Sex hormone-binding globulin raises lumbar fracture risk
Genetically higher SHBG increased lumbar fracture risk with an odds ratio of 1.201 in FinnGen and 1.005 in UK Biobank, mediated primarily by bone density.
Medicine
In human genome-wide association datasets from FinnGen, the UK Biobank, and IEU OpenGWAS, researchers used a two-sample bidirectional and mediation Mendelian randomization framework to assess how sex hormone-binding globulin (SHBG) influences lumbar fracture risk. Genetically predicted SHBG was causally associated with increased lumbar fracture risk, yielding an odds ratio of 1.201 in FinnGen (P = .021) and 1.005 in the UK Biobank (P = .002).
Genetically higher SHBG exerted negative effects on lumbar bone mineral density (OR = 0.934; P = .0029) and C-reactive protein (OR = 0.921; P = .0065), alongside a slight reduction in insulin medication use (OR = 0.9963; P = 6.1 × 10^-6). Mediation analysis indicated that 64.8% of SHBG's effect on fracture risk was mediated via bone mineral density, 63.8% through C-reactive protein, and 38.7% through insulin pathways.
Why it matters
Bone loss and osteoporotic fractures are primary contributors to morbidity and functional decline in older populations. Uncovering the endocrine and inflammatory mechanisms downstream of SHBG helps clarify how sex hormone regulation drives skeletal fragility.
Caveats
The study is based entirely on statistical inference from genetic summary data rather than prospective interventions, and results are limited to the cohorts analyzed.
The paper
The People’s Hospital of Chuxiong Yi Autonomous Prefecture
Medicine · 2 Oct 2026
