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

Abstract

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.

Glaucoma is a leading cause of irreversible blindness worldwide, affecting approximately 3.5% of individuals 40 years or older.^1,2 Ocular hypertension (OHT) primarily arises from impaired aqueous humor outflow due to trabecular meshwork (TM) dysfunction and extracellular matrix remodeling in the anterior segment, whereas primary open-angle glaucoma (POAG) involves subsequent retinal ganglion cell (RGC) degeneration driven by neuroinflammation, oxidative stress, and vascular dysregulation in the posterior segment.^3,4 Glaucoma pathophysiology is complex and multifactorial, with growing evidence highlighting neuroinflammation as a central mechanism linking cellular stress, immune activation, and progressive retinal ganglion cell loss.⁵

The receptor activator of NF-κB ligand (RANKL) and its receptor RANK activate downstream NF-κB signaling, forming an inflammatory axis implicated in neuroinflammation and potentially in glaucomatous pathophysiology.^6–9 This pathway integrates cellular stress responses with neuroinflammatory processes that may contribute to RGC injury.^6,7,10 These stress signals promote sustained NF-κB activation and may amplify glial reactivity and inflammatory burden.^11–13 Experimental studies demonstrate that suppression of NF-κB signaling reduces glial overactivation and protects against RGC degeneration, supporting its role as a key mediator of neuroinflammatory injury in glaucoma.^12,14,15

Beyond its involvement in RGC injury in the posterior segment, NF-κB signaling contributes to structural and functional changes within the TM of the anterior segment, a key regulator of aqueous humor outflow, and may be modulated by upstream RANKL/RANK signaling.^9,16,17 Inflammatory cascades involving NF-κB signaling promote TM stiffening and fibrosis in experimental systems, and modulation of RANKL signaling may attenuate these fibrotic changes.^17,18 Outside the context of glaucoma, the RANKL/RANK axis is one of the most extensively characterized pathways in bone metabolism,¹⁹ a role that has established RANKL inhibition as a major therapeutic strategy in osteoporosis. Notably, both glaucoma and osteoporosis are age-related conditions that share common biological mechanisms, including chronic low-grade inflammation, oxidative stress, and dysregulated tissue remodeling.^20–22 Aging-associated inflammatory signaling, particularly NF-κB activation, has been implicated in retinal neurodegenerative processes as well as osteoporotic bone loss, suggesting a potential mechanistic link between these two conditions.^23,24

Denosumab, a fully human monoclonal antibody against RANKL, is widely prescribed for osteoporosis to prevent fractures by suppressing osteoclast formation, activity, and survival.^19,25,26 Unlike bisphosphonates, which bind to bone mineral and indirectly impair osteoclast function,^27,28 denosumab specifically blocks RANKL–RANK interactions and downstream NF-κB signaling.^29–31 Given that this same signaling axis is also implicated in glaucomatous neuroinflammation,^6–9 denosumab may potentially influence neuroinflammatory effects beyond bone health. However, the potential influence of the RANKL inhibitor denosumab on glaucoma risk has not been systematically investigated. To address this gap, we conducted a multinational, propensity score matched cohort study comparing the incidence of OHT and POAG in adults 40 years or older.

Methods

Study Design and Data Source

This retrospective cohort study was conducted using the TriNetX analytics network, which compiles deidentified health records from more than 200 million patients across 160 healthcare organizations in 21 countries. The database includes demographics, diagnoses, treatments, and laboratory results. All analyses were performed in a Health Insurance Portability and Accountability Act (HIPAA)-compliant secure environment with automatic masking of patient counts ≤ 10.

Study Population and Outcomes

Individuals diagnosed with osteoporosis were categorized into two distinct groups: patients receiving denosumab therapy and those receiving bisphosphonate therapy. To enhance clinical relevance, we restricted the study population to individuals 40 years or older, given that the incidence of both glaucoma and osteoporosis rises substantially beyond this age.^1,32,33 We included patients with osteoporosis (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] M81) who initiated denosumab (Anatomical Therapeutic Chemical [ATC] code M05BX04) or bisphosphonate therapy (ATC code M05BA) between 2013 and 2023. The primary outcomes were POAG (ICD-10-CM H40.11) and OHT (ICD-10-CM H40.05). These code-based definitions were intended to capture clinically coded OHT and POAG. Prior validation studies have demonstrated that ICD-based definitions for glaucoma have an accuracy of approximately 88% for identifying glaucoma and 81% for subtype classification.³⁴ To ensure no history of glaucoma prior to the index date, those with prior glaucoma (ICD-10-CM H40–H42), intraocular pressure–lowering medications, or retinal disease were excluded. Intraocular pressure–lowering medications included prostaglandin analogs (e.g., latanoprost, bimatoprost, travoprost, tafluprost), beta-blockers (e.g., timolol, betaxolol, carteolol), carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide), alpha-agonists (e.g., brimonidine), rho kinase inhibitors (e.g., netarsudil), and miotics (e.g., pilocarpine). Retinal diseases were defined using ICD-10-CM codes under H35 (retinal disorders), including macular degeneration, retinal vascular disorders, retinal detachment–related conditions, and other retinal pathologies. Both cohorts were required to have at least two prescriptions for the respective therapy within 6 to 12 months after the index date. The denosumab cohort was required to have a 1-year bisphosphonate washout period prior to the index date to minimize residual effects of prior bisphosphonate exposure and reduce potential exposure misclassification, thereby ensuring a clear distinction between treatment groups. The bisphosphonate cohort consisted of patients without any prior denosumab exposure.

Statistical Analysis

Baseline characteristics were assessed within 12 months prior to the index date, and only participants with complete data were included. Propensity score matching (1:1 nearest neighbor without replacement) was conducted to pair denosumab and bisphosphonate users, with covariate balance defined as a standardized mean difference (SMD) < 0.1. The SMD quantifies the difference in covariates between the two groups, and values below 0.1 indicate negligible imbalance. The propensity score model incorporated demographics (age, sex, race), lifestyle factors (smoking), and comorbidities including hypertension, ischemic heart disease, atrial fibrillation/flutter, heart failure, cerebrovascular disease, type 2 diabetes mellitus (T2DM), dyslipidemia, obesity, and neoplasms. Medication use was also considered, specifically systemic corticosteroids. Renal function, assessed by estimated glomerular filtration rate (eGFR; Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2021), was included as a laboratory covariate and categorized into six strata consistent with chronic kidney disease (CKD) staging: <15, 15–29, 30–44, 45–59, 60–89, and ≥90 mL/min/1.73 m². The eGFR values were defined based on the most recent available measurement within the 12 months prior to the index date to reflect renal function at study entry. Diagnosis and medication codes are listed in Supplementary Table S1.

Participants were followed for up to 5 years to evaluate predefined outcomes. Within the TriNetX platform, missing data are not imputed, except that eGFR is automatically calculated from reported serum, plasma, or blood creatinine values when sex and age are available. Analyses were conducted in August 2025 using Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), and Kaplan–Meier curves were generated to illustrate cumulative incidence. Patients were censored at the time of their last documented follow-up.

To evaluate the robustness of our findings and reduce potential misclassification, we performed sensitivity analyses that extended the follow-up to 10 years, required at least one ophthalmology visit during the observation period to ensure diagnostic ascertainment, and incorporated an expanded set of cardiometabolic medication covariates. These included antidiabetic medications (insulins, biguanides, sulfonylureas, glucagon-like peptide-1 [GLP-1] receptor agonists, sodium-glucose cotransporter 2 [SGLT2] inhibitors, dipeptidyl peptidase-4 [DPP-4] inhibitors, alpha-glucosidase inhibitors, and thiazolidinediones), lipid-lowering therapy (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), and antihypertensive agents (renin–angiotensin system inhibitors, beta-blockers, and calcium channel blockers).

To further evaluate the robustness and reproducibility of our findings, we conducted a validation analysis restricted to patients within the TriNetX US network, which is comprised of 65 participating healthcare organizations in the United States and reflects relatively more standardized clinical practices and coding systems. The same inclusion and exclusion criteria, exposure definitions, and propensity score matching procedures were applied as in the primary analysis.

Subgroup analyses were performed by age (40–75 vs. ≥75 years), sex (female vs. male), race (White, Black, Asian), T2DM status (yes vs. no), and systemic corticosteroid use (yes vs. no). Within each subgroup analysis, denosumab and bisphosphonate users were propensity score matched to balance baseline characteristics. As a result, the sample size of each subgroup analysis could differ from that of the overall cohort.

Ethics Statement

This study was approved by the Institutional Review Board of Taichung Veterans General Hospital (CE24430C-1). Research procedures were consistent with the tenets of the Declaration of Helsinki and Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines (Supplementary Table S2).

Results

The final study population included 47,312 individuals in both the denosumab and bisphosphonates groups, all without a prior glaucoma diagnosis at baseline. After propensity score matching, all SMDs were <0.1, indicating adequate covariate balance between the two groups. A flow diagram of the study population is presented in Figure 1, and the propensity score distributions before and after matching are shown in Supplementary Figure S1. The mean age at baseline was nearly identical between the two groups, with 71.4 ± 9.4 years in the denosumab cohort and 71.5 ± 9.5 years in the bisphosphonate cohort. Baseline demographic characteristics, comorbidities, and medication use were well balanced across cohorts (Table). Participants were followed for up to 5 years to assess the incidence of OHT and POAG. The mean follow-up duration was 1428.7 ± 460.9 days in the denosumab group and was 1462.6 ± 457.1 days in the bisphosphonates group.

Figure 1.

Flowchart of study design. The flowchart illustrates the selection of individuals 40 years or older without a prior diagnosis of glaucoma. Participants were categorized into denosumab and bisphosphonates groups. The denosumab group was defined by the date of first denosumab prescription between 2013 and 2023, whereas the bisphosphonates group was defined by the date of first bisphosphonate prescription during the same period, which served as the index date. All individuals were required to have a documented diagnosis of osteoporosis prior to the index date, with no history of glaucoma, use of intraocular pressure–lowering medications, or retinal disease at baseline.

Table.

Baseline Demographics

	Before Propensity Score Matching			After Propensity Score Matching
	Denosumab	Bisphosphonates	SMD	Denosumab	Bisphosphonates	SMD
Total, n	52,407	83,142	—	47,312	47,312	—
Age (y), mean ± SD	72.3 ± 9.6	68.8 ± 9.7	<0.001	71.4 ± 9.4	71.5 ± 9.5	0.008
Female, n (%)	45,307 (86.5)	72,750 (87.5)	0.031	41,245 (87.2)	41,237 (87.2)	0.001
Race,* n (%)
White	33,751 (64.4)	60,397 (72.6)	0.178	32,210 (68.1)	32,332 (68.3)	0.006
Black	1,280 (2.4)	5,053 (6.1)	0.181	1,264 (2.7)	1,288 (2.7)	0.003
Asian	6,559 (12.5)	5,899 (7.1)	0.183	4,925 (10.4)	4,747 (10.0)	0.012
Smoking, n (%)	595 (1.1)	1,415 (1.7)	0.048	574 (1.2)	552 (1.2)	0.004
Comorbidities, n (%)
Hypertension	19,669 (37.5)	35,481 (42.7)	0.105	18,064 (38.2)	17,808 (37.6)	0.011
Hyperlipidemia	18,180 (34.7)	36,011 (43.3)	0.177	17,260 (36.5)	17,218 (36.4)	0.002
Ischemic heart disease	5,008 (9.6)	6,891 (8.3)	0.044	4,304 (9.1)	4,141 (8.8)	0.012
Cerebrovascular disease	2,921 (5.6)	4,268 (5.1)	0.020	2,560 (5.4)	2,415 (5.1)	0.014
Atrial fibrillation and flutter	3,430 (6.5)	4,421 (5.3)	0.052	2,936 (6.2)	2,878 (6.1)	0.005
Heart failure	2,354 (4.5)	3,228 (3.9)	0.030	1,975 (4.2)	1,870 (4.0)	0.011
Type 2 diabetes mellitus	5,793 (11.1)	10,122 (12.2)	0.035	5,182 (11.0)	4,947 (10.5)	0.016
Neoplasms	13,655 (26.1)	20,848 (25.1)	0.022	12,300 (26.0)	12,223 (25.8)	0.004
Obesity	2,443 (4.7)	5,641 (6.8)	0.091	2,335 (4.9)	2,263 (4.8)	0.007
CKD stage 1	10,936 (20.9)	21,678 (26.1)	0.123	10,568 (22.3)	10,697 (22.6)	0.007
CKD stage 2	16,967 (32.4)	29,976 (36.1)	0.078	15,883 (33.6)	16,349 (34.6)	0.021
CKD stage 3a	6,729 (12.8)	9,028 (10.9)	0.061	5,766 (12.2)	5,742 (12.1)	0.002
CKD stage 3b	4,035 (7.7)	3,495 (4.2)	0.148	2,857 (6.0)	2,749 (5.8)	0.010
CKD stage 4	1,616 (3.1)	915 (1.1)	0.139	879 (1.9)	835 (1.8)	0.007
CKD stage 5	640 (1.2)	425 (0.5)	0.077	376 (0.8)	359 (0.8)	0.004
Corticosteroid, n (%)	15,452 (29.5)	25,431 (30.6)	0.024	14,001 (29.6)	14,023 (29.6)	0.001

^*The racial and ethnic classifications (White, Black or African American, and Asian) are directly taken from the original terminology provided in the TriNetX database. Specifically, “Black or African American” has been shortened to “Black” due to space constraints.

Lower Risk of Glaucoma Associated With Denosumab Use

The results demonstrated that individuals receiving denosumab had significantly lower risks of developing OHT (HR = 0.72; 95% CI, 0.59–0.88) and POAG (HR = 0.63; 95% CI, 0.53–0.75), compared with those treated with bisphosphonates (Fig. 2). Kaplan–Meier survival curves (Fig. 3) further supported these findings, showing consistently lower cumulative incidence in the denosumab group over 5 years, with significant between-group differences for OHT (log-rank P = 0.0016) and POAG (log-rank P < 0.0001), reflecting an association between denosumab use and lower glaucoma incidence.

Figure 2.

Association of denosumab use with OHT and POAG. The figure summarizes the risk of developing OHT and POAG among participants 40 years or older, comparing those treated with denosumab and those receiving bisphosphonates. The denosumab group demonstrated significantly lower risks of both outcomes compared with the bisphosphonate group.

Figure 3.

Cumulative incidence of OHT and POAG in patients receiving denosumab versus bisphosphonates. Shown are cumulative incidence curves for the 5-year incidence of (A) OHT and (B) POAG among participants ≥ 40 years of age. Curves compare patients treated with denosumab (red line) and those receiving bisphosphonates (blue line). Associations were estimated from propensity score matched cohorts using Cox proportional hazards models.

Sensitivity Analyses

The association between denosumab use and reduced POAG risk (HR = 0.72; 95% CI, 0.53–0.97) remained robust in sensitivity analyses that applied longer follow-up, stricter diagnostic requirements (including the requirement for at least one ophthalmology visit during follow-up), and additional adjustment for cardiometabolic medication use, including antidiabetic, lipid-lowering, and antihypertensive therapies.

Validation Analyses

In the validation analysis restricted to the TriNetX US network, the results remained consistent with the primary analysis. Denosumab use 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. These findings support the robustness and reproducibility of the observed associations. Detailed estimates are shown in Supplementary Table S3.

Subgroup Analyses

Across all demographic and clinical subgroups, denosumab use was consistently associated with a lower risk of glaucoma compared with bisphosphonates. For OHT, the lower risk was evident among participants ≥ 75 years old (HR = 0.71; 95% CI, 0.56–0.91), females (HR = 0.71; 95% CI, 0.56–0.88), and White individuals (HR = 0.68; 95% CI, 0.54–0.87). Similar findings were observed in patients without T2DM (HR = 0.70; 95% CI, 0.55–0.90). The results are illustrated in Figure 4.

Figure 4.

Association between denosumab use and OHT across different subgroups. The figure summarizes the risk of developing OHT among individuals treated with denosumab versus bisphosphonates, stratified by age, sex, race, T2DM status, and systemic steroid use. Denosumab use was consistently associated with lower risks of OHT, particularly among older adults, females, White individuals, and those without T2DM. Each subgroup cohort was independently derived from the TriNetX platform to ensure complete propensity score matching; therefore, the sample size within each stratum may differ from that of the overall analysis. In accordance with TriNetX data privacy policies, exact event counts are suppressed when the number of outcomes is ≤10. An arrowhead indicates that the upper bound of the 95% CI exceeded the displayed axis range (maximum shown: 2.0).

For POAG, denosumab was consistently associated with a significantly lower risk across most strata, including participants 40 to 75 years old (HR = 0.53; 95% CI, 0.38–0.76), those ≥ 75 years (HR = 0.66; 95% CI, 0.54–0.80), females (HR = 0.62; 95% CI, 0.51–0.75), and males (HR = 0.53; 95% CI, 0.28–0.97). By race, decreased risks were observed in White (HR = 0.73; 95% CI, 0.58–0.91) and Asian (HR = 0.35; 95% CI, 0.16–0.75) individuals. Lower risks were also evident in patients without T2DM (HR = 0.62; 95% CI, 0.50–0.76). Consistent patterns were also noted among corticosteroid users (HR = 0.61; 95% CI, 0.51–0.74). The results are illustrated in Figure 5.

Figure 5.

Association between denosumab use and POAG across different subgroups. The figure summarizes the risk of developing POAG among individuals treated with denosumab versus bisphosphonates, stratified by age, sex, race, T2DM status, and systemic steroid use. Denosumab use was consistently associated with lower risks of POAG, particularly among older adults, females, White and Asian participants, corticosteroid users, and those without T2DM. Each subgroup cohort was independently derived from the TriNetX platform to ensure complete propensity score matching; therefore, the sample size within each stratum may differ from that of the overall analysis. In accordance with TriNetX data privacy policies, exact event counts are suppressed when the number of outcomes is ≤10.

Discussion

In this large-scale cohort study of individuals ≥40 years of age, denosumab use was associated with a lower risk of developing OHT and POAG compared with bisphosphonate therapy. These findings were robust across sensitivity and validation analyses, as well as various demographic and clinical strata.

Denosumab and the RANKL/RANK–NF-κB Signaling Axis in Glaucoma

Denosumab, a fully human monoclonal antibody against RANKL, is a widely used antiresorptive therapy for osteoporosis.^25,35,36 By binding RANKL with high affinity, it prevents activation of RANK on osteoclast precursors and mature osteoclasts, thereby suppressing their differentiation, function, and survival.^25,35,36 This action effectively reduces bone resorption and lowers fracture risk.^35–37 Importantly, through RANKL inhibition, denosumab may also engage pathogenic pathways implicated in glaucoma.

RANKL/RANK–NF-κB signaling constitutes an important upstream inflammatory axis relevant to glaucomatous neurodegeneration.^6–8 Cellular stress, including oxidative and endoplasmic reticulum stress, activates NF-κB signaling and may interact with this axis through excessive reactive oxygen species, glial activation, and the release of cytokines such as TNF-α and interleukins.^{13,18,38–40} Through sustained NF-κB signaling, these processes promote RGC injury and amplify neuroinflammatory cascades.^12–15 Under pathological conditions, glial cells may also produce RANKL, which reinforces NF-κB activity and sustains neuroinflammation.^6–8,10 Experimental studies indicate that suppression of NF-κB signaling may lessen microglial overactivation, stabilizes the redox environment, and reduces RGC loss in models of glaucomatous neurodegeneration.^14,15,41 Furthermore, prior evidence from human ocular disease has demonstrated dysregulated RANKL/RANK pathway expression and supported its role in ocular inflammation, angiogenesis, and retinal vascular dysfunction, collectively suggesting a potential link to glaucoma pathophysiology.⁸

In the anterior segment, RANKL/RANK–NF-κB signaling contributes to TM dysfunction, a key determinant of aqueous humor outflow and intraocular pressure regulation.^9,17 Experimental studies demonstrate that RANKL is upregulated in stressed TM cells, with NF-κB regulating inflammatory and extracellular matrix remodeling responses.⁹ NF-κB activation promotes extracellular matrix deposition and α-SMA accumulation in TM cells, contributing to fibrosis and increased outflow resistance, and experimental models further indicate that modulation of the MyD88/NF-κB pathway may attenuate these fibrotic changes.¹⁷

Glaucoma Risk in Subgroup Analyses

Aging is a major risk factor for glaucoma and is associated with oxidative stress, mitochondrial dysfunction, and NF-κB–mediated inflammation affecting both TM function and RGC survival.^20,21,42,43 Consistent with this, lower glaucoma risk with denosumab was observed in both middle-aged and older individuals in our study. Glucocorticoids can raise intraocular pressure, and individuals predisposed to POAG tend to exhibit greater sensitivity to steroid-induced pressure elevation.⁴⁴ We observed a lower glaucoma risk among corticosteroid users, indicating that denosumab may demonstrate a comparable risk-lowering pattern in this high-risk population. Notably, denosumab is known to more effectively inhibit RANKL-mediated pathways activated during glucocorticoid exposure,^45,46 providing a potential biological context for this observation.

Taken together, inhibition of the RANKL/RANK axis provides a biologically plausible context for the observed association between the RANKL inhibitor denosumab and glaucoma risk. By modulating cellular stress–related and NF-κB–associated inflammatory pathways, RANKL blockade may influence processes relevant to neurodegeneration and aqueous humor outflow regulation. In contrast, some reports have indicated that bisphosphonates have been associated, albeit rarely, with ocular inflammatory adverse events, including uveitis, episcleritis, and scleritis.⁴⁷

Strengths, Limitations, and Future Directions

This study leveraged a large, multinational real-world database with over 90,000 matched patients, allowing robust comparisons between denosumab and bisphosphonates. Propensity score matching balanced demographic, clinical, and laboratory factors, and findings were consistent across sensitivity, validation, and subgroup analyses, supporting the reliability of the results.

This study has several limitations. First, the reliance on ICD-10-CM diagnosis codes may lead to outcome misclassification, as clinical data, such as intraocular pressure, visual field testing, and optic nerve imaging, were unavailable. However, as noted in the Methods section, prior validation studies indicate that ICD-based definitions for glaucoma have an accuracy of approximately 88% for identification and 81% for subtype classification.³⁴ Second, the retrospective observational design precludes causal inference, and residual confounding from unmeasured factors, such as systemic inflammatory states, cannot be fully excluded. Third, the multinational nature of TriNetX may introduce heterogeneity in diagnostic practices and coding behaviors, although US-specific validation analyses yielded consistent results. Fourth, medication exposure was determined by prescription records, which may not reflect actual patient adherence. Fifth, certain subgroup analyses were limited by small event numbers, resulting in wider confidence intervals and reduced statistical power. Finally, competing risk by death may influence incidence estimates in this older cohort. Because the TriNetX platform does not support Fine–Gray subdistribution hazard models, death is treated as censoring. To address this, we conducted age-stratified analyses. The consistent association between denosumab and lower POAG risk in both middle-aged (40–75 years) and older (≥75 years) groups suggests that the findings are not solely driven by differential survival, though residual bias may remain.

Future prospective studies and mechanistic investigations are warranted to clarify the role of RANKL inhibition in glaucoma pathophysiology, explore dose–response relationships, integrate biomarker-based assessments (e.g., RANKL expression in aqueous humor or TM tissue), and utilize patient-level data for more robust competing risk modeling.

Conclusions

In this large, real-world cohort of patients receiving osteoporosis treatment, RANKL inhibitor denosumab use was associated with lower risks of OHT and POAG compared with bisphosphonate therapy. These findings were consistent across sensitivity, validation, and subgroup analyses. The study does not prove that RANKL inhibitors cause the reduced risk of glaucoma. It only shows an association. Future studies, including in vivo and in vitro experiments, as well as prospective longitudinal studies, are warranted to further elucidate the underlying mechanisms.