glucagon-like-peptide-1 and Fractures--Bone

Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture.. To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist.. Population-based new-user cohort study.. Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015.. Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist.. The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR).. 79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]).. Unmeasured confounding, measurement error, and low fracture rate.. In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists.. Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

Topics: Aged; Canagliflozin; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Fractures, Bone; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors

The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans.

Topics: Animals; Bone and Bones; Bone Density; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Obesity; Osteoblasts; Osteocalcin; Osteoclasts

Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.

Topics: Animals; Bone Remodeling; Comorbidity; Diabetes Mellitus, Type 2; Disease Models, Animal; Fractures, Bone; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Mice; Mice, Knockout

Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF-β/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed antidiabetic drugs include incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, and GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic-lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Fractures, Bone; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Like Growth Factor I; Metformin

This review summarizes current knowledge about glucagon-like peptide 1 receptor agonists (GLP-1 RA) and their effects on bone metabolism and fracture risk. Recent in vivo and in vitro experiments indicated that GLP-1 RA could improve bone metabolism. GLP-1 could affect the fat-bone axis by promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone mesenchymal precursor cells (BMSCs), which express the GLP-1 receptor. GLP-1 RA may also influence the balance between osteoclasts and osteoblasts, thus leading to more bone formation and less bone resorption. Wnt/β-catenin signalling is involved in this process. Mature osteocytes, which also express the GLP-1 receptor, produce sclerostin which inhibits Wnt/β-catenin signalling by binding to low density lipoprotein receptor-related protein (LRP) 5 and preventing the binding of Wnt. GLP-1 RA also decreases the expression of sclerostin (SOST) and circulating levels of SOST. In addition, GLP-1 receptors are expressed in thyroid C cells, where GLP-1 induces calcitonin release and thus indirectly inhibits bone resorption. Furthermore, GLP-1 RA influences the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system by increasing OPG gene expression, and thus reverses the decreased bone mass in rats models. However, a recent meta-analysis and a cohort study did not show a significant relationship between GLP-RA use and fracture risk. Future clinical trials will be necessary to investigate thoroughly the relationship between GLP-1 RA use and fracture risk in diabetic patients.

Topics: Animals; beta Catenin; Bone Density; Calcitonin; Diabetes Mellitus, Type 2; Fractures, Bone; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Osteoporosis; RANK Ligand; Risk; Wnt Signaling Pathway

Traditional anti-diabetic drugs may have negative or positive effects on risk of bone fractures. Yet the relationship between the new class glucagon-like peptide-1 receptor agonists (GLP-1 RA) and risk of bone fractures has not been established. We performed a meta-analysis including randomized controlled trials (RCT) to study the risk of bone fractures associated with liraglutide or exenatide, compared to placebo or other active drugs. We searched MEDLINE, EMBASE, and clinical trial registration websites for published or unpublished RCTs comparing the effects of liraglutide or exenatide with comparators. Only studies with disclosed bone fracture data were included. Separate pooled analysis was performed for liraglutide or exenatide, respectively, by calculating Mantel-Haenszel odds ratio (MH-OR). 16 RCTs were identified including a total of 11,206 patients. Liraglutide treatment was associated with a significant reduced risk of incident bone fractures (MH-OR=0.38, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (MH-OR=2.09, 95% CI 1.03-4.21). Publication bias and heterogeneity between studies were not observed. Our study demonstrated a divergent risk of bone fractures associated with different GLP-1 RA treatments. The current findings need to be confirmed by future well-designed prospective or RCT studies.

Topics: Diabetes Mellitus, Type 2; Exenatide; Fractures, Bone; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk; Venoms

Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of bone fractures independent of the use of antidiabetic medications. Furthermore, antidiabetic medications could directly affect bone metabolism. Recently, the use of dipeptidyl peptidase-4 inhibitors has been associated with a lower rate of bone fracture. The aim of the present meta-analysis was to assess whether patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP-1Ra) present a lower incidence of bone fracture compared with patients using other antidiabetic drugs.. A search on Medline, Embase, and http://www.clinicaltrials.gov, as well as a manual search for randomized clinical trials of T2DM treated with either a GLP-1Ra or another antidiabetic drug for a duration of ≥24 weeks was conducted by two authors (GM, AM) independently.. Although 28 eligible studies were identified, only seven trials reported the occurrence of at least a bone fracture in one arm of the trial. The total number of fractures was 19 (13 and six with GLP-1Ra and comparator, respectively). The pooled Mantel-Haenszel odds ratio for GLP-1Ra was 0.75 (95% confidence interval 0.28-2.02, P = 0.569) in trials versus other antidiabetic agents.. Although preliminary, our study highlighted that the use of GLP-1Ra does not modify the risk of bone fracture in T2DM compared with the use of other antidiabetic medications.

Topics: Diabetes Mellitus, Type 2; Exenatide; Fractures, Bone; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Treatment Outcome; Venoms

This review considers the therapeutic choices currently faced by people with type 2 diabetes and those caring for them when glucose levels initially controlled with lifestyle management and metformin start to rise. While sulphonylureas are familiar agents and cheaper than other alternatives, they cause hypoglycaemia and modest weight gain, and robust outcome data are still lacking. Dipeptidyl peptidase 4 inhibitors ('gliptins') have an attractive pharmacological and adverse effect profile, but their effects on the cardiovascular system are also uncertain. Thiazolidinediones ('glitazones') are effective glucose-lowering agents, but cause weight gain and increase the risk of fracture, while the cardiovascular benefits hoped for in association with 'insulin-sensitization' have not been as expected. Glucagon-like peptide-1 agonists will not be acceptable as initial second-line agents for many people as they are injectable rather than oral. Well-powered 'head-to-head' clinical trials of adequate duration are therefore required to allow evidence-based decisions on second-line therapy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Fractures, Bone; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Metformin; Risk Factors; Sulfonylurea Compounds; Thiazolidinediones; Weight Gain

Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Animals; Bone and Bones; Bone Density; Fractures, Bone; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Mice

To evaluate the correlation between levels of serum vitamin D and glucagon-like peptide-1 (GLP-1) in elderly patients with bone fractures.. This study included 56 patients and 31 control subjects. The patients included were those aged ≥65 years who were admitted to our hospital with a diagnosis of bone fracture. The control group comprised age-matched, healthy individuals. Levels of serum vitamin D and GLP-1 were measured and compared between the 2 groups.. Significant differences were noted between the groups in terms of serum levels of vitamin D (p < 0.001) and serum levels of GLP-1 (p < 0.001). A positive correlation was observed between serum levels of vitamin D and GLP-1.. Serum levels of GLP-1 were found to be significantly lower in elderly patients with bone fracture compared to healthy adults. In addition, a significant correlation was found between decreased vitamin D and GLP-1 levels. These results may therefore demonstrate the protective effects of GLP-1 on bone structure and metabolism, similar to those of vitamin D.

Topics: Aged; Aged, 80 and over; Female; Fractures, Bone; Glucagon-Like Peptide 1; Humans; Ketone Bodies; Male; Vitamin D