In the present study, two different PLGA-Alginate scaffolds, a hydrogel (HY) and a solid sponge (SS), were developed for β-estradiol and BMP-2 sustained delivery for bone regeneration in osteoporosis. β-Estradiol and BMP-2 were encapsulated in PLGA and PLGA-Alginate microspheres respectively. Scaffolds were characterized in vitro in terms of porosity, water uptake, release rate and HY rheological properties. BMP-2 release profiles were also analysed in vivo. The bone regeneration induced by both HY and SS was evaluated using a critical-sized bone defect in an osteoporotic (OP) rat model. Compared to HY, SS presented 30% higher porosity, more than double water absorption capacity and almost negligible mass loss compared to the 40% of HY. Both systems were flexible and fit well the defect shape, however, HY has the advantage of being injectable. Despite both delivery systems had similar composition and release profile, bone repair was around 30% higher with SS than with HY, possibly due to its longer residence time at the defect site. The incorporation of mesenchymal stem cells obtained from OP rats did not result in any improvement or synergistic effect on bone repair.