Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis. A multiple drug regimen may be considered for several diseases to reduce the glucocorticoids (GCs) dose and to minimize their side effects. Many of these drugs as well as GCs may modulate cyclic adenosine monophosphate (cAMP) level. Accordingly, the present study aimed to investigate the possible role of cAMP in prednisolone-induced osteoporosis in rats through co-administration of drugs that modulate cAMP level as salbutamol, theophylline and propranolol. Methods: The experiments were performed on male albino Wistar rats. The effects of prednisolone (5 mg/kg, s.c. daily) and/or salbutamol (2 mg/kg, ip daily), theophylline (75 mg/kg, ip daily) and propranolol (10 mg/kg, ip daily) administered for 30 consecutive days on the skeletal system were studied. Bone mineral density (DXA), bone cAMP and turnover markers in serum were determined. Moreover, histopathological and X-ray examination were performed. Results: Prednisolone induced severe bone damage. Also salbutamol, theophylline and propranolol caused unfavorable skeletal changes when administrated alone or in combination with prednisolone. The bone cAMP was elevated by 9- folds in rats receiving prednisolone alone, resulting in severe bone damage as indicated by biochemical as well as histopathological findings. Likewise, it was elevated by 1-fold in rats concurrently administered prednisolone and theophylline compared to the negative control rats accompanied with moderate bone damage. Unpredictably, the bone cAMP increased by 4-folds in theophylline-treated rats and no histopathological alterations were observed. Conclusion: These findings confirmed that cAMP not involved in the mechanism by which prednisolone induced osteoporosis.