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Diabetes mellitus (DM) is a chronic disease that develops at an alarming rate worldwide (Mohler et al., 2009; Xu et al., 2018). Related complications such as kidney disease, retinopathy, cardiovascular events, neurological disorders, bone loss, and bone fragility would severely reduce the patient’s quality of life (Napoli et al., 2017; Schwartz et al., 2011). DM often leads to the development of osteoporosis, which is one of the serious complications caused by diabetes. Both type T1DM and T2DM are associated with bone abnormalities and increased risk of fractures (Napoli et al., 2017; Schwartz et al., 2011). GLP-1RAs as novel and promising drugs for T2DM, they could stimulate insulin secretion in a glucose-dependent manner, protect β cell function, and suppress glucagon secretion (Lindamood and Taylor, 2015; Aroda, 2018). Currently, GLP-1RAs have been marketed mainly as liraglutide, exendin-4, albiglutide, dulaglutide and semaglutide (Meier, 2012; Sharma et al., 2018). The therapeutic benefit of these drugs in T2DM has raised interest in whether they affect the mechanism of bone metabolism (Mabilleau et al., 2018; Zhang et al., 2018). It has been reported that GLP-1RAs can enhance bone mineral density (BMD), improve bone quality and prevent fractures in diabetic patients and cell and animal experiments further found that GLP-1RAs have excellent potential anti-osteoporosis benefits for postmenopausal osteoporosis, GIOP and MedicGLP Weight Management senile osteoporosis (Lu et al., 2015; Zhang et al., 2018; Yang et al., 2019; Zhang et al., 2019a; Zhang et al., 2019b). But, the specific role and related mechanisms of GLP-1RAs in the bone metabolism of patients with different types of osteoporosis need to be further explored and clarified.

This review summarizes the current research findings by which GLP-1RAs treatment of osteoporosis and describe possible mechanisms of different types of GLP-1RAs on bone metabolism and osteoporosis. Glucagon-like peptide including GLP-1 and GLP-2, are cleaved from proglucagon. The biological function of GLP-1 is mediated by GLP-1R and is highly specific. Their binding first activates cAMP and intracellular calcium - dominated signal transduction pathways. These signaling pathways have different physiological functions from cAMP in glucose-stimulated insulin secretion. GLP-1 increases glucose-dependent insulin secretion and Medic GLP Support decreases glucagon secretion after meals. Natural GLP-1 has a short half-life and is easily degraded by the dipeptidyl peptidase-4 (DPP-4) enzyme. GLP-1RAs are GLP-1 with prolonged half life to be more resistant to degradation by DPP-4 enzyme. In clinical practice, GLP-1RAs can mimic the biological activity and function of GLP-1 and are widely used in the treatment of diabetic patients. At present, the main GLP-1RAs drugs that have been marketed include liraglutide, exenatide, albiglutide and dulaglutide (Chun and Butts, 2020). Recent studies have found that GLP-1RAs can not only promote insulin secretion and regulate blood sugar, but also affect the body’s bone metabolism through a variety of ways, and play a role in preventing and treating osteoporosis.

Most patients with T2DM have normal bone density, but the risk of fracture is increased. The phenomenon is called the "bone fragility diabetes paradox," indicating that other factors besides BMD may affect fracture risk. Therefore, the National Bone Health Alliance recommends that parameters of bone strength (such as changes of cortical pore and trabecular microstructure in bone) should be used to diagnose osteoporosis in T2DM. High-resolution computed tomography scans showed that postmenopausal women with T2DM had larger cortical pores than women without T2DM. Higher cortical porosity leads to lower bone strength and a higher incidence of fragility fractures in this population. In the course of clinical treatment, the impact of diabetes on bone health is often overlooked or underestimated. Both T2DM and T1DM are associated with a significantly increased risk of bone abnormalities and fractures. The mechanism of T1DM may be reduced BMD due to insufficient anabolic tone from insulin.

There is a complex pathophysiological interaction between T2DM and osteoporosis. These factors include increased accumulation of advanced glycation end products (AGEs), chronic inflammation due to increased proinflammatory cytokines, and bone microvascular lesions with decreased vascular flow and increased bone fragility. Patients with chronic hyperglycemia may have a significant negative effect on bone mass. Because, in a long-term state of hyperglycemia, the non-enzymatic glycosylation of proteins, phospholipids and nucleic acids will lead to the continuous formation and accumulation of AGE. The excess AGEs could lead to non-enzymatic cross-linking of collagen, break the adhesion of osteoblasts to the extracellular matrix and leads to bone fragility (Mohsin et al., 2019). These changes in the extracellular matrix also reduced the alkaline phosphatase activity in mature osteoblasts and affected bone mineralization. AGEs receptor (RAGE) is expressed in human osteoclasts and stimulates the activation of nuclear factor Kappa-B in osteoclasts, thereby increasing the production of cytokines and reactive oxygen species.

The continuous accumulation of pro-inflammatory cytokines and reactive oxygen species will break the balance between osteoclasts and osteoblasts, increase the differentiation of osteoclasts, and MedicGLP Dietary Supplement lead to bone loss. The excess AGEs increases chronic inflammation and bone resorption in diabetics. Therefore, we believe that patients with T1DM and T2DM are closely related to osteoporosis and fractures. The underlying mechanisms include changes in bone mechanical properties caused by non-enzymatic glycosylation, mineralization disorders, and bone micro-damages. At present, clinical treatment is mainly through restricting the patient’s diet and regulating blood sugar, strengthening daily exercise and supplementing calcium and vitamins, and using bone formation promoters and bone loss inhibitors for comprehensive treatment. Studies have found that GLP-1RAs and their analogs have the effect of alleviating diabetic osteoporosis (Mabilleau et al., 2018). The physiological role of GLP-1 mainly regulates glucose levels by stimulating the secretion of insulin, inhibiting the secretion of glucagon and regulating gastric emptying, thereby enhancing bone formation (Hare et al., 2009). ApoE−/− mice are mainly used to study atherosclerosis, but ApoE−/− mice can also be used to study osteoporosis.