The P2X(7) receptor is thought to be involved in bone physiology in a pro-osteogenic manner. Therefore, we examined associations between genetic variations in the P2X(7) receptor gene and bone mineral density (BMD). We found an association between four non-synonymous polymorphism of the human P2X(7) receptor and the risk of osteoporosis. The purpose of this study was to determine whether genetic variation in the P2X(7) receptor gene (P2RX7) is associated with decreased BMD and risk of osteoporosis in fracture patients. Six hundred ninety women and 231 men aged a parts per thousand yen50 years were genotyped for 15 non-synonymous P2RX7 SNPs. BMD was measured at the total hip, lumbar spine and femoral neck. Four non-synonymous SNPs were associated with BMD. The Ala348Thr gain-of-function polymorphism was associated with increased BMD values at the lumbar spine (p = 0.012). Decreased hip BMD values were associated with two loss-of-function SNPs in the P2RX7, i.e., in subjects homozygous for the Glu496Ala polymorphism as well as in subjects carrying at least one variant allele of the Gly150Arg polymorphism (p = 0.018 and p = 0.011; respectively). In men, we showed that subjects either heterozygous or homozygous for the Gln460Arg gain-of-function polymorphism in the P2RX7 had a significantly 40 % decrease in risk of a lower T-score value (OR = 0.58 [95%CI, 0.33-1.00]). Thus, genetic aberrations of P2X7R function are associated with lower BMD and increased osteoporosis risk. Therefore, detection of non-synonymous SNPs within the P2RX7 might be useful for osteoporosis risk estimation at an early stage, potentially enabling better osteoporosis prevention and treatment.