Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH-deficiency. Quantification of the trans-pubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25-30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH-antagonist transgenic) and complete (GH-receptor-null) loss of GH signalling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signalling.. In order to determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG)-treatment and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG-treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-1 axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-1, failed to exacerbate the compromised femoral strength in the dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH-deficiency do not exert a significant influence over the strength of cortical bone.