Three to four years of therapy with the bisphosphonates alendronate and zoledronic acid, taken at doses used to treat osteoporosis, did not decrease the risk of incident breast cancer in postmenopausal women, according to a report published online Aug. 11 in JAMA Internal Medicine.
In a post hoc analysis of data from two large multicenter, randomized, double-blind, controlled clinical trials assessing the effectiveness of alendronate or zoledronic acid for osteoporosis, the development of incident breast cancer was not significantly different between women taking the drugs and women taking placebo, said Trisha F. Hue, Ph.D., of the department of epidemiology and biostatistics at the University of California, San Francisco, and her associates.
Numerous previous observational studies, as well as a metaanalysis pooling the data from several observational studies, had shown that bisphosphonates taken for osteoporosis significantly lowered the risk of breast cancer by 32%-39%. Their findings, however, may have been confounded by indication, because other conditions in postmenopausal women – notably, low levels of estradiol and high levels of sex hormone–binding globulin (SHBG) – are strongly associated both with low bone density, fractures, and bone loss with a low risk of ER-positive breast cancer, Dr. Hue and her associates said. Thus, they suggested, the postmenopausal women who are most likely to be given bisphosphonates for bone health already have a lower risk of breast cancer.
Such confounding can be averted by using a randomized trial design, so Dr. Hue and her colleagues assessed whether bisphosphonates reduced incident breast cancer by analyzing data from the Fracture Intervention Trial (FIT) and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT).
Among the 6,194 FIT participants in this study, there were 103 cases of invasive breast cancer during a mean of 3.8 years of follow-up. The incidence of breast cancer was 1.8% (57 women) among women taking alendronate and 1.5% (46 women) in those taking placebo, a nonsignificant difference in favor of placebo.
Among the 7,580 HORIZON-PFT participants in this study, there were 62 cases of invasive breast cancer during 3 years of follow-up. The incidence of breast cancer was 0.9% (33 women) among women taking zoledronic acid and 0.8% (29 women) among those taking placebo, which was, again, a nonsignificant difference in favor of placebo, the investigators said (JAMA Intern. Med. 2014 Aug. 11 [doi:10.1001/jamainternmed.2014.3634]).
The total of breast cancer cases was relatively small, so Dr. Hue and her associates pooled the data from both studies to increase the sample size. The combined incidence of breast cancer was 1.3% (90 women) taking bisphosphonates and 1.1% (75 women) taking placebo – again, a nonsignificant difference favoring placebo.
The discrepancy between these findings from randomized controlled trials and the results of previous observational studies illustrates "the hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done)" and highlights the value of confirming such findings in randomized controlled trials, Dr. Hue and her associates said.
This study received no industry support. FIT was supported by Merck, and HORIZON-PFT was supported by Novartis; both companies were involved in data collection and management. Dr. Hue reported no potential financial conflicts of interest. One of her associates reported serving as a consultant for Merck Sharpe & Dohme.