Recently, there has been much controversy over whether patients with
prostate cancer should be treated with bisphosphonates not only to
decrease pain, but to prevent metastasis.
This brief review summarizes the known data in this area. The main
points made in the discussion are highlighted in previews appearing
at the beginning of each section of the article.
Preview: Bisphosphonates inhibit bone destruction by
osteoclasts. They are not very effective in inhibiting osteoblasts,
which build bone and are the main cause of metastatic prostate cancer lesions.
Although tumor cells may directly destroy bone, most tumor-related
bone destruction appears to be due to substances released by the
tumor that stimulate osteoclasts. Bisphosphonates effectively inhibit
bone resorption by interfering with osteoclast activity through
multiple mechanisms, some of which are still not clearly understood.
These drugs have a high affinity for calcium and, once administered,
bind to hydroxyapatite in areas of exposed bone mineral where active
bone remodeling is occurring, making the bone surfaces less available
to osteoclastic resorption. Bisphosphonates prevent the migration of
osteoclasts toward bone and inhibit the recruitment of osteoclastic
precursors at the bone marrow level, thus decreasing osteoclast
numbers. They may also induce osteoclastic apoptosis.[1,2]
Several bisphosphonates have been used successfully to treat
conditions associated with abnormal osteoclastic activity, such as
hypercalcemia, Pagets disease, and osteolytic skeletal
metastases. In these populations, bisphosphonate treatment is
associated with decreased pain scores, improved performance status,
better quality of life, and a significant decrease in skeletal
events, such as fractures, spinal cord compressions, and bony pain
requiring palliative radiation.[1-4]
Preview: In breast cancer patients, bisphosphonates have
been shown to decrease pain at metastatic sites. One bisphosphonate,
pamidronate (Aredia), reduced skeletal complications from 64% to 51%
over 2 years when compared with placebo but showed no effect on
survival or quality of life. Breast cancer patients often have both
osteolytic and osteoblastic lesions.
Several recent trials of bisphosphonates in breast cancer patients
have shown statistically significant decreases in bone pain and
skeletal complications (fractures, spinal cord compression, and the
need for palliative external-beam radiation).[3,4] Long-term
follow-up data were recently published from two large, multicenter,
randomized, double-blind, placebo-controlled trials comparing the
efficacy of pamidronate plus antineoplastic treatment with
antineoplastic treatment alone in women with advanced breast
A total of 751 patients receiving either endocrine therapy (protocol
18) or chemotherapy (protocol 19) at study enrollment were randomized
to receive either pamidronate, 90 mg IV every 3 to 4 weeks, or
placebo in addition to their primary treatment. All patients were
allowed to change their anticancer treatment at any time during the
study. The primary end point was the skeletal morbidity rate, defined
as the number of skeletal complications divided by the time on the
trial. Secondary end points were bone pain scores, analgesic use,
quality of life, and performance status.
Both mean and individual skeletal morbidity rates were significantly
better in the pamidronate group after 24 cycles: Mean skeletal
morbidity rate (including hypercalcemia) was 2.5 skeletal
complications per year in the pamidronate group vs 4.0 in the placebo
group. Median times from study entry to first skeletal complication
were 7.0 and 12.7 months in the placebo and pamidronate groups,
respectively. Median time to new pathologic fracture was 12.8 months
in the placebo group and 25.2 in the pamidronate group. Median time
to palliative bone radiation was 16.0 months in the placebo group and
had not yet been reached in the pamidronate group.
Although mean pain and analgesia scores had declined by the last
study visit in both groups, the magnitude of the decline was
significantly less in the pamidronate group. Eastern Cooperative
Oncology Group (ECOG) performance status and quality of life
decreased from baseline to last study visit in both groups, and there
was no difference in survival between the two groups. It should also
be noted that 69.5% of patients in the pamidronate arm and 75.7% of
those in the placebo arm were removed from the study without
completing the planned 24 months of treatment because of adverse
events, unsatisfactory response, death, refusal of therapy, or other
Based on these results, the authors concluded that the addition of
pamidronate to antineoplastic therapy is more effective than
antineoplastic therapy alone in preventing skeletal complications and
palliating symptoms in breast cancer patients with osteolytic bone metastases.
A recent consensus statement developed by the American Society of
Clinical Oncology (ASCO) recommends the use of intravenous
pamidronate (90 mg IV every 3 to 4 weeks) in patients with metastatic
breast cancer who are receiving systemic anticancer therapy (hormonal
or chemotherapy) and who have clear evidence of osteolytic bone
destruction. The guidelines specifically do not recommend
bisphosphonate therapy for breast cancer patients with no evidence of
bone metastases or for patients with positive bone scans but no
evidence of either bone destruction or localized bone pain.
Another recent study demonstrated that, despite its efficacy in
reducing skeletal events, pamidronate therapy is associated with
substantial cost per avoided skeletal event. We certainly do not
advocate that any patient be denied bisphosphonate treatment on the
basis of cost. Rather, we merely wish to call attention to the fact
that this is an expensive treatment option that should not be used
indiscriminately in situations where there is no clear evidence of
potential benefit to patients.
Preview: Theoretically, bisphosphonates could affect the
formation of prostate cancer metastases since both osteoclastic and
osteoblastic activity appears to be necessary for the formation of
metastatic osteoblastic bone disease.
Since bisphosphonates relieve bone pain by inhibiting osteolysis, it
seems surprising that they should have an effect on bone pain in
advanced prostate cancer, which is primarily osteoblastic. Studies
suggest, however, that there is a symbiotic relationship between
osteoclasts and osteoblasts in most metastatic bone disease, although
one type generally predominates.
Although the majority of metastatic lesions in prostate cancer are
osteoblastic, there is histologic and bio-
chemical evidence of synchronous osteoclastic bone resorption in
these lesions.[8,9] Hence, a decrease in osteoclastic activity could
conceivably have an effect on primarily sclerotic prostate cancer
bone lesions. In fact, studies have shown that bisphosphonates
decrease indices of bone resorption, which are above the normal range
in 50% to 80% of prostate cancer patients. Furthermore, research
in tumor cell lines indicates that these drugs may also inhibit the
adhesion of tumor cells to bone, thereby preventing or delaying the
development of new bony metastatic lesions.
Preview: Clinical studies evaluating the use of
bisphosphonates to treat bone pain in patients with prostate cancer
have yielded conflicting results.
Clinical studies of the bisphosphonates in patients with metastatic
prostate cancer have produced contradictory results: Some have shown
durable improvements in bone pain and quality of life, some have
demonstrated only transient improvement, and others have found no
effect at all.[12-14] The two bisphosphonates used most commonly in
prostate cancer to date are clodronate (which is not currently
available in the United States) and pamidronate. Because these drugs
have very poor oral bioavailability, they are most effective when
given as intravenous infusions, although some studies have followed
initial infusional therapy with high-dose oral maintenance
Pamidronate is administered in doses ranging from 30 to 60 mg weekly
to 90 to 120 mg every 3 or 4 weeks; in general, this agent has been
shown to reduce pain in 50% of patients with painful metastatic bone
lesions.[15,16] Duration of response ranges from 4 to 24 weeks, and
patients can be safely re-treated with additional intravenous doses
when pain symptoms recur. All trials seem to suggest the importance
of continued bisphosphonate treatment to maintain low levels of
osteoclastic activity, either through repeated infusions or with oral
A randomized, double-blind study of another bisphosphonate,
etidronate (Didronel), randomized 57 patients to one of four
treatment arms: IV etidronate (7.5 mg/kg for 3 days) followed by oral
etidronate (400 mg/d); IV etidronate followed by oral placebo; IV
placebo followed by oral etidronate; or IV and oral placebo.
Although follow-up was only 1 month, none of the etidronate regimens
showed a significant effect on analgesic use or symptom relief.
As mentioned above, all of the bisphosphonates have poor oral
bioavailability, with only 0.5% to 4% of an oral dose being
absorbed.[18,19] Furthermore, the high doses of drug required in oral
regimens are associated with a host of potential gastrointestinal
side effects, including nausea, vomiting, abdominal cramping,
bloating, diarrhea, and esophagitis.
Although intravenous bisphosphonates are generally well tolerated,
approximately 10% of patients treated with intravenous pamidronate
experience pain flares 24 to 48 hours after administration, which may
last for days or weeks. Transient fever also has been reported in
approximately 25% to 30% of patients treated with the intravenous
formulation of this drug; it occurs 12 to 24 hours after
administration and is self-limited.
Pamidronate is not metabolized by the human body, and approximately
25% to 40% of the intravenously administered dose is excreted by the
kidneys. Although animal studies have shown that pamidronate can
cause renal damage, several studies of patients with normal renal
function have failed to demonstrate the development of renal
impairment with weekly pamidronate doses given over either 1 or 2 hours.[20,21]
Several new, more potent bisphosphonates that are currently
undergoing clinical investigation show promising potential.
Olpadronate was recently tested in 28 patients with prostate cancer
and painful bony metastases. All patients received 4 mg/d
intravenously for 5 days; the first 12 received no further treatment,
and the last 16 received oral maintenance doses of 200 mg/d. Overall,
76% of patients reported a decrease in pain after the infusion; this
response was still evident at 3 months in those who were receiving
oral maintenance. Ongoing trials are assessing the efficacy of a
single 20-mg intravenous dose of olpadronate.
Zoledronate, a bisphosphonate 100 times more potent than pamidronate,
is being tested at low doses of 0.1 to 8.0 mg in 5-minute infusions
and appears to be well tolerated. Although none of the newer
bisphosphonates is currently available on the US market, trials of
these agents may provide important evidence regarding the efficacy of
bisphosphonates in the treatment of painful bony metastases in
prostate cancer patients.
Preview: Evidence regarding the role of bisphosphonates in
preventing the development of bone metastases is currently unavailable.
Existing data suggest that treatment with bisphosphonates is most
effective in palliating symptoms and decreasing skeletal events in
patients with osteolytic bone metastases. The question of whether
bisphosphonates are effective in preventing or delaying the
development of bony metastatic disease is also of great interest to
oncologists. Unfortunately, relatively few published studies have
used prevention of new metastatic bone disease as a primary end
point. The results of two small studies in women with breast cancer
suggested that clodronate reduced the incidence of subsequent bone
metastases, but another study showed an opposite effect, with more
metastatic bone disease developing in the clodronate-treated group.[23-25]
Although studies of bisphosphonates in prostate cancer patients with
metastatic bone lesions have shown some benefit in terms of pain
relief, to date very few data support the use of bisphosphonates in
prostate cancer patients who show no evidence of bony metastasis.
Such use is still considered experimental. Although ongoing trials
are examining bisphosphonate prophylaxis in patients with breast
cancer, further research needs to be done to determine the risks and
benefits of using bisphosphonates in the early stages of prostate cancer.
Bisphosphonates have been shown to effectively reduce the incidence
of skeletal events in breast cancer patients with destructive bone
metastases. However, the data supporting their use to prevent further
metastases in breast cancer patients are inconclusive. These agents
have not been shown to increase patient survival or quality of life.
Although, theoretically, prostate cancer metastases involve both
osteoclasts and osteoblasts, one would predict that bisphosphonates
would have a lesser effect in the advanced prostate cancer patient
than has been observed in the breast cancer patient, whose metastases
involve predominantly osteoclasts.
Therefore, although the bisphosphonates are safe and have only mild
side effects in the majority of men, at present, no data are
available to support their use to prevent the development of future
metastasis. Since trials to test this hypothesis are underway and the
answer will not be known for several years, the individual patient
and physician must decide whether this is a worthwhile avenue of treatment.
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