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Bone
Metastases In Prostate Cancer And Therapy With Zometa.
(February 2005)
If a man’s prostate cancer is not cured by primary therapy
there is a greater than 70% likelihood that during the course of his
illness he will experience metastases to bone and suffer morbidity and
possibly mortality from this spread. In current literature the
consequences of bone metastases are grouped under the term “skeletal
related events (SRE)”: pathological fractures, spinal chord compression,
hypercalcemia, and the need for palliative radiotherapy. The median
survival for men after a SRE is about 1 and 1/2 usually symptomatic years.
Why is bone - usually the axial skeleton, ribs, and
proximal extremities such a preferred site of metastatic spread? One
predisposing factor is the copious blood flow to these areas of red marrow
offering ample exposure to circulating cancer cells. But the liver and
lungs also are heavily perfused and yet are much less successfully
colonized. Intriguing evidence suggests that chemotactic beacons from the
bone guide cancer cells to selectively home to marrow stromal cells and
the bone matrix. Once there, prostate cell adhesion molecules - a variety
of integrins - stick to their matching ligands ... and a metastases is
born. The expanding cluster of malignant cells in association with their
stromal counterpart drastically alter the local bone metabolism, promoting
angiogenesis and releasing bone resorbing factors, and disrupt the
delicate balance between the bone building osteoblasts and lytic
osteoclasts that governs the constant remodeling of bone.
Osteoclasts nest in pockets in extracellular bone matrix like fists in
baseball mitts and a tight interface is essential for facilitating the
lytic proteases to break down the collagen matrix. Embedded in this matrix
are immobilized cytokines - transforming growth factor beta,
insulin-like growth factors, fibroblast and platelet-derived growth
factors - which are released into the local region. Unfortunately, these
very bone derived factors have an proliferative effect on invading cancer
cells. The paracrine secretion of cytokines from cancer cells and stroma
have a stimulating effect on the osteoclasts leading to a vicious circle
of osteolysis. Despite the conventional association of the term
“osteoblastic” with the bony lesions of prostate cancer there is abundant
ongoing osteolysis. There is evidence that bone resorption precedes bone
formation.
The bisphosphonates potently inhibit osteoclastic bone
resorption and two major subtypes are (1) non-nitrogen containing, such as
the familiar Fosamax, and (2) nitrogen containing, such as the earlier
Pamidronate and the current, 1000 times more potent, Zometa.
Bisphosphonates, analogues of pyrophosphate, are avidly attracted to the
hydroxyapatite particles of bone, replacing pyrophospate. Because of this
avidity, a bisphosphonate serves as the bone targeting agent for the
99m-Technetium bone scan. The bisphosphonates home to the osteoclast/bone
matrix interface of the pocket and inhibit osteoclastic activity and
possibly promote osteoclast apoptosis. The bisphosphonate is released only
when resorption or metastatic invasion occurs. Additionally, early
evidence suggests that Zometa may be antiangiogenic, decrease tumor
invasiveness and adhesion to bone, and inhibit proliferation and induce
apoptosis of malignant cells.
The organic matrix of bone is 90% type I collagen - laid
down by osteoblasts - and its dissolution is conveniently measured by
analyzing the quantity of the urinary excretion of the collagen breakdown
fragment, type I collagen cross-linked N-telopeptide (NTX), which is
proportional to the total extent of bone lysis. Zometa, a nitrogen
containing bisphosphonate, performs one, possibly two, major functions: it
inhibits resorption at the osteoclast/matrix interface, but additionally
there is evidence accumulating that it also may poison osteoblasts,
interfering with cell signaling and effecting apoptosis, and in the same
maner may be cytocidal to nearby prostate cancer cells.
Androgen deprivation (AD) stimulates osteoclastic activity
and the associated loss of bone mineral density. Dr. Higano, at the
University of Washington, was among the authors who, having searched the
electronic literature for the accumulated data, published “Osteoporosis in
men with prostate carcinoma receiving androgen deprivation therapy”,
Cancer 2004, Mar 1. They reported a 2% to 8% bone loss in the lumbar spine
and a 1.8% to 6.5% loss in the hip over a 12 month period, and recommended
that “clinical management should be dictated by the results of
radiographic and DXA skeletal assessment”. Baseline DXA scans seem
appropriate, if not for every man, at least especially indicated for those
who are at high risk for incurring osteoporosis (T score > 2.5) during
ensuing AD therapy, i.e., men with a family history of osteoporosis, heavy
alcohol intake or heavy smoking, low body weight, corticosteroid usage, or
significant co-morbidities. Dr. Oliver Sartor, a prostate cancer
specialist at LSU Medical Center, recommends repeating the DXA scan yearly
during AD therapy and he tailors management based on the results. In
another article Dr. Higano reported a 4.5% bone loss in the lumbar spine
and 2.5% in the hips over the initial 9 months in a program of
intermittent AD therapy. At the end a median “off” period of 8 months
a 1.5% recovery was seen at the L/S spine, but there was no significant
improvement at the hip. Since the occurrence of pathologic fractures are
inversely proportional to bone density, there is a need to control bone
loss in men whose testosterone is lowered by treatment.
The measurement of urinary N-telopeptide (uNTX-I) can
monitor the extent the lytic process. A value of less than 50 nmol/mmol
urinary creatinine (“units”) is normal for healthy young adults and < 100
units was chosen arbitrarily to divide “low risk” from “high risk” (> 100
units) in men on AD therapy in the excellent article by Brown et al (JNCI,
January 5, 2005), “Bone Turnover Markers as Predictors of Skeletal
Complications in Prostate Cancer, Lung Cancer, and Other Solid Tumors”.
The frequency of adverse outcomes in 203 men under treatment for
metastatic prostate cancer (excluding anti-resorptive agents) was reported
using this < 100 vs. > 100 cut off point. The outcome events analyzed were
SRE, bone disease progression and death. Baseline uNTX-I values > 100
units were predictive of a negative outcome. Over a 24 month period the >
100 unit group had a 3.25 relative risk (RR) for SRE compared to the <100
cohort, and a 2.02 RR for disease progression. The median survival for the
entire prostate cancer group was 16.8 months, but when stratified for
baseline uNTX levels survival in the < 100 unit group was 22.8 months vs.
11.9 months for > 100 units. If the predictive values of uNTX measurement
can be further validated, this test might be applied to men with prostate
cancer at a time of less tumor burden and serve as a guide to earlier
therapeutic intervention.
Smith (J.Urol June 2003) reported benefit of Zometa
treatment in preserving bone density in an early intervention trial that
studied men with no distant metastases who were beginning androgen
deprivation therapy: “Randomized Controlled Trial of Zoledronic Acid [Zometa]
to Prevent Bone Loss in Men Receiving Androgen Deprivation Therapy for
Nonmetastatic [M0] Prostate Cancer”. A total of 106 men were divided
between treatment for one year with Zometa 4 mg every three
months or a placebo. Mean bone mineral density in the lumbar spines of
the treated group showed a 5.6% increase compared to a decrease
of 2.2% in the placebo cohort; and in the femoral neck there was a
1.2% increase vs. a 2.1% decrease.
The currently standard use of Zometa is in treatment of
prostate cancer patients with demonstrated skeletal metastases. The
long-term benefits of this strategy were presented by Saad et al (JNCI
June 2, 2004) in “Long-Term Efficacy of Zoledronic Acid for the Prevention
of Skeletal Complications in Patients with Metastatic Hormone-Refractory
Prostate Cancer”. They report results at 24 months of 122 men who
completed a total of months on study. Zometa 4-mg was administered via a
15-minute infusion every 3 weeks for 15 months as compared a
placebo. A SRE developed in 38% of the treated group versus 49% for
controls, and in the Zometa arm the first new lesion occurred at a
median of 488 days versus 321 days in the control group. Subsequent
correspondence regarding this article pointed out an unusual, and
currently unexplained, development of avascular necrosis of the jaw with
prolonged use of Zometa and cited that “osteopetrosis, a disease
characterized by pain, mandibular osteomyelitis, and recurrent fractures
has been reported during prolonged use (i.e., > 24 months) of certain
[nitrogen containing] potent bisphosphonates.”
A discussion of the intriquing possibility that nitrogen-
containing bisphosphonates have anti-cancer activity will have to await
more data. However, a model exists for this possibility. There is strong
belief that in the treatment of myeloma Zometa has an anti-proliferative
and apoptotic action on myeloma cells, and early data suggests that Zometa
may have a similar effect upon prostate cancer cells.
[References are available upon request]
Bottom Line:: The benefits of
the bisphosphonate Zometa in the treatment of advanced prostate cancer is
well established. Studies suggest that its earlier application can prevent
bone loss from androgen deprivation and prevent and postpone deleterious
skeletal complications with their attendant morbidity.
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