Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Clinical Pharmacology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2080-e2086. doi: 10.1210/clinem/dgab915.
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.
To determine whether circulating DHEAS is causally associated with LS-BMD and fracture risk in women.
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).
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.
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.
最近四项临床试验的汇总分析表明，脱氢表雄酮（DHEA）治疗可增加女性腰椎骨密度（LS-BMD）。内源性肾上腺源性硫酸脱氢表雄酮（DHEAS）对女性 LS-BMD 和骨折风险的因果影响尚不清楚。
确定循环 DHEAS 是否与女性 LS-BMD 和骨折风险存在因果关系。
采用来自最大女性特异性全基因组关联研究（GWAS）荟萃分析的血清 DHEAS 遗传预测因子的两样本 Mendelian 随机化研究（n=8565）。通过遗传因素骨质疏松症联合会提供的女性特异性 GWAS 汇总统计数据获得与双能 X 射线吸收法（DXA）衍生的骨密度（BMD）相关的遗传关联（n=22900），而来自英国生物库的 238565 名白种人女性的个体水平数据则用于与骨折（11564 例前臂骨折，2604 例髋部骨折）和通过超声（eBMD）估计脚跟 BMD 的关联。
1 SD 遗传上增加的血清 DHEAS 水平与 LS-BMD 增加 0.21 SD（P=0.01）和 eBMD 增加 0.08 SD（P<0.001）相关。遗传预测的 DHEAS 降低了前臂骨折风险（每增加 1 SD 的 DHEAS，比值比为 0.70，95%CI 为 0.55-0.88），而与髋部骨折无显著因果关联。
遗传预测的血清 DHEAS 增加了女性的 LS-BMD 和前臂骨折风险。基于本研究和之前 DHEA 治疗的随机对照试验的结果，我们提出内源性肾上腺源性 DHEA(S)和药理学 DHEA 治疗均可改善女性的骨骼健康。
