Osteoporosis is the most common bone disorder worldwide and is associated with a reduced quality of life with important clinical and economic consequences. The most widely accepted etiopathogenic hypothesis on the origin of osteoporosis and its complications is that they are a consequence of the synergic action of environmental and genetic factors. Bone is constantly being remodelled through anabolic and catabolic pathways in which inflammation, the NF-kB pathway and the renin-angiotensin-aldosterone system (RAAS) are crucial. The aim of our study was to determine whether polymorphisms in genes implicated in inflammation, the NF-kB pathway and RAAS modified the risk of osteoporotic fracture. We analysed 221 patients with osteoporotic fracture and 354 controls without fracture from the HORTEGA sample after 12–14 years of follow up. In addition, we studied the genotypic distribution of 230 single nucleotide polymorphisms (SNPs) in genes involved in inflammation, NF-kB pathway and RAAS. Our results showed that be carrier of the C allele of the rs2228145 IL6R polymorphism was the principal genetic risk factor associated with osteoporotic fracture. The results also showed that variant genotypes of the rs4762 AGT, rs4073 IL8, rs2070699 END1 and rs4291 ACE polymorphisms were important genetic risk factors for fracture. The study provides information about the genetic factors associated with inflammation, the NF-kB pathway and RAAS, which are involved in the risk of osteoporotic fracture and reinforces the hypothesis that genetic factors are crucial in the etiopathogenesis of osteoporosis and its complications.