Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all‐cause mortality in adults, compared with bisphosphonates: An analysis of real‐world, cohort data, with a systematic review and meta‐analysis

Abstract Aim To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long‐term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all‐cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta‐analysis. Methods A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long‐term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random‐effects meta‐analysis. Risk of bias and evidence quality were assessed using Cochrane‐endorsed tools. Results Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78‐0.88]). Secondary analysis showed significant risk reduction in all‐cause mortality (0.79 [0.72‐0.87]) and foot ulceration (0.67 [0.53‐0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta‐analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79‐0.87]) (I 2 = 10.76%). Conclusions This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all‐cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D.