Long-term association between phthalate exposure in pregnancy and midlife bone mineral density among women in Mexico City

Phthalates are widespread endocrine-disrupting chemicals (EDCs) that may affect bone metabolism, though human studies remain limited. This study investigated the long-term associations between measures of phthalate exposure during pregnancy, a period of heightened bone activity, and midlife bone mineral density (BMD). Participants were women in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort who had gestational phthalate measurements and midlife BMD assessments (n = 180), including 60 who received calcium supplementation during pregnancy and first year postpartum as part of a clinical trial. Nine phthalate metabolites were measured in urine samples collected at up to three pregnancy trimesters, corrected for specific gravity, and a molar sum was calculated for di-2-ethylhexyl phthalate metabolites (ΣDEHP). BMD of the spine, hip, and forearm were assessed using dual-energy X-ray absorptiometry (DXA) at a mean age of 50.1 years. We used linear models to estimate differences in BMD per doubling of geometric mean concentrations of individual phthalates across pregnancy, adjusting for perinatal calcium supplementation status, age at midlife and pre-pregnancy BMI. Effect modification by perinatal calcium supplementation was tested through interaction terms and sensitivity analyses additionally adjusted for menopausal status. Quantile-based g-computation was used to evaluate the overall effect of the phthalate mixtures. Most phthalate metabolites were inversely associated with spine and hip BMD, whereas some showed significant positive associations with forearm BMD. Perinatal calcium supplementation significantly modified associations between phthalate metabolites and spine BMD, showing consistent negative trends in the placebo group and positive trends in the supplementation group (ΣDEHP, p-interaction = 0.03). For example, a doubling in ΣDEHP was associated with 0.12 lower spine BMD in the placebo group (95%CI= -0.27, 0.03) and 0.28 higher spine BMD in the supplementation group (95%CI: -0.03, 0.59). Similar patterns were seen for hip BMD. Mixture analysis results aligned with single-pollutant findings. Phthalate exposure during pregnancy was associated with midlife BMD in a site-specific manner. Calcium supplementation in pregnancy and first year postpartum modified these associations at the spine and hip, suggesting a potential protective role.