Glaucoma and osteoporosis may seem clinically distant, but they share several biological threads: aging, chronic inflammation, oxidative stress, and tissue remodeling. A new multinational real-world study suggests that one osteoporosis treatment, denosumab, may be associated with a lower risk of ocular hypertension and primary open-angle glaucoma compared with bisphosphonate therapy.
The retrospective cohort study, published in Investigative Ophthalmology & Visual Science, examined adults aged 40 years or older with osteoporosis using the TriNetX analytics network, which includes deidentified health records from more than 200 million patients across 160 healthcare organizations in 21 countries. Researchers compared patients receiving denosumab, a receptor activator of NF-κB ligand (RANKL) inhibitor, with those receiving bisphosphonates.
The final analysis included 94,624 patients: 47,312 in the denosumab group and 47,312 in the bisphosphonate group. The cohorts were well balanced for age, sex, race, smoking status, comorbidities, corticosteroid use, and renal function. Patients with prior glaucoma, intraocular pressure-lowering medication use, or retinal disease were excluded at baseline.
Over five years, denosumab use was associated with significantly lower risks of both ocular hypertension and primary open-angle glaucoma. Compared with bisphosphonates, denosumab was linked to a 28 percent lower risk of ocular hypertension and a 37 percent lower risk of primary open-angle glaucoma.
The findings also held up across multiple sensitivity analyses. These included extending follow-up to 10 years, requiring at least one ophthalmology visit to strengthen diagnostic validity, and adjusting for additional cardiometabolic medications. A validation analysis restricted to the US TriNetX network produced similar results, supporting the reproducibility of the association.
So, why might a bone drug matter to the eye? Denosumab blocks RANKL, preventing activation of the RANK/NF-κB signaling pathway. In bone, this suppresses osteoclast activity and reduces fracture risk. In the eye, the same inflammatory signaling axis has been implicated in retinal ganglion cell injury, glial activation, trabecular meshwork dysfunction, extracellular matrix remodeling, and impaired aqueous humor outflow. The study authors suggest that RANKL inhibition could, in theory, modulate both neuroinflammatory and pressure-related mechanisms relevant to glaucoma.
While there are noted limitations with the study – e.g., the outcomes were based on ICD-10-CM diagnosis codes, and the database lacked granular ophthalmic data such as intraocular pressure measurements, visual fields, optic nerve imaging, or OCT – the results still open an interesting line of inquiry. If RANKL inhibition is genuinely influencing glaucoma risk, it could point to new inflammatory targets in glaucoma pathophysiology.
