Biosilicate® and Bio-Oss® are two commercially available bone substitutes, however, little is known regarding their efficacy in osteoporotic conditions. The purpose of this study was to evaluate the osteogenic properties of both materials, at tissue and molecular level. Thirty-six Wistar rats were submitted to ovariectomy (OVX) for inducing osteoporotic conditions and sham surgery (SHAM) as a control. Bone defects were created in both femurs, which were filled with Biosilicate® or Bio-Oss®, and empty defects were used as control. For the healthy condition both Biosilicate® and Bio-Oss® did not improve bone formation after 4 weeks. Histomorphometric evaluation of osteoporotic bone defects with bone substitutes showed more bone formation, significant for Bio-Oss®. Molecular biological evaluation was performed by gene-expression analysis (Runx-2, ALP, OC, OPG, RANKL). The relative gene expression was increased with Biosilicate® for all genes in OVX rats and for Runx-2, ALP, OC and RANKL in SHAM rats. In contrast, with Bio-Oss®, the relative gene expression of OVX rats was similar for all three groups. For SHAM rats it was increased for Runx-2, ALP, OC and RANKL. Since both materials improved bone regeneration in osteoporotic conditions, our results suggest that bone defects in osteoporotic conditions can be efficiently treated with these two bone substitutes.