Blood Vessels and Vascular Niches in Bone Development and Physiological Remodeling.
Frontiers in cell and developmental biology
Recent advances in our understanding of blood vessels and vascular niches in bone convey their critical importance in regulating bone development and physiology. The contribution of blood vessels in bone functions and remodeling has recently gained enormous interest because of their therapeutic potential. The mammalian skeletal system performs multiple functions in the body to regulate growth, homeostasis and metabolism. Blood vessels provide support to various cell types in bone and maintain functional niches in the bone marrow microenvironment. Heterogeneity within blood vessels and niches indicate the importance of specialized vascular niches in regulating skeletal functions. In this review, we discuss physiology of bone vasculature and their specialized niches for hematopoietic stem cells and mesenchymal progenitor cells. We provide clinical and experimental information available on blood vessels during physiological bone remodeling.
10.3389/fcell.2020.602278
Type H blood vessels in bone modeling and remodeling.
Theranostics
In the mammalian skeletal system, osteogenesis and angiogenesis are intimately linked during bone growth and regeneration in bone modeling and during bone homeostasis in bone remodeling. Recent studies have expanded our knowledge about the molecular and cellular mechanisms responsible for coupling angiogenesis and bone formation. Type H vessels, termed such because of high expression of Endomucin (Emcn) and CD31, have recently been identified and have the ability to induce bone formation. Factors including platelet-derived growth factor type BB (PDGF-BB), slit guidance ligand 3 (SLIT3), hypoxia-inducible factor 1-alpha (HIF-1α), Notch, and vascular endothelial growth factor (VEGF) are involved in the coupling of angiogenesis and osteogenesis. This review summarizes the current understanding of signaling pathways that regulate type H vessels and how type H vessels modulate osteogenesis. Further studies dissecting the regulation and function of type H vessels will provide new insights into the role of bone vasculature in the metabolism of the skeleton. We also discuss considerations for therapeutic approaches targeting type H vessels to promote fracture healing, prevent pathological bone loss, osteonecrosis, osteoarthritis, and bone metastases.
10.7150/thno.34126
Bone Microvasculature: Stimulus for Tissue Function and Regeneration.
Tissue engineering. Part B, Reviews
Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity. Impact statement Bone vasculature is imperative in the process of bone development, regeneration, and remodeling. Alterations or disruption of the bone vasculature leads to loss of bone homeostasis and the development of bone diseases. In this study, we review the role of vasculature on bone diseases and how vascular tissue engineering strategies, with a detailed emphasis on the role of stem cells and growth factors, will contribute to bone therapeutics.
10.1089/ten.TEB.2020.0154
The physiology of bone blood flow: a review.
McCarthy Ian
The Journal of bone and joint surgery. American volume
INTRODUCTION:Bone circulation plays an important role in bone physiology, but has been relatively poorly studied, because most techniques of circulatory research are difficult to apply to bone. This article summarizes briefly some of the important aspects of the physiology of bone blood flow most relevant to orthopaedics. METHODS:The gold standard for experimental measurement of bone blood flow is the radioactive microsphere technique, though advances are being made in other techniques, such as positron emission tomography, laser and ultra-sound Doppler velocimetry, and near infrared spectroscopy, that may provide useful clinical measurement in the future. RESULTS:Multiple vascular pathways contribute to an adaptive response to traumatic disruption of bone circulation. The microcirculation is not merely a passive conduit for blood flow, but plays an active role in controlling bone processes such as osteochondral ossification. DISCUSSION:The pathophysiology of bone circulation has been associated with osteonecrosis, but more and more evidence is pointing to the importance of bone circulation in fracture repair and osteoporosis, both of which are potentially very exciting areas for future studies.
10.2106/JBJS.F.00890
Bone as an endocrine organ relevant to diabetes.
Booth Sarah L,Centi Amanda J,Gundberg Caren
Current diabetes reports
There are well-established associations between diabetes and fracture risk and yet the mechanism underlying these associations are controversial. Guided by a series of mouse studies, a specific form of the bone protein, osteocalcin, was proposed to be the mechanistic link between these two chronic diseases. Translation to humans initially appeared elusive in part because serum concentrations of osteocalcin are a biomarker of bone turnover and not necessarily specific to the biology of this protein. The suitability of the mouse model for the study of osteocalcin as a therapeutic target also appears ambiguous. With greater discrimination of the different forms of osteocalcin present in circulation and inclusion of multiple measures of bone turnover, evidence currently does not support osteocalcin as a protein critical to the diabetes and fracture association in humans.
10.1007/s11892-014-0556-3
Bone, sweet bone--osteoporotic fractures in diabetes mellitus.
Hamann Christine,Kirschner Stephan,Günther Klaus-Peter,Hofbauer Lorenz C
Nature reviews. Endocrinology
Diabetes mellitus adversely affects the skeleton and is associated with an increased risk of osteoporosis and fragility fractures. The mechanisms underlying low bone strength are not fully understood but could include impaired accrual of peak bone mass and diabetic complications, such as nephropathy. Type 1 diabetes mellitus (T1DM) affects the skeleton more severely than type 2 diabetes mellitus (T2DM), probably because of the lack of the bone anabolic actions of insulin and other pancreatic hormones. Bone mass can remain high in patients with T2DM, but it does not protect against fractures, as bone quality is impaired. The class of oral antidiabetic drugs known as glitazones can promote bone loss and osteoporotic fractures in postmenopausal women and, therefore, should be avoided if osteoporosis is diagnosed. A physically active, healthy lifestyle and prevention of diabetic complications, along with calcium and vitamin D repletion, represent the mainstay of therapy for osteoporosis in patients with T1DM or T2DM. Assessment of BMD and other risk factors as part of the diagnostic procedure can help design tailored treatment plans. All osteoporosis drugs seem to be effective in patients with diabetes mellitus. Increased awareness of osteoporosis is needed in view of the growing and aging population of patients with diabetes mellitus.
10.1038/nrendo.2011.233
Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism.
Bone
The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors.
10.1016/j.bone.2018.03.012
Reactive oxygen species adversely impacts bone marrow microenvironment in diabetes.
Mangialardi Giuseppe,Spinetti Gaia,Reni Carlotta,Madeddu Paolo
Antioxidants & redox signaling
UNLABELLED:Significance: Patients with diabetes mellitus suffer an excess of cardiovascular complications and recover worse from them as compared with their nondiabetic peers. It is well known that microangiopathy is the cause of renal damage, blindness, and heart attacks in patients with diabetes. This review highlights molecular deficits in stem cells and a supporting microenvironment, which can be traced back to oxidative stress and ultimately reduce stem cells therapeutic potential in diabetic patients. RECENT ADVANCES:New research has shown that increased oxidative stress contributes to inducing microangiopathy in bone marrow (BM), the tissue contained inside the bones and the main source of stem cells. These precious cells not only replace old blood cells but also exert an important reparative function after acute injuries and heart attacks. CRITICAL ISSUES:The starvation of BM as a consequence of microangiopathy can lead to a less efficient healing in diabetic patients with ischemic complications. Furthermore, stem cells from a patient's BM are the most used in regenerative medicine trials to mend hearts damaged by heart attacks. FUTURE DIRECTIONS:A deeper understanding of redox signaling in BM stem cells will lead to new modalities for preserving local and systemic homeostasis and to more effective treatments of diabetic cardiovascular complications.
10.1089/ars.2014.5944
Insulin resistance and bone: a biological partnership.
Conte Caterina,Epstein Solomon,Napoli Nicola
Acta diabetologica
Despite a clear association between type 2 diabetes (T2D) and fracture risk, the pathogenesis of bone fragility in T2D has not been clearly elucidated. Insulin resistance is the primary defect in T2D. Insulin signalling regulates both bone formation and bone resorption, but whether insulin resistance can affect bone has not been established. On the other hand, evidence exists that bone might play a role in the regulation of glucose metabolism. This article reviews the available experimental and clinical evidence on the interplay between bone and insulin resistance. Interestingly, a bilateral relationship between bone and insulin resistance seems to exist that unites them in a biological partnership.
10.1007/s00592-018-1101-7
Impact of diabetes and its treatments on skeletal diseases.
Yan Wenbo,Li Xin
Frontiers of medicine
Diabetes mellitus is an enormous menace to public health globally. This chronic disease of metabolism will adversely affect the skeleton if not controlled. Both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are associated with an increased risk of osteoporosis and fragility fractures. Bone mineral density is reduced in T1DM, whereas patients with T2DM have normal or slightly higher bone density, suggesting impaired bone quality is involved. Detrimental effects of T1DM on the skeleton are more severe than T2DM, probably because of the lack of osteo-anabolic effects of insulin and other pancreatic hormones. In both T1DM and T2DM, low bone quality could be caused by various means, including but not limited to hyperglycemia, accumulation of advanced glycosylation end products (AGEs), decreased serum levels of osteocalcin and parathyroid hormone. Risk for osteoarthritis is also elevated in diabetic population. How diabetes accelerates the deterioration of cartilage remains largely unknown. Hyperglycemia and glucose derived AGEs could contribute to the development of osteoarthritis. Moreover, it is recognized that oral antidiabetic medicines affect bone metabolism and turnover as well. Insulin is shown to have anabolic effects on bone and hyperinsulinemia may help to explain the slightly higher bone density in patients with T2DM. Thiazolidinediones can promote bone loss and osteoporotic fractures by suppressing osteoblastogenesis and enhancing osteoclastogenesis. Metformin favors bone formation by stimulating osteoblast differentiation and protecting them against diabetic conditions such as hyperglycemia. Better knowledge of how diabetic conditions and its treatments influence skeletal tissues is in great need in view of the growing and aging population of patients with diabetes mellitus.
10.1007/s11684-013-0243-9
Type 2 diabetes and bone.
Leslie William D,Rubin Mishaela R,Schwartz Ann V,Kanis John A
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
There is a growing body of research showing that diabetes is an independent risk factor for fracture. Type 2 diabetes (T2D), which predominates in older individuals and is increasing globally as a consequence of the obesity epidemic, is associated with normal or even increased dual-energy x-ray absorptiometry (DXA)-derived areal bone mineral density (BMD). Therefore, the paradoxical increase in fracture risk has led to the hypothesis that there are diabetes-associated alterations in material and structural properties. An overly glycated collagen matrix, confounded by a low turnover state, in the setting of subtle cortical abnormalities, may lead to compromised biomechanical competence. In current clinical practice, because BMD is central to fracture prediction, a consequence of this paradox is a lack of suitable methods, including FRAX, to predict fracture risk in older adults with T2D. The option of adding diabetes to the FRAX algorithm is appealing but requires additional data from large population-based cohorts. The need for improved methods for identification of fracture in older adults with T2D is an important priority for osteoporosis research.
10.1002/jbmr.1759
Vitamin D, sub-inflammation and insulin resistance. A window on a potential role for the interaction between bone and glucose metabolism.
Garbossa Stefania Giuliana,Folli Franco
Reviews in endocrine & metabolic disorders
Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and recently it has been implicated in the pathogenesis of sub-inflammation, insulin resistance and obesity. The two main forms of vitamin D are cholecalciferol (Vitamin D3) and ergocalciferol (Vitamin D2): the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Vitamin D increases the production of some anti-inflammatory cytokines and reduces the release of some pro-inflammatory cytokines. Low levels of Vitamin D are also associated with an up-regulation of TLRs expression and a pro-inflammatory state. Regardless of the effect on inflammation, Vitamin D seems to directly increase insulin sensitivity and secretion, through different mechanisms. Considering the importance of low grade chronic inflammation in metabolic syndrome, obesity and diabetes, many authors hypothesized the involvement of this nutrient/hormone in the pathogenesis of these diseases. Vitamin D status could alter the balance between pro and anti-inflammatory cytokines and thus affect insulin action, lipid metabolism and adipose tissue function and structure. Numerous studies have shown that Vitamin D concentrations are inversely associated with pro-inflammatory markers, insulin resistance, glucose intolerance and obesity. Interestingly, some longitudinal trials suggested also an inverse association between vitamin D status and incident type 2 diabetes mellitus. However, vitamin D supplementation in humans showed controversial effects: with some studies demonstrating improvements in insulin sensitivity, glucose and lipid metabolism while others showing no beneficial effect on glycemic control and on inflammation. In conclusion, although the evidences of a significant role of Vitamin D on inflammation, insulin resistance and insulin secretion in the pathogenesis of obesity, metabolic syndrome and type 2 diabetes, its potential function in treatment and prevention of type 2 diabetes mellitus is unclear. Encouraging results have emerged from Vitamin D supplementation trials on patients at risk of developing diabetes and further studies are needed to fully explore and understand its clinical applications.
10.1007/s11154-017-9423-2
The Interplay Between Bone and Glucose Metabolism.
Cipriani Cristiana,Colangelo Luciano,Santori Rachele,Renella Mario,Mastrantonio Monia,Minisola Salvatore,Pepe Jessica
Frontiers in endocrinology
The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia , production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.
10.3389/fendo.2020.00122
Diabetes Drug Effects on the Skeleton.
Chandran Manju
Calcified tissue international
Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone. The use of insulin has been associated with an increased risk of fragility fractures though it is not clear whether it is due to direct influence of insulin or whether it is mediated through hypoglycemia and increased falls risk. The overall effect of incretin mimetics appears to be beneficial; however, this has to be elucidated further. The bone effects of pramlintide, a synthetic analog of amylin, have not been explored fully. Finally, issues regarding bone safety of SGLT2 (sodium-dependent glucose transporter 2) inhibitors, the newest anti-diabetic medications on the market are of concern. The purpose of this review is to provide a comprehensive overview of the effect of these medications on bone metabolism and the studies exploring the risk or lack thereof of these medications on bone loss and fragility fractures.
10.1007/s00223-016-0203-x
The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders.
Takashi Yuichi,Kawanami Daiji
International journal of molecular sciences
Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders.
10.3390/ijms23042376
MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus.
Hough F S,Pierroz D D,Cooper C,Ferrari S L,
European journal of endocrinology
Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.
10.1530/EJE-15-0820
Obesity, Type 2 Diabetes and Bone in Adults.
Walsh Jennifer S,Vilaca Tatiane
Calcified tissue international
In an increasingly obese and ageing population, type 2 diabetes (T2DM) and osteoporotic fracture are major public health concerns. Understanding how obesity and type 2 diabetes modulate fracture risk is important to identify and treat people at risk of fracture. Additionally, the study of the mechanisms of action of obesity and T2DM on bone has already offered insights that may be applicable to osteoporosis in the general population. Most available evidence indicates lower risk of proximal femur and vertebral fracture in obese adults. However the risk of some fractures (proximal humerus, femur and ankle) is higher, and a significant number fractures occur in obese people. BMI is positively associated with BMD and the mechanisms of this association in vivo may include increased loading, adipokines such as leptin, and higher aromatase activity. However, some fat depots could have negative effects on bone; cytokines from visceral fat are pro-resorptive and high intramuscular fat content is associated with poorer muscle function, attenuating loading effects and increasing falls risk. T2DM is also associated with higher bone mineral density (BMD), but increased overall and hip fracture risk. There are some similarities between bone in obesity and T2DM, but T2DM seems to have additional harmful effects and emerging evidence suggests that glycation of collagen may be an important factor. Higher BMD but higher fracture risk presents challenges in fracture prediction in obesity and T2DM. Dual energy X-ray absorptiometry underestimates risk, standard clinical risk factors may not capture all relevant information, and risk is under-recognised by clinicians. However, the limited available evidence suggests that osteoporosis treatment does reduce fracture risk in obesity and T2DM with generally similar efficacy to other patients.
10.1007/s00223-016-0229-0
Skeletal fragility in diabetes.
Rubin Mishaela R
Annals of the New York Academy of Sciences
Fracture risk is heightened in patients with both type 1 diabetes (T1D) and type 2 diabetes (T2D). Although bone mineral density by dual-energy X-ray absorptiometry is decreased in T1D, it is paradoxically increased with T2D. To predict fracture risk, the Fracture Risk Assessment Tool (FRAX) can be used in diabetes patients, albeit with refinement. Skeletal abnormalities in diabetes include alterations in microarchitecture in T1D and T2D as well as compromised impact microindentation in T2D. Changes in bone microvasculature, advanced glycation end product accumulation, and bone formation may underlie these findings. When fractures occur in T1D and T2D, consequences are worse than in nondiabetic patients with regard to both morbidity and mortality. With regard to treatment, antiresorptive osteoporosis therapies appear to be effective in the setting of diabetes.
10.1111/nyas.13463
Impact of Type 2 Diabetes Mellitus and Antidiabetic Medications on Bone Metabolism.
Lee Hae Sang,Hwang Jin Soon
Current diabetes reports
PURPOSE OF REVIEW:This review focuses on the complex interactions between hyperglycemia and bone fragility and the effects of antidiabetic medications on bone metabolism. RECENT FINDINGS:Type 2 diabetes (T2D) is associated with increased risk of bone fracture even in those with increased or normal bone mineral density (BMD). The pathophysiology of diabetic bone disease is not completely understood, but it is thought to be multifactorial and associated with complex cross talk among factors such as AGEs, IGF-1, enteric hormones, and pro-inflammatory cytokines. Treatment for T2D may have an impact on bone metabolism. Diabetic bone disease should be considered a serious complication of long-standing T2D.
10.1007/s11892-020-01361-5
New insights on diabetes and bone metabolism.
Moreira Carolina A,Barreto Fellype C,Dempster David W
Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia
Diabetes mellitus is a common chronic metabolic disease worldwide whose prevalence has increased during the last decades. Besides its more commonly recognized complications, such as macrovascular disease, retinopathy, nephropathy and neuropathy, diabetes related bone disease has gained growing attention. Diabetic patients are more prone to fracture than the general population as well as to low turnover bone disease in the chronic kidney disease setting. In this review, we discuss the relationship between diabetes and bone as well as the pathogenesis of bone fragility in T2D.
10.5935/0101-2800.20150077
Type 2 diabetes mellitus and bone.
Compston J
Journal of internal medicine
Type 2 diabetes (T2DM) is a rapidly growing public health problem. It is associated with an increased risk of fracture, particularly of the hip, despite normal or high bone mineral density. Longer duration of disease and poor glycaemic control are both associated with higher fracture risk. The factors underlying increased fracture risk have not been clearly established, but increased falls risk, obesity, sarcopenia and co-morbidities are likely to contribute. The basis for reduced bone strength despite higher bone mineral density remains to be fully elucidated. Bone turnover is reduced in individuals with T2DM, with evidence of impaired bone formation. Most studies indicate normal or superior trabecular bone structure although reduced lumbar spine trabecular bone score (TBS) has been reported. Deficits in cortical bone structure have been demonstrated in some, but not all, studies whilst reduced bone material strength index (BMSi), as assessed by microindentation, has been a consistent finding. Accumulation of advanced glycation end products in bone may also contribute to reduced bone strength. The use of FRAX in individuals with T2DM underestimates fracture probability. Clinical management should focus on falls prevention strategies, avoidance of known risk factors, maintenance of good glycaemic control and bone protective intervention in individuals at high risk of fracture. Dietary and surgical strategies to reduce weight have beneficial effects on diabetes but may have adverse effects on skeletal health. Future research priorities include better definition of the mechanisms underlying increased fracture risk in T2DM and optimal strategies for identifying and treating those at high risk.
10.1111/joim.12725
Skeletal Metabolism, Fracture Risk, and Fracture Outcomes in Type 1 and Type 2 Diabetes.
Sellmeyer Deborah E,Civitelli Roberto,Hofbauer Lorenz C,Khosla Sundeep,Lecka-Czernik Beata,Schwartz Ann V
Diabetes
Fracture risk is significantly increased in both type 1 and type 2 diabetes, and individuals with diabetes experience worse fracture outcomes than normoglycemic individuals. Factors that increase fracture risk include lower bone mass in type 1 diabetes and compromised skeletal quality and strength despite preserved bone density in type 2 diabetes, as well as the effects of comorbidities such as diabetic macro- and microvascular complications. In this Perspective, we assess the developing scientific knowledge regarding the epidemiology and pathophysiology of skeletal fragility in patients with diabetes and the emerging data on the prediction, treatment, and outcomes of fractures in individuals with type 1 and type 2 diabetes.
10.2337/db16-0063
Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus.
Palui Rajan,Pramanik Subhodip,Mondal Sunetra,Ray Sayantan
World journal of diabetes
The risk of fracture is increased in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). However, in contrast to the former, patients with T2DM usually possess higher bone mineral density. Thus, there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes. Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk. Moreover, some antidiabetic medications further enhance the fragility of the bone. On the other hand, antiosteoporosis medications can affect the glucose homeostasis in these patients. It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk. Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature. With the advancement in imaging technology, newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes. The purpose of this review is to explore the pathophysiology behind poor bone health in diabetic patients. Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.
10.4239/wjd.v12.i6.706
Bone Microarchitecture in Type 1 Diabetes: It Is Complicated.
Keenan Hillary A,Maddaloni Ernesto
Current osteoporosis reports
Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of "bone quality," rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health.
10.1007/s11914-016-0338-8
The impact of diabetes and diabetes medications on bone health.
Gilbert Matthew P,Pratley Richard E
Endocrine reviews
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. 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. Animal models indicate a potential role for incretin hormones in bone metabolism, but there are only limited data on the impact of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists on bone health in humans. Animal models also have demonstrated a role for amylin in bone metabolism, but clinical trials in patients with type 1 diabetes with an amylin analog (pramlintide) have not shown a significant impact on bone metabolism. The effects of insulin treatment on fracture risk are inconsistent with some studies showing an increased risk and others showing no effect. Finally, although there is limited information on the latest class of medications for the treatment of T2DM, the sodium-glucose co-transporter-2 inhibitors, these drugs do not seem to increase fracture risk. Because diabetes is an increasingly common chronic condition that can affect patients for many decades, further research into the effects of agents for the treatment of T2DM on bone metabolism is warranted. In this review, the physiological mechanisms and clinical impact of diabetes treatments on bone health and fracture risk in patients with T2DM are described.
10.1210/er.2012-1042
Advanced Glycation End Products, Diabetes, and Bone Strength.
Yamamoto Masahiro,Sugimoto Toshitsugu
Current osteoporosis reports
Diabetic patients have a higher fracture risk than expected by their bone mineral density (BMD). Poor bone quality is the most suitable and explainable cause for the elevated fracture risk in this population. Advanced glycation end products (AGEs), which are diverse compounds generated via a non-enzymatic reaction between reducing sugars and amine residues, physically affect the properties of the bone material, one of a component of bone quality, through their accumulation in the bone collagen fibers. On the other hand, these compounds biologically act as agonists for these receptors for AGEs (RAGE) and suppress bone metabolism. The concentrations of AGEs and endogenous secretory RAGE, which acts as a "decoy receptor" that inhibits the AGEs-RAGE signaling axis, are associated with fracture risk in a BMD-independent manner. AGEs are closely associated with the pathogenesis of this unique clinical manifestation through physical and biological mechanisms in patients with diabetes mellitus.
10.1007/s11914-016-0332-1
Type 2 diabetes mellitus and fracture risk.
Dede Anastasia D,Tournis Symeon,Dontas Ismene,Trovas George
Metabolism: clinical and experimental
Increased fracture risk, traditionally associated with type 1 diabetes, has lately been of great concern in patients with type 2 diabetes. A variable increase in fracture risk has been reported, ranging from 20% to 3-fold, depending on skeletal site, diabetes duration and study design. Longer disease duration, the presence of diabetic complications, inadequate glycemic control, insulin use and increased risk for falls are all reported to increase fracture risk. Patients with type 2 diabetes display a unique skeletal phenotype with either normal or more frequently increased, bone mineral density and impaired structural and geometric properties. Recently, alterations in bone material properties seem to be the predominant defect leading to increased bone fragility. Accumulation of advanced glycation end-products and changes in collagen cross-linking along with suppression of bone turnover seem to be significant factors impairing bone strength. FRAX score has been reported to underestimate fracture risk and lumbar spine BMD is inadequate in predicting vertebral fractures. Anti-diabetic medications, apart from thiazolidinediones, appear to be safe for the skeleton, although more data are needed. Optimal strategies to reduce skeletal fragility in type 2 diabetic patients are yet to be determined.
10.1016/j.metabol.2014.09.002
Diabetic Bone Disease and Diabetic Myopathy: Manifestations of the Impaired Muscle-Bone Unit in Type 1 Diabetes.
Journal of diabetes research
Type 1 diabetes is associated with complications affecting muscle and bone, with diabetic bone disease and diabetic myopathy becoming increasingly reported in the past few decades. This review is aimed at succinctly reviewing the literature on the current knowledge regarding these increasingly identified and possibly interconnected complications on the musculoskeletal system. Furthermore, this review summarizes several nonmechanical factors that could be mediating the development and progression of premature musculoskeletal decline in this population and discusses preventative measures to reduce the burden of diabetes on the musculoskeletal system.
10.1155/2022/2650342
Lifestyle Management of Diabetes: Implications for the Bone-Vascular Axis.
Pieralice Silvia,Vigevano Francesca,Del Toro Rossella,Napoli Nicola,Maddaloni Ernesto
Current diabetes reports
PURPOSE OF REVIEW:To describe the main pathways involved in the interplay between bone and cardiovascular disease and to highlight the possible impact of physical activity and medical nutrition therapy on the bone-vascular axis. RECENT FINDINGS:Diabetes increases the risk of both cardiovascular disease and bone fragility fractures, sharing common pathogenic pathways, including OPG/RANK/RANKL, the FGF23/Klotho axis, calciotropic hormones, and circulating osteogenic cells. This may offer new therapeutic targets for future treatment strategies. As lifestyle intervention is the cornerstone of diabetes treatment, there is potential for an impact on the bone-vascular axis. Evidence published suggests the bone-vascular axis encompasses key pathways for cardiovascular disease. This, along with studies showing physical activity plays a crucial role in the prevention of both bone fragility and cardiovascular disease, suggests that lifestyle intervention incorporating exercise and diet may be helpful in managing skeletal health decline in diabetes. Studies investigating the controversial role of high-fiber diet and dietary vitamin D/calcium on bone and cardiovascular health suggest an overall benefit, but further investigations are needed in this regard.
10.1007/s11892-018-1060-y
Pathophysiology of Bone Fragility in Patients with Diabetes.
Palermo Andrea,D'Onofrio Luca,Buzzetti Raffaella,Manfrini Silvia,Napoli Nicola
Calcified tissue international
It has been well established that bone fragility is one of the chronic complications of diabetes mellitus, and both type 1 and type 2 diabetes are risk factors for fragility fractures. Diabetes may negatively affect bone health by unbalancing several pathways: bone formation, bone resorption, collagen formation, inflammatory cytokine, muscular and incretin system, bone marrow adiposity and calcium metabolism. The purpose of this narrative review is to explore the current understanding of pathophysiological pathways underlying bone fragility in diabetics. In particular, the review will focus on the peculiar cellular and molecular system impairment that may lead to increased risk of fracture in type 1 and type 2 diabetes.
10.1007/s00223-016-0226-3
Sweet Bones: The Pathogenesis of Bone Alteration in Diabetes.
Al-Hariri Mohammed
Journal of diabetes research
Diabetic patients have increased fracture risk. The pathogenesis underlying the status of bone alterations in diabetes mellitus is not completely understood but is multifactorial. The major deficits appear to be related to a deficit in mineralized surface area, a decrement in the rate of mineral apposition, deceased osteoid surface, depressed osteoblast activity, and decreased numbers of osteoclasts due to abnormal insulin signaling pathway. Other prominent features of diabetes mellitus are an increased urinary excretion of calcium and magnesium, accumulation of advanced glycation end products, and oxidative stress leading to sweet bones (altered bone's strength, metabolism, and structure). Every diabetic patient should be assessed for risk factors for fractures and osteoporosis. The pathogenesis of the bone alterations in diabetes mellitus as well as their molecular mechanisms needs further study.
10.1155/2016/6969040
Effect of anti-diabetic drugs on bone metabolism: Evidence from preclinical and clinical studies.
Adil Mohammad,Khan Rashid Ali,Kalam Abul,Venkata Shiva Kumar,Kandhare Amit Dattatraya,Ghosh Pinaki,Sharma Manju
Pharmacological reports : PR
Diabetes mellitus is associated with abnormal bone health and an increased risk of fracture even though patients have normal or higher BMD. The mechanisms behind diabetes mellitus- induced various skeletal disorders remain unclear. Anti-diabetic drugs may have negative or positive impact on bone metabolism. For instance, thiazolidinediones increases the bone loss and risk of fracture possibly through PPARγ activation in bone marrow cells and hamper osteoblastogenesis via decreasing Runx2 transcription factor, IGF-1 and Wnt signalling pathways. In contrast, metformin and sulfonylureas have a neutral or positive effect on bone health and reduced risk of fracture. Results from the preclinical and clinical studies convey conflicting findings over insulin safety profile on bone health. Incretin-based therapy (GLP-1 receptor agonist and DPP-4 inhibitors) and SGLT2 inhibitors are currently marketed anti- diabetic drugs. While evidence from animal studies suggest that incretin-based therapy have anabolic effect on bone, limited clinical data of DPP-4 inhibitors and GLP-1 receptor agonist indicated a neutral effect on the bone health and risk of fracture. SGLT2 inhibitors may cause bone loss or increase fracture risk due to altered calcium, phosphate and sodium concentration. Therefore, safety concerns of anti-diabetic drugs are crucial for the management of diabetes mellitus. In this review, analysis of the available evidence for effect of anti-diabetic drugs on the bone metabolism and fracture risk in diabetes mellitus is described.
10.1016/j.pharep.2017.05.008
Diabetes, bone and glucose-lowering agents: basic biology.
Lecka-Czernik Beata
Diabetologia
Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI: 10.1007/s00125-017-4283-6 ). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.
10.1007/s00125-017-4269-4
Mapping Knowledge Landscapes and Emerging Trends of the Links Between Bone Metabolism and Diabetes Mellitus: A Bibliometric Analysis From 2000 to 2021.
Frontiers in public health
Background:Diabetes mellitus (DM) have become seriously threatens to human health and life quality worldwide. As a systemic metabolic disease, multiple studies have revealed that DM is related to metabolic bone diseases and always induces higher risk of fracture. In view of this, the links between bone metabolism (BM) and DM (BMDM) have gained much attention and numerous related papers have been published. Nevertheless, no prior studies have yet been performed to analyze the field of BMDM research through bibliometric approach. To fill this knowledge gap, we performed a comprehensive bibliometric analysis of the global scientific publications in this field. Methods:Articles and reviews regarding BMDM published between 2000 and 2021 were obtained from the Web of Science after manually screening. VOSviewer 1.6.16, CiteSpace V 5.8.R3, Bibliometrix, and two online analysis platforms were used to conduct the bibliometric and visualization analyses. Results:A total of 2,525 documents including 2,255 articles and 270 reviews were retrieved. Our analysis demonstrated a steady increasing trend in the number of publications over the past 22 years ( = 0.989). The United States has occupied the leading position with the largest outputs and highest H-index. University of California San Francisco contributed the most publications, and Schwartz AV was the most influential author. Collaboration among institutions from different countries was relatively few. The journals that published the most BMDM-related papers were and . Osteoporosis and related fractures are the main bone metabolic diseases of greatest concern in this field. According to co-cited references result, "high glucose environment," "glycation end-product" and "sodium-glucose co-transporter" have been recognized as the current research focus in this domain. The keywords co-occurrence analysis indicated that "diabetic osteoporosis," "osteoarthritis," "fracture risk," "meta-analysis," "osteogenic differentiation," "bone regeneration," "osteogenesis," and "trabecular bone score" might remain the research hotspots and frontiers in the near future. Conclusion:As a cross-discipline research field, the links between bone metabolism and diabetes mellitus are attracting increased attention. Osteoporosis and related fractures are the main bone metabolic diseases of greatest concern in this field. These insights may be helpful for clinicians to recognize diabetic osteopenia and provide more attention and support to such patients.
10.3389/fpubh.2022.918483
Bone damage in type 2 diabetes mellitus.
Carnevale V,Romagnoli E,D'Erasmo L,D'Erasmo E
Nutrition, metabolism, and cardiovascular diseases : NMCD
This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone "quality". The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX).
10.1016/j.numecd.2014.06.013
Derangement of calcium metabolism in diabetes mellitus: negative outcome from the synergy between impaired bone turnover and intestinal calcium absorption.
The journal of physiological sciences : JPS
Both types 1 and 2 diabetes mellitus (T1DM and T2DM) are associated with profound deterioration of calcium and bone metabolism, partly from impaired intestinal calcium absorption, leading to a reduction in calcium uptake into the body. T1DM is associated with low bone mineral density (BMD) and osteoporosis, whereas the skeletal changes in T2DM are variable, ranging from normal to increased and to decreased BMD. However, both types of DM eventually compromise bone quality through production of advanced glycation end products and misalignment of collagen fibrils (so-called matrix failure), thereby culminating in a reduction of bone strength. The underlying cellular mechanisms (cellular failure) are related to suppression of osteoblast-induced bone formation and bone calcium accretion, as well as to enhancement of osteoclast-induced bone resorption. Several other T2DM-related pathophysiological changes, e.g., osteoblast insulin resistance, impaired productions of osteogenic growth factors (particularly insulin-like growth factor 1 and bone morphogenetic proteins), overproduction of pro-inflammatory cytokines, hyperglycemia, and dyslipidemia, also aggravate diabetic osteopathy. In the kidney, DM and the resultant hyperglycemia lead to calciuresis and hypercalciuria in both humans and rodents. Furthermore, DM causes deranged functions of endocrine factors related to mineral metabolism, e.g., parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor-23. Despite the wealth of information regarding impaired bone remodeling in DM, the long-lasting effects of DM on calcium metabolism in young growing individuals, pregnant women, and neonates born to women with gestational DM have received scant attention, and their underlying mechanisms are almost unknown and worth exploring.
10.1007/s12576-016-0487-7
Bone: Another potential target to treat, prevent and predict diabetes.
Liu Dong-Mei,Mosialou Ioanna,Liu Jian-Min
Diabetes, obesity & metabolism
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.
10.1111/dom.13330
The effects of diabetes therapy on bone: A clinical perspective.
Journal of diabetes and its complications
The effects of diabetes and diabetes therapy on bone are less known among clinicians. Traditionally, the emphasis of diabetes therapy has been on reducing cardiovascular risk by facilitating reductions in weight, blood pressure, blood sugar, systemic inflammation, and lipid levels. Now, with ample research demonstrating that patients with diabetes are more susceptible to bone fractures relative to controls, there has been a greater or renewed interest in studying the effects of diabetes therapy on bone. Interestingly, the majority of antidiabetic agents positively affect bone, but a few have detrimental effects. Specifically, although insulin has been demonstrated to be anabolic to bone, the rate of hypoglycemic episodes are increased with exogenous infusion; consequently, there is an increased fall and fracture frequency. Other agents such as thiazolidinediones have more direct negative effects on bone through transcriptional regulation. Even metabolic surgery, to a varying operation-dependent extent, exacerbates bone strength and may heighten fracture rate. The remaining diabetes agents seem to have neutral or positive effects on bone. With the increasing incidence of diabetes, it is more pertinent than ever to fully comprehend the effects of diabetes-related therapeutic modalities.
10.1016/j.jdiacomp.2018.04.005
Multifactorial effects of hyperglycaemia, hyperinsulinemia and inflammation on bone remodelling in type 2 diabetes mellitus.
Shahen V A,Gerbaix M,Koeppenkastrop S,Lim S F,McFarlane K E,Nguyen Amanda N L,Peng X Y,Weiss N B,Brennan-Speranza T C
Cytokine & growth factor reviews
Bones undergo continuous cycles of bone remodelling that rely on the balance between bone formation and resorption. This balance allows the bone to adapt to changes in mechanical loads and repair microdamages. However, this balance is susceptible to upset in various conditions, leading to impaired bone remodelling and abnormal bones. This is usually indicated by abnormal bone mineral density (BMD), an indicator of bone strength. Despite this, patients with type 2 diabetes mellitus (T2DM) exhibit normal to high BMD, yet still suffer from an increased risk of fractures. The activity of the bone cells is also altered as indicated by the reduced levels of bone turnover markers in T2DM observed in the circulation. The underlying mechanisms behind these skeletal outcomes in patients with T2DM remain unclear. This review summarises recent findings regarding inflammatory cytokine factors associated with T2DM to understand the mechanisms involved and considers potential therapeutic interventions.
10.1016/j.cytogfr.2020.04.001
Fracture risk assessment in diabetes mellitus.
Frontiers in endocrinology
Growing evidence suggests that diabetes mellitus is associated with an increased risk of fracture. Bone intrinsic factors (such as accumulation of glycation end products, low bone turnover, and bone microstructural changes) and extrinsic factors (such as hypoglycemia caused by treatment, diabetes peripheral neuropathy, muscle weakness, visual impairment, and some hypoglycemic agents affecting bone metabolism) probably contribute to damage of bone strength and the increased risk of fragility fracture. Traditionally, bone mineral density (BMD) measured by dual x-ray absorptiometry (DXA) is considered to be the gold standard for assessing osteoporosis. However, it cannot fully capture the changes in bone strength and often underestimates the risk of fracture in diabetes. The fracture risk assessment tool is easy to operate, giving it a certain edge in assessing fracture risk in diabetes. However, some parameters need to be regulated or replaced to improve the sensitivity of the tool. Trabecular bone score, a noninvasive tool, indirectly evaluates bone microstructure by analyzing the texture sparsity of trabecular bone, which is based on the pixel gray level of DXA. Trabecular bone score combined with BMD can effectively improve the prediction ability of fracture risk. Quantitative computed tomography is another noninvasive examination of bone microstructure. High-resolution peripheral quantitative computed tomography can measure volume bone mineral density. Quantitative computed tomography combined with microstructure finite element analysis can evaluate the mechanical properties of bones. Considering the invasive nature, the use of microindentation and histomorphometry is limited in clinical settings. Some studies found that the changes in bone turnover markers in diabetes might be associated with fracture risk, but further studies are needed to confirm this. This review focused on summarizing the current development of these assessment tools in diabetes so as to provide references for clinical practice. Moreover, these tools can reduce the occurrence of fragility fractures in diabetes through early detection and intervention.
10.3389/fendo.2022.961761
Diabetes Mellitus and Bone Metabolism.
Kasperk Christian,Georgescu Carmen,Nawroth Peter
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association
Diabetes mellitus and bone metabolism affect mesenchymal tissues and have numerous epidemiological and pathophysiological associations in common. Diabetes mellitus affects bone metabolism and increases fracture risk. The pathophysiological mechanims how type 1 and type 2 diabetes impair bone metabolism and bone strength may differ which is outlined in this review. Direct metabolic effects in additon to centrally controlled endocrine loops exert suppressive effects on bone formation and may also stimulate bone Resorption. Decreased bone formation in combination with increased bone resorption strongly increases fracture risk.
10.1055/s-0042-123036
The Impact of Diet on Bone and Fracture Risk in Diabetes.
Current osteoporosis reports
PURPOSE OF REVIEW:The purpose of this review is to summarize the recently published scientific evidence on the effects of diet on diabetes and skeletal health. RECENT FINDINGS:The impact of diet on overall health has been a growing topic of interest among researchers. An inappropriate eating habit is a relatively modified risk factor for diabetes in adults. Parallel with the significant increase in the incidence of diabetes mellitus worldwide, many studies have shown the benefits of lifestyle modifications, including diet and exercise for people with, or at risk of developing, diabetes. In the last years, accumulating evidence suggests that diabetes is a risk factor for bone fragility. As lifestyle intervention represents an effective option for diabetes management and treatment, there is potential for an effect on bone health. Healthy lifestyle is critical to prevent bone fragility. However, more studies are needed to fully understand the impact of diet and weight loss on fracture risk in diabetics.
10.1007/s11914-022-00725-y
Impact of diabetes mellitus simulations on bone cell behavior through in vitro models.
Li Yihan,Shrestha Annie,Zhang Hongmei,Li Lingjie,Li Dize,Fu Tiwei,Song Jinlin,Ji Ping,Huang Yuanding,Chen Tao
Journal of bone and mineral metabolism
Diabetes mellitus (DM) is related to impaired bone healing and an increased risk of bone fractures. While it is recognized that osteogenic differentiation and the function of osteoblasts are suppressed in DM, the influence of DM on osteoclasts is still unclear. Hyperglycemia and inflammatory environment are the hallmark of DM that causes dysregulation of various pro-inflammatory cytokines and alternated gene expression in periodontal ligament cells, osteoblasts, osteocytes, osteoclasts, and osteoclast precursors. A methodological review on conceptual and practical implications of in vitro study models is used for DM simulation on bone cells. Several major databases were screened to find literature related to the study objective. Published literature within last 20 years that used in vitro DM-simulated models to study how DM affects the cellular behavior of bone cells were selected for this review. Studies utilizing high glucose and serum acquired from diabetic animals are the mainly used methods to simulate the diabetic condition. The combination with various simulating factors such as lipopolysaccharide (LPS), hydrogen peroxide (HO), and advanced glycation end products (AGEs) have been reported in diabetic situations in vitro, as well. Through screening procedure, it was evident DM-simulated conditions exerted negative impact on bone-related cells. However, inconsistent results were found among different reported studies, which could be due to variation in culture conditions, concentrations of the stimulating factors and cell lineage, etc. This manuscript has concisely reviewed currently existing DM-simulated in vitro models and provides valuable insights of detailed components in simulating DM conditions in vitro. Studies using DM-simulated microenvironment revealed that in vitro simulation negatively impacted periodontal ligament cells, osteoblasts, osteocytes, osteoclasts, and osteoclast precursors. Contrarily, studies also indicated beneficial influence on bone-related cells when such conditions are reversed.
10.1007/s00774-020-01101-5
Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review.
Frontiers in endocrinology
One of the complications from chronic hyperglycemia and insulin resistance due to type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-gonadal axis in men is the high prevalence of hypogonadotropic hypogonadism (HH). Both T2DM and hypogonadism are associated with impaired bone health and increased fracture risk but whether the combination results in even worse bone disease than either one alone is not well-studied. It is possible that having both conditions predisposes men to an even greater risk for fracture than either one alone. Given the common occurrence of HH or hypogonadism in general in T2DM, a significant number of men could be at risk. To date, there is very little information on the bone health men with both hypogonadism and T2DM. Insulin resistance, which is the primary defect in T2DM, is associated with low testosterone (T) levels in men and may play a role in the bidirectional relationship between these two conditions, which together may portend a worse outcome for bone. The present manuscript aims to review the available evidences on the effect of the combination of hypogonadism and T2DM on bone health and metabolic profile, highlights the possible metabolic role of the skeleton, and examines the pathways involved in the interplay between bone, insulin resistance, and gonadal steroids.
10.3389/fendo.2020.607240
Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility.
Eller-Vainicher C,Cairoli E,Grassi G,Grassi F,Catalano A,Merlotti D,Falchetti A,Gaudio A,Chiodini I,Gennari L
Journal of diabetes research
Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients.
10.1155/2020/7608964
The Emerging Role of Bone-Derived Hormones in Diabetes Mellitus and Diabetic Kidney Disease.
Frontiers in endocrinology
Diabetic kidney disease (DKD) causes the greatest proportion of end-stage renal disease (ESRD)-related mortality and has become a high concern in patients with diabetes mellitus (DM). Bone is considered an endocrine organ, playing an emerging role in regulating glucose and energy metabolism. Accumulating research has proven that bone-derived hormones are involved in glucose metabolism and the pathogenesis of DM complications, especially DKD. Furthermore, these hormones are considered to be promising predictors and prospective treatment targets for DM and DKD. In this review, we focused on bone-derived hormones, including fibroblast growth factor 23, osteocalcin, sclerostin, and lipocalin 2, and summarized their role in regulating glucose metabolism and DKD.
10.3389/fendo.2022.938830
Impact of Diabetes Mellitus on Bone Health.
Murray Cliodhna E,Coleman Cynthia M
International journal of molecular sciences
Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field.
10.3390/ijms20194873
The pathologic continuum of diabetic vascular disease.
Orasanu Gabriela,Plutzky Jorge
Journal of the American College of Cardiology
Hyperglycemia can promote vascular complications by multiple mechanisms, with formation of advanced glycation end products and increased oxidative stress proposed to contribute to both macrovascular and microvascular complications. Many of the earliest pathologic responses to hyperglycemia are manifest in the vascular cells that directly encounter elevated blood glucose levels. In the macrovasculature, these include endothelial cells and vascular smooth muscle cells. In the microvasculature, these include endothelial cells, pericytes (in retinopathy), and podocytes (in renal disease). Additionally, neovascularization arising from the vasa vasorum may promote atherosclerotic plaque progression and contribute to plaque rupture, thereby interconnecting macroangiopathy and microangiopathy.
10.1016/j.jacc.2008.09.055
The osteocyte as a signaling cell.
Physiological reviews
Osteocytes, former osteoblasts encapsulated by mineralized bone matrix, are far from being passive and metabolically inactive bone cells. Instead, osteocytes are multifunctional and dynamic cells capable of integrating hormonal and mechanical signals and transmitting them to effector cells in bone and in distant tissues. Osteocytes are a major source of molecules that regulate bone homeostasis by integrating both mechanical cues and hormonal signals that coordinate the differentiation and function of osteoclasts and osteoblasts. Osteocyte function is altered in both rare and common bone diseases, suggesting that osteocyte dysfunction is directly involved in the pathophysiology of several disorders affecting the skeleton. Advances in osteocyte biology initiated the development of novel therapeutics interfering with osteocyte-secreted molecules. Moreover, osteocytes are targets and key distributors of biological signals mediating the beneficial effects of several bone therapeutics used in the clinic. Here we review the most recent discoveries in osteocyte biology demonstrating that osteocytes regulate bone homeostasis and bone marrow fat via paracrine signaling, influence body composition and energy metabolism via endocrine signaling, and contribute to the damaging effects of diabetes mellitus and hematologic and metastatic cancers in the skeleton.
10.1152/physrev.00043.2020
Type 2 diabetes and the skeleton: new insights into sweet bones.
Shanbhogue Vikram V,Mitchell Deborah M,Rosen Clifford J,Bouxsein Mary L
The lancet. Diabetes & endocrinology
Substantial evidence shows that skeletal fragility should be considered among the complications associated with type 2 diabetes. Individuals with type 2 diabetes have increased fracture risk, despite normal bone mineral density (BMD) and high BMI-factors that are generally protective against fractures. The mechanisms underlying skeletal fragility in diabetes are not completely understood, but are multifactorial and likely include effects of obesity, hyperglycaemia, oxidative stress, and accumulation of advanced glycation end products, leading to altered bone metabolism, structure, and strength. Clinicians should be aware that BMD measurements underestimate fracture risk in people with type 2 diabetes, and that new treatments for diabetes, with neutral or positive effects on skeletal health, might play a part in the management of diabetes in those at high risk of fracture. Data for the optimum management of osteoporosis in patients with type 2 diabetes are scarce, but in the absence of evidence to the contrary, physicians should follow guidelines established for postmenopausal osteoporosis.
10.1016/S2213-8587(15)00283-1
Bone fragility in diabetes: novel concepts and clinical implications.
Hofbauer Lorenz C,Busse Björn,Eastell Richard,Ferrari Serge,Frost Morten,Müller Ralph,Burden Andrea M,Rivadeneira Fernando,Napoli Nicola,Rauner Martina
The lancet. Diabetes & endocrinology
Increased fracture risk represents an emerging and severe complication of diabetes. The resulting prolonged immobility and hospitalisations can lead to substantial morbidity and mortality. In type 1 diabetes, bone mass and bone strength are reduced, resulting in up to a five-times greater risk of fractures throughout life. In type 2 diabetes, fracture risk is increased despite a normal bone mass. Conventional dual-energy x-ray absorptiometry might underestimate fracture risk, but can be improved by applying specific adjustments. Bone fragility in diabetes can result from cellular abnormalities, matrix interactions, immune and vascular changes, and musculoskeletal maladaptation to chronic hyperglycaemia. This Review summarises how the bone microenvironment responds to type 1 and type 2 diabetes, and the mechanisms underlying fragility fractures. We describe the value of novel imaging technologies and the clinical utility of biomarkers, and discuss current and future therapeutic approaches that protect bone health in people with diabetes.
10.1016/S2213-8587(21)00347-8
Bone disease in diabetes: another manifestation of microvascular disease?
Shanbhogue Vikram V,Hansen Stinus,Frost Morten,Brixen Kim,Hermann Anne P
The lancet. Diabetes & endocrinology
Type 1 and type 2 diabetes are generally accepted to be associated with increased bone fracture risk. However, the pathophysiological mechanisms of diabetic bone disease are poorly understood, and whether the associated increased skeletal fragility is a comorbidity or a complication of diabetes remains under debate. Although there is some indication of a direct deleterious effect of microangiopathy on bone, the evidence is open to question, and whether diabetic osteopathy can be classified as a chronic, microvascular complication of diabetes remains uncertain. Here, we review the current knowledge of potential contributory factors to diabetic bone disease, particularly the association between diabetic microangiopathy and bone mineral density, bone structure, and bone turnover. Additionally, we discuss and propose a pathophysiological model of the effects of diabetic microvascular disease on bone, and examine the progression of bone disease alongside the evolution of diabetes.
10.1016/S2213-8587(17)30134-1
Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus.
Nature reviews. Endocrinology
Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.
10.1038/s41574-021-00555-5
Mechanisms of diabetes mellitus-induced bone fragility.
Napoli Nicola,Chandran Manju,Pierroz Dominique D,Abrahamsen Bo,Schwartz Ann V,Ferrari Serge L,
Nature reviews. Endocrinology
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.
10.1038/nrendo.2016.153
Microvascular Dysfunction in Diabetes Mellitus and Cardiometabolic Disease.
Horton William B,Barrett Eugene J
Endocrine reviews
This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.
10.1210/endrev/bnaa025