Corrigendum: Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria.

[This corrects the article DOI: 10.3389/fendo.2019.00700.].

Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria.

Recent studies showed that in patients with type 2 diabetes mellitus (T2DM), Sodium-dependent glucose transporters 2 inhibitor (SGLT2I) may cause potential adverse effects on the skeleton such as increasing the risk of fracture. This risk is possibly mediated by effects induced by all SGLT2I class drugs, but whether Dapagliflozin aggravates osteoporosis in patients with T2DM remains controversial. Therefore, we designed this study to explore how Dapagliflozin affects the metabolism and the quality of bone in T2DM animal models. The effect of Dapagliflozin on the skeleton was evaluated on male ZDF (Zucker Diabetic Fatty) rats-a rat model of diet induced spontaneous T2DM. Dapagliflozin was administrated via gavage at the dosage of 10 mg/kg/day. Bone tissue mineral density and the microarchitecture of tibiae were measured with micro-CT and biomechanics characteristic of the femora were tested using a three-point bending test. Serum bone biomarkers and other metabolic parameters were also tested via ELISA or other assays. Our results found that diabetic rats demonstrated symptoms of osteoporosis and Dapagliflozin could help to alleviate these defections caused by diabetes. Compared to the negative controls, the serum CT (calcitonin) level in ZDF rats as well as the uric calcium and phosphate levels were elevated, and these symptoms were alleviated by Dapagliflozin. Tibiae of Dapagliflozin treated rats demonstrated decreased cortical tissue mineral density while trabecular tissue mineral density and mean bone mineral density received a rise when compared to the matched controls. ZDF rats also showed defections in femora stiffness which could be relieved by Dapagliflozin administration. The mechanism of Dapagliflozin affecting bone quality is possibly connected to the suppression of serum calcitonin and excretion of calcium via urine rose by hyperglycemia. In conclusion, Dapagliflozin can prevent osteoporosis in ZDF rats by alleviating hypercalciuria.

Irbesartan attenuates advanced glycation end products-mediated damage in diabetes-associated osteoporosis through the AGEs/RAGE pathway.

AIMS: Diabetes-associated osteoporosis is mainly caused by the formation and accumulation of advanced glycation end products (AGEs). Angiotensin II type 1 receptor blocker (ARB) has anabolic bone effects on the physicochemical properties of the bone in diabetes. We hypothesized that ARB could inhibit AGEs-induced deleterious effects. MAIN METHODS: In this study, we chose seven-week-old Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice. After 12 week intervention by irbesartan, the microarchitecture and mechanical strength of the bone of seven-week-old db/db mice were investigated systematically. Meanwhile, the molecular mechanisms of the osteoblasts were analyzed, after AGEs or irbesartan were added to the culture. Also, intracellular formation of reactive oxygen species (ROS) was measured with DCF fluorescence. KEY FOUNDINGS: Results showed that 12-week irbesartan treatment could dramatically improve trabecular bone microarchitecture through increasing BV/TV (p = 0.003, +46.7%), Tb.N (p = 0.020, +52.0%), and decreasing that of Tb.Sp (p = 0.005, -21.2%) and SMI (p = 0.007, -26.4%), comparing with the db/db group. Irbesartan could also substantially raise biomechanical parameters including max load (p = 0.013, +20.7%), fracture load (p = 0.014, +70.5%), energy absorption (p = 0.019, +99.4%). Besides, it could inhibit AGEs-induced damage of cell proliferation and osteogenic differentiation of osteoblasts, as well as suppressing the activation of apoptosis caused by AGEs. Moreover, co-incubation with irbesartan could prevent the AGEs-induced increase of intracellular oxidative stress and RAGE expression in osteoblasts. SIGNIFICANCE: In conclusion, this study suggested that irbesartan might play a protective role in diabetes-related bone damages by blocking the deleterious effects of AGEs/RAGE-mediated oxidative stress. This may provide a revolutionary benefits to therapy with irbesartan on diabetic osteoporosis.

ACE inhibitors and the risk of fractures: a meta-analysis of observational studies.

A meta-analysis was conducted to evaluate the effect of treatment with angiotensin-converting enzyme inhibitors on the risk of fractures. All the included articleswere retrieved from MEDLINE, EMBASE and the Cochrane Database. Trial eligibility and methodological quality were assessed before data extraction. Relative risk (RR) with corresponding 95% confidence intervals (95% CI) were used to assess the effect. Six case-control studies with11,387,668 participants met the inclusion criteria and were included in the meta-analysis. A small but significant risk effect on fractures was shown in the overall analysis of angiotensin-converting enzyme inhibitor users compared with nonusers (Pooled RR 1.27; 95% CI 1.01-1.60), although a relatively high heterogeneity was found across studies. In the stratified analysis, therewas no statistically significant association in the subgroups of hip fracture (Pooled RR 1.14; 95% CI 0.73-1.76) and the study quality (Pooled RR 1.13; 95% CI 0.89-1.44), while the over 65-year-old angiotensin-converting enzyme inhibitor users showed a stronger risk effect on fractures (Pooled RR 2.06; 95% CI 1.53-3.17). Moreover, age was found to be contributed a large part of the high heterogeneity across the included studies. This study demonstrated that the use of angiotensin-converting enzyme inhibitors might have a small but significant risk effect on fractures, especially for the over 65-year-old users. These results should be interpreted with caution as the relatively high heterogeneity across studies. Additional multiple observational studies and high quality data from randomized controlled trials are needed to confirm these findings.

[A cross-sectional survey of blood pressure control in overweight or obese type 2 diabetic patients in Guangdong province].

OBJECTIVE: To investigate the current situation and influential factors of blood pressure (BP) control in type 2 diabetic patients with overweight or obesity in Guangdong province. METHODS: From August 2011 to March 2012, type 2 diabetic patients with overweight or obesity were recruited from 60 hospitals in 20 cities of Guangdong province, and received standard questionnaires. The conditions of demographic data, clinical examinations, the most recent laboratory assessment, history of disease and drug therapy were recorded. RESULTS: A total of 4029 patients were collected with age of (58.9 ± 12.9) years, and body mass index (BMI) of (27.28 ± 2.76) kg/m². Among the participants, controlled BP was achieved in 23.8% patients. Multiple logistic regression analysis showed that older age, obesity, previous history of hypertension and inadequate glycemic control were the independent factors related to unsatisfactory blood pressure control rate. Among the patients with hypertension, 53.5% took 1 kind of antihypertensive drug, 32.5% took two, and 11.3% took three or more. CONCLUSIONS: Type 2 diabetic patients with overweight or obesity in Guangdong province have poor BP control. Thus, active lifestyle interventions and drug therapy as a comprehensive management way should be taken for the population so as to reduce their cardiovascular events.