The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7(-/-) strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7(-/-) became significantly altered in the BALB/cJ P2X7(-/-) when compared to their wild type littermates. The BALB/cJ P2X7(-/-) showed reduced levels of serum C-telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7(-/-) mice strongly influences the bone phenotype of the P2X7(-/-) mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies.