Associations of serum estrogen and iron metabolism biomarkers with lumbar disc degeneration in women: a multilevel mediation analysis

Intervertebral disc degeneration (IDD) is a major contributor to low back pain. In women, postmenopausal status is associated with greater lumbar disc degeneration, estradiol decline, and systemic iron accumulation. We investigated the associations among estradiol, iron metabolism biomarkers, and lumbar disc degeneration, focusing on potential indirect associations involving iron metabolism. This retrospective cross-sectional study included 150 women with lumbar MRI, clinical data, and previously stored residual serum samples, contributing 750 disc-level observations. After ethics approval and study-specific written informed consent, estradiol and iron metabolism biomarkers were measured in the stored samples. Lumbar discs from L1/L2 to L5/S1 were graded using the modified Pfirrmann system. Estradiol was specified as the exposure, and serum iron, ferritin, soluble transferrin receptor, and total iron-binding capacity were evaluated as candidate mediators. Mediation analyses combined a two-step modeling strategy with g-computation, with 95% confidence intervals obtained from 2000 participant-level bootstrap samples. Higher estradiol levels were associated with less severe lumbar disc degeneration. On the expected modified Pfirrmann-grade scale, serum iron and ferritin showed nonzero indirect effects (iron: NIE, − 0.095 [95% CI, − 0.217 to − 0.023]; ferritin: NIE, − 0.101 [95% CI, − 0.205 to − 0.037]). On the severe-degeneration scale, ferritin showed an indirect effect with a confidence interval excluding zero (NIE, − 0.4 percentage points [95% CI, − 1.1 to − 0.1]), whereas the estimate for serum iron included zero. The ferritin-related signal was most evident at L2–L4. Higher estradiol levels were associated with less severe lumbar disc degeneration, and ferritin showed the most consistent indirect-effect signal. These findings are compatible with a potential involvement of altered iron metabolism but do not establish causal mediation.