
The routine use of bone scans during initial
staging of patients diagnosed with prostate cancer
remains controversial. Current prostate diagnosis
and treatment guidelines from the European Association of Urology (EAU), National Comprehensive
Cancer Network, and the European Society for
Medical Oncology recommend that radionuclide
bone scans be performed at initial staging if
patients have prostate-specific antigen (PSA) levels
>20 ng/ml, chronic bone pain, or fractures [10–12].
Two independent retrospective analyses, one in
Europe and one in China, identified baseline
PSA > 20 ng/ml and alkaline phosphatase (ALP)
>90 U/l as significant risk factors for the presence
of bone metastases at diagnosis [13,14]. A retrospective analysis was performed of 406 patients
with prostate cancer who had received a staging
bone scan irrespective of their PSA serum level and
histology [13]. Results from this study indicated that
bone scans were positive in 41 (10%) patients and
that EAU guidelines supporting the use of bone
scans in patients whose PSA levels are >20 ng/ml
were useful with respect to clinical value [13].
Similar conclusions were reached in a retrospective
analysis of 96 patients with prostate cancer (29 of
whom had bone metastases) and baseline assessments of PSA and ALP and a baseline radionuclide
bone scan. Median concentrations of serum PSA and
ALP were significantly higher in patients with bone
metastases ( p < 0.01) [14]. Moreover, the percentage
of patients with bone scan results was higher in
patients with PSA > 20 ng/ml or ALP > 90 U/l versus
patients with PSA < 20 ng/ml or ALP < 90 U/l [14].
The Early Prostate Cancer program investigated
the optimal PSA cut-off level for recommending
bone scans after local therapy for prostate cancer
[15]. In this retrospective analysis, data were
obtained from protocol-specified bone scans
and PSA reports of 4061 patients randomized to
standard care alone in the Early Prostate Cancer
program [15]. The analysis included 5048 bone
scans, and similar to current guidelines and results
from other retrospective analyses, the incidence
of positive bone scans was low in patients with
PSA < 5 ng/ml or < 20 ng/ml who were managed
by watchful waiting [15]. Investigators from this
study also concluded that bone scans are not
indicated in and do not provide any prognostic
value for patients with prostate cancer who have
low PSA levels [15].
The natural history of disease progression in
patients with nonmetastatic prostate cancer and
rising PSA levels despite ADT is variable. However,
specific risk factors for developing bone metastases
have been identified. Smith et al [16] conducted a
randomized, placebo-controlled clinical trial to
evaluate the effectiveness of zoledronic acid on
time to first bone metastasis in patients with
prostate cancer, no bone metastases, and rising
PSA levels despite ADT [16]. Although this trial was
terminated before completion of accrual because
the event rate was lower than anticipated, the
placebo arm of the trial was used to study the
natural history of disease in this patient population
[16]. Patients had castrate testosterone levels at
study entry, documentation of PSA progression,
and no radiographic evidence of bone metastases.
Bone scans were performed on these patients every
4 mo [16]. At the 2-yr analysis, 33% of patients had
developed one or more bone metastasis, and median
bone metastasis-free survival was 32 mo. Baseline
PSA and PSA velocity were found to be independent
predictors of time to first bone metastasis and bone
metastasis-free survival. Specifically, in univariate
analyses, baseline PSA levels >10 ng/ml (relative risk
[RR], 2.96; 95% confidence interval [CI], 1.63–5.38;
p < 0.001) and high PSA velocity (RR, 1.47 for each
european urology supplements 6 (2007) 677–682
Fig. 1 – Cox proportional hazard estimates of time to first
bone metastasis indicate that baseline PSA >10 ng/ml and
high PSA velocity are significant risk factors for shorter
time to first bone metastasis in both univariate and
multivariate analyses. PSA: prostate-specific antigen.
*For each log (ng/ml)/yr increase in PSA velocity. Data from
Smith MR, et al [16].
log (ng/ml)/yr increase in PSA velocity; 95%CI, 1.23–
1.75; p < 0.001) were associated with shorter time to
bone metastasis (Fig. 1) [16]. Baseline PSA and PSA
velocity remained statistically significant in multivariate analyses ( p < 0.001 for both; Fig. 1) [16].
Furthermore, in univariate and multivariate analyses, baseline PSA > 10 ng/ml and high PSA velocity
were significantly associated with shorter bone
metastasis-free survival ( p < 0.001 for both; Fig. 2)
[16]. In univariate analyses, Gleason scores >7 were
also associated with shorter bone metastasis-free
679
Fig. 2 – Cox proportional hazard estimates of bone
metastasis-free survival indicate that baseline
PSA >10 ng/ml and high PSA velocity are significant risk
factors for shorter time to first bone metastasis in both
univariate and multivariate analyses. PSA: prostatespecific antigen. *For each log (ng/ml)/yr increase in PSA
velocity. Data from Smith MR, et al [16].
survival (RR, 1.62; 95%CI, 0.96–2.75; p = 0.07; Fig. 2)
[16]. Kaplan-Meier estimates of time to bone
metastasis or death demonstrated that a PSA of
>24 ng/ml and a PSA doubling time of <6.3 mo are
also associated with shorter bone metastasis-free
survival (Fig. 3) [16].
A second aspect of bone health involves the
development of SREs. Once bone metastases have
developed, PSA parameters appear to have limited
utility in predicting risk of SRE. For example,
Fig. 3 – Kaplan Meier time to bone metastasis or death according to tertiles of (A) prostate-specific antigen (PSA) and (B) PSA
doubling time (PSADT). Reprinted with permission from the American Society of Clinical Oncology. Smith MR, et al. Natural
history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005, vol.
23, issue 13, 2918–25 [16].
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european urology supplements 6 (2007) 677–682
Fig. 4 – Androgen-deprivation therapy (ADT) decreases bone mineral density in the lumbar spine and hip [8] and increases
risk of fracture [19] in patients with prostate cancer. Adapted from Mittan D and Bruder J, et al. J Clin Endocrinol Metab,
Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs, volume 87, number 8, 2002,
pages 3656–61, copyright 2002, The Endocrine Society [8]; and reprinted from J Urol, volume 157, Daniell HW, et al,
Osteoporosis after orchiectomy for prostate cancer, pages 439–44, copyright 1997, with permission from the American
Urological Association [19].
Table 1 – Bisphosphonates may provide benefits to patients with HSPC by preventing BMD loss during ADT
Alendronate
Pamidronate
Zoledronic acid
Study
No. of patients
Bruder et al [20]
Smith et al [21]
Casey et al [22]
22
47
139
Smith et al [23]
106
BMD versus ADT alone
Alendronate (plus ADT) prevented bone loss at the spine and hip ( p < 0.05)
Pamidronate (plus ADT) " mean BMD in the hip and lumbar spine ( p 0.02 for both)
Zoledronic acid (plus ADT) " mean BMD at the lumbar spine, femoral neck,
and hip ( p 0.0012 for all)
Zoledronic acid (plus ADT) " mean BMD at the lumbar spine, femoral neck,
trochanter, and total hip, whereas placebo # mean BMD ( p < 0.001 for all)
HSPC: hormone-sensitive prostate cancer; BMD: bone mineral density; ADT: androgen-deprivation therapy.
approximately 7% of patients with hormone-sensitive prostate cancer (HSPC) and PSA < 2 ng/ml
experienced one or more on-study SRE in a trial in
patients with one or more bone metastasis secondary to prostate cancer (n = 308) who received
intravenous zoledronic acid 4 mg every 4 wk for
15 mo in addition to standard therapy [17]. Although
this proportion of patients is lower than that
reported for the overall trial population, which
included both hormone-refractory and hormonesensitive patients (23.0%), these results demonstrate that low PSA levels do not mean that patients
are not at risk for SREs [17]. However, although the
benefits of bisphosphonate therapy have been
demonstrated in patients with bone metastases
from hormone-refractory prostate cancer (HRPC),
prospective data are needed to determine the
optimal role of bisphosphonate therapy in patients
with bone metastases from HSPC. A phase 3,
randomized Cancer and Leukemia Group B
(CALGB-90202) trial of zoledronic acid for the
prevention of SREs in patients with bone metastases from prostate cancer undergoing ADT is
currently underway to address this issue [18].
As previously stated, ADT decreases BMD and
increases fracture risk in patients with HSPC (Fig. 4)
[8,19]. This bone loss may exacerbate pre-existing
osteopenia or osteoporosis, which is prevalent in
patients newly diagnosed with prostate cancer.
Notably, preclinical evidence demonstrated that
androgen-deficient mice developed significantly
more bone metastases compared with control mice,
suggesting that excess bone resorption caused by
ADT may stimulate metastasis of prostate cancer
cells to the bone [9]. Zoledronic acid significantly
reduced the incidence of bone metastases in both
normal and androgen-deficient mice [9]. Although
no bisphosphonate has received regulatory approval
specifically for this patient population, clinical data
indicate that bisphosphonates may prevent BMD
loss during ADT, thereby lowering fracture risk
(Table 1) [20–23].
2.
Conclusions
In conclusion, patients with prostate cancer are at a
high risk for the development of bone metastases,
european urology supplements 6 (2007) 677–682
emphasizing the need for tools that may assist in
identifying patients who may be most in need of
therapeutic intervention. Prostate-specific antigen
levels and PSA velocity in patients with prostate
cancer have been identified as important risk factors
and may help identify patients who are at high risk
for bone metastases. Although HRPC and prostate
cancer that has spread to the bone represent an
incurable disease state, the concerted efforts of a
multidisciplinary team can provide meaningful
treatment benefits [7]. Awareness of risk factors
for bone metastases and fractures may enable
urologists to identify skeletal health issues before
they result in potentially disabling morbidity. The
use of bone-targeted bisphosphonates for patients
who are at high risk for bone metastases and
fractures may reduce the incidence of skeletal
complications in these men.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
Authorship
[9]
Dr. Petrylak was responsible for the generation of
this article, controlling the content from its inception, and gave final approval of the submitted
version. ProEd Communications, Inc provided medical editorial assistance.
Conflicts of interest
[10]
[11]
[12]
Dr. Petrylak has received honoraria from Novartis
Pharmaceuticals Corporation for advisory boards.
[13]
Role of the funding source
This article was supported by an unrestricted educational grant provided by Novartis Pharmaceuticals
Corporation.
[14]
[15]
Acknowledgments
Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
I thank Carol Sledz, PhD, ProEd Communications,
Inc, for her medical editorial assistance with this
manuscript.
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