A growing body of evidence indicates that treatment with glucagon-like peptide-1 (GLP-1) receptor agonists can be beneficial for patients with osteoporosis. However, the underlying mechanism by which GLP-1 receptor agonists improve osteoporosis remains unclear. In this study, we assessed the anti osteoporosis effects of Exendin-4, a highly potent GLP-1 receptor agonist, using a rat senescent osteoblast model. We found that Exendin-4 improved proliferation of senescent osteoblasts, as indicated by MTT assay and ALP activity detection. RT-qPCR revealed that Exendin-4 up-regulated the expression of bone metabolism genes (OPG, RANKL, BGP) and down-regulated the expression of aging-related genes (p16, p21, p53). Meanwhile, we observed a sustained increase in IGF-1 receptor (IGF-1R) expression, and not GLP-1 receptor (GLP-1R) expression, in senescent osteoblasts treated with Exendin-4. Furthermore, intervention with Exendin-4 in senescent osteoblasts increased IGF-1, p-PI3K, and p-Akt protein levels, as shown by western blot analysis. Finally, downregulation of IGF-1 by RNAi inhibited the anti-osteoporosis effects of Exendin-4, which is associated with the IGF-1/PI3K/Akt signaling pathway. In summary, these results indicate that the GLP-1 receptor agonist Exendin-4 promotes proliferation of senescent osteoblasts by up-regulating IGF-1R expression and activating the IGF-1/PI3K/Akt signaling pathway, thereby preventing senile osteoporosis. (C) 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).