Article

Effects of Glucagon‐Like Peptide‐1 Receptor Agonist on Bone Mineral Density and Bone Turnover Markers: A Meta‐Analysis

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Abstract

Aims Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) may promote bone formation, but conversely, they could also weaken bones due to the reduction in mechanical load associated with weight loss. However, the clinical effects in humans have not been clearly demonstrated. This meta‐analysis aimed to evaluate whether GLP‐1RAs affect BMD and bone turnover markers. Material and Methods PubMed, Embase, and Scopus were searched on June 13, 2024. The eligibility criteria were: (1) human studies, (2) receiving a GLP‐1RA for more than 4 weeks, (3) an untreated control group or a placebo group, (4) reporting of at least one BMD or bone turnover marker, and (5) an RCT design. The risk of bias was assessed using the Cochrane risk of bias 2 tool. Fixed‐ or random‐effects meta‐analysis was performed according to heterogeneity. Results Seven studies were included in the meta‐analysis. GLP‐1RAs did not significantly change BMD in the femoral neck (mean difference [MD], 0.01 g/cm ² ; 95% CI, −0.01–0.04 g/cm ² ), in the total hip (MD, −0.01 g/cm ² ; 95% CI, −0.02–0.01 g/cm ² ), and in the lumbar spine (MD, 0 g/cm ² ; 95% CI, −0.02–0.02 g/cm ² ). C‐terminal telopeptide of type 1 collagen (CTX), a bone resorption marker, significantly increased after GLP‐1RA treatment (MD, 0.04 μg/L; 95% CI, 0.01–0.07 μg/L). GLP‐1RAs did not significantly change bone formation markers such as procollagen type 1 N‐terminal propeptide, bone‐specific alkaline phosphatase, osteocalcin. Conclusions GLP‐1RA did not affect BMD and bone formation markers. However, GLP‐1RAs led to a significant increase in CTX.

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Background Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. Methods This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < −1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Findings Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m² (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 μg/L [95% CI −5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 μg/L versus placebo 62.3 μg/L [95% CI −10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5–307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine −0.018 g/cm³ [95% CI −0.031 to −0.005]; p = 0.007); ETD total hip −0.020 g/cm² ([95% CI −0.032 to −0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [−0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD −6.8 kg [95% CI −8.8 to −4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. Interpretation In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Funding 10.13039/501100024075Region of Southern Denmark, 10.13039/501100009708Novo Nordisk Foundation, and 10.13039/501100008218Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.
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Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Article
Aims To evaluate the association between glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and the risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). Materials and methods We conducted a systematic literature search in PubMed, Embase, the Cochrane Library, and Web of Science from inception to February 28, 2018, and identified eligible randomized controlled trials. The following data were extracted from each study: first author, year of publication, sample size, patient characteristics, study design, intervention drug, control drug, follow‐up time, and incident bone fracture events. A meta‐analysis was conducted using Review Manager 5.3 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for dichotomous variables. Results A total of 38 studies with 39, 795 patients with T2DM were included. There were 241 incident bone fracture cases (107 in the GLP‐1 RAs group and 134 in the control group). Compared with patients who received placebo and other anti‐diabetic drugs, those who received GLP‐1 RAs treatment showed a pooled OR of 0.71 (95% CI, 0.56‐0.91) for bone fracture. Subgroup analysis showed that treatments with liraglutide and lixisenatide were associated with significantly reduced risk of bone fractures (ORs, 0.56 [95% CI, 0.38‐0.81] and 0.55 [95% CI, 0.31‐0.97], respectively). However, other GLP‐1 RAs did not show superiority to placebo or other anti‐diabetic drugs. Moreover, these beneficial effects were dependent on the duration of GLP‐1 RAs treatment, only a GLP‐1 RAs treatment period of > 52 weeks could significantly lower the risk of bone fracture in patients with T2DM (OR, 0.71; 95% CI, 0.56‐0.91). Conclusions Compared with placebo and other anti‐diabetic drugs, liraglutide and lixisenatide were associated with a significant reduction in the risk of bone fractures, and the beneficial effects were dependent on the duration of treatment.
Article
Objective This study aimed to investigate the effects of liraglutide on bone metabolism markers in rat models with glucocorticoid-induced osteoporosis (GIOP), including the effects on bone mass, bone tissue microstructure, bone biomechanics, and bone turnover markers. Method Thirty male Sprague–Dawley rats aged 8 weeks were randomly divided into three groups: the control group (n = 10) was intramuscularly injected with an equal volume of 0.9% sodium chloride, the dexamethasone group (n = 10) was intramuscularly injected with dexamethasone at 1 mg/kg (twice a week) to induce GIOP, the dexamethasone plus liraglutide group (n = 10) was subcutaneously injected with liraglutide at 200 μg/kg daily, simultaneously. The bilateral femurs and the fifth lumbar vertebrae were collected after 12 weeks to perform micro-computed tomography and bone biomechanical examinations. Also, tartrate-resistant acid phosphatase (TRACP), cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I), alkaline phosphatase (ALP), and osteocalcin (OC) were tested. Results The bone mineral density (BMD), bone microstructure, and bone biomechanical markers reduced significantly in the dexamethasone group compared with the control group. The bone resorption indicators (TRACP and CTX-I) increased, while the bone formation indicators (ALP and OC) decreased. After liraglutide treatment, BMD, bone microstructure, and bone biomechanical markers improved significantly. Moreover, TRACP and CTX-I decreased significantly, while ALP and OC increased compared with the dexamethasone group. Conclusions Liraglutide improved BMD, bone microstructure, and bone strength and reversed GIOP, primarily through the reduction of bone resorption and promotion of bone formation.
Article
Introduction: Drug-induced bone loss remains the major cause of vertebral and hip fractures and significantly associated to morbidity and mortality. This article will review the common drugs identified as the causes of bone loss and the risk factors and management in European countries. Areas covered: Apart from glucorticoid - the most reputed cause of osteoporosis, many different drugs could cause harmful skeletal disorders. The antiepileptics, hormonal therapy, GnRH antagonists, aromatase inhibitors are well-known cause of bone loss. Osteoporosis and fractures risk also increased with calcineurin inhibitors, antiretroviral drugs, selective inhibitors of serotonin reuptake, loop diuretics, heparins, oral anticoagulants, high doses of thyroxine and proton pump inhibitors. Expert opinion: Drugs are an important secondary cause of osteoporosis. Healthcare professionals should routinely reassess the requirement for drugs and use the lowest dosage and shortest duration. Lifestyle changes, adequate calcium, vitamin D supplement or initiation of the osteoporotic treatment should be recommended after initiation of high-risk agents. Appropriate monitoring of bone status and initiating osteoporosis treatment if indicated are recommended when drugs having potential deleterious effects on bone are used, particularly in high-risk patients. The update and further studies would provide concluded evidences of controversial drugs induced bone loss and determine the best prevention and treatment strategies.
Article
Liraglutide, a glucagon-like peptide-1 receptor agonist, is an anti-diabetic medicine associated with a reduced risk of fracture in diabetic patients. In the present study, rats with streptozotocin (STZ)-induced diabetes and/or bilateral ovariectomy (OVX) were treated with liraglutide for eight weeks. Liraglutide treatment increased insulin secretion and managed blood glucose levels in the rats following STZ-induced diabetes. In addition, STZ- and OVX-induced reduction of femoral bone mineral density and destruction of bone microarchitecture were alleviated by liraglutide. STZ decreased, whereas OVX increased, serum osteocalcin (OC) level (a bone formation marker) and osteoblast counts in the trabecular bone. OVX, however not STZ, markedly increased the level of serum c-terminal telopeptide of type 1 collagen (CTX-1, a bone resorption marker) and osteoclast counts in the trabecular area. Liraglutide treatment significantly increased serum OC levels in all three osteoporotic models, however had minimal effects on osteoblast counts. Furthermore, liraglutide significantly decreased serum CTX-1 level and osteoclast numbers in OVX and STZ+OVX rats. Furthermore, the present study examined the mRNA expression and serum concentrations of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL), and liraglutide significantly decreased the RANKL/OPG ratio compared with the untreated rats, indicating that osteoclastogenesis was inhibited by liraglutide. In summary, the results suggested that liraglutide ameliorates STZ+OVX-induced bone deterioration in the rat model, primarily through the inhibition of osteoclastogenesis. These preliminary findings propose a potentially beneficial effect of liraglutide on the bone health of postmenopausal diabetic patients.
Article
Objective: There is growing evidence that weight loss is associated with increased fracture risk in the general population. As patients with diabetes often lose weight intentionally or unintentionally, we aimed to investigate prospectively the relationship between weight loss from maximum body weight and fracture risk. Research design and methods: A total of 4,706 Japanese participants with type 2 diabetes (mean age 66 years), including 2,755 men and 1,951 postmenopausal women, were followed for a median of 5.3 years and were divided according to weight loss from maximum weight: <10%, 10% to <20%, 20% to <30%, and ≥30%. The primary outcomes were fragility fractures defined as fractures at sites of hip and spine. Results: During the follow-up period, fragility fractures occurred in 198 participants. The age- and sex-adjusted incidence rates per 1,000 person-years in all participants were 6.4 (<10% weight loss from maximum body weight), 7.8 (10% to <20%), 11.7 (20% to <30%), and 19.2 (≥30%) (Pfor trend <0.001). Multivariate-adjusted hazard ratios for fragility fractures compared with reference (<10% weight loss) were 1.48 ([95% CI] 0.79-2.77) in the 10% to <20% group, 2.23 (1.08-4.64) in 20% to <30%, and 5.20 (2.15-12.57) in ≥30% in men, and 1.19 (0.78-1.82) in 10% to <20%, 1.62 (0.96-2.73) in 20% to <30%, and 1.97 (0.84-4.62) in ≥30% in postmenopausal women. Conclusions: The current study demonstrates that ≥20% body weight loss from maximum weight is a significant risk factor for fragility fractures in patients with type 2 diabetes, especially in men.
Article
Type 2 diabetes mellitus prevalence and morbidity are increasing. Osteoporotic fractures are among the 'non-classical' complications of diabetes and been overlooked for a long time, maybe because of their complex diagnostic and therapeutic approach. The usual tools for preventing fragility fractures (such as the fracture risk assessment tool and bone densitometry) underestimate risk of fractures in type2 diabetic patients. New techniques, such as trabecular bone score or bone turnover markers, could be useful, but greater scientific evidence is required to recommend their use in clinical practice. The special characteristics of their pathophysiology result in decreased bone remodeling with normal or even increased bone mineral density, but with low quality. These changes lead to the occurrence of osteoporotic fractures without evidence of densitometric changes, which could be called 'the diabetic paradox'. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.
Article
Objective: Patients with type 2 diabetes have an increased risk of fragility fractures; the cause is unclear but is likely multifactorial. Some diabetes treatments induce bone loss, accentuating underlying skeletal fragility and increasing fracture risk. This subgroup analysis aimed to compare long-term effects of liraglutide and glimepiride on bone mineral density (BMD) in patients with type 2 diabetes. Methods: LEAD-3, a 52-week, double-blind, active-control, phase III, multicenter trial, investigated the efficacy of liraglutide (1.2 and 1.8 mg/day) versus glimepiride monotherapy in type 2 diabetes. A 52-week, open-label extension followed, in which participants remained on randomized therapy. A subgroup of participants underwent BMD measurement by dual-energy X-ray absorptiometry at baseline, 52, and 104 weeks. The main outcome measure was change from baseline in total body BMD at 52 and 104 weeks, assessed by analysis of covariance. Results: A total of 746 patients with type 2 diabetes aged 19 to 79 years were randomized into the main trial. Of these, 61 patients (20 assigned to liraglutide 1.8 mg/day, 23 to liraglutide 1.2 mg/day, 18 to glimepiride 8 mg/day) had BMD measurements. Baseline age, body mass index, diabetes duration, glycated hemoglobin, and total BMD were similar across treatment groups. There was no apparent difference in mean total BMD change from baseline in patients receiving liraglutide 1.8 or 1.2 mg/day or glimepiride 8 mg/day at 52 or 104 weeks. Conclusion: In this small subgroup analysis, liraglutide monotherapy did not negatively affect total BMD in a 2-year prospective study, suggesting it may not exacerbate the consequences of bone fragility.
Article
Context: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). Objective: To describe the effects of canagliflozin on bone fracture risk. Design and setting: Randomized phase 3 studies in patients with T2DM. Patients and interventions: Canagliflozin 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N=10194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, CANagliflozin cardioVascular Assessment Study [CANVAS]; N=4327) and a pooled population of 8 non-CANVAS studies (N=5867). Outcome: Measures: Incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs were assessed. Results: The incidence of fractures was similar with canagliflozin (1.7%) and non- canagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) versus placebo (2.6%) that was balanced between upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) versus non-canagliflozin (1.9%) in the overall population that was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. Conclusions: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with prior history/risk of cardiovascular disease, and with lower baseline eGFR and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.
Article
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 fat-bone axis by promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone mesenchymal precursor cells (BMSCs), which express GLP-1 receptor. GLP-1 RA may also influence the balance between osteoclasts and osteoblast, thus lead to more bone formation and less bone resorption. Wnt/β-catenin signaling is involved in this course. Mature osteocytes, which also express GLP-1 receptor, produce sclerostin which inhibits Wnt/β-catenin signaling 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 SOST/sclerostin and circulating levels of sclerostin. 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, 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 deeply investigate the relationship between GLP-1 RA use and fracture risk in diabetic patients.
Article
Exendin-4 was found to be beneficial to the skeleton in diabetic rodents. In this study, we assessed the changes of bone mineral densities (BMDs) and quality in non-diabetic ovariectomized (OVX) rats after treatment with exendin-4. The regulatory role of exendin-4 on osteoblastogenesis and adipogenesis in rat bone marrow stromal cells (BMSCs) was also explored. Three months after sham surgery or OVX, 18 5-month-old female Wistar rats were divided into three groups and received the following treatment for 8 weeks: (1) Sham + vehicle; (2) OVX + vehicle; and (3) OVX + exendin-4 20 µg/kg/day. Micro-CT and three-point bending test were used to evaluate the BMDs, bone morphometric parameters, and biomechanical properties. Real-time PCR and Western blot were performed to measure gene and protein expression after exendin-4 treatment in adipogenesis and osteoblastogenesis of rat BMSCs. Exendin-4 could improve trabecular volume, thickness, and number, increase BMD, and reduce trabecular spacing in the lumbar spine and femur of OVX rats. Exendin-4 had little impact on the mechanical resistance of femurs to fracture. When rat BMSCs were treated with exendin-4, the mRNA expression levels of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and collagen α1 (Coll-1) were increased, while those of peroxisome proliferators activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBPα) decreased. Exendin-4 treatment also resulted in increased expression levels of p38, p42/44, and β-catenin proteins. Exendin-4 was anabolic to bone in OVX rats possibly by facilitating osteoblastogenesis while repressing adipogenesis during BMSC lineage differentiation.
Article
Recent studies indicate that glucagon-like peptide 1 (GLP-1) regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. To investigate the role of GLP-1 RAs on bone formation and weight loss induced bone mass reductions. Randomized control study. Out-patient research hospital clinic. Thirty-seven healthy obese women. BMI 34±0.5 kg/m(2), age 46±2 years. After a low-calorie diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2mg/day) for 52 weeks. In case of weight gain, up to two meals per day could be substituted with a low-calorie diet product in order to maintain the weight loss. Total, pelvic and arm-leg bone mineral content (BMC) and bone markers (CTX-1 and P1NP) were investigated before, after weight loss and after 52 weeks weight maintenance. Primary end points: Change in BMC and bone markers after 52 weeks weight maintenance with or without GLP-1 RA treatment. Total, pelvic and arm-leg BMC decreased during weight maintenance in the control group (p<0.0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was 4 times greater in the control group compared to the liraglutide group (estimated difference 27g (95% CI 5-48), p=0.01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7±3 μg/L) vs a 2% (-1±4 μg/L) decrease in the control group (p<0.05). The bone resorption marker CTX-1 did not change during the weight loss maintenance phase. Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low calorie-diet, supporting its role as a safe weight-lowering agent.
Article
The aim of this study is to compare the antiresorptive effect of hormone therapy and oral ibandronate in postmenopausal osteoporotic women by measuring bone mineral density (BMD) and degradation products of C-terminal telopeptide of type I collagen (CTX) using serum crosslaps ELISA. The study is a randomized comparative trial. About 60 women with age > 40 years, having either surgical or medical menopause with T- or Z-score below -2.5 SD were included in the study. They were randomized into two groups of 30 each; one group received conventional hormone therapy (group I) and the other group received ibandronate monthly (group II). The treatment was given for 6 months. The BMD increased from 0.894 g/cm(2) to 0.933 g/cm(2) (p < 0.01) in group I and from 0.865 g/cm(2) to 0.934 g/cm(2) (p < 0.01) in group II. The increase in BMD in group I (4.3%) was less than group II (7.9%) which was significant (p < 0.01). The serum CTX levels also showed significant reduction in both groups after 6 months of therapy; more reduction was seen in group II as compared to group I (41.5% vs. 4.6%, p < 0.01). Ibandronate can be used as a substitute to hormone therapy in women presenting with osteoporosis. Long-term studies are needed to authenticate the observation. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Article
Objective: The use of thiazolidinediones (TZDs) has been associated with increased fracture risk. We performed a comprehensive literature review and meta-analysis to estimate the risk of fractures with TZDs Methods: We searched MEDLINE, Embase and the Cochrane Database, from inception to May 2014. We included all randomized trials that described the risk of fractures or changes in bone mineral density (BMD) with TZDs. We pooled data with odds ratios (ORs) for fractures and the weighted mean difference in BMD. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I(2) statistic. Results: We included 24,544 participants with 896 fracture cases from 22 randomized controlled trials. Meta-analysis showed that the significantly increased incidence of fracture was found in women (OR=1.94; 95%CI: 1.60-2.35; P<0.001), but not in men (OR=1.02; 95%CI: 0.83-1.27; P=0.83). For women, the fracture risk was similar in rosiglitazone (OR=2.01; 95%CI: 1.61-2.51; P<0.001) and pioglitazone (OR=1.73; 95%CI: 1.18-2.55; P=0.005) treatment and appeared to be similar for participants aged <60years old (OR=1.89; 95%CI: 1.51-2.36; P<0.001) and aged ≥60years old (OR=2.07; 95%CI: 1.51-2.36; P<0.001). There was a non-significant trend towards increased risk of fractures in different cumulative durations of TZD exposure. TZD treatment was also associated with significant changes in BMD among women at the lumbar spine(weighted mean difference: -0.49%, 95%CI: -0.66% to -0.32%; P<0.001), the femoral neck (weighted mean difference: -0.34%, 95%CI: -0.51% to -0.16%; P<0.001) and the hip(weighted mean difference: -0.33%, 95%CI: -0.52% to -0.14%; P<0.001). Conclusions: Our results suggest that TZD treatment is associated with an increased risk of fractures in women, effects of rosiglitazone and pioglitazone are similar, fracture risk is independent of age and fracture risk has no clear association with duration of TZD exposure.
Article
Patients suffering from type 2 diabetes mellitus (T2DM) present a higher risk of suffering from bone fracture independently of the anti-diabetic medications usage. Furthermore, anti-diabetic 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 GLP-1 receptor agonists (GLP-1Ra) present a lower incidence of bone fracture as compared with other anti-diabetic drugs. A search on Medline, Embase, www.clinicaltrials.gov and hand-search for randomized clinical trials of T2DM treated with either a GLP-1Ra or another anti-diabetic drug for a duration of ≥24 weeks was conducted by two authors independently. Although we identified 28 eligible studies, only 7 trials reported occurrence of at least a bone fracture in one arm of the trial. The total number of fractures was 19 (13 and 6 with GLP-1Ra and comparator, respectively). The pooled Mantel-Haenszel odd ratio for GLP-1Ra was 0.75 (95% CI 0.28-2.02, p=0.569) in trials versus other anti-diabetic agents. Although in a preliminary manner, our study highlighted that the use of GLP-1Ra did not modify the risk of bone fracture in T2DM as compared with other anti-diabetic medications.
Article
Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have anti-osteoporotic effects, especially in aged postmenopausal situation, is not confirmed yet. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX) induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 were administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks treatment of exendin-4 slowed down the body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced the bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased urinary DPD/creatinine ratio and serum CTX-I and increased serum ALP, OC and P1NP levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing OPG/RANKL ratio, but also promoted bone formation by increasing the expressions of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous anti-osteoporotic agents. In conclusion, these findings demonstrated for the first time the anti-osteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis. © 2013 American Society for Bone and Mineral Research.
Article
Aim: Glucagon-like peptide-1 (GLP-1) receptor participates in the control of bone resorption in GLP-1 knockout mice. Also, GLP-1 induces an insulin- and parathyroid hormone-independent osteogenic action through osteoclasts and osteoblasts in insulin-resistant and type 2 diabetic rats. Osteocytes are now considered central to bone homeostasis. A secreted product of osteocytes, sclerostin, inhibits bone formation. However, the effect of GLP-1 on osteocytes remains unclear. Therefore, we investigated the effect of GLP-1 on bone mineral density (BMD), and the cellular and molecular mechanisms associated with osteocytes. Main methods: We investigated the presence of GLP-1 receptors in osteocyte-like MLO-Y4 cells and osteocytes of rat femurs through RT-PCR, Western blot and confocal microscopy, and investigated the effect of exendin-4 on the expression of mRNA (by quantitative real-time RT-PCR) and protein (by Western blot) of SOST/sclerostin in osteocyte-like MLO-Y4 cells during culture under normal or high-glucose (30 mM) conditions, and measured circulating levels of sclerostin, osteocalcin, and tartrate-resistant alkaline phosphatase (TRAP) 5b and femoral BMD in type 2 diabetic OLETF rats treated with exendin-4. Key findings: GLP-1 receptor was present on MLO-Y4 cells and osteocytes of rat femurs. Exendin-4 reduced the mRNA expression and protein production of SOST/sclerostin under normal or high-glucose conditions in MLO-Y4 cells. Exendin-4 reduced serum levels of sclerostin, increased serum levels of osteocalcin, and increased femoral BMD in type 2 diabetic OLETF rats. Significance: These findings suggest that exendin-4 might increase BMD by decreasing the expression of SOST/sclerostin in osteocytes in type 2 diabetes.
Article
In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ∼2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.
Article
Intentional weight loss is an important component of treatment for overweight patients with type 2 diabetes, but the effects on bone density are not known. We used data from the Look AHEAD trial to determine the impact of an intensive lifestyle weight loss intervention (ILI) compared with diabetes support and education (DSE) on changes in bone mineral density (BMD) over 12 months. Overweight and obese adults with type 2 diabetes were randomly assigned to ILI or DSE. In a substudy of BMD conducted at 5 of 16 clinical centers, hip, spine, and whole body dual X-ray absorptiometry scans were obtained at baseline and 1-year later on 642 of 739 ILI and 632 of 740 DSE participants. At baseline, mean age was 58.4 years, and average body mass index was 35.2 kg/m(2). Total hip BMD T-score was <-2.5 in 1% and <-1.0 in 8%. At 1 year, weight loss was greater in ILI than DSE (-8.6% versus -0.7%), and glycemic control and fitness were also improved. Bone loss over 1 year was greater in ILI at the total hip (-1.4% versus -0.4%; p < 0.001) and femoral neck (-1.5% versus -0.8%; p = 0.009), but change in BMD for the lumbar spine and whole body did not differ between groups. In ILI, bone loss at the total hip was independently associated with weight loss in men and women and with poorer glycemic control in men, but was not associated with changes in fitness. One year of an intensive lifestyle intervention in adults with type 2 diabetes, resulting in weight loss, was associated with a modest increase in hip bone loss despite improved fitness and glycemic control.
Article
The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation.
Article
GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required if clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" [OIS]). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0, and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest an RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.
Article
This article deals with inconsistency of relative (rather than absolute) treatment effects in binary/dichotomous outcomes. A body of evidence is not rated up in quality if studies yield consistent results, but may be rated down in quality if inconsistent. Criteria for evaluating consistency include similarity of point estimates, extent of overlap of confidence intervals, and statistical criteria including tests of heterogeneity and I(2). To explore heterogeneity, systematic review authors should generate and test a small number of a priori hypotheses related to patients, interventions, outcomes, and methodology. When inconsistency is large and unexplained, rating down quality for inconsistency is appropriate, particularly if some studies suggest substantial benefit, and others no effect or harm (rather than only large vs. small effects). Apparent subgroup effects may be spurious. Credibility is increased if subgroup effects are based on a small number of a priori hypotheses with a specified direction; subgroup comparisons come from within rather than between studies; tests of interaction generate low P-values; and have a biological rationale.
Article
In the GRADE approach, randomized trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomized trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias--whether for randomized trials or observational studies--authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias.
Article
Preclinical studies suggest that incretin-based therapies may be beneficial for the bone; however, clinical data are largely lacking. We assessed whether the differential effects of these therapies on body weight differed with respect to their effect on bone mineral density (BMD) and markers of calcium homeostasis in patients with type 2 diabetes (T2D). Sixty-nine metformin-treated patients with T2D were randomized to exenatide twice daily (n = 36) or insulin glargine once daily (n = 33). Total body BMD, measured by dual-energy X-ray absorptiometry, and serum markers of calcium homeostasis were assessed before and after 44-week treatment. Exenatide or insulin glargine treatment decreased body weight by 6%. Endpoint BMD was similar in both groups after 44-week therapy (LSmean ± s.e.m. between-group difference -0.002 ± 0.007 g/cm(2) ; p = 0.782). Fasting serum alkaline phosphatase, calcium and phosphate remained unaffected. Forty-four-week treatment with exenatide or insulin glargine had no adverse effects on bone density in patients with T2D, despite differential effects on body weight.
Article
Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.
Article
Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
Article
Moderate weight loss alters bone turnover and reduces bone mineral density in overweight men and women. However, it is not known whether bone turnover is normalized during weight maintenance postweight loss. Thus, the objective of the present study was to examine changes in serum bone turnover markers during 9 months of weight maintenance following weight reduction on a very low-energy diet (VLED) in obese men and women. Thirty-seven men (n = 13) and women (n = 24) aged 50 +/- 9.8 years underwent 3 months of weight reduction on a VLED ( approximately 500 kcal/d) followed by 9 months on either a low-carbohydrate or low-fat weight maintenance diet ( approximately 1600 kcal/d). Concentrations of osteocalcin (OC) and C-terminal peptide of type I collagen (CTX) in serum were measured using enzyme-linked immunosorbent assay at baseline and at months 3, 6, and 12. Serum parathyroid (PTH) concentrations were measured using a chemiluminescent immunoassay at all 4 time points. Data were analyzed using a 3-factor-repeated measures analysis of variance. Average weight loss was 19% +/- 3% and, during the 9-month weight maintenance period, average weight gain was approximately 3%, with no differences due to diet composition. Serum concentrations of OC and CTX significantly increased after weight reduction and remained elevated during weight maintenance. Serum PTH was reduced after weight loss. Percent changes in OC and CTX were correlated during weight maintenance (r = -0.437, p = 0.008), but not during weight loss. Percent changes in CTX and body weight were negatively correlated during weight loss (r = -0.474, p = 0.003) and maintenance (r = -0.455, p = 0.006). Weight loss induced via a VLED may result in an imbalance between bone formation and resorption and accelerate remodeling. The deleterious effect of energy restriction on bone remodeling rate appears to persist during weight maintenance.