The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment

Abstract

Metformin is a widely-used anti-diabetic drug in patients with type 2 diabetic mellitus (T2DM) due to its safety and efficacy in clinical. The classic effect of metformin on lowering blood glucose levels is to inhibit liver gluconeogenesis that reduces glucose production as well as increases peripheral glucose utilization. However, the factors such as hyperglycemia, insulin deficiency, reduced serum levels of insulin-like growth factor-1 (IGF-1) and osteocalcin, accumulation of advanced glycation end products (AGEs), especially in collagen, microangiopathy, and inflammation reduced bone quality in diabetic patients. However, hyperglycemia, insulin deficiency, reduced levels of insulin-like growth factor-1 (IGF-1) and osteocalcin in serum, accumulation of advanced glycation end products (AGEs) in collagen, microangiopathy, and inflammation, reduce bone quality in diabetic patients. Furthermore, the imbalance of AGE/RAGE results in bone fragility via attenuating osteogenesis. Thus, adequate glycemic control by medical intervention is necessary to prevent bone tissue alterations in diabetic patients. Metformin mainly activates adenosine 5′ -monophosphate-activated protein kinase (AMPK), and inhibits mitochondrial respiratory chain complex I in bone metabolism. In addition, metformin increases the expression of transcription factor runt-related transcription factor2 (RUNX2) and Sirtuin protein to regulate related gene expression in bone formation. Until now, there are a lot of preclinical or clinical findings on the application of metformin to promote bone repair. Taken together, metformin is considered as a potential medication for adjuvant therapy in bone metabolic disorders further to its antidiabetic effect. Taken together, as a conventional hypoglycemia drug with multifaceted effects, metformin has been considered a potential adjuvant drug for the treatment of bone metabolic disorders.

Skeletal Effects of a Prolonged Oral Metformin Treatment in Adult Wistar Rats

“…Other investigators also found no differences in BMD and/or BMC in the whole skeleton, tibiae and femurs of rodents with experimental MetS [13,44]. In the same line, several researchers have been unable to demonstrate changes induced by fructose-rich or high fat/high fructose (HF/HF) diets in dynamic (MS/BS, MAR, BFR, cortical bone area, and cortical thickness) and/or static (BV/TV Tb.N, Tb.Sp, Tb.Th, Ob.S/BS, Oc.S/BS) histomorphometric parameters [13,15,43],…”

“…Other investigators also found no differences in BMD and/or BMC in the whole skeleton, tibiae, and femurs of rodents with experimental MetS 13 44 . In the same line, several researchers have been unable to demonstrate changes induced by fructose-rich or high fat/high fructose (HF/HF) diets in dynamic (MS/BS, MAR, BFR, cortical bone area, and cortical thickness) and/or static (BV/TV Tb.N, Tb.Sp, Tb.Th, Ob.S/BS, Oc.S/BS) histomorphometric parameters 13 15 43 , or in bone biomechanical properties 44 . Thus, given our present results and those of other investigators, it is suggested that rodent models of fructose-induced MetS are not associated with significant alterations of bone tissue.…”

“…The insulin-sensitizer metformin (MET) is frequently prescribed to lessen the metabolic abnormalities in patients with type 2 diabetes mellitus and/or MetS. Interestingly, glycemic control by MET was suggested to enhance bone formation [14,15]. Indeed, several in vitro studies reported positive effects of MET in BMSC and osteoblastic cells [16,17].…”

“…Interestingly, glycemic control by MET was suggested to enhance bone formation [14,15]. Indeed, several in vitro studies reported positive effects of MET in BMSC and osteoblastic cells [16,17].…”

Association of metformin use with fracture risk in type 2 diabetes: A systematic review and meta-analysis of observational studies

“…It affects several aging-related processes, including bone deterioration, by suppressing cellular senescence and chronic inflammation and promoting autophagy ( 27 , 28 ). Previous studies demonstrated that metformin directly promoted osteoblastic differentiation of different kinds of stem cells (including umbilical cord mesenchymal stem cells ( 29 ), adipose-derived stem cells ( 30 ), dental pulp stem cells ( 31 ), and bone marrow derived mesenchymal stem cells ( 32 ), enhanced the anabolic action of the bone (including beneficial effects on bone microarchitecture, bone mineral density, and bone turnover markers), and improved bone quality in patients with T2DM ( 33 – 36 ). Furthermore, a previous report suggested a potential benefit of metformin in contributing to decreased bone cancer risk in T2DM patients ( 37 ).…”