Nitrogen-based Bisphosphonate Use and Ovarian Cancer Risk in Women Aged 50 Years and Older

Abstract

Background: There are few readily modifiable risk factors for epithelial ovarian cancer; preclinical studies suggest bisphosphonates could have chemopreventive actions. Our study aimed to assess the association between use of nitrogen-based bisphosphonate medicine and risk of epithelial ovarian cancer, overall and by histotype.

Methods: We conducted a case-control study nested within a large, linked administrative dataset including all Australian women enrolled for Medicare, Australia's universal health insurance scheme, between July 2002 and December 2013. We included all women with epithelial ovarian cancer diagnosed at age 50 years and older between July 1, 2004, and December 31, 2013 (n = 9367) and randomly selected up to 5 controls per case, individually matched to cases by age, state of residence, area-level socioeconomic status, and remoteness of residence category (n = 46 830). We used prescription records to ascertain use of nitrogen-based bisphosphonates (ever use and duration of use), raloxifene, and other osteoporosis medicines (no nitrogen-based bisphosphonates, strontium and denosumab). We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression.

Results: Ever use of nitrogen-based bisphosphonates was associated with a reduced risk of epithelial ovarian cancer compared with no use (OR = 0.81, 95% CI = 0.75 to 0.88). There was a reduced risk of endometrioid (OR = 0.51, 95% CI = 0.33 to 0.79) and serous histotypes (OR = 0.84, 95% CI = 0.75 to 0.93) but no association with the mucinous or clear cell histotypes.

Conclusion: Use of nitrogen-based bisphosphonates was associated with a reduced risk of endometrioid and serous ovarian cancer. This suggests the potential for use for prevention, although validation of our findings is required.

Figure 1.

Flowchart of the selection of cases and controls for the study. SEIFA = Socio-Economic Indexes for Areas.

Figure 2.

E-values for the associations between (A) nitrogen-based bisphosphonate use and risk of epithelial ovarian cancer and (B) nitrogen-based bisphosphonate use and risk of endometrioid epithelial ovarian cancer histotype. The E-value indicates the strength of association required between the exposure and the unmeasured confounder and the confounder and the outcome to remove the observed association. Thus, here, the relative risk for the relationship between the confounder and nitrogen-based bisphosphonates, and the confounder and epithelial ovarian cancer would need to be at least 1.77 (lower 95% CI = 1.53) (or values per the curve). The equivalent value for the endometrioid histotype is 3.33 (lower 95% CI = 1.85). If 1 of the 2 parameters is smaller than the E-value, the other must be larger, as defined by the plotted curve (26, 27). CI = confidence interval.