Sex Hormones Mediate Intensive Lifestyle Intervention-Induced Bone Mineral Density Changes: Look AHEAD Sex Hormone Study.

Abstract

The Look AHEAD (Action in Health for Diabetes) randomized controlled trial, which compared an Intensive Lifestyle Intervention (ILI) to Diabetes Support and Education (DSE) in people with overweight/obesity and type 2 diabetes (T2D), showed a greater decline in bone mineral density (BMD) along with greater weight loss in the ILI group. Because weight loss interventions change sex hormones and also affect BMD, understanding the role of sex hormones on these changes has implications for bone health in people with diabetes. We assessed sex hormone mediation on BMD changes due to ILI, by sex, among postmenopausal women and older men over 4 years of follow-up. In the Look AHEAD Sex Hormone Ancillary Study, we applied structural equation models to estimate the effects of ILI (vs DSE) on hip, femoral neck, and whole-body BMD after 4 years of follow-up, temporally mediated by sex hormones estradiol (E2), total testosterone, bioavailable testosterone, and sex hormone binding globulin (SHBG) measured at 1 year after baseline (nadir of weight loss). In women, an ILI-associated decrease in estradiol of 14% from baseline to year 1 mediated a decline in whole-body BMD (-1.15 mg/cm2, 95% CI: -2.54, -0.21). In men, an ILI-associated increase of 11% in total testosterone mediated a decline of hip BMD (-1.18 mg/cm2, 95% CI: -2.68, -0.13). ILI-associated changes in estradiol and total testosterone resulted in whole-body and hip bone loss, providing insights in the potential role of sex hormones in bone loss accompanying weight loss in older adults with T2D who are at a higher risk of bone fractures.