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Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggests that these agents may play a role in reducing recurrent breast cancer as well.

The effect of Zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant Letrozole: The Z-FAST study 5-year final follow-up

Zoledronic acid ( Zometa ) is effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors.
Z-FAST ( Zometa - Femara Adjuvant Synergy Trial ) study focused on 602 postmenopausal women with stage I to IIIa estrogen or progesterone receptor-positive breast cancer. The Researchers randomized patients to immediate Zoledronic acid or delayed Zoledronic acid. The delayed group received it only if the T-score dropped below two or a clinical fracture occurred.
After five years, patients in the immediate treatment arm had a bone mineral density increase of 6.2 percent in their lumbar spine area, while those in the delayed arm had a decrease of 2.4 percent. In the hip area, the increase was 2.6 percent with immediate treatment compared with a 4.1 percent decrease with delayed treatment
. Fractures occurred in 10.7 percent of the patients treated immediately and 12.4 percent of the patients who received delayed treatment.
There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated.

Oral bisphosphonate and breast cancer: prospective results from the Women's Health Initiative

Results of a new analysis of data from the Women's Health Initiative ( WHI ) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates.
In the 150,000-plus cohort of generally healthy postmenopausal women, the Researchers found that women who used bisphosphonates, mostly Alendronate ( Fosamax ), had 32 percent fewer cases of invasive breast cancer compared to women who did not use such drugs.
However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed. Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The Researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users. Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the Researchers found that only 64 women developed breast cancer, and most of those cases ( 50 ) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.

Use of bisphosphonates and risk of postmenopausal breast cancer

The use of bisphosphonates for more than one year was associated with a 29 percent reduction in the risk of postmenopausal breast cancer.
Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview.
The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34 percent.
This reduction remained significant, at 29 percent, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.
Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.

Comparison of Denosumab versus Zoledronic acid on the incidence of skeletal-related events in breast cancer patients with bone metastases

Among patients with bone metastasis from breast cancer, Denosumab ( Prolia ) was superior to Zoledronic acid in reducing the incidence of complications from bone metastases.
Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with subcutaneous Denosumab or intravenous Zoledronic acid every four weeks.
Denosumab works by inhibiting RANKL, which regulates osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Randomised placebo controlled trial studying short term biological effects of the combination of Letrozole and Zoledronic acid on invasive breast cancer

Preoperative combination therapy with Letrozole ( Femara ) and Zoledronic acid is safe and effective, but more research is needed to verify the impact on overall survival or reduced morbidity.
Nigel J. Bundred and colleagues conducted a study to determine whether the addition of the bisphosphonate Zoledronic acid to treatment with Letrozole increased cell death or lowered proliferation.
Letrozole is an oral, non-steroidal aromatase inhibitor used for treatment of local or metastatic breast cancer that is hormone receptor-positive. Zoledronic acid, also known as Zoledronate, is used to prevent bone fractures in patients with cancers like prostate cancer and multiple myeloma, or for treatment of bone metastases.
Researchers conducted the study in 109 postmenopausal women with early, invasive hormone receptor-positive breast cancer. Patients were randomized and treated for 14 days with placebo, Letrozole 2.5 mg per day, or to Letrozole with adjuvant use of Zoledronic acid 4 mg intravenously two to four days before surgery.
While the addition of Zoledronic acid was safe, results showed no other benefits compared with Letrozole use alone.

Source: American Association for Cancer Research, 2009


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