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Bisphosphonate treatment did not reduce risk for postmenopausal breast cancer
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Treatment with bisphosphonates for osteoporosis provided no protective effect against the risk for invasive postmenopausal breast cancer, according to an analysis of results from two randomized, double blind, placebo-controlled trials.
These results contradict findings from observational studies that suggest bisphosphonates may suppress the proliferation of estrogen-sensitive breast cancer cells.
“These observational study results may be confounded, because among postmenopausal women, low levels of estrogen and high levels of sex hormone-binding globulin are strongly associated with both a decreased risk of estrogen receptor-positive breast cancer and low bone mineral density, as well as faster bone loss and a higher risk of fracture, which are all indications for prescribing bisphosphonates in osteoporotic women,” researcher Trisha F Hue, PhD, MPH, and colleagues from the University of California, San Francisco wrote.
Hue and colleagues evaluated data from the FIT trial and the HORIZON-PFT trial to determine whether use of bisphosphonates reduced incidence of postmenopausal breast cancer.
The FIT trial evaluated daily oral alendronate sodium for the treatment of osteoporosis in 6,459 women aged 55 to 81 years. Researchers randomly assigned 3,236 women to alendronate, and 3,223 were assigned placebo. Median follow-up was 3.8 years.
The 3-year international HORIZON-PFT trial included 7,765 women aged 65 to 89 years who were randomly assigned to IV infusions of zoledronic acid 5 mg (n=3,889) or placebo (n=3,876).
Blinded reviews of the adverse event databases of each study identified breast cancer incidence among trial participants. Hue and colleagues defined an incident case of breast cancer as any new breast cancer event that took place after randomization in either trial. Women with recurrent breast cancer or breast cancer history were excluded.
Researchers used a log-rank test to evaluate incident breast cancer cases in the bisphosphonate groups vs. the placebo groups, and to calculate hazard ratios for the two cohorts.
In the FIT study, researchers observed no significant difference between incident breast cancer rates in the alendronate group and the placebo group (1.8% vs. 1.5%; HR: 1.24; 95% CI, 0.85-1.83).
In the HORIZON-PFT trial, researchers observed no significant difference between breast cancer incidence in the zoledronic acid and placebo groups (0.9% vs. 0.8%; HR=1.15; 95% CI, 0.7-1.89).
Joseph S. Ross
When researchers pooled data from both trials, they calculated an HR of 1.2 (95% CI, 0.89-1.64).
“Whereas these findings highlight why it is so important for new therapies to be evaluated using randomized clinical trials, they also reinforce the importance of assessing the methodological rigor of observational studies before interpreting real-world effects,” Joseph S. Ross, MD, MHS, assistant professor of medicine and of public health at Yale School of Medicine and a
Although findings in the current analysis differ from those of previous observational studies, they do not necessarily detract from the value of the prior results, Ross emphasized.
“Observational studies are particularly valuable for clinical situations unlikely to be tested using randomized clinical trials, and many provide valid and reliable real-world evidence,” Ross wrote. “Thus, whereas we all can remember examples of when randomized clinical trials and observational studies differed, less memorable are the even more numerous examples in which results were consistent. In the end, we should be open to all types of evidence and rely on rigorous clinical science to guide practice.”
Disclosure: One researcher reports a consultant relationship with Merck Sharp & Dohme.
Perspective
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Charles L. Shapiro, MD
As history shows, treatment benefits based on non-randomized observational studies and relatively small-randomized phase 2 trials are often proven wrong (eg, high-dose chemotherapy with stem cell support or PARP inhibition combined with chemotherapy in women with advanced triple-negative breast cancers) when a properly powered phase 3 trial is performed. With this mind, do bisphosphonates prevent or treat breast cancer when combined with standard treatments?Data from non-randomized case-control, observational studies and meta-analyses showed a possible association between bisphosphonate use and decreased risks for developing breast cancer. Hue and colleagues made a substantial contribution by reporting the results of two large randomized placebo-controlled trials of oral alendronate or zoledronic acid in nearly 15,000 postmenopausal women with osteoporosis. The trials — individually and in aggregate — show no differences in the incidence of breast cancer between the bisphosphonate and placebo treatment arms with mean follow-up of about 3 to 4 years. These results are high-quality level one evidence, and now it can be stated with more certainty that bisphosphonates do not decrease the risk for breast cancer.
Whether bisphosphonates are treatments for breast cancer has been studied in multiple randomized trials without a clear consensus. The world was set ablaze with the findings of ABCSG 12 trial, in which estrogen receptor-positive premenopausal women treated with medical ovarian ablation were randomly assigned to either tamoxifen or aromatase inhibitor, with a secondary randomization to zoledronic acid 4 mg every 6 months for 3 years vs. no zoledronic acid (Gnant M. Lancet Oncol. 2011;12:631-641).
Overall, researchers observed a statistically significant improvement in DFS, but not OS, in the zoledronic acid arm. Subsequently, several larger trials in which women received chemotherapy did not show this benefit overall, or in premenopausal women, but did so in the subset analyses of women who were postmenopausal (Coleman R. N Engl J Med. 2011;365:1396-1405. Paterson AH. Lancet Oncol. 2012;13:734-742). The results of subset analyses are problematic, and whether bisphosphonates improve clinical outcomes is still uncertain and not standard of care.
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