Osteoporosis is a common and complex disease with strong genetic influence; however, the vast majority of genetic variance for osteoporosis-related phenotypes remains undiscovered. We have employed µCT to scan hindlimbs of 940 Collaborative Cross mice (CC) across 59 strains incorporating varying ages and genders, and generated data on parameters including BV/TV, Tb.N, Tb.Sp, Tb.Th, SMI, DA and Ct.Th from reconstructed femur images. Genomapping was performed to identify candidate genes responsible for bone mass and microarchitecture. We then correlated these genes with variation in human osteoporosis datasets. Based on trabecular BV/TV, candidate genes Epha5, Itga1, Pelo and Itga2 were identified in females and Snx27 and Tnxip in males. Comparison of young and old mice revealed loci on chromosome 11 and 17 in female mice, containing several candidate genes including, Fam83g, Kcnj12 and Rnf112; whereas loci on chromosomes 2 and 12 were seen in male cohorts, indicating potential candidate genes Apob, Gdf7, Ankrd60 and Matn3. Analysis of genetic regions regulating DA in female mice showed a peak on chromosome 18, which includes the genes Nfatc1, Setbp1, Ska1, and Lipg. We then correlated variation in candidate genes with human osteoporosis genetic datasets and identified significant SNPs for femoral neck BMD at the TXNIP, SETBP1 and NFATC1 loci. Previous studies have demonstrated the importance of Nfatc1 in osteoclast biology, and genetic polymorphisms in ITGA1 and APOB have previously been associated with human BMD. Furthermore, global knockout of Snx27 in mice results in skeletal dysplasia and reduced bone volume, indicating the relevance of the identified genes to bone biology in mice and humans. Our study is the first to identify TXNIP and SETBP1 as modulators of BMD in humans. These results verify the success of our screening program for identification of novel osteoporosis susceptibility genes, and have identified several new genes for further study.