The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.