Insulin-like growth factor binding protein-2 (IGFBP-2) is a 36 kD protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2-/- mice, to +/+colony controls. Igfbp2-/- males had shorter femurs and were heavier than controls, but were not insulin resistant. Serum IGF-I levels in Igfbp2-/- mice were 10% higher than +/+ controls at 8 weeks of age; in males, this was accompanied by a 3 fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared to +/+ controls. The skeletal phenotype of the Igfbp2-/- mice was gender and compartment-specific: Igfbp2 -/- females had increased cortical thickness with a greater periosteal circumference compared to controls, while male Igfbp2-/- males had reduced cortical bone area, and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae, than +/+ controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2 -/- males and in vitro, both CFU-AP+ pre-osteoblasts, and TRAP+ osteoclasts were significantly less abundant than in +/+ male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2-/- males. Lysates from both osteoblasts and osteoclasts in the Igfbp2-/- males had PTEN levels that were significantly higher than +/+ controls, and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender and compartment specific changes in Igfbp2-/- mice. IGFBP-2 may regulate bone turnover in both an IGF-I- dependent and independent manner.