Abstract Background: osteoporosis is a highly polygenic trait characterized by low bone mineral density (BMD) and/or fragility fractures. Over the past decade, polygenic risk scores (PRS) are an emerging tool to try to predict the risk of complex disorders with a genetic component. Objective: to analyze the capacity of different PRSs to predict osteoporosis in the Spanish population. Material and methods: our dataset consisted of two differentiated groups. The first group included osteoporosis cases diagnosed and treated at the Marques de Valdecilla University Hospital (n = 304; 293 women) while the second group consisted of people from the overall Spanish population (n = 3199; 1458 women). Four previously generated PRSs were compared with generalized linear models. Results: the osteoporosis group showed a significantly higher genetic risk compared to the control group in 3 PRSs (PRS-1 p = 1e-7; PRS-2 p = 1.87e-15; PRS-3 p = 0.1477; PRS-4 p = 8.98e-9). In addition, in these PRSs, the individuals in the upper quartile of risk had a significantly higher risk of osteoporosis, compared to those individuals in the other quartiles (PRS-1 OR, 1.83; PRS-2 OR, 2.11; PRS-3 OR, 0.96; PRS-4 OR, 1.72). Conclusions: in summary, the application of PRSs shows significant differences between the overall Spanish population and patients with osteoporosis, which is suggestive of its utility within strategies for the identification of subjects at risk based on clinical-genetic criteria.