Clinical Study Of The Effect Of Bisphosphonates On Glucose Metabolism And Incidence Of Type 2 Diabetes In Patients With Osteoporosis

Objective: Osteoporosis and T2DM(type 2 diabetes mellitus),the incidence of T2 DM is increasing in the world,and the two diseases often coexist in the same patient.Bone metabolism and glucose metabolism are closely related,and bones regulate glucose metabolism mainly through The realization of osteocalcin,basic research has shown that OCN(osteocalcin)has a positive regulatory effect on glucose metabolism.Bisphosphonates are currently widely used in clinical anti-osteoporosis treatment,this anti-bone resorption treatment will reduce Bone turnover markers including OCN.Basic research suggests that the reduction of OCN caused by anti-bone resorption therapy may have a negative regulatory effect on glucose metabolism and may increase the occurrence of type 2 diabetes.However,clinical research suggests that bisphosphonates The use of salt did not increase the risk of T2 DM in patients with osteoporosis,nor did it increase glucose metabolism indicators.The mechanism of the relationship between the two is still unclear.Therefore,this study has adopted META analysis and randomized age and gender matching.In contrast to retrospective clinical studies,we will further explore whether the clinical use of ZA(zoledronic acid)anti-bone resorption treatment affects the glucose metabolism of patients with osteoporosis and increases the risk of type 2 diabetes and its possible underlying mechanism.Methods: MATE analysis method: Searched databases: English databases include: Pub Med,EMBASE,Web of Science databases,OVID and Cochrane databases;Chinese databases include: VIP Chinese Journal Service Platform,Wanfang Database,China Knowledge Network(updated on October 2020month).The relationship between bisphosphonates and the risk of T2 DM was assessed by using 95% confidence intervals(CIs)and hazard ratios(HR).Retrospective research method: Collected 226 patients with primary osteoporosis who received intravenous infusion of zoledronic acid in the Department of Endocrinology of our hospital from January 2017 to January2020,and were followed up for at least one year and excluded the diagnosis of T2 DM.Randomly selected 226 people who were diagnosed as osteoporosis by dual-energy X-ray bone density instrument at the health check-up center of our hospital during the same period and excluded T2 DM but not infused with zoledronic acid as the control group.Both groups of patients were treated with oral vitamin D(alfacalcidol tablets(Liqing)or vitamin D drops(Xingsha Pharmaceutical))and calcium carbonate tablets(Caerqi)600 mg/d.Collect the general data of the two groups of patients at baseline and follow-up one year later,bone metabolism indicators,blood sugar and other biochemical indicators,thyroid function indicators,and the number of new type 2 diabetes cases one year later.Compare the effects of zoledronic acid anti-osteoporosis treatment on the glucose metabolism of patients with osteoporosis and the incidence of type2 diabetes,and compare the differences of various indicators before and after treatment in the treatment group,and analyze the correlation between bone metabolism indicators and glucose metabolism indicators To further explore the possible mechanism of the interaction between bone metabolism and sugar metabolism.Results: 1.The META analysis included four cohort studies with a total of566,542 clinical subjects.The results show that bisphosphonate anti-bone resorption therapy can reduce the risk of T2DM(HR,0.72,95% CI,0.60-0.85,respectively),especially for etidronate and alendronate users(HR,0.62;95% CI,0.40-0.97 and HR,0.69;95% CI,0.56-0.85).In addition,in the female subgroup,subjects exposed to bisphosphonates did not increase the risk of T2DM(HR,0.81;95% CI,0.52-1.26;z = 0.92,p = 0.355),and in the male subgroup In the group,subjects exposed to bisphosphonates reduced the risk of T2DM(HR,0.73;95% CI,0.62-0.85;p <0.001;).2.Results of a randomized controlled retrospective clinical study of age and gender matching2.1 Comparison of baseline values between the treatment group and the control group and general data and biochemical indicators after treatment(1)Comparison of the baseline values between the treatment group and the control group for age,gender,BMI,blood pressure,LDL(low density lipoprotein cholesterin),AST(Aspartate aminotransferase),TC(total cholesterol),TBIL(total bilirubin),TP(Total protein),HDL(high density lipoprotein cholesterin),TG(triglyceride),UA(uric Acid),ALT(Alanine aminotransferase),FPG(asting blood glucose),AG(average blood sugar),Hb A1c(glycated hemoglobin),no statistical difference Academic significance(P>0.05).(2)There was no statistically significant difference between the baseline values of the treatment group and the control group(P>0.05),but after treatment,the treatment group compared with the control group,the biochemical indicators of the treatment group indicated that blood glucose(FPG,AG,Hb A1c)was significantly reduced(P<0.00);blood lipid profile TC,LDL decreased(P<0.05,P<0.01),TG showed a decreasing trend,HDL showed a rising trend but the difference was not statistically significant;TBIL significantly increased(P<0.00),SBP decreased(P<0.05).The BMI of the treatment group was lower than that of the control group(P<0.05).(3)Comparing the treatment group with the control group,there were 6newly diagnosed diabetic patients in the treatment group and 5 newly diagnosed diabetic patients in the control group for one year.The analysis results of confounding factors of adjustment,age,BMI,blood pressure and blood lipid showed that the treatment group 2 The incidence and risk of type diabetes did not increase.The HR value and 95% CI were: HR=0.673,CI: 0.146-3.106.2.2 Comparison of general data and biochemical indicators before and after the treatment group and the control group(1)In the treatment group,the FPG in the one-year follow-up after ZA treatment was significantly lower than that before treatment(P<0.05),and the residual glucose metabolism indexes AG,GSP,and Hb A1 c showed a downward trend.Comparing the control group followed up for one year,FPG,AG and Hb A1 c increased significantly after one year(P<0.00).(2)There was no significant difference in general data,biochemical indexes and thyroid function indexes except blood sugar before and after treatment in the treatment group(P>0.05).In the control group,the TC and TG increased(P<0.05)and LDL showed a rising trend before and after one year of follow-up,but the difference was not statistically significant(P>0.05),and the HDL trend was not obvious.The systolic blood pressure and TBIL were increased(P<0.05,P<0.01),and there was no significant difference in the changes of remaining biochemical indexes(P>0.05).2.3 Comparison of bone metabolism indexes before and after treatment in the treatment group and the correlation between changes in bone metabolism indexes and changes in glucose metabolism indexes(1)Comparison of bone metabolism indexes of treatment group before and after ZA treatment: PTH(Parathyroid hormone),25-OHD(25-hydroxy vitamin D)increased(P<0.05,P< 0.01),Ca(calcium),P(phosphorus),ALP(Alkaline phosphatase)decreased(P<0.05),especially the bone turnover markers OCN,Total P1NP(type 1 procollagen N-terminal propeptide),β-CTX(β-C-termial telopeptide of type 1 collage)were significantly decreased(P<0.00),5-NT(5Compared with nucleotidase)and CT(Calcitonin),the difference was not statistically significant(P>0.05).(2)Spearman correlation analysis showed that the changes of OCN andβ-CTX were significantly negatively correlated and positively correlated with the changes of Hb A1c(r=-0.288,P<0.01;r=0.227,P<0.05),and were correlated with FPG,AG,GSP has no obvious correlation;the change of t P1 NP has no obvious correlation with the change of FPG,AG,GSP,Hb A1 c.The changes of 25 OHD,Ca,P,PTH,ALP,TC,TG,LDL,HDL have no obvious correlation with the changes of FPG,AG,GSP,Hb A1 c.Conclusion: 1.META analysis found that bisphosphonate anti-osteoporosis treatment does not increase the risk of T2 DM in patients with osteoporosis,but can reduce the risk of T2 DM in patients with osteoporosis,especially in male patients.2.This study found that the changes in bone formation marker osteocalcin(OCN)were negatively correlated with the changes in Hb A1 c,which is consistent with the results reported in in vitro studies,suggesting that OCN has a beneficial regulatory effect on glucose metabolism.In this clinical study,it was found that although OCN was significantly reduced after zoledronic acid treatment,the patients found that FPG,AG,and Hb A1 c levels were also reduced after one year of treatment.Increase the risk of T2 DM,and even found that the effect of zoledronic acid on the blood sugar of patients with osteoporosis showed a decreasing trend.This is consistent with the conclusion drawn by our META analysis.This conclusion is inconsistent with the hypothesis that exposure to bisphosphonates from basic experiments leads to a decrease in OCN,which in turn increases the risk of type 2 diabetes.3.The reason for this phenomenon may be that the regulation of zoledronic acid on sugar metabolism is not only communicated through OCN,but may be related to the beneficial regulation of reduced CTX on the production of sugar metabolism,and may even be related to vitamin D levels and azoles.Ledronic acid is related to its beneficial effects on lipid metabolism.The mechanism of this phenomenon is not yet fully understood,and there is still a need to design better large-scale clinical studies,especially prospective studies for further exploration.