Risedronate sodium was formulated into polylactide-co-glycolic acid microspheres for pulmonary delivery using the w/o/w double emulsion technique. Sodium chloride was used as osmogen in either the internal or external aqueous phase to surface-engineer the particles to achieve favorable properties. The prepared microspheres were characterized for the surface morphology, entrapment efficiency, in vitro release behavior, particle size, surface area, aerodynamic as well as powder flow properties. Furthermore, the safety of the drug and the selected formula were assessed by MTT viability test performed on Calu-3 cell line as well as histopathological lung tissue examination. A novel in vivo approach based on the radiolabeling of risedronate sodium with I(125) was developed in order to assess its deposition in the bones of male albino rats. The majority of the prepared microspheres exhibited high entrapment efficiency, sustained release profile up to 15 days, suitable geometric and aerodynamic particle sizes as well as good flow properties. The safety of the drug and the selected formula were proven by the high cell viability percentage of Calu-3 cells as well as the normal lung histology after intra-tracheal administration. The in vivo study showed high bone deposition for risedronate sodium following the pulmonary route, suggesting that it could be utilized as an alternative route of administration for delivery of bisphosphonates.