New Bisphosphonates Under Study for Bone Metastases
New Bisphosphonates Under Study for Bone Metastases
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 administered.
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 test systems.
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.