The Effects Of Angiotensin Converting Enzyme And Kinin Kallikrein System On Primary Osteoporosis

Osteoporosis and hypertension are two common diseases in elder subjects,which always co-existed in one subject.The effects of anti-hypertensive drugs on bone mineral density(BMD)and bone loss got more and more research interests in the past few years.However,the results of the effect of angiotensin converting enzyme inhibitor(ACEI)on osteoporosis were still controversial.Based on this context,in this study,we performed a series of clinical experiment and an animal study to investigate the effects of ACEI on BMD and bone loss,and explore the effect of kallikrein-kinin system(KKS)in this process.Finally,we performed a correlation analysis about the relationship between single-nucleotide polymorphisms(SNPs)in ACE,kallikrein gene and osteoporosis.The main parts of this study are as follows:PART Ⅰ The relationship between ACEI and BMD in elder Chinese.AimsWe aimed to analyze the relationship of ACEI and ARB with BMD in elderly population from community health service centers in Nanchang city,Jiangxi province.MethodsA total of 964 female and 1176 male respondents were included in this study,with an average age of 65 years(60-74 years).The questionnaire was used to collect the general information,demographic indicators,disease history and medication history of the respondents.The BMD of lumbar spine and hip was measured by dual energy X-ray absorptiometry.ResultsThe BMD of hip(0.716 vs.0.830g/cm2),femoral neck(0.619 vs.0.683g/cm2)and lumbar spine(0.776 vs.0.992g/cm2)were significantly lower in females than in males.The proportion of ACEI use in female was lower than that in male(8.6% vs.13.9%,P<0.01).Relative to female respondents,male respondents had higher rates of smoking history and alcohol consumption.Among 964 female respondents,ACEI users had higher body weight than non-users(58.5 vs.52.6kg),and BMD was higher in ACEI users than non-users at hip,femoral neck,and lumbar spine(P<0.01).Among 1176 male respondents,BMD at hip,femoral neck,and lumbar spine was also higher in ACEI users than in non-users(P<0.01).ConclusionsThe femoral neck BMD was significantly higher in ACEI users than in non-users in female respondents,and lumbar spine BMD was significantly higher in ACEI users than in non-users in male respondents.There was no significant difference in BMD between ARB users and non-users among male and female respondents.PART Ⅱ The effect of ACEI on bone loss in elder Chinese.AimsWe performed a case-control study,and investigate the effect of ACEI on bone loss in elder Chinese.The participants were elderly people who underwent physical examination in Donghu and Xihu community health service centers of Nanchang City,Jiangxi Province.MethodsInclusion criteria: hypertensive people aged between 60 and 70 years old,with blood pressure less than 160/100 mmhg,and osteopenia or osteoporosis detected by DXA were screened in the physical examination of residents.A total of 400 male and260 female subjects participated in this study and were randomly divided into two groups.The two groups of subjects received ACEI and ARB,respectively.The experimental period was 52 weeks.All patients received calcium and active vitamin D supplementation.Blood pressure was measured weekly,and outpatient follow-up was conducted monthly.After 52 weeks of drug therapy,BMD was measured again.ResultsThere was no significant difference in age,weight,and weight change between ACEI and ARB users in male respondents,while ACEI users had a significantly lower rate of hip,femoral neck,and lumbar spine bone loss than ARB users(P<0.05).In female respondents,ACEI and ARB users had no significant difference in age,weight and weight change,and ACEI users had a significantly lower rate of hip,femoral neck and lumbar spine bone loss than ARB users(P<0.01).ConclusionsACEI use significantly reduced the annual bone loss rate of hip,femoral neck and lumbar spine in male and female respondents.PART Ⅲ The effect of KKS on the process of ACEI on osteoporosis.AimsWe aimed to analyse the effect of ACEI on osteoporosis mediated by the KKS.MethodsFemale and male spontaneously hypertensive rats aged 6 months were used in this study.The effect of captopril on blood pressure and serum Ang II and bradykinin concentrations in normal rats was first determined.Second,castration was used to establish osteoporosis models in male and female rats.Captopril and bradykinin receptor blocker icatibant(HOE140)were given for 12 weeks after operation.Serum samples were collected for determination of Ang II and bradykinin concentrations and bone turnover markers.BMD and bone microstructure parameters were measured by micro-CT.Femoral samples were taken for mechanical testing to assess bone strength.ResultsThe results showed that captopril decreased blood pressure and serum Ang-II concentration,and increased serum bradykinin concentration(P<0.05).Captopril decreased serum Ang-II concentration after castration(P<0.05).In female rats,HOE140 increased serum Ang II concentrations(P<0.05).Captopril increased the serum concentration of bradykinin(P<0.05).In male rats,HOE140 decreased serum bradykinin concentration(P<0.05).Captopril significantly increased the urinary deoxypyridine-creatinine ratio(DPD/Cr)and serum osteocalcin concentration(P<0.05).HOE140 decreased urinary DPD/Cr in male rats(P<0.05)and increased osteocalcin concentration in female rats(P<0.05).Captopril increased cancellous bone mineral density in ovariectomized hypertensive rats(P<0.05),and HOE140 further increased cancellous bone mineral density(P<0.05),which was due to increased trabecular bone number.In mechanical test,ACEI increased bone strength(P<0.05),and HOE140 further improved bone strength(P<0.05).ConclusionsThe administration of ACEI increased bone mineral density,and the concomitant administration of BK receptor antagonist further increased bone mineral density.The results suggested that the effect of ACEI on bone mineral density was different in female and male rats.Part Ⅳ The relationship between single-nucleotide polymorphisms in ACE,kallikrein gene and postmenopausal osteoporosis.AimsWe aimed to analyze the relationship between rs1799752 and rs4291 of ACE gene and rs5516 of tissue kallikrein 1(KLK1)gene and postmenopausal osteoporosis in Han population in Nanchang,Jiangxi Province.MethodsA total of 125 postmenopausal women with osteoporosis and no fracture were enrolled as the osteoporosis group,and 122 postmenopausal women with normal bone mass were enrolled as the control group.ResultsCompared with the control group,There were no significant differences in age,BMI,menarche age,menopausal age,parity,family history of fracture,serum calcium,serum phosphorus,25-hydroxyvitamin D,PINP,and β-ctx between the two groups(P>0.05).There were significant differences in lumbar spine(L1-L4)BMD,total hip BMD,and femoral neck BMD between the two groups(P<0.05).The study took osteoporosis as the dependent variable,and the traditional factors(education level,BMI,reproductive history,etc.)and rs1799752,rs4291 and rs5516 polymorphism sites as independent variables,and conducted multivariate unconditional Logistic regression analysis.The results showed that there were significant differences in BMI,vitamin D level,estradiol,testosterone,P1 NP andβ-CTX between the osteoporosis group and the control group(P<0.05).DI and II genotypes of ACE rs1799752 were significantly different between the osteoporotic group and the control group(OR=1.013,95%CI=0.988,3.215,P<0.05).GG and CG genotypes of KLK1 rs5516 were significantly different between the osteoporotic group and the control group(OR=1)105,95%CI=0.798,2.358,P<0.05).There was no significant difference in rs4291 genotype between the two groups(P>0.05).The results showed that ACE gene rs1799752 and KLK1 gene rs5516 polymorphisms were associated with postmenopausal osteoporosis in Han population in Nanchang,Jiangxi Province.ConclusionsThe DI and II genotypes of rs1799752,CG and GG genotypes of rs5516 may be risk factors for postmenopausal osteoporosis in Han population in Nanchang area of Jiangxi Province.ACE gene rs4291 polymorphism is not associated with postmenopausal osteoporosis in Han population in Nanchang,Jiangxi province.In summary,ACEI are positively correlated with bone mineral density in elderly Chinese,and ACEI can reduce bone loss in elderly Chinese.The KKS mediates the effect of ACEI on osteoporosis.The polymorphism at rs1799752 of ACE gene and rs5516 of KLK1 gene is associated with postmenopausal osteoporosis in the Han population in Nanchang,Jiangxi Province.The polymorphism of rs4291 is not associated with postmenopausal osteoporosis in the Han population in Nanchang,Jiangxi Province.