Introduction
The skeleton is the most common site of recurrence of metastatic breast cancer,
and bone metastasis will occur in 49% to 85% of patients with breast cancer
during their lifetime.1,2 The morbidity from bone metastases in
patients with breast cancer represents a significant health problem, and the
major clinical manifestation involves osteolytic bone destruction.2
Depending on the extent of the disease and the site of metastasis, patients
may be asymptomatic, may develop hypercalcemia, or may experience chronic,
debilitating pain with a significant compromise in quality of life. In advanced
cases, significant complications such as spinal cord compression or pathologic
fracture of a long bone can result in permanent disabilities.
Tumor-induced osteolysis is essentially mediated by osteoclasts whose number
and activity appear to be influenced by factors produced in the bone marrow
microenvironment (osteoclast-stimulating factors) that act by a paracrine
mechanism.3 Bisphosphonates are specific inhibitors of osteoclastic
activity and have been used for the treatment of hypercalcemia associated
with malignancy.4 The bisphosphonates are a family of pyrophosphate
analogues that bind to bone hydroxyapatite and inhibit bone resorption locally.
A 90-mg 2-hour monthly infusion of the bisphosphonate has been associated
with reduced skeletal complications when used with chemotherapy or hormonal
therapy in patients with osteolytic bone metastases.5,6 Pamidronate
has been approved by the Food and Drug Administration for the treatment of
normocalcemic patients with myeloma-associated bone disease and osteolytic
lesions of metastatic breast cancer.
Biologic Mechanisms of the Bone Remodeling Process
The concomitant action of host components and mechanical factors has been
identified as being responsible for the constant remodeling of bone. The host
components include osteoblasts and osteoclasts (which are directly responsible
for the active process of remodeling) and cytokines and other humoral factors
(which act through a paracrine mechanism).7
Osteoblasts derived from hematogenous precursors produce collagen matrix
as well as osteocalcin, osteopontin, and osteonectin, the bone-specific proteins.
Osteoblasts are necessary for osteoclast activation and the functional dissolution
of the bone. Osteoclasts, derived from the monocyte-macrophage cell line,
are able to migrate and, when activated, dissolve the bone at attachment sites
in disparate parts of the skeleton. They are influenced by a variety of cytokines,
including macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating
factor, transforming growth factors (TGFs), and interleukin (IL)-6, most of
which are produced by activated osteoblasts.8
In normal bone remodeling, the relationship between osteoblastic and osteolytic
activity is balanced; this balance is termed "coupling." In pathologic or
metabolic conditions such as metastatic disease or osteoporosis, this equilibrium
can be altered, with the activity of one of the two cell types becoming prevalent
and resulting in defective bone formation.9
A variety of cytokines and tumor-derived proteins produced by breast cancer
cells are capable of osteoclastic activation. Parathyroid hormone-related
peptide (PTH-rP), TGF-alpha, TGF-beta, prostaglandin, IL-1, and IL-6 have been more
extensively investigated and appear to be among the most important osteoclast
activators in metastatic breast cancer. Among the various cytokines, extensive
investigations have been conducted on the role of PTH-rP, a peptide isolated
approximately 10 years ago that is responsible for the hypercalcemia associated
with malignancy. Experimental data derived from a series of studies using
MDA-231 breast cancer cells in a nude mouse model suggest that PTH-rP expression
in breast carcinoma cells may enhance the progression of metastatic disease
to the bone. Furthermore, an interesting interaction between TGF-beta seems to
play a critical role in the regulation of osteoclastic bone resorption and
PTH-rP expression and may facilitate the osteolytic process associated with
breast cancer invasion.10
Bisphosphonates and Their Mechanism of Action
Bisphosphonates are natural components that are characterized by a P-C-P
bound in their structure that is responsible not only for their binding to
mineralized bone matrix, but also for their inhibitory effects on bone resorption.11
They possess a carbon substitution for the oxygen of the pyrophosphate molecule
and are therefore resistant to enzymatic hydrolysis by endogenous bisphosphonates.
All bisphosphonates have a high affinity for hydroxyapatite crystals in bone,
thus stabilizing bone mineral and inhibiting its dissolution.
The precise mechanism of action of the bisphosphonates on bone cells and
bone resorption is not completely clear. Bisphosphonates inhibit osteoclastic
function in several ways, eg, by producing a direct toxic effect on the resorbing
osteoclasts, by promoting apoptosis, or by inhibiting the differentiation
of the osteoclasts into mature osteoclasts.12
Bisphosphonates inhibit bone resorption due to PTH, PTH-rP, corticosteroids,
retinoids, prostaglandins, and a variety of cytokines. The relative potency
of bisphosphonates depends on the unique chemical structure of their side
chains (Table 1). Etidronate, a first-generation agent, is the least potent
inhibitor of bone resorption among the clinically evaluated bisphosphonates.13
Clodronate and pamidronate, which were extensively evaluated in patients with
malignant diseases, have been determined to be more potent.11-14
Clodronate is approximately 10 times more potent than etidronate, whereas
pamidronate appears to be 10 times more potent than clodronate.15,16
Alendronate, which has a four-carbon amino side chain, displays high potency
(10 times that of clodronate) and effectively inhibits osteoclast bone resorption
at doses that do not impair bone mineralization.17
|
Table
1. — Antiresorption Potency of Various Bisphosphonates
|
| |
Relative
Potency
|
| First-Generation
Agents: |
|
Etidronate |
1 |
| Clodronate |
10 |
|
Tilundronate |
10 |
| Second-Generation
Agents: |
|
Pamidronate |
100 |
|
Alendronate |
1,000 |
| Third-Generation
Agents: |
|
Ibandronate |
10,000 |
|
Zoledronate |
20,000 |
Zoledronate and ibandronate represent third-generation agents. Clinical data
have demonstrated that these agents have an antiresorption potency that is
at least a thousandfold superior to the first-generation agents.18,19
Clinical applications of these bisphosphonates include treating conditions
associated with increased bone resorption, particularly osteolytic bone metastasis
from breast cancer and multiple myeloma.20,21 Tumor-induced hypercalcemia
and Paget’s disease of the bone have also been successfully managed with these
agents.
Data from a series of preclinical studies performed on animals led to clinical
trials of the use of bisphosphonates in the prevention of osteoporosis.
Since 1990, clinical trials using daily oral doses of alendronate in postmenopausal
women with osteoporosis have been conducted in many centers. These studies
demonstrated that daily treatment with alendronate progressively increases
the bone mass in the spine, hip, and total body and reduces the incidence
of vertebral complications (fractures and deformities) associated with severe
osteoporosis in postmenopausal women.17
The toxicity of bisphosphonates is strictly related to the route of administration
of these agents.11 The bisphosphonates are better tolerated when
administered by intravenous injections because their metabolism is exclusively
through renal excretion. Renal dysfunction is the main toxicity. The renal
toxicity associated with intravenous administration of bisphosphonates is
rare and is closely related to the drug dose and the rate of infusion. The
clinical introduction of newer agents may offer an advantageous solution in
terms of dosing that can prevent these unwanted effects.18,19
Some agents are administered orally, which is associated with poor absorption
(usually <1%) and significant gastrointestinal toxicity that may be as
severe as esophagitis and esophageal ulcers.
Bisphosphonates to Treat Breast Cancer
The occurrence of bone metastasis is a common event in the natural history
of breast cancer. In fact, bone localization is the most frequent site of
metastatic disease in patients with advanced breast cancer.
Cytotoxic chemotherapy or hormonal agents used systemically are the preferred
forms of treatment, but they usually are associated with only temporary control
of symptomatic disease. The ultimate prognosis in patients with metastatic
breast cancer of the bone is generally poor, but a proportion of these patients
may survive longer and thus require palliative treatment of the symptoms and
complications related to their bone metastases.
Alternative palliative bone-directed therapies involve localized radiation
therapy and radioactive bone-seeking agents (strontium-89 and samarium-153),
which usually are used to prevent pathologic fractions and reduce pain.22-24
Because of their activity as inhibitors of osteoclastic bone resorption,
bisphosphonates have been shown to be effective in the palliative treatment
of women with osteolytic bone metastases. The two most popular agents, clodronate
and pamidronate, have been extensively investigated in multicenter clinical
trials performed in the last 10 years (Table 2). These agents have demonstrated
efficacy in the management of malignancy-associated hypercalcemia, replacing
other agents such as calcitonin, corticosteroids, and plicamycin. Their use
in patients with metastatic breast cancer has been associated with a delay
in the onset of skeletal-related events and with improvement in pain control
and overall quality of life.25,26
|
Table
2. — Randomized Clinical Trials of Bisphosphonates
in Breast Cancer-Related Skeletal Disease
|
| Investigators |
Number
of
Patients |
Agent
(Dose) |
Bone
Pain |
Pathologic
Fractures |
HCM |
Survival |
| Paterson
et al27 |
173
|
Clodronate
(1600 mg/day orally)
|
Improved
|
Reduced
|
Reduced
|
No
benefit
|
| |
|
|
|
|
|
|
| van
Holten-Verzantvoort et al25 |
161
|
Pamidronate
(600 mg/300 mg/day orally)
|
Improved
|
Reduced
|
Reduced
|
No
benefit
|
| |
|
|
|
|
|
|
| Hortobagyi
et al28 |
751
|
Pamidronate
(90 mg IV every 3-4 weeks)
|
Improved
|
Reduced
|
Reduced
|
No
benefit
|
|
HCM = hypercalcemia
of malignancy
IV = intravenous
administration
|
A series of phase II studies demonstrated the activity of bisphosphonates
used as single agents in controlling symptomatic osteolytic bone metastases
and reducing bone pain. The symptomatic efficacy appeared to be dose dependent,
particularly for the oral agents, because of their poor absorption. These
interesting results prompted randomized clinical trials to evaluate the efficacy
of the drugs in the management of osteolytic bone disease.
In the first study, Paterson et al27 used a double-blind, randomized,
placebo-controlled trial to investigate oral clodronate at a dose of 1,600
mg/day. A total of 173 patients with osteolytic metastatic breast cancer were
enrolled, and 85 received clodronate. In those receiving clodronate, the rate
of all morbid skeletal events — including vertebral fractures and deformities
— was significantly reduced (P<0.001). No significant differences
in survival or side effects were observed between these two groups.
In 1993, van Holten-Verzantvoort et al25 published the results
of a randomized study using oral pamidronate in osteolytic metastatic breast
cancer. Eighty-one patients were treated with oral pamidronate; due to severe
gastrointestinal toxicity, a starting dose of 600 mg/day used in 29 patients
was reduced to 300 mg/day in 52 patients. When compared with 80 control patients,
the occurrence of hypercalcemia, severe bone pain, and impending fracture
decreased by 65%, 30%, and 50%, respectively. The effect was dose dependent;
unfortunately, there was a 23% drop-out rate due to severe gastrointestinal
toxicity.
Subsequent investigations have focused mainly on the intravenous administration
of pamidronate as palliative treatment. The results of two combined prospective,
placebo-controlled, randomized clinical trials of intravenous pamidronate
in patients with osteolytic bone metastases have been recently published by
Hortobagyi et al.28 Women with stage IV breast carcinoma who were
receiving cytotoxic chemotherapy (380 patients) or endocrine therapy (371
patients) and who had at least one lytic bone lesion were given either 90
mg of pamidronate during a 2-hour infusion monthly for two years or a placebo
infusion. After the results of the two studies were pooled, data from 367
patients treated with pamidronate and 384 patients given placebo were available
for analysis. The proportion of patients with any skeletal complications was
significantly less in the pamidronate group than in the placebo group at 15,
18, 21, and 24 months (P<0.001). In particular, the skeletal morbidity
rate (the number of complications per year) at 24 months was 2.4 for the pamidronate
group and 3.7 for the placebo group (P=0.001). The median time to the
first skeletal complication was 13.9 months in the pamidronate group and 7.0
months in the placebo group. The time of first fracture was increased from
12.8 to 25.2 months. Pain and analgesic use were also decreased among the
pamidronate patients. There was no survival difference between the two groups.
Furthermore, treatment with pamidronate did not prevent progression of disease
in the bone compared with the placebo.29 Interestingly, when the
two studies were analyzed separately, the reduction in skeletal-related events
appeared more evident in the group of patients receiving cytotoxic chemotherapy
(65% vs 46% for the placebo group) than for the group treated with hormonotherapy
(67% vs 56%). The reasons for the differences are not known at this time,
but these results may suggest a synergistic antitumor effect between bisphosphonates
and chemotherapy that requires further investigation.
Numerous attempts have been made in recent years to better define the biologic
modifications associated with bisphosphonate activity, and a number of biochemical
and serum protein markers have been proposed.30 Excretion of alkaline
phosphatase and urinary hydroxyproline has been considered to be a sensitive
and specific marker for monitoring disease progression in bone metastasis.31
Coleman et al32 have reported the results of an evaluation of serum
markers associated with bone resorption. N-telopeptide and c-telopeptide demonstrated
the greatest variations in inhibition by bisphosphonates. Considering the
low specificity and sensitivity of the present markers, none can be recommended
for routine use in clinical practice. Future clinical trials may better define
the role of these markers when used alone or in combination with others.
Once the efficacy of bisphosphonates as palliative treatment in metastatic
breast cancer is established, the next logical step involves testing the possibility
of preventing bone metastasis by using bisphosphonates.
Diel et al33 recently reported a study involving 302 patients
with primary breast cancer and tumor cells in the bone marrow. Patients were
randomized to either clodronate treatment at a dose of 1,600 mg/day orally
for two years (157 patients) or no therapy and standard follow-up (145 patients).
All patients received standard adjuvant treatment. Analysis performed at 36
months of follow-up revealed that clodronate treatment was associated with
a statistically significant reduction in the number of recurrences of
bone metastasis (12 vs 25 in the clodronate vs no treatment groups, respectively),
visceral metastases (13 vs 27), and deaths (6 vs 22). In addition, the average
number of bone metastases in clodronate-treated patients was significantly
lower than that in the control group.
Preliminary data are now available on a randomized trial conducted by Powles
et al,34 which completed accrual in June 1997 and involved 1,079
patients with breast cancer. Patients were randomized to receive either clodronate
1,600 mg/day orally or placebo. Preliminary data suggest a reduction in bone
metastases, particularly for postmenopausal patients. A longer follow-up period
will be required to evaluate whether the incidence of bone metastases and
eventually visceral metastases was reduced, as suggested by the intriguing
results reported by Diel and colleagues.
Future Directions
The use of bisphosphonates for the treatment of osteolytic lesions in the
setting of metastatic breast cancer has steadily increased in the last several
years. Randomized clinical trials have demonstrated a benefit, particularly
for pamidronate-treated patients, with a significant reduction in skeletal-related
complications and bone pain and an improvement in quality of life.
Based on these data, patients with osteolytic metastatic breast cancer should
be initiated on bisphosphonate treatment as early as possible after diagnosis.
Pamidronate given as an intravenous infusion every three or four weeks appears
to be the most effective treatment and is associated with fewer side effects.
This treatment should be continued for as long as efficacy is demonstrated.
Oral bisphosphonates, particularly clodronate, may replace pamidronate with
perhaps equivalent results but with less tolerance.
Future trials using a new generation of more potent bisphosphonates — zoledronate
and ibandronate — may offer more effective palliative options and, when used
in the setting of adjuvant treatment, are expected to clarify the role of
this class of drugs in the prevention of bone metastasis in patients with
breast cancer.
A phase I investigation of zoledronate has recently been completed. Doses
of 4 mg and 8 mg given as a short infusion (5 minutes) were well tolerated.18
Phase II trials are currently in progress. Markers of bone resorption will
also be routinely evaluated in treated patients to evaluate the variation
in clinical efficacy.
Many questions remain partially unanswered, including a detailed clarification
of the molecular targets of bisphosphonates and the mechanism of action by
which they affect osteoclast activity. Recent studies show that bisphosphonates
promote apoptosis of osteoclasts, but they also can affect tumor cells.35,36
In the setting of cancer, it is important to establish whether bisphosphonates
have antitumor effects and which bisphosphonates are the most effective in
this regard. No clinical data are presently available to suggest a possible
role of bisphosphonates in the management of osteolytic bone metastases due
to other solid tumors.
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