Differential effects of bisphosphonates and denosumab on primary breast cancer risk, potentially to be modified by statins

Abstract

Background The risks of osteoporosis and breast cancer are increasing in elderly women, as well as menopausal status related hyperlipidemia. Bisphosphonates and denosumab, varying in drug mechanisms and therapeutic effects are recommended medications for treatment of osteoporosis. The pharmacodynamics of bisphosphonates and statin overlap in one signal pathway. We aim to assess different effects of bisphosphonates and denosumab on breast cancer, possibly modifiable by statins use. Methods This cohort study includes 97,671 women elder than 50 years without previous history of malignancy. Results Over an average of 3.6 years follow up, 3020 women have received either denosumab (n=778) or bisphosphonates (n=2326) for osteoporosis, among them, 84 (84/3020=2.8%) patients have combination medication of both. Our data demonstrated significant difference in breast cancer occurrence after first year latency between denosumab ever prescription group (12/778, 1.54%) and bisphosphonates group (12/2326, 0.52%), P=0.0046; this significance is also proved by Log-rank test (p=0.0004). Although the breast cancer risk in bisphosphonates ever use group (12/2326, 0.52%), statins ever use group (99/15287, 0.65%), hormone users for menopausal symptoms (20/7631, 0.26%) are significantly lower than control patients (1032/74867, 1.38%), p<=0.004, there is no significant difference in breast cancer risk between denosumab group and control patients (p=0.6965). 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 but no synergistic effect in patients taking bisphosphonates. Large scale study with long term follow up is needed