Bisphosphonates Effects on Bone Health & Cancer

By Christin Melton
Published: Thursday, May 20, 2010
Bisphosphonates have been a hot topic at the past several SABCS meetings. This year was no exception. In addition to bisphosphonates’ protective effects on bone, researchers have been looking at whether they have anticancer effects. At last year’s SABCS, researchers reported preliminary results from a study showing that using zoledronic acid (Zometa) in conjunction with chemotherapy increased tumor shrinkage compared with chemotherapy alone. A study this year looked at the incidence of breast cancer in women taking alendronate (Fosamax). In addition, a second study reported results from a direct comparison of denosumab (Prolia) with zoledronic acid.

Do bisphosphonates protect against breast cancer?

A study presented at this year’s SABCS indicates that oral bisphosphonates may protect against the development of invasive breast cancer. Rowan Chlebowski, MD, PhD, medical oncologist, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, presented the new analysis of data from the Women’s Health Initiative (WHI), which is following >150,000 women. In an age-adjusted analysis, the women who reported using oral bisphosphonates at the start of the WHI study were 29% less likely to develop invasive breast cancer over 7.8 years of follow-up, compared with the women who said they did not take the drugs (P <.0001). More than 90% of the women were taking alendronate.

The new research builds on a study published in The New England Journal of Medicine earlier this year showing that the addition of zoledronic acid (Zometa) to adjuvant endocrine therapy improves disease-free survival rates in premenopausal patients with estrogen-responsive early breast cancer (Gnant H, et al, N Engl J Med, 2009;360:679-691). Preclinical and animal research has suggested that bisphosphonates may help fight cancer in a variety of ways: inducing apoptosis, reducing angiogenesis, or stimulating memory T-cells, Chlebowski said. This provided rationale for the study.

Using WHI data, Chlebowski and colleagues compared breast cancer rates in 2816 women who reported using oral bisphosphonates at the start of the study with rates for 151,952 women who reported they did not take the drugs. In the unadjusted analysis, there were 4.38 cases of invasive breast cancer per 1000 women not taking the drugs over the course of a year, compared with 3.29 cancers per 1000 women taking the drugs.

To adjust for the effect of potential bone mineral density differences among bisphosphonate users and nonusers on the rate of cancer occurrence, the researchers used patients’ hip fracture scores. The hip fracture score is a published, validated algorithm used in the WHI study. It takes into account 11 clinical factors evident in all WHI participants and calculates a 5-year probability of hip fracture. “Since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with higher breast cancer incidence, it’s important to correct for that,” Chlebowski explained.

Also at the meeting, a case-controlled study involving more than 4000 postmenopausal women provided supportive evidence for a protective effect with bisphosphonates. Data were reported by Gad Rennert, MD, Carmel Medical Center and Technion-Israel Institute of Technology, Haifa. He said women in the study who had breast cancer were 29% less likely to have taken oral bisphosphonates for at least 1 year than women who did not have breast cancer (HR, 0.71; CI, 0.57-0.90).

The two observational studies used different methodologies to arrive at the same basic result, adding to the strength of the findings, said Indiana University’s professor of medicine Theresa Guise, MD, who moderated a news briefing on the findings. Several ongoing randomized clinical trials are evaluating the impact of oral and intravenous (IV) bisphosphonates on the development of contralateral breast cancer, and these may “provide confirmation of these observational cohort studies within a year or two,” Chlebowski said.

Denosumab outperforms zoledronic acid

In a head-to-head comparison of two boneprotective agents on 2048 breast cancer patients with bone metastases, the RANK ligand inhibitor denosumab was superior to the standard-of-care bisphosphonate, zoledronic acid. The randomized study evaluated the effectiveness of the two agents in preventing skeletal-related events (SREs), defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. “Denosumab prevented more events, was better tolerated, and was more convenient for patients in this randomized doubleblind trial against what has been the standard of care for treating bone metastasis,” said Alison Stopeck, MD, of the University of Arizona Cancer Center, Tucson, who described study results at a press briefing.

Patients with bone metastases who had not been previously treated with IV bisphosphonates were randomized to treatment with subcutaneous denosumab (120 mg every 4 weeks) and IV placebo, or subcutaneous placebo and IV zoledronic acid (4 mg every 4 weeks), along with calcium and vitamin D supplements.

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