Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Prevents Osteopenia by Promoting Bone Formation and Suppressing Bone Resorption in Aged Ovariectomized Rats

Abstract

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal crosslinked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-kB ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

“…These positive effects of GLP-1 analogues on bone mass and architecture were confirmed in histology sections using bone histomorphometry. In contrast, GLP-1 agonists had no effect on cortical bone, also in agreement with most previous studies (36,37), although one recent paper did report a beneficial effect of LIR on cortical bone of T2DM rats that was associated with increases in cortical thickness and cortical area (36). This may have been the result of the higher dose of LIR used in this study and also the rats received the drug at week 2 of age, a time of high bone growth.…”

“…The demonstration that GLP-1 agonists improve trabecular bone mass in ovariectomised mice, confirms previous studies that have reported osteogenic effects of GLP-1 agonist treatment in normal, IR, T2DM and ovariectomised rodent models (32)(33)(34)(35)(36)(37). The novelty of our study is that we have investigated the longer term skeletal effect of LIR and Ex-4 in OVX mice, having administered these drugs daily for 4 weeks, and that we examined bone architecture together with bone cellular activity in situ.…”

“…This may have been the result of the higher dose of LIR used in this study and also the rats received the drug at week 2 of age, a time of high bone growth. Ma et al (37) found a greater effect of Ex-4 on trabecular bone than ours at a dose of 3 μg/kg/d, but the rats received the treatment for 16 weeks.…”

“…Silva and Gibson (55) have shown that it is more important to maintain trabecular number than thickness to preserve bone mass, indicating that drugs, such as GLP-1 agonists, which restore the number of trabeculae in bone, could be advantageous in individuals predisposed towards osteoporosis. Our results also indicate an improvement in trabecular architecture with GLP-1 agonist treatment and a normalising effect upon the OVX-impaired connectivity and anisotropy factors (Tb.Pf and SMI), an effect that has also been observed in short term studies with GLP-1 agonists in T2DM and IR (33,37). These positive effects of GLP-1 analogues on bone mass and architecture were confirmed in histology sections using bone histomorphometry.…”

“…3 days' infusion or daily injections of GLP-1 agonist for 3 days was shown to be anabolic in bone of normal, insulin-resistant (IR) and T2DM rodent models (32)(33)(34)(35)(36). In addition, it was recently demonstrated that long-term treatment with the GLP-1 agonist Ex-4 prevents osteopenia in aged ovariectomised rats, a model of bone loss that mimics osteoporosis (37). It is, however, unclear whether the mechanism of action of GLP-1 agonists in bone is direct through a functional GLP-1R expressed by bone cells or indirect via an increase in calcitonin production.…”