This study investigated the role of the prostaglandin (PG) pathway in locally applied, simvastatin-induced oral bone growth. The possibility of enhancing long-term bone augmentation with an alendronate-based carrier was initiated. Mandibles of 44 mature female rats were treated bilaterally with the following combinations: 2 mg of simvastatin in ethanol (SIM-EtOH), EtOH, 2 mg of simvastatin acid complexed with alendronate-beta-cyclodextrin conjugate (SIM/ALN-CD), ALN-CD, or ALN. Bone wash technology (injection of PBS and re-collection by suction) was used to sample injection sites at baseline (day 0), and 3, 7, 14, and 21 days post-treatment. After 21-24 or 48 days, histomorphometric analysis was done. The amount of PGE(2) in bone wash fluid was measured by ELISA, normalized by total protein, and compared between high and low bone growth groups (ANOVA) and correlated with subsequent bone histology at 21 days (Spearman). SIM-stimulated PGE(2) synthase and EP4 receptor mRNA in murine osteoblast and fibroblast cell lines were evaluated with real-time PCR. Single injections of 2 mg of SIM-EtOH induced significantly more new bone than control side after 21 days. PGE(2)/protein ratios peaked at day 7 and were correlated with the subsequent 21-day new bone width. The correlations at day 14 between PGE(2) and new bone width changed to a negative relationship in the test group. SIM-stimulated osteoblasts expressed increased mRNA levels of PGE receptor EP4, while SIM activated PGE synthesis in fibroblasts. SIM/ALN-CD tended to preserve bone long-term. Findings suggest that PGE pathway activation and higher levels of PGE(2) during the first week following SIM-induced bone growth are desirable, and alendronate-beta-cyclodextrin conjugates not only act as tissue-specific carriers, but preserve new bone.