Age at menarche and osteoporosis: A Mendelian randomization study

Purpose: Traditional epidemiological studies suggest that there is an association between age at menarche (years) (AAM) and bone mineral density (BMD) at the sites of the femoral neck and lumbar spine (FNK and LS BMD), indicating a potentially important relationship between AAM and the development of osteoporosis (OP). However, these findings may be influenced by unmeasured confounding factors that can obscure the true relationship between the phenotypic traits. Therefore, we performed Mendelian randomization (MR) analyses to determine whether there is a causal relationship between AAM and BMD (FNK and LS BMD), where late AAM may increase the risk of developing OP. Methods: Adopting a two-sample MR approach we incorporated genome-wide association (GWAS) summary statistics from the Reproductive Genetics (ReproGen) Consortium (n = 182,416) (females only) and the GEnetic Factors for OSteoporosis (GEFOS) Consortium (n = 53,236) (both males and females). Results: Using this MR approach we discovered that each additional year in AAM is associated with a modest reduction in FNK BMD ((3 = 0.072 se = 0.022, 95% CI (-0.115, -0.030), p = 0.001) and LS BMD ((beta = -0.072, se = 0.025, 95% CI (-0.121, -0.023), p = 0.004), and therefore influences OP susceptibility. Conclusions: This study demonstrates that AAM in females may play a causal role in OP etiology and provides novel insights into the pathophysiology of bone related diseases like osteoporosis, osteopenia and fracture. Summary: Our study demonstrates that AAM in females may play a causal role in OP etiology and provides novel insights into the pathophysiology of bone related diseases like osteoporosis, osteopenia and fracture. By adopting Mendelian Randomization approaches, our study was not susceptible to bias from unmeasured confounders or reverse causation.