Retinal biological age correlates with bone mineral density and fracture risk score and predicts incident osteoporosis

Osteoporosis often lacks accessible screening tools, leading to underdiagnosis and increased fracture risk. We explored the potential of a retinal aging biomarker, measured by the RetiAGE algorithm, in stratifying osteoporosis risk. Cross-sectional and prospective cohort study. The retinal biological aging biomarker, RetiAGE, indicates the probability of being older than 65 years, was derived from retinal photographs using a deep learning algorithm. In the cross-sectional PopulatION HEalth and Eye Disease PRofilE in Elderly Singaporeans (PIONEER) study with 1,965 participants with both retinal images and Dual-energy X-ray Absorptiometry (DEXA) measurements, we assessed the association of RetiAGE with bone mineral density (BMD) and BMD's standard deviation (SD) score (T-score), and major osteoporotic and hip fracture risk scores calculated from fracture assessment tool (FRAX) using linear regression models, and its association with osteoporosis using logistic model. In the prospective UK Biobank cohort with 43,938 participants with retinal photographs and without osteoporosis at baseline, we evaluated the association between RetiAGE and the onset of osteoporosis using multivariable Cox proportional hazard models. Subgroup analyses were performed by further adjusting for menopause, hormone replacement therapy and glucocorticoids in women. In the PIONEER study, older RetiAGE was inversely associated with BMD and T-scores in various femoral regions after adjusting for risk factors (all p < 0.05). Elevated RetiAGE was associated with an increased risk score of major osteoporotic and hip fractures (β coefficients of 0.48 and 0.29, per SD increment, respectively). In the UK Biobank participants, higher RetiAGE predicted future osteoporosis onset (hazard ratio, HR = 1.12, per SD increment, p = 0.001), with significant associations persisting in subgroup analyses (p < 0.001 in women; p = 0.011 in men). Accelerated retinal biological aging is associated with decreased BMD and an increased risk of osteoporosis and related fractures. Retinal age may provide a potential alternative for opportunistic risk screening.