Differential protective effects of bisphosphonates and denosumab on primary breast cancer risk, potentially to be modified by statins: a retrospective study using electronic health records

Abstract Background: The risks of osteoporosis and breast cancer are increasing in elderly women, as well as hyperlipidemia. Bisphosphonates and denosumab are recommended for treatment of osteoporosis, and statins are used for hyperlipidemia. There are different and overlapping pharmacodynamics among bisphosphonates, denosumab and statins. We aim to assess effects of bisphosphonates and denosumab on breast cancer, possibly affected by statins use.Methods: This retrospective cohort is consisted of 97,671 women elder than 50 years with no previous history of malignancy and no cancer other than breast during follow-up, including 778, 2326, 15287 and 7631denosumab, bisphosphonates, statins and hormone for postmenopausal symptoms ever users. Univariate and bivariate analysis, and the Cox Proportional Hazards multi-variate model are performed.Results: Over an average of 3.6 years follow up, the breast cancer risks counted after 365 days of latency are 1.54% (12/778) for denosumab, 0.52% (12/2326) for bisphosphonates, compared to 0.65% (99/15287) in statins ever use group, 0.26% (20/7631) in hormone users for menopausal symptoms and 1.38% (1032/74867) in control group. The significant difference of breast cancer risk between denosumab and bisphosphonates group (p=0.0047) is supported by the Log-rank test (p=0.0004). The multivariate model is in partial agreement with the uni- and bivariate analysis. Further subgroup analysis revealed that concurrent use of statins in denosumab prescribers lowered the breast cancer risk to 0.89% (2/224), but with no significantly change of breast cancer risk in bisphosphonates group (7/919, 0.762%).Conclusion : Our data suggest superior protective effects of bisphosphonates over denosumab on breast cancer risk in elderly women. Statins could potentially exert breast cancer protective effect in denosumab users with no synergistic effect in patients taking bisphosphonates. A large scale study with long term follow up is needed.