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Use of Bisphosphonates in Patients With Metastatic Bone Disease

Use of Bisphosphonates in Patients With Metastatic Bone Disease

ABSTRACT: Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Since these agents had demonstrated efficacy in treating other diseases associated with increased bone resorption, including cancer-related hypercalcemia and Paget’s disease of bone, studies were initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases. Recent, large, randomized, double-blind studies have shown the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma. [ONCOLOGY 12(11):1573-1579, 1998]

Introduction

Metastatic cancer in bone is a major cause of
misery for afflicted patients and may be associated with severe bone
pain, fractures, hypercalcemia, and, less commonly, spinal cord
compression and neurologic injury. Although chemotherapy, hormonal
manipulation, or radiation treatment may be used to palliate patients
with bone metastases, substantial morbidity from progressive skeletal
involvement remains a common problem.

Tumor-induced osteolysis or lytic bone disease is mediated by
osteoclast activation. Osteoclasts can be activated directly by
products produced by tumors or indirectly through other nonmalignant cells.

Bisphosphonates inhibit bone resorption by reducing osteoclastic
activity. These agents have been shown to be effective in treating
cancer-related hypercalcemia and Paget’s disease of bone, both
of which are associated with increased bone resorption. Based on
these findings, clinical trials were initiated to explore the use of
bisphosphonates in patients with osteolytic bone metastases.

This article summarizes the results of these clinical trials, with
particular focus on recent, large, randomized, double-blind trials
conducted in patients with bone metastases from breast cancer or
multiple myeloma. As background to this discussion, a brief review of
the pharmacology of bisphosphonates is provided.

Pharmacology of Bisphosphonates

Pyrophosphates are natural compounds that contain two phosphonate
groups bound to a common oxygen. In vitro, these compounds are potent
inhibitors of bone resorption. However, when used in vivo,
pyrophosphates are readily hydrolyzed by phosphatases, which renders
them ineffective in reducing bone resorption.[1,2]

If one simply substitutes a carbon for the oxygen, the pyrophosphate
molecule becomes resistant to hydrolysis and yet remains active as an
inhibitor of bone resorption. With the carbon substitution, these
synthetic compounds, known as bisphosphonates, contain two additional
chains of variable structure (called R1 and R2; see Figure
1
), which have given rise to a large number of different drugs (Table
1
).

Most bisphosphonates contain a hydroxyl group at the R1 position,
which gives them high affinity for calcium crystals and bone mineral.
Marked differences in antiresorptive potency result from differences
at the R2 site. Newer bisphosphonates, such as zol-edronate and
ibandronate, show nearly four to five logs more potency than
first-generation agents, such as etidronate (Didronel).

Bisphosphonates are poorly absorbed orally (usually < 1%),
probably due to their very poor lipophilic nature. Certain foods,
beverages, and medications can significantly alter drug absorption.
These agents also are poorly tolerated orally and have significant
gastrointestinal toxicity, particularly esophagitis and esophageal
ulcers. Thus, compliance has been a significant problem with this
route of administration.

The bisphosphonates are eliminated almost exclusively through renal
excretion. Significant nephrotoxicity can occur with these compounds,
although this is clearly related to the drug dose and rate of
infusion when given intravenously. Importantly, renal dysfunction
results from the R1 group, so that more potent newer bisphosphonates
with different R2 groups offer the opportunity for more convenient
dosing schedules without significant nephrotoxicity.

Because bisphosphonates have high affinity for bone mineral, the
drugs are highly concentrated in bone (approximately half of the
intravenous dose). In addition, these drugs preferentially bind to
bones that have high turnover rates. Thus, bisphosphonates are
concentrated at the exposed bone surface, which is actively
remodeling. They also bind more avidly with highly active trabecular
bone than with cortical bone, which has a much lower bone turnover rate.

Once bisphosphonates become a part of bone that is not remodeling,
they are biologically inactive. As a result, continued administration
of these drugs is required to achieve the desired lasting inhibition
of bone resorption.

Bisphosphonate Treatment of Bone Metastases

Because multiple myeloma and breast cancer are often accompanied by
bone involvement with osteolytic bone destruction, most clinical
trials of bisphosphonates have involved these two forms of cancer.
However, recent trials are assessing the effects of bisphosphonates
in treating bone metastases from other cancers, such as carcinoma of
the prostate.

Multiple Myeloma

Multiple myeloma is characterized by the accumulation of terminally
differentiated plasma cells in the bone marrow, and is accompanied by
a marked increase in osteoclast activity and proliferation. This
increase in osteoclast activity is mediated by the release of
osteoclast-stimulating factors.[3,4] These factors are produced
locally in the bone marrow microenvironment by cells of both tumor
and nontumor origin.

Bone pain, the major clinical manifestation of multiple myeloma, is
related to osteolytic bone destruction. Even patients who respond to
chemotherapy may exhibit progression of skeletal disease.[5,6]

Although early studies of bisphosphonates in patients with myeloma
suggested a reduction in bone pain and healing of lytic lesions, the
trials involved few patients and were open-label in design.[7-9] Six
large randomized trials of long-term bisphosphonate therapy have now
been published; these involved the use of either the first-generation
bisphosphonates etidronate or clodronate or the second-generation
aminobisphosphonate pamidronate (Aredia).[5,10-14]

Etidronate--In a Canadian study of etidronate,[5] 173 newly
diagnosed patients were entered, and 166 patients were randomized.
All patients received intermittent oral melphalan (Alkeran) and
prednisone as primary chemotherapy. Patients were then randomized to
receive either daily oral etidronate (5 mg/kg) or placebo until death
or termination of treatment due to side effects.

Although significant height loss occurred in both placebo- and
etidronate-treated patients, no difference was found between the two
arms. Similarly, there were no differences between the two arms with
respect to the other outcome measures (new fractures, hypercalcemic
episodes, and bone pain).

Clodronate--Three large randomized trials using oral
clodronate in myeloma patients have been published. In a Finnish
trial,[11] 350 newly diagnosed, previously untreated patients were
entered, 336 of whom were randomized to receive either clodronate
(2.4 g) or placebo daily for 2 years. All patients also received
intermittent oral melphalan and prednisolone.

Only 204 (61%) patients had had radiographs at both study entry and
after 2 years. Given this limitation, the proportion of patients with
progression of lytic lesions was lower in the clodronate-treated
group than in the placebo group (12% vs 24%; P = .026). However, the
two groups did not differ with regard to the progression of overall
pathologic fractures, as well as both vertebral and nonvertebral
fractures. In addition, the number of patients who developed
hypercalcemia was comparable in the two arms. Changes in pain index
and use of analgesics were similar in both arms.

Clodronate has also been evaluated in an open-label randomized German
trial.[12] In this study, 170 previously untreated patients were
randomized to receive either no bisphosphonate or oral clodronate
(1.6 g/d) for 1 year. All of the patients were also treated with
intravenous melphalan on day 1 and oral prednisone on days 1 through
4 every 4 weeks. Unfortunately, 52% of the participants prematurely
terminated treatment despite the short length of the study (1 year).

Patients in the two arms showed no difference in the progression of
bone disease, as assessed by plain radiographs. However, there was a
trend toward a reduced number of new progressive sites in the
clodronate-treated group after 6 months (P = .06), as well as 12
months (P = .09). The proportion of patients who were pain-free and
who were not using analgesics was higher in the clodronate group.
Because of the open design of this trial, one should be cautious in
interpreting the results relative to analgesic usage and pain
evaluation. No difference in performance status was observed.

Recently, the Medical Research Council (MRC) published the results of
a large trial that randomized 536 patients with recently diagnosed
myeloma to receive either oral clodronate (1.6 g) or placebo daily in
addition to alkylator-based chemotherapy.[13] The primary end points
of the trial were unclear. However, after combining the proportion of
patients who developed either nonvertebral fractures or severe
hypercalcemia (including those who left the trial due to severe
hypercalcemia), the investigators found a lower incidence of these
combined events in the clodronate-treated patients than in the
placebo-treated patients (P = .021). Nevertheless, the overall number
of patients who developed hypercalcemia was similar in the two arms.

In addition, the number of patients who experienced nonvertebral
fractures was lower in the clodronate group (P = .036). Although
vertebral fractures reportedly occurred significantly less frequently
in clodronate-treated patients than in placebo recipients, only half
of patients underwent even one post-baseline radiograph.

Back pain and poor performance status did not differ significantly
between the two groups except at one time point (24 months). The
proportion of patients requiring radiotherapy was similar in the two
groups. There also were no differences between the groups in time to
first skeletal event or overall survival.

It is somewhat surprising that this trial showed any benefit, given
the negative results of the Finnish trial, which used a higher daily
dose (2.4 g) of oral clodronate. The results of the MRC trial are
limited by the lack of clearly defined, predetermined, specific
primary and secondary end points. The lack of impact of this drug on
time to first skeletal event and use of radiotherapy is also problematic.

Pamidronate--Compared with etidronate and clodronate,
pamidronate is 100- and 10-fold more potent, respectively, in
preventing bone resorption in vitro. This agent is a potent inhibitor
of bone resorption at doses that do not affect bone
mineralization.[14] In multiple myeloma patients, results of
open-label trials lasting up to 24 months suggested that pamidronate
disodium might be effective in reducing skeletal complications of
multiple myeloma.

Based on these results, a randomized, double-blind study was
conducted to determine whether monthly 90-mg infusions of pamidronate
would reduce skeletal events in patients with mul-tiple myeloma who
were receiving chemotherapy, as compared with placebo.[10,15] This
study included 392 patients with Durie-Salmon stage III multiple
myeloma and at least one osteolytic lesion. Unlike the etidronate and
clodronate trials, which involved untreated patients, patients in the
pamidronate trial were required to receive an unchanged chemotherapy
regimen for at least 2 months before enrollment.

Patients were stratified according to the type of antimyeloma therapy
they were receiving at trial entry: first-line chemotherapy (stratum
1) or second-line or higher chemotherapy (stratum 2). Within each
stratum, patients were randomized to receive either pamidronate
disodium (90 mg) or placebo, each administered as a 4-hour
intravenous infusion at intervals of 4 weeks for 21 months.

Because of the expected loss of patients on the trial, it was
preplanned to analyze the primary efficacy variable (skeletal events)
after 9 cycles of treatment and to analyze survival and safety after
21 cycles. However, patients continued to be followed for skeletal
events during the entire 21 cycles of randomized treatment. Both the
primary end point, skeletal events (pathologic fractures, spinal cord
compression associated with vertebral compression fracture, surgery
to treat or prevent pathologic fracture or spinal cord compression
associated with vertebral compression fracture, or radiation to
bone), and secondary end points (hypercalcemia, bone pain, analgesic
drug use, performance status, and quality of life) were assessed monthly.

A total of 392 patients were enrolled in the study (205 patients
received pamidronate and 187 patients received placebo), although
efficacy was based on 377 patients. However, all 392 patients were
included in the safety assessments and survival analyses. The
chemotherapeutic regimens in the two groups were similar at study
entry and during the trial.

After nine cycles of therapy, the proportion of patients having any
skeletal event was 41% in the placebo group but only 24% in the
pamidronate group (P < .001). In addition, median skeletal
morbidity (defined as the number of skeletal events per year) was
half as high in pamidronate-treated patients as in placebo recipients
(P < .001). During the first nine treatment cycles, the proportion
of pamidronate-treated patients with skeletal events was lower in
both stratum 1 (first-line therapy) and stratum 2 (second-line or
higher therapy).

During these first nine cycles, patients who received pamidronate had
significant decreases in bone pain and required no increase in
analgesic usage. The pamidronate-treated patients also showed no
deterioration in performance status or quality of life at the end of
9 months.

Similar to the results after 9 cycles of therapy, the proportion of
patients developing any skeletal event and skeletal morbidity
continued to remain significantly lower in the pamidronate group than
in the placebo group during the additional 12 randomized treatment
cycles. However, the two treatment groups did not differ with respect
to the percentage of patients with healing or progression of
osteolytic lesions.

Overall survival in all 392 patients was not significantly different
between the two treatment groups. Although median survival did not
differ between the treatment groups in stratum 1 patients, median
survival time was 21 months for stratum 1 patients treated with
pam-idronate vs 14 months for their counterparts treated with placebo (Figure
2
).

In a double-blind, randomized trial, a Danish-Swedish cooperative
group compared oral pamidronate (300 mg/d) to placebo in 300 newly
diagnosed myeloma patients who were also receiving intermittent
melphalan and prednisone.[16] After a median duration of 18 months,
there were no significant differences between the two arms with
respect to either the primary end point, skeletal-related morbidity
(defined as bone fracture, surgery for impending fracture, vertebral
collapse, or increase in the number and/or size of lytic lesions) or
secondary end points (hypercalcemic episodes or survival). Fewer
episodes of severe pain and less height loss were observed in the
pamidronate-treated patients, however.

Treatment Recommendations--Results of these trials show that
the adjunctive use of bisphosphonates in addition to chemotherapy is
superior to chemotherapy alone in patients with stage III multiple
myeloma with respect to lessening bone complications. Bisphosphonate
treatment should now be considered for all patients with multiple
myeloma and at least one osteolytic lesion.

The three large long-term studies of clodronate show little impact of
the oral form of this drug on skeletal complications. In addition,
the lack of efficacy of oral pamidronate suggests that this route of
administration is unlikely to produce positive results in multiple
myeloma patients. Thus, the current drug of choice at present in the
United States is intravenous pamidronate. Although 90 mg monthly is
efficacious, the optimal duration and dose of intravenous pamidronate
are unknown. However, based on published results, patients should
receive at least 21 months of treatment.[15]

Whether intravenous pamidronate is effective in earlier-stage disease
or in patients without bone disease is unknown. However, recent in
vitro studies suggest that pamidronate may possess antimyeloma
properties, as demonstrated by its ability to induce apoptosis of
myeloma cells[17] and suppress the production of interleukin-6, an
important myeloma growth factor, by bone marrow stromal cells from
myeloma patients.[18]

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