We previously reported that a type II sodium phosphate (Na+-Pi) cotransporter (Npt2) protein is expressed in osteoclasts and that Pi limitation decreases osteoclast-mediated bone resorption in vitro. We also demonstrated that mice homozygous for the disrupted Npt2 gene (Npt2-/-) exhibit a unique age-dependent bone phenotype that is associated with significant hypophosphatemia. In the present study, we sought to identify the Npt2 cDNA in mouse osteoclasts and characterize the impact of Npt2 gene ablation on osteoclast function and bone histomorphometry. We demonstrate that the osteoclast Npt2 cDNA sequence is identical to that of the proximal renal tubule and, thus, not an isoform or splice variant thereof. Histomorphometric analysis revealed that, at 25 days of age, Npt2-/- mice exhibited a reduction in osteoclast number and eroded perimeters, relative to wild-type mice. Moreover, although the number of metaphyseal trabeculae was reduced in 25-day-old Npt2-/- mice, trabecular bone volume was normal due to increased trabecular width. At 115 days of age, the decrease in osteoclast index persisted in Npt2-/- mice relative to wild-type littermates. However, mineralizing and osteoblast surfaces and bone formation rates were increased, and, although trabecular number was still reduced, trabecular bone volume was higher than that of wild-type mice. These data demonstrate a link between osteoclast activity and trabecular development in young Npt2-/- mice, and suggest that an age-related adaptation to Npt2 deficiency is apparent in osteoclast and osteoblast function and bone formation. Copyright © 2001 Elsevier Science Inc.