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Key Words

Breast cancer, bone loss, denosumab, hormone receptor-positive, aromatase inhibitors. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

Treatment with the experimental drug denosumab increased bone density in postmenopausal women taking aromatase inhibitors (AIs) to prevent a recurrence of breast cancer. Although important questions remain about this finding, it suggests that denosumab may be an effective therapy for AI-related bone loss.

Source

Journal of Clinical Oncology, published online ahead of print, August 25, 2008 (see the journal abstract ⁵)
(J Clin Oncol. 2008 Aug 25. [Epub ahead of print])

Background

Many breast tumors are “estrogen sensitive,” meaning the hormone estrogen helps them to grow. Women whose tumors are estrogen sensitive are advised to take anti-estrogen drugs for at least five years after their initial treatment to reduce the risk of a relapse.

Tamoxifen was the first anti-estrogen drug shown to lower the risk of a breast cancer recurrence. However, several large clinical trials have shown that drugs called aromatase inhibitors (AIs) are more effective than tamoxifen at preventing the recurrence of estrogen-sensitive breast cancer. AIs also carry a lower risk of blood clots and endometrial cancer, both of which are possible side effects of tamoxifen. Three AI drugs (anastrozole [Arimidex®], exemestane [Aromasin®], and letrozole [Femara®]) are currently available in the United States.

AIs have their own side effects, however. Estrogen helps to protect bones from thinning. AIs block the production of estrogen, thereby reducing the amount of hormone in the body and speeding the loss of bone density. Tamoxifen works differently in the body and can actually protect against bone loss.

Women who are taking AIs to prevent a recurrence of breast cancer and who also have low bone density are sometimes also prescribed drugs called bisphosphonates. These drugs, which are FDA approved for prevention and treatment of osteoporosis (brittle bone disease), work by limiting further loss of bone density. Although the side effects of bisphosphonates are usually mild, in rare cases they can cause serious damage to the jaw or kidneys.

Denosumab is an investigational monoclonal antibody that inhibits a protein called RANK-ligand, which is involved in bone resorption. In a previous phase II study, treatment with denosumab for two years increased bone density in cancer-free postmenopausal women who had low bone mass.

The Study

This phase III study involved 252 women with low bone density who were receiving AI treatment to prevent a recurrence of breast cancer. All had completed cancer treatment with surgery, radiation, or chemotherapy. They could be taking any of the three currently available AI drugs. Some had previously taken tamoxifen or a different kind of anti-estrogen drug called raloxifene. Women who had osteoporosis or a history of spinal fractures, or who were taking bisphosphonates, were not eligible to enroll in this study.

Participants were randomly assigned to receive an injection of either denosumab or a placebo every six months. The trial was double-blinded, meaning that until it was over neither the women nor their doctors knew who was getting the drug and who was getting the placebo.

Study treatment continued for two years. All patients enrolled in the study were instructed to take daily supplements of calcium and vitamin D, which have been shown to modestly improve bone density in healthy postmenopausal women. The principal investigator for the study was Georgiana K. Ellis, M.D., of the Seattle Cancer Care Alliance in Seattle, Washington.

Results

After one year, women treated with denosumab had a 5.5 percent increase in bone density in the lumbar spine compared with women receiving a placebo. After two years, bone density in the lumbar spine increased 7.6 percent in the patients receiving denosumab. This benefit occurred regardless of how long women had been taking AIs, the type of AI they were taking, or whether they had previously taken tamoxifen.

Similar numbers of patients in both the denosumab and placebo groups reported experiencing adverse effects from treatment. The most common adverse effects were fatigue and pain in the joints, extremities, and back. Fifteen percent of patients receiving denosumab reported a serious adverse effect, compared with nine percent of patients receiving a placebo. However, none of these adverse effects were considered by the investigators to be treatment-related and no pattern of adverse effects could be identified to account for the difference between the two groups.

Limitations

While these results are quite promising, they should be confirmed and expanded upon before definitive recommendations are made, says Larissa Korde, M.D., M.P.H., a staff clinician in the National Cancer Institute’s Clinical Genetics Branch. In addition, she says, a number of questions remain. Most importantly, the study wasn’t designed to learn whether the bone density benefit seen with denosumab actually decreases the risk of fractures in women taking AIs.

Comments

Nonetheless, says Korde, “this study adds to the current data suggesting that denosumab may be an effective agent for the treatment or prevention of bone loss in postmenopausal women with breast cancer who are receiving AI therapy.”

She notes that a study directly comparing bisphosphonates and denosumab would shed light on the relative benefits and risks of each treatment approach. In June 2008, researchers presented trial results ⁶ at the American Society of Clinical Oncology annual meeting suggesting that breast cancer was less likely to spread to the bones or other organs in women who took the bisphosphonate drug zoledronic acid (Zometa®).

“If this finding is confirmed,” says Korde, “it would be important to know whether or not denosumab also has an effect on disease recurrence. If the two classes of drugs have similar effects on bone density, but one is better at preventing breast cancer recurrence, that would drive the choice of optimal therapy.”

Glossary Terms

An anticancer drug that is used to decrease estrogen production and suppress the growth of tumors that need estrogen to grow. It belongs to the family of drugs called nonsteroidal aromatase inhibitors.

A drug that prevents the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Aromatase inhibitors are used as a type of hormone therapy for postmenopausal women who have hormone-dependent breast cancer.

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.

A type of hormone made by the body that helps develop and maintain female sex characteristics and the growth of long bones. Estrogens can also be made in the laboratory. They may be used as a type of birth control and to treat symptoms of menopause, menstrual disorders, osteoporosis, and other conditions.

A drug used to treat advanced breast cancer and to prevent recurrent breast cancer in postmenopausal women who have already been treated with tamoxifen. It is also being studied in the treatment of other types of cancer. Exemestane causes a decrease in the amount of estrogen made by the body. It is a type of aromatase inhibitor. Also called Aromasin.

A protein on the surface of a cell to which a specific hormone binds. The hormone causes many changes to take place in the cell.

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered investigational in other diseases or conditions. Also called experimental.

A drug used to treat advanced breast cancer in postmenopausal women. Letrozole causes a decrease in the amount of estrogen made by the body. It is a type of aromatase inhibitor. Also called Femara.

A type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. There are many kinds of monoclonal antibodies. Each monoclonal antibody is made to find one substance. Monoclonal antibodies are being used to treat some types of cancer and are being studied in the treatment of other types. They can be used alone or to carry drugs, toxins, or radioactive materials directly to a tumor.

A study to test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results) and whether it works against a certain type of cancer.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A drug used to reduce the risk of invasive breast cancer in postmenopausal women who are at a high risk of developing the disease or who have osteoporosis. It is also used to prevent and treat osteoporosis in postmenopausal women and is being studied in the prevention and treatment of other conditions. Raloxifene blocks the effects of the hormone estrogen in the breast and increases the amount of calcium in bone. It is a type of selective estrogen receptor modulator (SERM). Also called raloxifene hydrochloride and Evista.

A process in which a substance, such as tissue, is lost by being destroyed and then absorbed by the body.

A drug used to treat certain types of breast cancer in women and men. It is also used to prevent breast cancer in women who have had ductal carcinoma in situ (abnormal cells in the ducts of the breast) and are at a high risk of developing breast cancer. Tamoxifen is also being studied in the treatment of other types of cancer. It blocks the effects of the hormone estrogen in the breast. Tamoxifen is a type of antiestrogen. Also called tamoxifen citrate and Nolvadex.