OBJECTIVES: The purinergic P2RX7 receptor (P2RX7) has been shown to play a role in the regulation of osteoblast and osteoclast activity. The aim of this study was to determine the presence of polymorphisms in exon 13 of the P2X7 gene and the association with osteoclast apoptosis in vitro and bone status in vivo. METHODS: A total of 1764 postmenopausal women were genotyped for three single nucleotide polymorphisms detected after sequencing of exon 13 of P2X7. Bone markers, bone mineral density of the hip and lumbar spine were determined at baseline and after 10 years, and vertebral fracture incidence after 10 years. In-vitro ATP-induced caspase-1 determinations were performed on osteoclasts from the different genotypes. RESULTS: Three polymorphisms were detected (Gln460Arg, Glu496Ala, and Ile568Asn). None of the polymorphisms was related to bone mineral density or changes in bone mineral density over 10 years in hormone replacement therapy naïve women. The Ile568Asn polymorphism was however, associated with effect of hormone replacement therapy. Furthermore, the 10-year fracture incidence was significantly associated with both the Glu496Ala and the Ile568Asn. The Glu496Ala polymorphism was closely related to ATP-induced osteoclast apoptosis in vitro, as osteoclasts from individuals homozygous for the C allele had significantly decreased apoptotic activity. CONCLUSION: The P2X7 Glu496Ala and the Ile568Asn single nucleotide polymorphisms are associated with 10-year fracture risk in postmenopausal women and response to hormone replacement therapy treatment. Further, the Glu496Ala polymorphism is strongly influencing osteoclast apoptosis in vitro, which could contribute to increased fracture risk.