BETHESDA, Md--Patients with malignant bone disease are benefiting from
more widespread use of currently available bisphosphonates, and a new generation
of bisphosphonate compounds under investigation appears to have higher
potency, allowing for smaller doses, researchers said at an NIH symposium
on the skeletal complications of malignancy.
Dr. Robert Coleman, reader in medical oncology, University of Sheffield,
England, reported that single high-dose infusions of pamidronate (Aredia)
can provide useful palliation in patients with bone metastases. A single
120 mg, two-hour infusion was given to 86 patients with progressive bone
metastases. No other systemic anticancer treatment or radiotherapy was
The high-dose infusion reduced both pain and analgesic consumption,
compared with placebo. The rate of bone resorption was reduced in the patients
receiving pamidronate, as indicated by concentrations of pyridinoline crosslinks
in the urine. The relief of symptoms lasted about eight weeks, with no
difference in response to treatment between breast cancer and other cancers.
Twenty-two of the patients who responded well received repeated infusions
of pamidronate, given every 2 to 27 weeks (median, 11 weeks) when pain
or immobility became a problem. In these patients, pain was significantly
reduced for a median of 47 weeks.
The treatment proved most beneficial in patients who had shown a modest
increase in the rate of bone resorption, Dr. Coleman said. For patients
with more aggressive disease, he noted, more potent bisphosphonates or
combined anticancer and bisphosphonate treatment may be required.
Dr. John A. Kanis, of the WHO Collaborating Centre for Metabolic Bone
Disease, University of Sheffield Medical School, England, said that clodronate
effectively inhibits bone resorption, and, unlike pamidronate, it can be
given either intravenously or orally.
Clodronate is a bisphosphonate of intermediate potency currently used
in Europe, primarily in the management of hypercalcemia. The most widely
used clodronate regimens are 300 mg given intravenously and repeated at
five-day intervals, or a single 1,500 mg infusion.
Double-blind prospective controlled studies suggest that the incidence
of bone pain, fracture, and hypercalcemia can be significantly decreased
in patients with metastatic breast cancer.
In addition, the use of long-term clodronate in myelomatosis significantly
decreases the progression of osteolytic bone lesions, risk of fractures,
and incidence of hypercalcemia.
These studies, Dr. Kanis said, raise the possibility that bone disease
might even be prevented in individuals at high risk.
Double-blind prospective studies in women with recurrent breast cancer
but no evidence of skeletal metastasis show a small decrease with clodronate
in the proportion of women who develop metastatic bone disease, and a large
and significant decrease in the number of skeletal metastases, associated
with a decrease in skeletal morbidity.
These observations suggest that clodronate can modify the natural history
of the expression of skeletal disease, Dr. Kanis said.
Dr. Peter Burckhardt, professor of medicine, University Hospital, Lausanne,
Switzerland, observed that currently available bisphosphonates, such as
clodronate and pamidronate, also have their difficulties. Low absorption
rate means that the patient must fast if the drug is being taken orally.
Intravenous administration generally requires an institutional setting,
and patients may tire of the repeated visits required.
Ibandronate, an aminobisphospho-nate now being tested in North America
and Europe, has higher potency and thus can be given in smaller doses by
IV bolus injections. This mode of administration may increase patient acceptance
of the therapy, he said.
Ibandronate has been tested according to various protocols, Dr. Burckhardt
said. Given intravenously as a bolus injection, it is effective in treating
tumor-induced hypercalcemia and bone re- sorption, as well as osteoporosis
in postmenopausal women.
Zoledronate, a More Potent Agent
Dr. J.J. Body, associate professor of internal medicine and oncology,
Institute Jules Bordet, Brussels, also argued that the development of more
potent bisphosphonates will simplify current therapeutic regimens and could
improve their therapeutic effectiveness.
Zoledronate is the most potent of the clinically tested compounds, he
said. It is a cyclic third-generation bisphosphonate, 100 to 850 times
more active than pamidronate in several in vivo and in vitro pharmacologic
The first therapeutic trial with zoledronate has been performed in patients
with tumor-induced hypercalce-mia. In this phase I multicenter study, a
single infusion proved effective at dose levels of 0.02 and 0.04 mg/kg
of body weight (1.2 mg and 2.4 mg total dose for an average 60 kg individual).
Five of five patients became normocalcemic after a dose of 0.02 mg/kg,
and 14 of 15 after a dose of 0.04 mg/kg.
The median time to normalization of serum calcium was two days, and
the median duration of action was 33 days, suggesting that zoledronate
has a faster onset and a longer duration of action than other clinically
tested bisphospho-nates. The agent was well tolerated; the only significant
side effect was an increase in body temperature in some patients.
Dr. Body noted that a phase I trial of zoledronate has been initiated
in patients with lytic bone metastases. The agent is being given monthly
as short infusions (5 minutes to 30 minutes) at doses between 0.1 mg and
8.0 mg. The investigators have seen an analgesic effect, he said, and the
effects on the biochemical markers of bone resorption appear to be greater
than those seen after 90 mg infusions of pamidronate.
These initial human data suggest that zoledronate can be administered
as convenient short IV infusions and lead to a more marked and more prolonged
inhibition of bone resorption than is currently possible with available
compounds, Dr. Body said. Future trials will be needed to determine if
prolonged treatment with this extremely potent bisphospho-nate can also
have a larger effect on the morbidity of bone metastases.