Endogenous DHEAS Is Causally Linked With Lumbar Spine Bone Mineral Density and Forearm Fractures in Women

CONTEXT: A recent pooled analysis of four clinical trials demonstrated that treatment with dehydroepiandrosterone (DHEA) increases lumbar spine bone mineral density (LS-BMD) in women. The causal effect of endogenous adrenal-derived DHEA sulphate (DHEAS) on LS-BMD and fracture risk in women is unknown. OBJECTIVE: To determine whether circulating DHEAS is causally associated with LS-BMD and fracture risk in women. METHODS: A 2-sample Mendelian randomization study using genetic predictors of serum DHEAS derived from the largest available female-specific genome wide association study (GWAS) meta-analysis (n = 8565). Genetic associations with dual-energy X-ray absorptiometry–derived BMD (n = 22 900) were obtained from female-specific GWAS summary statistics available from the Genetic Factors for Osteoporosis consortium while individual-level data of 238 565 women of white ancestry from the UK Biobank were used for associations with fractures (11 564 forearm fractures, 2604 hip fractures) and estimated heel BMD by ultrasound (eBMD). RESULTS: A 1 SD genetically instrumented increase in log serum DHEAS levels was associated with a 0.21 SD increase in LS-BMD (P = 0.01) and a 0.08 SD increase in eBMD (P < 0.001). Genetically predicted DHEAS decreased forearm fracture risk (odds ratio 0.70, 95% CI 0.55-0.88 per SD increase in DHEAS) while no significant causal association with hip fractures was observed. CONCLUSIONS: Genetically predicted serum DHEAS increases LS-BMD and decreases forearm fracture risk in women. Based on the results of the present study and previous randomized controlled trials of DHEA treatment, we propose that both endogenous adrenal-derived DHEA(S) and pharmacological DHEA treatment improve bone health in women.