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Urinary Phthalate Biomarkers and Bone Mineral Density in Postmenopausal Women

Katherine W Reeves 1Gabriela Vieyra 1Nydjie P Grimes 1Jaymie Meliker 2Rebecca D Jackson 3Jean Wactawski-Wende 4Robert Wallace 5R Thomas Zoeller 6Carol Bigelow 1Susan E Hankinson 1JoAnn E Manson 7Jane A Cauley 8Antonia M Calafat 9

J Clin Endocrinol Metab. 2021 Mar 23;dgab189.doi: 10.1210/clinem/dgab189. 


Background: Phthalates are endocrine-disrupting chemicals that could disrupt normal physiologic function, triggering detrimental impacts on bone. We evaluated associations between urinary phthalate biomarkers and BMD in postmenopausal women participating in the prospective Women’s Health Initiative (WHI).

Methods: We included WHI participants enrolled in the BMD substudy and selected for a nested case-control study of phthalates and breast cancer (N=1255). We measured thirteen phthalate biomarkers and creatinine in 2-3 urine samples per participant collected over 3 years, when all participants were cancer-free. Total hip and femoral neck BMD were measured at baseline and year 3, concurrent with urine collection, via dual energy x-ray absorptiometry. We fit multivariable generalized estimating equation models and linear mixed effects models to estimate cross-sectional and longitudinal associations, respectively, with stratification on postmenopausal hormone therapy (HT) use.

Results: In cross-sectional analyses, mono-3-carboxypropyl phthalate and the sum of di-isobutyl phthalate metabolites were inversely associated with total hip BMD among HT non-users, but not among HT users. Longitudinal analyses showed greater declines in total hip BMD among HT non-users and with highest concentrations of mono-3-carboxyoctyl phthalate (-1.80%, 95% CI -2.81 – -0.78%) or mono-carboxynonyl phthalate (-1.84%, 95% CI -2.80 – -0.89%); similar associations were observed with femoral neck BMD. Among HT users, phthalate biomarkers were not associated with total hip or femoral neck BMD change.

Discussion: Certain phthalate biomarkers are associated with greater percent decreases in total hip and femoral neck BMD. These findings suggest that phthalate exposure may have clinically important effects on BMD, and potentially fracture risk.