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Clinical Trial Results

Summaries of Newsworthy Clinical Trial Results
  • Posted: 09/11/2008

Denosumab May Help Prevent Bone Loss Related to Use of Aromatase Inhibitors

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.)

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)
(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 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.”

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