Low Doses of Zoledronic Acid Reduce Complications of Bone Metastases

Researchers at Cedars-Sinai Medical Center reportthat very low doses of a potent new bisphosphonate, zoledronic acid (Zometa), reduces the complications arising from multiplemyeloma and breast cancer that have metastasized to the bone. The study,published in Cancer (91[7]:1191-1200), shows that a 5-minute infusion ofzoledronic acid has the same effect as much higher doses of pamidronate(Aredia), a similar therapy administered over a 2-hour period.

"Not only was zoledronic acid effective in much lowerdoses, but we could give the drug to patients over a much shorter time than wecould with pamidronate," said James Berenson, md, director of the MultipleMyeloma and Bone Metastases Program at Cedars-Sinai Medical Center. "Thismeans a more potent and convenient alternative for patients battling thedebilitating effects of cancers that have spread to the bone."

Bisphosphonates vs Radiation

Both zoledronic acid and pamidronate are types ofbisphosphonates—compounds that work by slowing the production of cells thatdestroy bone. Under normal conditions, cells called osteoclasts remove old bone,after which cells called osteoblasts can begin building new bone. But whencancer spreads, the normal balance of the cells is disturbed and the osteoclastsare more active, causing bone fractures, pain, spinal cord compression, andhypercalcemia.

Radiation therapy is often required to help alleviate thesecomplications. However, radiation causes side effects such as extreme fatigueand lower levels of infection-fighting white blood cells. Alternatively,bisphosphonates cause fewer and less serious side effects, which includeflu-like symptoms and some bone pain, and can be given safely to patientsreceiving simultaneous chemotherapy or hormonal therapy. Thus, pamidronate andother bisphosphonates have been increasingly used for skeletal complications dueto cancers that have spread.

Zoledronic Acid vs Pamidronate

Earlier studies by Dr. Berenson and his colleagues have alreadyshown that a lower dose of zoledronic acid is safe and reduces the indicators ofbone loss, such as excess calcium in patients whose cancer had spread to thebone. The purpose of this current study is to determine whether zoledronic acidis as effective as pamidronate in reducing bone complications.

Investigators evaluated 280 patients with bone metastases due tometastatic breast cancer or multiple myeloma. Those who received zoledronic acidwere split into three groups by dosage, either 0.4, 2.0, or 4.0 mg, infused over5 minutes. Another group of patients received 90 mg of pamidronate infused over2 hours. Both drugs were administered once a month for 10 months. The treatmentwas considered effective if fewer than 30% of the group required radiationtherapy to the bone. Although some patients discontinued treatment due to deathor complications from their cancer, approximately 76% of all patients givenzoledronic acid and 82% in the pamidronate group completed at least 6 months ofthe study.

Radiation-Reducing Doses

The results show that zoledronic acid was as effective as themuch higher dose of pamidronate in reducing the need for radiation to bone. Inthe 2.0-mg and 4.0-mg zoledronic acid groups respectively, 19% and 21% ofpatients received radiation; 18% of patients in the pamidronate arm alsoreceived radiation. The lowest dose (0.4 mg) of zoledronic acid was found to besignificantly less effective than either the higher doses of zoledronic acid orpamidronate, with 24% receiving radiation.

"We found that the proportion of patients receivingradiation to bone in the zoledronic acid group was very comparable to thosepatients receiving the much higher dose of pamidronate," added Dr.Berenson. "Complications such as fractures, spinal cord compression…andhypercalcemia occurred less frequently in the patients receiving the higherdoses of zoledronic acid."

In addition, investigators found that the higher doses ofzoledronic acid increased bone density in the spine by almost 10%."Zoledronic acid may provide a much more convenient and effective therapyfor overcoming the skeletal complications of bone metastases," said Dr.Berenson.

Currently, Dr. Berenson and his team are conducting phase IIIclinical trials to further compare the effects of zoledronic acid andpamidronate in bone metastases.