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      Changes in the Bone Mineral Density of Femur Neck and Total Hip Over a 52-Week Treatment with Lobeglitazone

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      Diabetes & Metabolism Journal

      Korean Diabetes Association

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          Abstract

          Individuals with diabetes are at a high risk of both hip and non-hip fractures, regardless of the type of diabetes [1], and tend to be at a higher fracture risk at a given bone mineral density (BMD) than individuals without diabetes [2]. This could be because diabetes increases bone fragility by increasing the cortical porosity and decreasing the cortical area and bone material strength [3], in addition to causing bone loss. In addition to the classical risk factors for fracture, there are several others that are specific to diabetes, such as presence of diabetes for more than 10 years, treatment with thiazolidinedione (TZD) anti-diabetic agents, and the presence of diabetes-related complications [4]. TZDs act as ligands for peroxisome proliferator-activated receptor γ (PPAR-γ), which is expressed widely in the stromal cells of bone marrow, adipocytes, osteoblasts, and osteoclasts [5], and directly regulate the expression of genes involved in glucose homeostasis and adipogenesis; thereby, acting as insulin sensitizers. Although TZDs have better glycemic durability than sulfonylureas without increasing the risk of hypoglycemia [6], several clinically observed adverse effects, such as weight gain, edema, heart failure, and bone damage, reduce the prescription preference for TZDs [7]. In a recent meta-analysis of 22 randomized control trials, the risk of fracture in women using TZDs was approximately twice of that in women not using TZDs [8]. The reported mechanisms of action of TZDs on bones include increase in adipocyte formation [9], suppression of proosteoblast differentiation in mesenchymal stem cells [10], and promotion of osteoclast differentiation and activity [11 12]. In addition, TZDs activate adipokines and inflammatory cytokines [13 14], and regulate the energy metabolism affecting the skeleton [15]. Lobeglitazone is a novel PPAR-γ agonist with a substituted pyrimidine ring and a TZD moiety. Compared to other TZDs, its glucose-lowering effect is observed at a lower dose with fewer adverse reactions common to TZDs, such as weight gain, peripheral edema, and heart failure [7 16]. Lim et al. [17] evaluated the effects of a 52-week treatment with lobeglitazone on BMD, which is well-known to be adversely affected by TZDs. Compared to baseline, no statistically significant differences in the femur neck and total hip BMD were observed between lobeglitazone and placebo groups. In this study, only the BMD of the femur was measured because the femur bone has a substantial proportion of cortical bone [18]. Among the diabetic population, this measurement may be more relevant than the measurement of the BMD of the lumbar spine because fractures in individuals treated with TZDs typically occur at cortical skeletal sites [19]. Therefore, the results of this study are meaningful. Due to the small sample size and short study duration, the findings of this study can neither definitively define clinical risks nor generalize the conclusions to non-Asian individuals. Another study at a larger scale with a longer duration is needed to establish the long-term clinical benefits and risks of lobeglitazone. Moreover, considering that TZDs reduced the strength of the radius and tibia in women [20], the effects of lobeglitazone on peripheral bones should also be evaluated in future studies.

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          Most cited references 18

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          Thiazolidinediones

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            Mechanisms of disease: is osteoporosis the obesity of bone?

            Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.
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              In vivo assessment of bone quality in postmenopausal women with type 2 diabetes.

              Although patients with type 2 diabetes (T2D) are at significant risk for well-recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone "quality"). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50-80 years) including 30 patients diagnosed with T2D for >10 years and 30 age-matched, nondiabetic controls. Regional BMD was measured by dual-energy X-ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high-resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (-11.7%; p<0.001); following adjustment for body mass index (BMI) (-10.5%; p<0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (-9.2%; p=0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p<0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r=-0.41; p=0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.
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                Author and article information

                Journal
                Diabetes Metab J
                Diabetes Metab J
                DMJ
                Diabetes & Metabolism Journal
                Korean Diabetes Association
                2233-6079
                2233-6087
                October 2017
                24 October 2017
                : 41
                : 5
                : 374-376
                Affiliations
                Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.
                Author notes
                Corresponding author: Ji A Seo. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea. seo-ji-a@ 123456hanmail.net
                Article
                10.4093/dmj.2017.41.5.374
                5663676
                29086535
                Copyright © 2017 Korean Diabetes Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Editorial
                Clinical Diabetes & Therapeutics

                Endocrinology & Diabetes

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