The aim of the present study was to develop directly compressed compacts for mucoadhesive delivery of pamidronate disodium for the treatment of osteoporosis in the rat model induced by methylprednisolone. A blend of HPMC-4KM and thiolated chitosan was used as the biodegradable polymers for the formulation of mucoadhesive compacts. The drug-polymer characterization was done by different analytical techniques like FTIR, DSC, and XRD. Biochemical analysis, histopathology and SEM analysis of the trabecular region of the femur were done to confirm the induction and treatment of osteoporosis. The analytical characterization revealed the formation of polyelectrolyte complexes between the drug and polymer due to high compressional forces. Formulation T2 with thiolated chitosan/HPMC-4KM ratio of 0.5/1 showed superior swelling, mucoadhesive properties, and better drug release and was investigated for in vivo study. The compact formulation improved the serum biomarkers level and bone microarchitectural properties in the osteoporotic rats as revealed by histopathology and SEM analysis. The results indicated the potential use of thiolated polymer based mucoadhesive compacts as a rational tactic for osteoporosis therapy.