Suboptimal growth hormone (GH) replacement therapy during childhood is a major cause of osteopenia in young adults with childhood-onset GH deficiency (CO-GHD). This is primarily attributed to reduced bone formation in childhood. It is currently not known whether GHD also has adverse effects on bone metabolism in adult life. To examine the impact of GHD on calcium and bone metabolism in adults, we evaluated 50 men with CO pituitary failure at a mean age of 28.2+/-4.5 years, i.e., 8.8+/-4.1 years after the discontinuation of previous GH treatment for short stature. Thirty-three patients had multiple pituitary hormone deficiencies (MPHD) for which they received conventional replacement therapy, seventeen patients had isolated GHD (IGHD), and forty-nine age-matched men served as controls. Intestinal calcium absorption, serum calcium concentration, serum phosphate levels, and renal calcium and phosphate excretion were normal in IGHD and MPHD patients. IGHD patients had marginally elevated serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen (ICTP: 5.0+/-1.2 vs. 4.2+/-1.2 microg/l, p < 0.05), but other indices of bone turnover were normal. In contrast, MPHD patients had reduced levels of the carboxy-terminal propeptide of type I procollagen (PICP: 137+/-76 vs. 179+/-72 microg/l, p < 0.01), elevated serum ICTP levels (6.0+/-3.8 vs. 4.2+/-1.2 microg/l, p < 0.001), and reduced serum 1,25-dihydroxyvitamin D levels (55.1+/-16.7 vs. 73.0+/-23.0 pmol/l, p < 0.001). Multivariate regression analysis showed that the serum levels of bone resorption and bone formation markers in MPHD patients were correlated with the hydrocortisone, thyroxine, and testosterone replacement doses. There was no relationship with serum insulin-like growth factor I concentration. Panhypopituitary adults receiving conventional hormone replacement therapy are at risk to develop osteopenia either caused by reduced bone formation or by increased bone resorption activity. Predominantly, these abnormalities result from nonoptimal thyroid, gonadal, or adrenal hormone replacement therapy. GHD is not an important factor. In adults, GHD does not adversely affect intestinal calcium absorption or bone formation activity. Bone resorption activity may be slightly higher than normal, but the abnormality is too small to expect substantial bone loss as a consequence of GHD.