Denosumab linked to lower risk of ocular hypertension and primary open-angle glaucoma than bisphosphonates

Denosumab use was associated with lower 5-year risks of ocular hypertension (OHT) and primary open-angle glaucoma (POAG) than bisphosphonate therapy in adults with osteoporosis, according to a multinational retrospective cohort study published in Investigative Ophthalmology & Visual Science.¹

The analysis used the TriNetX analytics network, which contains de-identified electronic health record data from healthcare organizations across multiple countries. Researchers assessed adults aged 40 years and older with osteoporosis who started denosumab or bisphosphonate therapy between 2013 and 2023.¹

Why does this matter?

Osteoporosis and glaucoma are both strongly associated with ageing, so many patients seen in ophthalmology clinics may also be receiving systemic treatment for bone health. Denosumab is a monoclonal antibody that inhibits receptor activator of NF-κB ligand (RANKL), while bisphosphonates reduce bone resorption through effects on osteoclast activity.^2,3

The authors highlight a possible biological link between RANKL/RANK–NF-κB signalling and pathways involved in glaucoma, including neuroinflammation, retinal ganglion cell injury and trabecular meshwork dysfunction. However, this study was observational and did not directly test the proposed mechanism.^1,4–6

What did the study investigate?

The researchers compared patients with osteoporosis who received denosumab with those who received bisphosphonate therapy. After 1:1 propensity score matching, the final analysis included 94,624 patients, with 47,312 patients in each treatment group.¹

Patients were monitored for new diagnoses of OHT and POAG over 5 years. The study also included several additional analyses to test the robustness of the findings, including longer follow-up, a narrower analysis requiring an ophthalmology visit and further adjustment for cardiometabolic medications. Subgroup analyses explored whether the findings differed by age, sex, race, type 2 diabetes status and systemic corticosteroid use.¹

What do the data show?

Denosumab was associated with a lower risk of both OHT and POAG than bisphosphonate therapy. The hazard ratio was 0.72 for OHT (95% CI, 0.59–0.88) and 0.63 for POAG (95% CI, 0.53–0.75).¹

The difference between treatment groups was also seen in cumulative incidence analyses over 5 years. Similar patterns were reported when follow-up was extended, when the analysis was limited to patients with at least one ophthalmology visit and when additional cardiometabolic medications were included in the model.¹

A separate validation analysis using the TriNetX US network produced consistent results. In this analysis, denosumab was associated with a lower risk of OHT (HR = 0.70; 95% CI, 0.56–0.87) and POAG (HR = 0.68; 95% CI, 0.53–0.88) compared with bisphosphonate therapy.¹

Were the findings consistent across subgroups?

Subgroup analyses broadly supported the main finding, although the pattern varied by outcome.

For OHT, the lower risk associated with denosumab was most evident in adults aged 75 years and older, female patients, White individuals and patients without type 2 diabetes. For POAG, lower risk was reported in both age groups, both sexes, White and Asian participants, corticosteroid users and patients without type 2 diabetes.¹

The authors note that some subgroup analyses had small numbers of events, which widened confidence intervals and reduced statistical power.¹

What should ophthalmologists take from this?

The study suggests that osteoporosis treatment type may be associated with differences in subsequent OHT and POAG risk. For ophthalmologists, the findings add a potentially relevant signal when reviewing systemic medication histories in patients with glaucoma risk factors, particularly older adults and patients receiving corticosteroids.

However, the results should not be interpreted as evidence that denosumab prevents glaucoma. Treatment decisions for osteoporosis should remain based on established bone health indications and made in collaboration with the patient’s wider care team.

Limitations

The study was retrospective and observational, meaning it cannot prove that denosumab directly reduces OHT or POAG risk. Although propensity score matching was used to balance measured baseline characteristics, unmeasured confounding cannot be excluded.¹

OHT and POAG were identified using ICD-10-CM diagnosis codes rather than standardized clinical assessments. The database did not include key ophthalmic measures such as intraocular pressure, visual field testing or optic nerve imaging. Medication exposure was also based on prescription records, which may not fully reflect whether patients took treatment as prescribed.¹

The multinational nature of the TriNetX dataset may also introduce variation in coding and diagnostic practice across healthcare systems. In addition, death may have acted as a competing risk in this older population, but the database did not support competing-risk modelling using Fine–Gray methods.¹

Clinical takeaway

In this large real-world cohort study, denosumab use was associated with lower 5-year risks of OHT and POAG compared with bisphosphonate therapy among adults with osteoporosis. The findings were consistent across sensitivity and validation analyses, but remain hypothesis-generating. Prospective studies and mechanistic research are needed before any clinical recommendations can be made about RANKL inhibition and glaucoma risk.

References

1. Tsai C-Y, Weng C-H, Sheen Y-J, Chen J-P, Chen H-M, Tsai C-Y, et al. RANKL inhibition and the risk of ocular hypertension and primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2026;67(6):8. doi:10.1167/iovs.67.6.8.
2. Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet. 2022;399(10329):1080–1092.
3. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.
4. Acott TS, Vranka JA, Keller KE, Raghunathan V, Kelley MJ. Normal and glaucomatous outflow regulation. Prog Retin Eye Res. 2021;82:100897.
5. Tezel G. Molecular regulation of neuroinflammation in glaucoma: current knowledge and the ongoing search for new treatment targets. Prog Retin Eye Res. 2022;87:100998.
6. Li L, Liu Q, Shi L, et al. Baicalin prevents fibrosis of human trabecular meshwork cells via inhibiting the MyD88/NF-κB pathway. Eur J Pharmacol. 2023;938:175425.