Related Pages Prostate Cancer Home Page 1 NCI's gateway for information about prostate cancer. Supportive Care Trial Results 2 Provides links to clinical trial results about supportive care (care given to improve a patient's quality of life). Coping with Cancer 3 Managing side effects and complications caused by cancer and its treatment. Bisphosphonates and Cancer Patients 4 Cancer patients taking bisphosphonate drugs for the prevention of fractures due to bone metastases appear more likely to develop jaw disease than patients who do not take the drugs, according to an analysis published in the July 4, 2007, Journal of the National Cancer Institute.

Key Words: prostate cancer, zoledronate. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁵.)

Patients with advanced prostate cancer have a high risk of developing bone complications such as fractures, spinal cord compression, and bone pain. In a study published in the October 2, 2002, issue of the Journal of the National Cancer Institute (see the journal abstract), patients with prostate cancer that had spread to the bones had fewer fractures and other bone complications when they took a new drug, zoledronic acid (also called zolendronate or Zometa®) than when they took a placebo (a dummy substance).

However, the reduction in bone complications did not delay disease progression, lengthen survival, or improve quality of life for the men treated with zoledronic acid compared with those who received a placebo.

In an accompanying editorial, Christina Canil, M.D., and Ian Tannock, M.D., both of the University of Toronto in Ontario, Canada, write that “Zoledronic acid is a reasonable option for patients who do not respond to alternative therapies and who are at high risk for bone fractures or spinal cord compression, but currently zoledronic acid cannot be recommended as a standard therapy….”

William Dahut, M.D., agrees. Dahut is chief of the Genitourinary Clinical Research Section for the National Cancer Institute at the National Institutes of Health Clinical Center in Bethesda, Maryland.

“I hope that doctors will resist the temptation to recommend zoledronic acid for all patients with prostate cancer metastatic to bone,” says Dahut. “This study showed no survival advantage and a higher risk of some adverse effects for patients taking zoledronic acid. In addition, the cost of adding treatment with this drug is significant. For patients whose risk for bone complications is low, these disadvantages may outweigh the benefits of treatment.”

The multicenter trial, led by Fred Saad, M.D., of the University of Montreal’s Notre Dame Hospital in Quebec, Canada, involved 643 men with bone metastases of prostate cancer whose disease had progressed after hormonal therapy. The men’s average age was 72. They were randomly assigned to receive either 4 milligrams or 8 milligrams of zoledronic acid or a placebo by infusion every three weeks for 15 months. The trial was double-blinded—that is, neither doctors nor patients knew who was receiving the drug and who was receiving the placebo until the study’s end.

All study participants had a bone scan when they enrolled; follow-up bone scans were performed after six months and 15 months. Part way through the trial, the investigators reduced the 8 milligrams dose of zoledronic acid to 4 milligrams because some men receiving the higher dose developed kidney problems. (See the protocol summary ⁶.)

About a third of the men who entered the trial completed it. Of those who did not complete the study, most withdrew because of adverse effects or for other reasons; 77 men died.

Among the men who received 4 milligrams of zoledronic acid, 13 percent suffered bone fractures, compared with 22 percent of the men who received a placebo. Bone complications other than fractures occurred in 26 percent of the men treated with 4 milligrams of zoledronic acid, compared with 35 percent of those who received a placebo. These complications included spinal cord compression, bone surgery or radiation therapy, or a change in treatment as a result of bone pain.

Men in the group that began the study being treated with 8 milligrams of zoledronic acid (later reduced to 4 milligrams) did less well than those who received 4 milligrams from the start. Fifteen percent of them suffered fractures and 30 percent suffered another bone complication.

Average survival and time to disease progression were not significantly different in the three groups. Patients’ assessments of their quality of life, including pain, also did not differ significantly. Flu-like symptoms (fatigue, anemia, joint pain, fever, and swelling in the legs) were slightly more common among men in the two groups treated with zoledronic acid than in those who received a placebo.

It is puzzling that patients who started the study on a higher dose of zoledronic acid did less well than those on the lower dose, says NCI’s Dahut. “There is no obvious explanation why patients who received 8 milligrams of the study drug should have more bone complications than those who received 4 milligrams.”

Zoledronic acid is a new drug in a class known as bisphosphonates. Other bisphosphonate drugs are used to treat cancer that has spread to the bones in patients with breast cancer and multiple myeloma. Zoledronic acid was approved by the U.S. Food and Drug Administration in February 2002 for the prevention of bone complications in prostate cancer.

Preliminary data from this study were presented in May 2002 at the American Urological Association annual meeting. A brief follow-up report was published in the June 2, 2004, issue of the Journal of the National Cancer Institute (see the journal abstract), providing 24 months of data.

Glossary Terms

A drug or substance used to treat hypercalcemia (abnormally high blood calcium) and bone pain caused by some types of cancer. Forms of bisphosphonates are also used to treat osteoporosis and for bone imaging. Bisphosphonates inhibit a type of bone cell that breaks down bone. Also called diphosphonate.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, hormonal therapy, and hormone treatment.

A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion.

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-tuh-SEEZ).

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

In medicine, treatment that experts agree is appropriate, accepted, and widely used. Health care providers are obligated to provide patients with standard therapy. Also called best practice and standard of care.

A drug used to treat patients with hypercalcemia (high blood levels of calcium) caused by cancer. It is also used together with other drugs to treat multiple myeloma and to prevent bone fractures and reduce bone pain in people who have cancer that has spread to the bone. It is a type of bisphosphonate. Also called zoledronic acid and Zometa.