Time-varying exposure to anti-osteoporosis drugs and risk of first-time hip fracture: a population wide study within the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS)

Purpose To investigate whether bisphosphonates and denosumab reduced the risk of first-time hip fracture in Norwegian women when adjusting for a medication-based comorbidity index. Methods Norwegian women aged 50–89 in 2005–2016 were included. The Norwegian prescription database (NorPD) supplied data on exposures to bisphosphonates, denosumab, and other drugs for the calculation of the Rx-Risk Comorbidity Index. Information on all hip fractures treated in hospitals in Norway was available. Flexible parametric survival analysis was used with age as time scale and with time-varying exposure to bisphosphonates and denosumab. Individuals were followed until hip fracture or censoring (death, emigration, age 90 years), or 31 December 2016, whichever occurred first. Rx-Risk score was included as a time-varying covariate. Other covariates were marital status, education, and time-varying use of bisphosphonates or denosumab with other indications than osteoporosis. Results Of 1,044,661 women 77,755 (7.2%) were ever-exposed to bisphosphonate and 4483 (0.4%) to denosumab. The fully adjusted hazard ratios (HR) were 0.95 (95% confidence interval (CI): 0.91–0.99) for bisphosphonate use and 0.60 (95% CI: 0.47–0.76) for denosumab use. Bisphosphonate treatment gave a significantly reduced risk of hip fracture compared with the population after 3 years and denosumab after 6 months. Fracture risk was lowest in denosumab users who had previously used bisphosphonate: HR 0.42 (95% CI: 0.29–0.61) compared with the unexposed population. Conclusions In population-wide real-world data, women exposed to bisphosphonates and denosumab had a lower hip fracture risk than the unexposed population after adjusting for comorbidity. Treatment duration and treatment history impacted fracture risk.