Identifying modifiable factors and their causal effects on osteoporosis risk

Osteoporosis is the most common disease affecting bone health, and previous studies have identified many risk factors for it. However, the diversity and co-occurrence of risk factors were underestimated in those hypothesis-driven studies. Here we collected data of 491,344 participants from the UK Biobank with more than 17 years of follow-up data for 642 modifiable risk factors. First, we performed an exposure wide association study to identify the factors associated with osteoporosis and generated a composite score for each domain. Then multivariate Cox regression was applied to evaluate the joint effects of risk factors. Finally, Mendelian randomization was used to verify the causal effects. The results showed that osteoporosis is associated with exposure factors from many domains. The results of Mendelian randomization study suggested that irritable bowel syndrome (OR 2.869(1.412-5.831), P = 0.0036), standing height (OR 1.163(1.012-1.337), P = 0.0331) and trunk fat-free mass (OR 1.247(1.017-1.530), P = 0.0341) were potential causal risk factors for osteoporosis, and body mass index (BMI) (OR 0.801(0.675-0.949), P = 0.0103) was associated with reduced risk. Joint analysis suggested that favorable physical measures, health and medical history and lifestyle status could significantly reduce the risk of osteoporosis, especially in men. This study provided a valuable reference for osteoporosis prevention and intervention.