Mechanisms of diabetes mellitus-induced bone fragility
TL;DR: Factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism, as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.
Abstract: The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.
Citations
More filters
Geneva College1, University of Southern Denmark2, Washington University in St. Louis3, Università Campus Bio-Medico4, Lund University5, Singapore General Hospital6, University of Sheffield7, American University of Beirut8, St. Michael's Hospital9, University of Toronto10, University of British Columbia11, Fujita Health University12, International Osteoporosis Foundation13, University of California, San Francisco14, University of Manitoba15
TL;DR: An algorithm is proposed for the identification and management of diabetic patients at increased fracture risk and the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population of adults with diabetes.
Abstract: Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.
219 citations
Cites background from "Mechanisms of diabetes mellitus-ind..."
...Epidemiological data on diabetes patients taking sulphonylureas has revealed an increased risk of fractures [16]....
[...]
...However, clinical data confirms in vitro data that metformin has either a neutral or a possible beneficial effect on fractures, making this widely used medication a safe option regarding bone health [16]....
[...]
TL;DR: Recent studies have uncovered that Wnt signaling directly reprograms cellular metabolism by stimulating aerobic glycolysis, glutamine catabolism as well as fatty acid oxidation in osteoblast-lineage cells, revealing an important regulatory axis between bone anabolic signals and cellular bioenergetics.
Abstract: The adult human skeleton is a multifunctional organ undergoing continuous remodeling. Homeostasis of bone mass in a healthy adult requires an exquisite balance between bone resorption by osteoclasts and bone formation by osteoblasts; disturbance of such balance is the root cause for various bone disorders including osteoporosis. To develop effective and safe therapeutics to modulate bone formation, it is essential to elucidate the molecular mechanisms governing osteoblast differentiation and activity. Due to their specialized function in collagen synthesis and secretion, osteoblasts are expected to consume large amounts of nutrients. However, studies of bioenergetics and building blocks in osteoblasts have been lagging behind those of growth factors and transcription factors. Genetic studies in both humans and mice over the past 15 years have established Wnt signaling as a critical mechanism for stimulating osteoblast differentiation and activity. Importantly, recent studies have uncovered that Wnt signaling directly reprograms cellular metabolism by stimulating aerobic glycolysis, glutamine catabolism as well as fatty acid oxidation in osteoblast-lineage cells. Such findings therefore reveal an important regulatory axis between bone anabolic signals and cellular bioenergetics. A comprehensive understanding of osteoblast metabolism and its regulation is likely to reveal molecular targets for novel bone therapies.
205 citations
Cites background from "Mechanisms of diabetes mellitus-ind..."
...icance as patients with either type I or type II diabetes exhibit increased risk in bone fracture [148, 149]....
[...]
TL;DR: Melatonin significantly reduced the level of ferroptosis and improved the osteogenic capacity of MC3T3-E1 through activating the Nrf2/HO-1 pathway in vivo and in vitro and confirmed that melatonin can inhibit the ferroPTosis of osteoblasts through activating NRF2/ HO-1 signaling pathway to improve bone microstructure.
Abstract: Ferroptosis is recently identified, an iron- and reactive oxygen species- (ROS-) dependent form of regulated cell death. This study was designed to determine the existence of ferroptosis in the pathogenesis of type 2 diabetic osteoporosis and confirm that melatonin can inhibit the ferroptosis of osteoblasts through activating Nrf2/HO-1 signaling pathway to improve bone microstructure in vivo and in vitro. We treated MC3T3-E1 cells with different concentrations of melatonin (1, 10, or 100 μM) and exposed them to high glucose (25.5 mM) for 48 h in vitro. Our data showed that high glucose can induce osteoblast cytotoxicity and the accumulation of lipid peroxide, the mitochondria of osteoblast show the same morphology changes as the erastin treatment group, and the expression of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) is downregulated, but these effects were reversed by ferroptosis inhibitor ferrastatin-1 and iron chelator deferoxamine (DFO). Furthermore, western blot and real-time polymerase chain reaction were used to detect the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1); osteogenic capacity was evaluated by alizarin red S staining and the expression of osteoprotegerin, osteocalcin, and alkaline phosphatase; the results showed that the expression levels of these proteins in osteoblasts with 1, 10, or 100 μM melatonins were significantly higher than the high glucose group, but after using Nrf2-SiRNA interference, the therapeutic effect of melatonin was significantly inhibited. We also performed in vivo experiments in a diabetic rat model treated with two concentrations of melatonin (10, 50 mg/kg). Dynamic bone histomorphometry and micro-CT were used to observe the rat bone microstructure, and the expression of GPX4 and Nrf2 was determined by immunohistochemistry. Here, we first report that high glucose induces ferroptosis via increased ROS/lipid peroxidation/glutathione depletion in type 2 diabetic osteoporosis. More importantly, melatonin significantly reduced the level of ferroptosis and improved the osteogenic capacity of MC3T3-E1 through activating the Nrf2/HO-1 pathway in vivo and in vitro.
150 citations
TL;DR: Bone adipocytes, collectively termed marrow adipose tissue (MAT), reside in the bone marrow in close contact to bone cells and haematopoietic cells and could represent a new therapeutic target for multiple diseases from osteoporosis to leukaemia.
Abstract: Marrow adipocytes, collectively termed marrow adipose tissue (MAT), reside in the bone marrow in close contact to bone cells and haematopoietic cells. Marrow adipocytes arise from the mesenchymal stem cell and share their origin with the osteoblast. Shifts in the lineage allocation of the mesenchymal stromal cell could potentially explain the association between increased MAT and increased fracture risk in diseases such as postmenopausal osteoporosis, anorexia nervosa and diabetes. Functionally, marrow adipocytes secrete adipokines, such as adiponectin, and cytokines, such as RANK ligand and stem cell factor. These mediators can influence both bone remodelling and haematopoiesis by promoting bone resorption and haematopoietic recovery following chemotherapy. In addition, marrow adipocytes can secrete free fatty acids, acting as a energy supply for bone and haematopoietic cells. However, this induced lipolysis is also used by neoplastic cells to promote survival and proliferation. Therefore, MAT could represent a new therapeutic target for multiple diseases from osteoporosis to leukaemia, although the exact characteristics and role of the marrow adipocyte in health and diseases remain to be determined.
145 citations
TL;DR: Animal studies have provided new insights into pathogenic mechanisms that identify cause-and-effect relationships that are difficult to perform in human studies.
Abstract: The susceptibility and severity of periodontal diseases is made more severe by diabetes, with the impact on the disease process inversely proportional to the level of glycemic control. Although type 1 diabetes mellitus and type 2 diabetes mellitus have different etiologies, and their impact on bone is not identical, they share many of the same complications. Studies in animals and humans agree that both forms of diabetes increase inflammatory events in periodontal tissue, impair new bone formation, and increase expression of RANKL in response to bacterial challenge. High levels of glucose, reactive oxygen species, and advanced glycation end-products are found in the periodontium of diabetic individuals and lead to increased activation of nuclear factor-kappa B and expression of inflammatory cytokines such as tumor necrosis factor and interleukin-1. Studies in animals, moreover, suggest that there are multiple cell types in periodontal tissues that are affected by diabetes, including leukocytes, vascular cells, mesenchymal stem cells, periodontal ligament fibroblasts, osteoblasts, and osteocytes. The etiology of periodontal disease involves the host response to bacterial challenge that is affected by diabetes, which increases the expression of RANKL and reduces coupled bone formation. In addition, the inflammatory response also modifies the oral microbiota to render it more pathogenic, as demonstrated by increased inflammation and bone loss in animals where bacteria are transferred from diabetic donors to germ-free hosts compared with transfer from normoglycemic donors. This approach has the advantage of not relying upon limited knowledge of the specific bacterial taxa to determine pathogenicity, and examines the overall impact of the microbiota rather than the presumed pathogenicity of a few bacterial groups. Thus, animal studies have provided new insights into pathogenic mechanisms that identify cause-and-effect relationships that are difficult to perform in human studies.
140 citations
References
More filters
Journal Article•
TL;DR: In this article, the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.
17,108 citations
TL;DR: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia, with the lowest risk being in those with HbA1c values in the normal range (<6.0%).
Abstract: Objective: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Outcome measures: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA 1c adjusted for possible confounders at diagnosis of diabetes. Results: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA 1c was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P Conclusions: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA 1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA 1c values in the normal range (
8,102 citations
Journal Article•
TL;DR: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.
7,395 citations
TL;DR: It is concluded that osteoporotic fractures are a significant cause of morbidity and mortality, particularly in the developed countries.
Abstract: Objective The aim of this study was to quantify the global burden of osteoporotic fracture worldwide. Methods The incidence of hip fractures was identified by systematic review and the incidence of osteoporotic fractures was imputed from the incidence of hip fractures in different regions of the world. Excess mortality and disability weights used age- and sex-specific data from Sweden to calculate the Disability Adjusted Life Years (DALYs) lost due to osteoporotic fracture. Results In the year 2000 there were an estimated 9.0 million osteoporotic fractures of which 1.6 million were at the hip, 1.7 million at the forearm and 1.4 million were clinical vertebral fractures. The greatest number of osteoporotic fractures occurred in Europe (34.8%). The total DALYs lost was 5.8 million of which 51% were accounted for by fractures that occurred in Europe and the Americas. World-wide, osteoporotic fractures accounted for 0.83% of the global burden of non-communicable disease and was 1.75% of the global burden in Europe. In Europe, osteoporotic fractures accounted for more DALYs lost than common cancers with the exception of lung cancer. For chronic musculo-skeletal disorders the DALYs lost in Europe due to osteoporosis (2.0 million) were less than for osteoarthrosis (3.1 million) but greater than for rheumatoid arthritis (1.0 million). Conclusion We conclude that osteoporotic fractures are a significant cause of morbidity and mortality, particularly in the developed countries.
3,774 citations