There is accumulating evidence that genetic variations play an important role in osteoporosis by reducing bone mass and increasing the risk of fragility fractures. Many different genetic variants with mild effects contribute to the regulation of bone mineral density and fracture risk. Investigating the effect of genetic variants in osteoporosis may elucidate new mechanisms of bone homeostasis and possibly create new effective pharmaceutical targets for osteoporosis in the future. In the present study, data from genome-wide association studies, candidate gene association studies, and meta-analysis studies have been used to select stronger candidate genetic variants for further study. Iranian population samples were utilized in this project to investigate the effect of these selected genetic variants. Functional studies examined the association with genetic variants and the function of osteoclast cells and in the allelic expression imbalance (AEI) in target cells. The analysis of AEI was used to investigate the effect of cis-acting factors on the transcribed SNPs in the target cells via evaluation of cDNA from tissues expressing those transcribed SNPs in the heterozygous individual. The preliminary analysis of the Iranian population data showed features similar to other populations. There were also statistically significant associations between BMD and risk SNPs: VDRrs731236, P2RX7-rs3751143, RANK-rs884205, RANKL-rs9594738, RANKLrs9594759, LRP5-rs2306862, OPG-rs2073618, OPG-rs11995824, OPG-rs4355801, and ESR1-rs2077647. There were statistically significant associations between osteoclast number and risk allele of RANKL rs9594759 /rs1021188 SNPs. These associations are in the direction that would be expected from risk alleles of BMD. AIE analysis suggested evidence of cis acting effects in both osteoclast culture and blood samples for two risk SNPs, ESR1-rs2504063 and VDR-rs731236 which were each associated with BMD in the Iranian population. This study and other same studies helps to improve our knowledge about the role of genetic variation in osteoporosis with the goal of providing a genetic profile can be used for genetic screening tests for the identification of individual at risk of osteoporosis. A suitable genetic profiling test helps to find useful treatment. Novel pathways that contribute to control of BMD could be identified, improving our knowledge about the effect of genetic variation with the possibility of producing new therapeutic agents.