Zoledronic Acid Prevents Bone Loss During Estrogen-Suppression Treatment of Breast Cancer
Breast cancer, bone loss, zoledronic acid, aromatase inhibitor, anastrozole (Arimidex®), tamoxifen (Nolvadex®), goserelin (Zoladex®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.) (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Zoledronic acid can prevent treatment-induced bone loss in premenopausal women undergoing total estrogen suppression after surgery for hormone-responsive breast cancer. Because lack of estrogen can cause bone loss, effective strategies are needed for patients taking drugs that reduce the amount of estrogen in the body.
Journal of Clinical Oncology, published online Dec. 11, 2006; in print March 1, 2007 (see the journal abstract).
(J Clin Oncol. 2007 Mar 1;25(7):820-8. Epub 2006 Dec 11]
Some breast cancer tumors grow in response to the hormone estrogen. Such tumors are called hormone-receptor-positive. After surgery, women with this kind of breast cancer often take drugs to suppress the production of estrogen and cut their risk of a recurrence.
Estrogen-suppressing drugs include goserelin (Zoladex®)and aromatase inhibitors such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®). Tamoxifen (Nolvadex®) interferes with the effect of estrogen on the tissues. Each work somewhat differently and have different side effects. Aromatase inhibitors can cause loss of bone density, which can lead to osteoporosis and increase the risk of bone fractures.
The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) is a phase III clinical trial that tested whether zoledronic acid could prevent treatment-induced bone loss in premenopausal women undergoing total estrogen suppression after surgery to remove their hormone-receptor-positive tumors. (ABCSG-12 is a substudy of a larger treatment trial, described elsewhere.) Zoledronic acid belongs to a class of drugs called bisphosphonates, which prevent the body from breaking down bone.
The study’s 401 participants were randomly assigned to receive one of four therapeutic regimens:
- Goserelin and tamoxifen therapy for three years (103 participants)
- Goserelin and tamoxifen therapy for three years, with the addition of zoledronic acid given intravenously once every six months (100 participants)
- Goserelin and anastrozole therapy for three years (94 participants)
- Goserelin and anastrozole therapy for three years, with the addition of zoledronic acid given intravenously once every six months (104 participants)
Researchers measured participants’ bone density using special x-ray scans at the start of the study and after 6, 12, and 36 months of treatment. The bone densitometry scans of the lumbar spine (lower back) and trochanter (part of a bone in the leg) allowed researchers to identify cases of osteopenia (bone loss) and osteoporosis (severe bone loss).
The trial was a collaborative effort of the Austrian Breast and Colorectal Cancer Study Group. The lead author of the study was Michael F. X. Gnant, M.D., from the Medical University of Vienna, Austria.
Participants who did not receive zoledronic acid lost bone density to a statistically significant degree, with those on the anastrozole/goserelin combination experiencing greater decreases than those on tamoxifen/goserelin.
After 36 months of treatment, patients receiving anastrozole/goserelin without zoledronic acid lost 17.4 percent of the bone mass in their lumbar spine and 11.3 percent in their trochanter, while patients receiving tamoxifen/goserelin without zoledronic acid lost 11.6 percent of the bone mass in their lumbar spine and 5.1 percent in their trochanter. In contrast, bone density remained stable in all participants who received zoledronic acid.
Among participants who received anastrozole/goserelin without zoledronic acid, the percentage of those with osteopenia in the lower back rose from 24 percent at the start of the trial to 54 percent after 36 months. The number of women in this group suffering from osteoporosis also rose, from 1 percent to 25 percent.
In contrast, none of the participants treated with zoledronic acid in addition to anastrozole/goserelin developed osteoporosis of the lumbar spine, though the number of osteopenia cases did increase by 15 percent.
No bone fractures were observed in any participant during the trial. The expected side effects were observed for each drug combination and were not worsened by the addition of zoledronic acid.
[Note: longer-term data from this trial were subsequently published in the September 2008 Lancet Oncology; see the journal abstract.]
While zoledronic acid did stabilize bone density, the question remains whether such stabilization will reduce the risk of bone fractures in the long run, explained Jo Anne Zujewski, M.D., a breast cancer specialist with the National Cancer Institute’s Division of Cancer Treatment and Diagnosis. “What we really care about is fractures,” she said.
The authors acknowledge that additional trials are needed to test “whether premenopausal patients undergoing adjuvant treatment with [estrogen-suppressing drugs] may be at greater risk for fractures later in life,” and to find out which bisphosphonate treatment regimen will provide the best protective benefit.
“The results of this study indicate that zoledronic acid…effectively and safely prevents loss of [bone density] in premenopausal patients treated with either tamoxifen or anastrozole in combination with [goserelin],” stated the authors. “This is the first report to demonstrate that the combination of a bisphosphonate with an AI can effectively and safely prevent [cancer-treatment induced bone loss] in premenopausal women with early-stage breast cancer.”
If zoledronic acid does indeed prevent bone fractures in addition to stabilizing bone density, “we’ll be able to use whichever endocrine therapy works in our patients without worrying so much about osteoporosis,” said Zujewski.
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