The interaction between glucocorticoids (GC) and PTH has been suggested to play a role in the pathogenesis of GC-induced osteopenia. The present studies were designed to examine the effect of acute (5-h) or chronic (4-week) GC administration in vivo on 1) cAMP release by the isolated perfused dog tibia before (basal) and after the addition of synthetic bovine PTH-(l-34) [syn bPTH-(l-34)](stimulated) to the perfusate in vitro, in the presence or absence of the phosphodiesterase inhibitor 3-isobutyl-l-methyl-xanthine (IBMX; 1 mM), and 2) the percent arteriovenous difference of immunoreactive PTH across bone. Acute administration of 6 mg/kg methylprednisolone (MP) did not affect the basal release of cAMP from bone (6.9 ± 1.6 pmol/min in control us. 6.1 ± 1.2 pmol/min in MP-treated animals); however, syn bPTH-(l-34) stimulated release of cAMP was higher in the MP-treated animals (45 ±8. 1 pmol/ min) than in controls (26.8 ± 3.0 pmol/min). When IBMX was added to the perfusate, basal cAMP release was not different in control and MP-treated bone (17.2 ± 2.1 pmol/min in control us. 19.1 ±1.9 pmol/min in MP-treated bone), and syn bPTH-(1-34)-stimulated release of cAMP was equivalent in both groups. In contrast, chronic prednisone therapy lead to a decrease in both basal and PTH-stimulated release of cAMP from bone (3.1 ± 0.4 and 6.9 ± 1.6 pmolmin for basal, and 13.1 ± 1.7 and 26.8 ± 3.0 pmol/min for stimulated values, respectively). However, the percent changes from the basal levels were not different in the two groups. These results were correlated with histological studies of rib biopsies obtained from these animals, which showed evidence of osteopenia and decreased bone turnover. Neither acute nor chronic GC administration had any effect on arterio-venous differences for PTH across the bone. Thus, these studies demonstrate that 1) acute administration of MP enhances the response of bone to PTH, an effect that is not apparent in the presence of the phosphodiesterase inhibitor IBMX; and 2) chronic prednisone therapy decreased basal and PTH-stimulated cAMP release, an effect that correlated with histological evidence of decreased bone turnover.