Bisphosphonate use associated with decreased risk for postmenopausal breast cancer

Two studies support growing data on association.

The use of bisphosphonates, commonly used in postmenopausal women to prevent osteoporosis, may also result in a decreased risk for breast cancer.

The results of two large studies, published in the Journal of Clinical Oncology, showed that postmenopausal women who were taking bisphosphonates had about a 30% reduced risk for breast cancer compared with women who were not taking bisphosphonates.

Writing in an accompanying editorial, Michael Gnant, MD, of the Medical University of Vienna, Austria, called the results of these studies “profound and intriguing.”

However, Gnant also said the results are currently only hypothesis-generating and should be interpreted with caution.

“As correctly noted by the authors, several potential confounding factors may have influenced the observed outcomes, including age, ethnicity, tobacco use, alcohol use, physical activity, baseline bone mineral density, BMI, prior hormone therapy, calcium and vitamin D supplementation, number of pregnancies, duration of breast-feeding, and other unknown factors that may interact with breast cancer risk in these healthy women,” he wrote.

WHI results

In the first study, Rowan T. Chlebowski, MD, PhD, a medical oncologist with Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, and colleagues examined data on oral bisphosphonate use and invasive breast cancer in women enrolled in the Women’s Health Initiative (WHI).

A hip fracture prediction model that did not incorporate BMD was compared with the total hip BMD in 10,418 WHI participants who had both measurements. These two measurements were compared so researchers could determine whether the hip fracture risk score “could be used to adjust for BMD differences between bisphosphonate users and nonusers to control for potential confounding by indication.”

For this analysis, 154,768 women who had not used tamoxifen or raloxifene, and who did not have breast cancer, were included. Of those, 2,816 reported using oral bisphosphonates at study entry.

Data indicated that the fracture risk score was associated with both BMD (P<.001) and breast cancer incidence (P=.03). For this reason, the researchers incorporated the risk score into regression analyses to adjust for BMD difference between women who used bisphosphonates and those who did not.

The mean follow-up was 7.8 years. At this time, women using bisphosphonates had a 32% lower incidence of invasive breast cancer (95% CI, 0.52-0.88). A reduced incidence of invasive estrogen receptor-positive breast cancers (HR=0.7; 95% CI, 0.52-0.94) and estrogen receptor-negative breast cancers was also found, although the association with estrogen receptor-negative cancers was not statistically significant.

An increased incidence of ductal carcinoma in situ was found to be associated with bisphosphonate use.

Northern Israel Study

The Breast Cancer in Northern Israel Study was a population-based case-control study. In it, Gad Rennert, MD, PhD, of the Clalit Health Services National Israeli Cancer Control Center, Haifa, Israel, and colleagues assessed the use of bisphosphonates in 4,039 postmenopausal women and age-, clinic- and ethnic-matched controls.

They found that more than 1 year of bisphosphonate use was associated with a reduced risk for breast cancer (OR=0.61; 95% CI, 0.50-0.76).

Even after adjustment for known risk factors for breast cancer, including age, family history, ethnicity and BMI, women who had taken bisphosphonates still had a 28% reduced risk for breast cancer.

Duration of use

Despite having similar results for a reduced breast cancer incidence, the two studies had conflicting findings about the duration of bisphosphonate use necessary to confer this benefit. Chlebowski and colleagues found that the association between bisphosphonate use and reduced incidence of breast cancer was linked with short-term use of the drug (see table 1), suggesting that bisphosphonates may delay breast cancer but not prevent it, according to Gnant.

Table 1: WHI - Duration of Use of Bisphosphonates Affected Breast Cancer Incidence

Duration of Use	HR	95% CI
Less than 2 years	0.50	0.38-0.67
2 to 5 years	0.86	0.64-1.17
More than 5 years	0.83	0.53-1.27

Source: Chlebowski RT. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.2095.

Rennert and colleagues found a reduced incidence of breast cancer after 1 year of use of bisphosphonates; however, their data indicated that this association persisted for more than 5 years of exposure (see Table 2).

Table 2: Breast Cancer in Northern Israel Study - Duration of Use of Bisphosphonates Affected Breast Cancer Incidence

Duration of Use	OR	95% CI
Less than 1 year	0.93	0.61-1.42
More than 1 year	0.61	0.50-0.76
More than 2 years	0.59	0.47-0.75
More than 3 years	0.57	0.44-0.74
More than 4 years	0.61	0.45-0.84
More than 5 years	0.51	0.34-0.75

Source: Rennert G. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.1113.

Gnant said differences in the study populations and criteria for bisphosphonate use between the two studies may explain the inconsistency.

“Taken together, the results of the two studies in this issue of the Journal of Clinical Oncology are important additional steps toward understanding several unresolved issues, including how best to target the early precursors of malignancy and the role of the microenvironment in tumor development,” Gnant wrote.

Chlebowski RT. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.2095.

Gnant M. J Clin Oncol. 2010;doi:10.1200/JCO.2010.29.6327.

Rennert G. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.1113.