RANKL Inhibition and the Risk of Ocular Hypertension and Primary Open-Angle Glaucoma.

Purpose: To investigate whether the receptor activator of NF-κB ligand (RANKL) inhibitor denosumab is associated with a lower risk of developing ocular hypertension (OHT) and primary open-angle glaucoma (POAG) compared with bisphosphonate therapy in patients with osteoporosis. Methods: We conducted a multinational, retrospective cohort study using the TriNetX network from 2013 to 2023. Adults 40 years or older with osteoporosis who received denosumab were propensity score matched 1:1 to those receiving bisphosphonates. The primary outcomes were incident OHT and POAG within 5 years. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Sensitivity analyses included extending follow-up to 10 years, requiring an ophthalmology visit to strengthen diagnostic validity, and adjusting for additional cardiometabolic medications. Subgroup analyses further stratified participants by age, sex, race, diabetes, and corticosteroid use. Results: After 1:1 propensity score matching, a total of 94,624 patients (47,312 in each cohort) were included in each cohort. Compared with bisphosphonate therapy, denosumab use was associated with a significantly lower risk of developing OHT (HR = 0.72; 95% CI, 0.59-0.88) and POAG (HR = 0.63; 95% CI, 0.53-0.75). These associations remained robust across all sensitivity analyses and were consistently observed across major patient subgroups. Conclusions: Among adults with osteoporosis, denosumab use was associated with significantly lower risks of OHT and POAG compared with bisphosphonate therapy. These findings highlight the potential ocular relevance of RANKL inhibition and support further investigation into its clinical implications through prospective studies.