AMPK pathway is the main distinguished mechanism of action for metformin. • AMPK induces osteogenesis and inhibits adipogenesis of bone marrow stem cells. • Metformin increases bone mass and reduces fracture risk in clinical studies.
Does metformin increase bone density and mineralization?
It has also been reported that metformin can increase bone density and mineralization in alveolar bones through osteoblast differentiation in ligature-induced periodontitis in rats [ 134 ].
What is the mechanism of action of metformin?
AMPK pathway is the main distinguished mechanism of action for metformin. AMPK induces osteogenesis and inhibits adipogenesis of bone marrow stem cells. Metformin increases bone mass and reduces fracture risk in clinical studies. Metformin can be considered as an adjuvant in bone disorders and bone cancers.
Does metformin suppress RANKL signaling in osteoclasts?
In osteoclasts, metformin can suppress RANKL signaling and it can increase osteoprotegrin expression by osteoblasts leading to reduced osteoclasts number and prevention of bone loss [ 130, 131 ].
How do osteoclasts dissolve bone mineral?
Osteoclasts dissolve bone mineral by massive acid secretion and secrete specialized proteinases that degrade the organic matrix, mainly type I collagen, in this acidic milieu.
What does metformin do for bones?
Metformin increases bone mass and reduces fracture risk in clinical studies. Metformin can be considered as an adjuvant in bone disorders and bone cancers.
Does metformin slow bone healing?
The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing.
Does metformin cause decreased bone density?
For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women. In contrast, metformin and sulfonylureas do not appear to have a negative effect on bone health and may, in fact, protect against fragility fracture.
Can metformin help with osteoporosis?
Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism.
What helps broken bones heal faster?
The three key steps to faster bone healing are: Alignment of the broken bone fragments. Stability and support at the fracture site through immobilization. Healthy lifestyle choices that promote healing.
How does type 2 diabetes affect fracture healing?
Recently, there has been increasing evidence suggesting that T2DM also adversely affects the skeletal system, causing detrimental bone effects such as bone quality deterioration, loss of bone strength, increased fracture risk, and impaired bone healing.
Does metformin cause osteopenia?
Abstract. Osteoporosis is the most important metabolic bone disease in patients with diabetes mellitus. Several studies have documented that metformin is osteogenic in vitro. In contrast, others showed no effect of metformin on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells.
What happens during bone deposition?
Bone deposition is the process whereby new bone is formed. To understand bone remodeling, and the factors that lead to pathological problems with bone, you need to know about three cell types found in bone. Osteoblasts are the cells involved in bone deposition, the formation of new bone.
Which diabetic medication causes osteoporosis?
One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis.
What are the side effects of metformin?
Side effects of metforminFeeling sick (nausea) Take metformin with food to reduce the chances of feeling sick. ... Being sick (vomiting) Take small, frequent sips of water or squash to avoid dehydration. ... Diarrhoea. ... Stomach ache. ... Loss of appetite. ... A metallic taste in the mouth.
Does metformin cause bone pain?
Conclusions: People with diabetes taking metformin were less likely to report back, knee, neck/shoulder and multisite musculoskeletal pain than those not taking metformin. Therefore, when treating these patients, clinicians should be aware that metformin may contribute to fewer reports of musculoskeletal pain.
Can metformin cause bowel inflammation?
Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.
Does metformin cause bone pain?
Conclusions: People with diabetes taking metformin were less likely to report back, knee, neck/shoulder and multisite musculoskeletal pain than those not taking metformin. Therefore, when treating these patients, clinicians should be aware that metformin may contribute to fewer reports of musculoskeletal pain.
Which diabetic medication causes osteoporosis?
One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis.
What are the side effects of metformin?
Side effects of metforminFeeling sick (nausea) Take metformin with food to reduce the chances of feeling sick. ... Being sick (vomiting) Take small, frequent sips of water or squash to avoid dehydration. ... Diarrhoea. ... Stomach ache. ... Loss of appetite. ... A metallic taste in the mouth.
Does type 2 diabetes cause bone loss?
Did you know that diabetes can also affect your bone health? Individuals with Type 1 diabetes (the loss of insulin produced by the pancreas) or Type 2 diabetes (the body's inability to use insulin and a slow loss of one's ability to make insulin) have an increased risk of bone fractures and osteoporosis.
What is the role of AMPK in bone formation?
In last decade, AMPK has been distinguished to play an important role in regulation of energy homeostasis in cells and it is an essential mediator for many hormones affecting metabolism of protein, fat and glucose [ [71], [72], [73], [74]] ( Fig. 1 ). AMPK activation depends on AMP/ATP ratio and upon activation; it turns off anabolic pathways and switches on catabolic pathways within the cell [ [75], [76], [77] ]. In fact there is two probable mechanisms for activation of AMPK: a) enhanced AMP/ATP ratio and b) activation by signaling and regulatory subunit of AMPK [ 9 ]. In the process of signaling activation there are three kinase/phosphatase enzymes (LKB1, CaMKKb and TAK1) that may have regulatory effects on AMPK [ [78], [79], [80] ]. AMPK has three subunits (α, β, γ) that can be activated by AMP adherence to α subunit [ 81 ]. In general, α, β and γ subunits of AMPK play an important role in the type and speed of AMPK regulation [ 82, 83 ]. There are α1, α2, β1, β2, γ1, γ2 and γ3 subunits encoded by 7 genes forming 12 possible AMPK heterotrimers in different regulations [ 84 ]. Catalytic process is regulated by α subunit. β subunit not only has glycogen binding domain, but also it can bridle α and γ subunits by tethering domain, and γ subunit is responsible for regulatory nucleotides binding [ 80, 85 ]. Energy production and catabolic pathways promotion by AMPK generates energy and ATP to keep normal cell function and also it can up-regulate transcription of glucose transporter 4 (GLUT4) genes [ 86, 87 ]. In fact, as an important phenomenon, AMPK restricts energy consumption to ensure cell survival. In other words, AMPK rations energy in cell and for this purpose, it inhibits protein synthesis and cell growth and also it adjusts cell cycle arrest through down-regulation of mammalian target of rapamycin (mTOR), which is hyper-activated in most tumor cells [ [88], [89], [90], [91] ]. The regulation of metabolic pathways by AMPK occurs by phosphorylating metabolic enzymes involved in glucose, glycogen and lipid metabolisms [ [92], [93], [94], [95], [96], [97], [98] ]. A study has reported that AMPK can stimulate osteogenesis in MC3T3-E1 cells and suppress adipogenesis in 3T3-L1 cells via AMPK-Gfi1-OPN axis pathway [ 99 ]. Adipocytes and osteoblasts have common cell progenitors known as mesenchymal stromal cells (MSC) or bone marrow stromal cells (BMSC). Regulation of Runx2 and a newly discovered pathway, Wnt/b-catenin, by AMPK can differentiate MSCs into osteoblasts (osteoblastogenesis), while, expression of PPARγ-2 suppresses osteoblast differentiation and make MSCs differentiate into adipocytes [ 70, 100, 101] ( Fig. 2 ). PPARγ-1 isoform can establish osteoclastogenesis and bone resorption by increasing receptor activator of nuclear factor kappa-B ligand (RANKL) and c-FOS signaling [ 15, 102 ]. Interestingly, AMPK decreases adipogenesis in vitro by b-catenin phosphorylation and PPARγ suppression [ 103 ]. Furthermore, the activity of PPARγ can be modified directly by AMPK via phosphorylation [ 104 ]. Activation of AMPK reduces bone resorption via suppression of the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) [ 105, 106 ]. Another study has suggested that AMPK can suppress RANKL-induced osteoclast formation [ 107 ]. It has been shown that osteoclasts are derived from multinucleated giant cells (monocyte-macrophage lineages) in the presence of two cytokines, M-CSF and RANKL [ 108 ]. Mevalonate pathway which plays a role in pernylation of regulatory proteins like Ras and Rho GTPase, has a negative influence on bone tissue and it has been reported that AMPK can adjust mevalonate pathway through suppression of HMG-COA reductase [ 109, 110 ].
How many people have diabetes?
World health organization has reported that about 422 million people all over the world suffer from diabetes [ 1 ]. Diabetes mellitus (DM) is a metabolic disorder characterized by high blood glucose that affects many organs in the body. Ability of insulin production by pancreas in type 1 diabetes mellitus (T1DM) and usage of insulin and its receptors in type 2 diabetes mellitus (T2DM) are demolished [ 2, 3 ]. Although, patients with T1DM are at higher risk of bone fractures due to low bone mineral density (BMD), there is an increased incidence of fractures in T2DM patients despite high body mass index (BMI) and normal or even high BMD [ 4 ]. Several factors may lead to this fact including renal failure, antidiabetic drugs, and increased prevalence of falls [ 5 ]. Previous studies have investigated the biochemical bone turnover markers in T2DM patients and have reported lower bone formation markers in these patients [ 6 ]. Furthermore, in vitro studies have revealed that hyperglycemic conditions leads to adipogenic differentiation rather than osteogenesis as well as impaired growth and enhanced apoptosis in osteoblasts [ 7 ]. T2DM is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance [ 8 ], but the exact mechanism illustrating their effects on bone metabolism is not clear. However, it seems logical that antidiabetic medications and glycemic control may have beneficial effects in bone tissue. Antidiabetic medications mainly include insulin therapy in T1DM and hyperglycemic correction and insulin sensitization in T2DM by oral antidiabetic drugs (metformin, thiazolidinediones, and sulfonylureas) [ 9 ]. Insulin therapy in T1DM patients have been shown to increase bone mass possibly by direct anabolic effects of insulin on bone metabolism [ 3, 10 ], although, there are some reports about the association of insulin treatment with risk of bone fractures [ 11 ]. Thiazolidinediones (TZDs) are a class of antidiabetic agents such as rosiglitazone and troglitazone that exert their effects by activating peroxisome proliferator-activated receptor γ (PPAR γ). Despite their beneficial effects in insulin sensitizing and diabetes glycemic control, clinical and epidemiological studies have shown increased fracture risk in patients receiving TZDs, particularly in women [ 12, 13 ]. The exact mechanism for this adverse effect on bone is not clear, but one reason is the negative effect of PPARγ activation on bone remodeling. Activation of PPARγ by TZDs stimulates the differentiation of precursor mesenchymal stem cells (MSCs) into adipocyte lineage, rather than osteoblast formation. Therefore, TZDs increase the risk of fractures while they enhance insulin sensitivity [ 14, 15 ]. On the other hand, metformin an antidiabetic drug belonging to bigunide compounds have shown to shift the progenitor cells into osteoblasts [ 16 ]. The antidiabetic effects of metformin occurs by stimulation of AMP activated protein kinase (AMPK) as a result of blocking the mitochondrial respiratory chain and enhanced AMP/ATP ratio [ 9 ]. Metformin has direct osteogenic effects on bone through AMPK and Runt related transcription factor 2 (Runx2) and indirect effects by hyperglycemic correction [ 16 ]. In this study, we will review and discuss the molecules linking diabetes and bone metabolism, molecular mechanisms of metformin in bone formation, and preclinical and clinical application of metformin in various bone disorders and malignancies.
What is the mechanism of action of metformin?
AMPK pathway is the main distinguished mechanism of action for metformin. AMPK induces osteogenesis and inhibits adipogenesis of bone marrow stem cells. Metformin increases bone mass and reduces fracture risk in clinical studies. Metformin can be considered as an adjuvant in bone disorders and bone cancers.
How do sulfonylureas work?
The main defined sulfonylureas mechanism of action in the β-cells plasma membrane is by occupation of ATP-sensitive K-channels leading to insulin release [ 173 ]. Second generation sulfonylureas such as glimepiride and glibenclamide are more potent than the older ones [ 174 ]. To the best of our knowledge there is no report on beneficial effect of sulfonylureas on bone tissue except a report about positive indirect effect of sulfonylureas on bone tissue [ 135 ]. As we know this class of drugs act through insulin release and insulin is distinguished as a bone anabolic factor which acts through IRS signaling and glucose uptake regulation. Animal models indicated that in the lack of IRS genes, osteopenia and reduction in osteoblast/osteoclast function and impaired bone turnover would be more probable [ 175, 176 ]. Insulinopenia in T1DM impairs osteoblast function and also bone formation markers like osteocalcin and procollagen type I will decrease due to insulinopenia [ 177 ]. Insulin therapy in diabetic patients can prevent osteopenia and osteoporosis [ 178 ].
What are the diseases that affect bone?
Bones can be affected by many diseases like diabetes, chronic liver diseases, chronic kidney diseases, malnutrition, gastrointestinal disorders, metastatic cancers and metabolic disorders [ [117], [118], [119] ]. As discussed above diabetic patients are at higher risk of bone fractures and thus it seems that antidiabetic medications may have beneficial effects in bone disorders. Standard treatment for DM includes insulin therapy, biguanides (metformin), thiazolidinediones (pioglitazone, rosiglitazone, troglitazone), sulfonylureas (glibanclimide, glimepiride) and DPP-4 inhibitors (sitagliptin, vildagliptin).
Is T1DM a bone fracture?
Although, patients with T1DM are at higher risk of bone fractures due to low bone mineral density (BMD ), there is an increased incidence of fractures in T2DM patients despite high body mass index (BMI) and normal or even high BMD [ 4 ].
How many people die from bone metastasis?
About 350,000 people in the USA die each year from bone metastasis of breast, prostate and lung cancers and interestingly the bulk of tumorous cells can be found in bones at the death time. In addition, the incidence of metastasis to bone increases if patients with breast or prostate cancers live more than 1 year.
When was metformin first used?
See in References. ], was introduced as a medication for type 2 diabetes (T2D) in 1957. As the first-line oral antihyperglycemic agent, metformin is recommended in all stages of either monotherapy or the therapy combined with other oral antihyperglycemic drugs and insulin [ 1.
Does metformin affect bone?
Recently, the effect of metformin on bone metabolism has been analyzed. Metformin relies on organic cation transporters (OCT1), a polyspecific cell membrane of the solute carrier 22A (SLC22A) gene family, to facilitate its intracellular uptake and action on complex I of the respiratory chain of mitochondria. These changes activate the cellular energy sensor AMP-activated protein kinase (AMPK). Thus, the increased cellular AMP/ATP ratio causes a dramatic and progressive activation of insulin and lysosomes, resulting in a decrease in intracellular glucose level, which promotes osteoblast proliferation and differentiation. AMPK also phosphorylates runt-related transcription factor 2 (Runx2) at S118, the lineage-specific transcriptional regulators, to promote osteogenesis. Metformin phosphorylates extracellular signal-regulated kinase (ERK), stimulates endothelial and inducible nitric oxide synthases (e/iNOS), inhibits the GSK3 β /Wnt/ β -catenin pathway, and promotes osteogenic differentiation of osteoblasts. The effect of metformin on hyperglycemia decreases intracellular reactive oxygen species (ROS) and advanced glycation end-products (AGEs) in collagen, and reduced serum levels of insulin-like growth factors (IGF-1) were beneficial for bone formation. Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism. The aim of this review was to elucidate the mechanisms of metformin on osteoblasts in insulin-deficient diabetes.
Does AMPK increase bone mass?
AMPK signaling activation may stimulate bone formation and increase bone mass in skeletal physiology. However, the phosphorylation level of AMPK α subunits showed different results in the osteoblast differentiation, which was associated with decreased AMPK activity [ 58.
Why are osteoclasts important?
Osteoclasts allow skeletal mineral to be used to manage extracellular calcium activity, which is an important adaptation for life on land, and solid skeletal structure to be replaced by hollow architecture that has a superior strength-to-weight ratio.
What is the role of osteoclasts in the human body?
Their specialized role is central to a process that continuously removes and replaces segments of the skeleton in the higher vertebrates. Osteoclasts allow skeletal mineral to be used to manage extracellular calcium activity, which is an important adaptation ...
What is the role of osteoclasts in the skeletal system?
Osteoclasts allow skeletal mineral to be used to manage extracellular calcium ac …. Osteoclasts are multinucleated monocyte-macrophage derivatives that degrade bone. Their specialized role is central to a process that continuously removes and replaces segments of the skeleton in the higher vertebrates. Osteoclasts allow skeletal mineral ...
How do osteoclasts dissolve bone?
Osteoclasts dissolve bone mineral by massive acid secretion and secrete specialized proteinases that degrade the organic matrix, mainly type I collagen, in this acidic milieu.