Calcium phosphate cements (CPCs) including poly(D,L-lactic-co-glycolic) acid (PLGA) microparticles are promising candidates for bone regenerative applications. Previous studies with CPC/PLGA demonstrated that the material is non-toxic, biocompatible and osteoconductive. However, the outcome of these studies was based on healthy individuals and consequently does not provide information on bone substitute material performance in a compromised situation, such as osteoporosis. Therefore, this study comparatively evaluated the performance of injectable CPC/PLGA in healthy (SHAM) and osteoporotic rats (OVX) using a rat femoral condyle defect with implantation periods of 4 and 12 weeks. It was hypothesized that in OVX rats the degradation of CPC/PLGA would increase due to a higher osteoclastic activity present in osteoporotic animals and that the obtained space would be rapidly filled with newly formed bone. The results revealed an accelerated degradation of the used CPC/PLGA in osteoporotic animals, but bone formation was less compared to that in healthy animals at 4 and 12 weeks after implantation. In addition, after 4 weeks, the amount of newly formed bone under osteoporotic conditions was less in the femoral condyle defect compared to that present in a non-defect, osteoporotic control femoral condyle, but equal after 12 weeks. On the other hand, in healthy animals, the amount of newly formed bone in the femoral condyle defect was equal to that present in a non-defect control femoral condyle at 4 weeks, while higher after 12 weeks. This indicates that bone regeneration at a defect site under osteoporotic conditions is slower, but can reach native amounts after longer time periods. Consequently, bone regenerative treatments under osteoporotic conditions seem to require additional empowerment of bone substitute materials.