Beyond Estrogen Deficiency: The Independent Role of FSH in Site-Specific Bone Loss in Midlife Women

Follicle-stimulating hormone (FSH) was independently associated with lumbar spine (LS) bone mineral density (BMD), while estradiol (E2) predicted femoral neck BMD. A threshold effect for FSH (~ 15 mIU/mL) suggests site-specific and non-linear hormonal influences on bone during the menopausal transition. To investigate the association between serum FSH levels and BMD in midlife women, and to determine whether these associations persist after adjustment for E2 and age, with particular attention to site-specific effects. We conducted a cross-sectional study of 224 women aged 45-60 years, selected from an institutional database. Inclusion required simultaneous measurements of serum FSH, E2, and BMD at the LS, femoral neck (FN), and total hip (TH) by dual-energy X-ray absorptiometry. Women using anti-osteoporotic drugs, hormone therapy, or medications affecting bone, were excluded. Analyses included non-parametric tests, Spearman's correlations, multivariable linear regression with log-transformed hormones and stepwise BIC selection, and segmented regression. FSH rose progressively across menopausal stages, while E2 declined,, paralleling lower BMD values. Higher FSH correlated inversely with LS (ρ = -0.26, p < 0.001) and FN-BMD (ρ = -0.29, p = 0.041), while E2 correlated positively with LS-BMD (ρ = 0.22, p = 0.018). In multivariable models, log-FSH remained independently associated with LS-BMD (β = -0.072, p = 0.009), whereas log-E2 was the only predictor at FN-BMD (β = 0.138, p = 0.020). No predictors were retained for TH-BMD. Segmented regression identified a breakpoint at ~ 15 mIU/mL of FSH, below which LS-BMD declined steeply (β = -0.007 g/cm² per mIU/mL), with a plateau thereafter. FSH and E2 exert distinct, site-specific influences on bone. FSH was independently associated with LS-BMD and showed a threshold effect, while E2 was more relevant to FN. These findings suggest that menopausal bone loss is not solely estrogen-driven but also involves gonadotropin-mediated mechanisms.