The Role of Antidiabetic Drugs in Bone Health: Assessing the Risk of Osteoporosis Subtypes and Fractures Using Mendelian Randomization

Gaorong Deng,1,2 Liping Wu,3 Shui Xiong,4 Junxin Zhou,4 Zongfang Li1,2 1Department of Biodiagnostics and Biotherapy, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China; 2Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China; 3College of Life Science, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi, People’s Republic of China; 4Department of Orthopaedics, Nanchang University Affiliated Rehabilitation Hospital, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Zongfang Li, Email [email protected]: Osteoporosis leads to decreased bone density and an increased risk of fractures, with diabetic patients being particularly vulnerable. This study aims to evaluate the effects of five common antidiabetic drugs—Metformin, GLP-1 receptor agonists, SGLT2 inhibitors, Insulin, and Gliclazide—on the risk of osteoporosis subtypes and fractures, using Mendelian Randomization (MR) to ensure result accuracy.Methods: Data from multiple Genome-Wide Association Studies (GWAS) databases were employed to assess the relationships between the use of these antidiabetic drugs and osteoporosis risk. The analysis utilized Mendelian Randomization techniques to minimize confounding and reverse causation, ensuring robust results.Results: The findings reveal that: Metformin is significantly negatively associated with osteoporosis (OR [95% CI]: 0.00936 [0.0011– 0.0806], p = 2.11× 10⁻5), indicating a potential bone-protective effect by reducing bone resorption and enhancing osteoblast activity through the activation of the AMPK pathway. GLP-1 receptor agonists are significantly positively associated with osteoporosis with pathological fractures (OR [95% CI]: 1.1247 [1.0043– 1.2594], p = 0.0420), suggesting a potential increase in fracture risk. SGLT2 inhibitors show a weak negative association with osteoporosis (OR [95% CI]: 0.8987 [0.8092– 0.9980], p = 0.0429), though the effect is minor and unstable. Gliclazide significantly increases the risk of pathological fractures (OR [95% CI]: 1.03E+08 [1.28E+02– 8.32E+12], p = 0.0395), indicating a need for caution in its use among patients at high fracture risk.Discussion: The results highlight the potential bone-protective role of Metformin, which may be suitable for patients at high fracture risk. On the other hand, the use of GLP-1 receptor agonists and Gliclazide should be carefully considered, especially in individuals with osteoporosis or at high risk of fractures. These findings emphasize the importance of personalized medication management in diabetic patients to optimize bone health.Keywords: Mendelian randomization, osteoporosis, pathological fracture, antidiabetic drugs, metformin, GLP-1 receptor agonists, SGLT2 inhibitors, gliclazide