We prepared an injectable depot system for the long-term delivery of alendronate using a solid/water/oil/water multiple emulsion technique with poly(lactic-co-glycolic acid) as a carrier. The microparticles were spherical with smooth surfaces, ranging from 20 to 70 μm in size. The microspheres (ALD-HA-RG504H-MC70) were optimally prepared by introducing a viscous material (hyaluronic acid) and a co-solvent system in the inner aqueous and oil phases, respectively, and showed a significantly increased drug encapsulation efficacy (>70%); the initial burst release was <10% after 1 day. In vitro drug release from ALD-HA-RG504H-MC70 followed zero-order kinetics for approximately 4 weeks and the alendronate plasma level was maintained for more than 1 month after intramuscular injection in rabbits. The ovariectomized (OVX) rats with ALD-HA-RG504H-MC70 injected intramuscularly (0.9 mg alendronate/kg/4 weeks) had 112% and 482% increased bone mineral density and trabecular area in the tibia than the OVX controls, respectively, and showed significant improvements in trabecular microarchitecture and bone strength. Furthermore, the major biomarkers of bone turnover revealed that ALD-HA-RG504H-MC70 suppressed effectively the progression of osteoporosis and facilitated new bone formation. Therefore, this sustained release depot system may improve patient compliance and therapeutic efficacy by reducing dose amounts and frequency with minimal adverse reactions.