New Bisphosphonates Under Study for Bone Metastases

BETHESDA, Md--Patients with malignant bone disease are benefiting frommore widespread use of currently available bisphosphonates, and a new generationof bisphosphonate compounds under investigation appears to have higherpotency, allowing for smaller doses, researchers said at an NIH symposiumon 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 single120 mg, two-hour infusion was given to 86 patients with progressive bonemetastases. No other systemic anticancer treatment or radiotherapy wasadministered.

The high-dose infusion reduced both pain and analgesic consumption,compared with placebo. The rate of bone resorption was reduced in the patientsreceiving pamidronate, as indicated by concentrations of pyridinoline crosslinksin the urine. The relief of symptoms lasted about eight weeks, with nodifference in response to treatment between breast cancer and other cancers.

Twenty-two of the patients who responded well received repeated infusionsof pamidronate, given every 2 to 27 weeks (median, 11 weeks) when painor immobility became a problem. In these patients, pain was significantlyreduced for a median of 47 weeks.

The treatment proved most beneficial in patients who had shown a modestincrease in the rate of bone resorption, Dr. Coleman said. For patientswith more aggressive disease, he noted, more potent bisphosphonates orcombined anticancer and bisphosphonate treatment may be required.

Clodronate Studies

Dr. John A. Kanis, of the WHO Collaborating Centre for Metabolic BoneDisease, University of Sheffield Medical School, England, said that clodronateeffectively inhibits bone resorption, and, unlike pamidronate, it can begiven either intravenously or orally.

Clodronate is a bisphosphonate of intermediate potency currently usedin Europe, primarily in the management of hypercalcemia. The most widelyused clodronate regimens are 300 mg given intravenously and repeated atfive-day intervals, or a single 1,500 mg infusion.

Double-blind prospective controlled studies suggest that the incidenceof bone pain, fracture, and hypercalcemia can be significantly decreasedin patients with metastatic breast cancer.

In addition, the use of long-term clodronate in myelomatosis significantlydecreases the progression of osteolytic bone lesions, risk of fractures,and incidence of hypercalcemia.

These studies, Dr. Kanis said, raise the possibility that bone diseasemight even be prevented in individuals at high risk.

Double-blind prospective studies in women with recurrent breast cancerbut no evidence of skeletal metastasis show a small decrease with clodronatein the proportion of women who develop metastatic bone disease, and a largeand significant decrease in the number of skeletal metastases, associatedwith a decrease in skeletal morbidity.

These observations suggest that clodronate can modify the natural historyof the expression of skeletal disease, Dr. Kanis said.

Dr. Peter Burckhardt, professor of medicine, University Hospital, Lausanne,Switzerland, observed that currently available bisphosphonates, such asclodronate and pamidronate, also have their difficulties. Low absorptionrate 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 Americaand Europe, has higher potency and thus can be given in smaller doses byIV bolus injections. This mode of administration may increase patient acceptanceof the therapy, he said.

Ibandronate has been tested according to various protocols, Dr. Burckhardtsaid. Given intravenously as a bolus injection, it is effective in treatingtumor-induced hypercalcemia and bone re- sorption, as well as osteoporosisin 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 morepotent bisphosphonates will simplify current therapeutic regimens and couldimprove their therapeutic effectiveness.

Zoledronate is the most potent of the clinically tested compounds, hesaid. It is a cyclic third-generation bisphosphonate, 100 to 850 timesmore active than pamidronate in several in vivo and in vitro pharmacologictest systems.

The first therapeutic trial with zoledronate has been performed in patientswith tumor-induced hypercalce-mia. In this phase I multicenter study, asingle infusion proved effective at dose levels of 0.02 and 0.04 mg/kgof 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, andthe median duration of action was 33 days, suggesting that zoledronatehas a faster onset and a longer duration of action than other clinicallytested bisphospho-nates. The agent was well tolerated; the only significantside effect was an increase in body temperature in some patients.

Dr. Body noted that a phase I trial of zoledronate has been initiatedin patients with lytic bone metastases. The agent is being given monthlyas short infusions (5 minutes to 30 minutes) at doses between 0.1 mg and8.0 mg. The investigators have seen an analgesic effect, he said, and theeffects on the biochemical markers of bone resorption appear to be greaterthan those seen after 90 mg infusions of pamidronate.

These initial human data suggest that zoledronate can be administeredas convenient short IV infusions and lead to a more marked and more prolongedinhibition of bone resorption than is currently possible with availablecompounds, Dr. Body said. Future trials will be needed to determine ifprolonged treatment with this extremely potent bisphospho-nate can alsohave a larger effect on the morbidity of bone metastases.