An increase in the prevalence of diabetes, especially type 2 diabetes mellitus has been witnessed over the past few decades. Besides cardiomyopathy and nephropathy, risk of mortality and morbidity is also higher due to skeletal abnormalities and bone fractures in diabetic population. This could be attributed to the fact that patients with diabetes mellitus have lower bone quality in contrast to their non-diabetic counterparts, mainly due to hyperglycemia, toxic effects of advanced glycosylation end-products (AGEs) on bone tissue, and impaired bone microvascular system. AGEs may also underline the development of osteoarthritis and further osteoporosis.¹ Despite being two separate clinical entities, diabetes mellitus and osteoporosis are likely to occur together.² Patients with type 2 diabetes mellitus are also at higher risk of fragility fractures, which could be mostly due to a combination of factors, including greater risk of falling, regional osteopenia, and impaired bone quality.³ Therefore, achievement of optimal glycemic control, while minimizing the risk of hypoglycemia and avoiding medications with proven negative effect on bone metabolism, combined with osteoporosis treatment are of paramount importance in people with diabetes.^4,5 With regard to this, researchers are actively looking for potential prevention and treatment of osteoporosis in this set of patients.²

Unlike thiazolidinediones and insulin that may have a negative effect on bone health, metformin, a leading drug used to manage type 2 diabetes has shown osteogenic effects.^2,4,6 In addition, studies have shown that deterioration of bone microarchitecture caused by insulin deficiency can be prevented by the intake of metformin.² It may also protect against fragility fractures.³ In a Danish retrospective case-control study, metformin was shown to remarkably reduce the fracture risk.⁵

It is believed that metformin modulates its effect through the adenosine monophosphate-activated protein kinase (AMPK) pathway. According to recent studies, AMPK is a vital mediator of homeostasis, involved in glucose metabolism as well as in osteogenesis. AMPK can directly influence the production of mature and good quality bone by reducing osteoclasts, increasing osteoblast formation, and enhancing bone mineral deposition. As an activator of AMPK, metformin also upregulates osteogenesis. Furthermore, metformin can influence osteogenesis through a non-AMPK pathway, such as the fructose 1-6 phosphatase pathway, by reducing glucose levels.^1,2,7

Thus, metformin, a widely used oral hypoglycemic drug, has been shown to improve bone quality and reduce the risk of fractures in patients with diabetes, besides improving glycemic control and insulin sensitivity.¹

References

1. Bahrambeigi S, Yousefi B, Rahimi M, et al. Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed Pharmacother. 2019 Jan;109:1593-1601.
2. Aung M, Amin S, Gulraiz A, et al. The Future of Metformin in the Prevention of Diabetes-Related Osteoporosis. Cureus. 2020;12(9):e10412.
3. Gilbert MP, Pratley RE. The impact of diabetes and diabetes medications on bone health. Endocr Rev. 2015 Apr;36(2):194-213.
4. Montagnani A, Gonnelli S, Alessandri M, et al. Osteoporosis and risk of fracture in patients with diabetes: an update. Aging ClinExp Res. 2011 Apr;23(2):84-90.
5. Guja C, Guja L, Miulescu RD. Effect of type 2 diabetes medications on fracture risk. Ann Transl Med. 2019;7(20):580.
6. Li X, Guo Y, Yan W, et al. Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal. Plos One. 2015;10(12):e0146152.
7. Jiating L, Buyun J, Yinchang Z. Role of Metformin on Osteoblast Differentiation in Type 2 Diabetes. Biomed Res Int. 2019;2019:9203934.