血清瘦素、脂联素和内脂素与骨质疏松相关性研究

硕士学位论文血清瘦素、脂联素及内脂素与骨质疏松相关性研究Correction between serum leptin ,adiponectin,visfatinand osteoporosis专业名称：老年医学学位申请人：雷淑玲导师：楼慧玲教授广州医科大学·广州二零一四年五月目录缩略词表 (1)中文摘要 (2)英文摘要 (5)前言 (10)材料与方法 (12)结果 (18)讨论 (29)结论 (34)展望 (35)参考文献 (36)综述 (41)致谢 (54)学位论文原创性声明 (55)学位论文知识产权权属声明 (55)关于学位论文使用授权的说明 (55)缩略词表缩略词表（Abbreviation）缩写词英文全称中文全称OPObT2DM LPT APN VST OCNβ-CTXPINPBMD TGTC LDL HDL OsteoporosisObesityType of 2 diabetesLeptinAdiponectinVisfatinOsteocalcinC-treminal telopeptide ofI collagenN-aminoterminal propeptideof type I collagenBone mineral densityTriglycerideCholesterinHigh density lipoproteinLow density lipoprotein骨质疏松肥胖2型糖尿病瘦素脂联素内脂素骨钙素β-I型胶原羧基端肽I型前胶原氨基前肽骨密度甘油三酯胆固醇高密度脂蛋白低密度脂蛋白广州医科大学硕士学位论文血清瘦素、脂联素及内脂素与骨质疏松的相关性研究硕士研究生：雷淑玲导师：楼慧玲教授中文摘要背景：目前，骨质疏松（osteoporosis，op）和肥胖(obesity，ob)是两个常见的慢性疾病，并随着人口的肥胖化和老龄化，骨质疏松发病率逐年上升。

患者常出现身高缩短、骨痛及驼背甚至骨折等临床表现，但OP的具体发病机制尚不明确。

既往研究表明肥胖与骨密度之间有正相关关系，在肥胖人中，骨矿物质密度（BMD）增加，骨折的风险下降。

而近年来文献报道肥胖是骨质疏松危险因素之一[1][2][3],绝经后妇女由于体内雌激素水平下降，脂肪重新分布，脂肪主要堆积的部位集中在腹腔脏器和皮下的组织，往往容易出现肥胖。

其中积聚在腹腔脏器称内脏型肥胖，皮下组织堆积称皮下脂肪型肥胖。

肥胖不仅影响负重骨如腰椎和髋骨,也可以通过脂肪组织产生大量的脂肪细胞因子和促炎症细胞因子。

肥胖常伴低炎症反应，引发脂肪因子与炎症因子（TNF-a 、IL-1，IL-2，IL-6等）改变，通过RANKL/OPG 途径，诱导成骨细胞形成与破骨细胞吸收失衡，骨量下降，进一步发展骨质疏松[4]。

据国内外最新文献报道【5】【6】【7】[8]，可知，脂肪细胞因子与肥胖相关性代谢关系密切，其中如瘦素（leptin, LPT）、脂联素(adiponectin, APN)、内脂素（visfatin VSF）对骨质疏松发病有一定临床意义，但这三种脂肪细胞因子联合检测的价值对OP 患者关系尚缺乏相应的研究。

目的:（1）以横断面研究来探讨脂肪因子在肥胖相关性代谢介导骨质疏松人群水平分布情况；（2）探讨脂肪因子与肥胖相关性代谢介导骨质疏松BMD及骨代谢指标相关性；进而深入理解脂肪因子介导肥胖相关性代谢在骨质疏松发病机制中作用和临床意义。

方法：通过2013年6月至2013年12月在广州市第一人民医院门诊就诊患者，中文摘要采用法国DMS公司生产的双能X线骨密度，按照WHO 诊断骨质疏松标准测定128例患者骨密度。

其中男性57例，平均年龄（73.30±8.98）岁，女性71例，平均年龄（71.55±9.14）岁。

收集患者基本信息及各项检测指标（身高、体重、BMI、性别、年龄、骨密度、空腹血糖、糖化血红蛋白、血脂、β-CTX、PINP、骨钙素），采用ELISA检测血清脂联素、瘦素、内脂素水平。

并根据骨密度、性别、BMI、血糖、血脂等进行分组。

应用统计学软件19.0进行数据分析。

结果：（1）脂联素与BMD关系：与正常组对比，脂联素水平在骨质疏松（op）组显著升高P<0.001；进一步以op患者为研究对象进行分组，在肥胖组脂联素与BMD 负相关（r=-0.488，P=0.001），与BMI不相关（r=-0.248，P=0.088）；调整性别、年龄后，仍负相关；在非肥胖组脂联素与BMD负相关（r=-0.313，P=0.018），与BMI不相关（r=-0.255，P=0.094），调整性别、年龄后，仍负相关；在血脂异常中，脂联素与BMD负相关（r=-0.645，P=0.000），调整性别、年龄后，仍负相关；在血脂正常组中，脂联素与BMD负相关（r=-0.353，P=0.004）调整性别、年龄后，仍负相关；在糖尿病患者中，脂联素与BMD负相关（R=-0.392，P=0.012），调整性别、年龄后，仍负相关；同样在非糖尿病患者中，脂联素与BMD负相关（R=-0.430，P=0.001）调整性别、年龄后，仍负相关；提示脂联素与骨质疏松发生关系密切，独立于肥胖、血脂水平之外。

（2）瘦素与BMD关系：在肥胖或糖尿病时，瘦素与BMD负相关(r = -0.391 P = 0.011 vs r = -0.387, P = 0.014)，调整年龄、性别后，瘦素仍负相关；而在非肥胖时瘦素与BMD不关联；在糖代谢紊乱时，内脂素与BMD显著正相关（R=0.315，P=0.047），校正年龄、性别，内脂素与BMD仍正相关（R=0.447，P=0.005），提示瘦素可能是介导肥胖与骨质疏松的关键因子，内脂素对骨密度作用可能与糖尿病发生有关。

（3）脂肪因子与骨代谢指标相关分析显示：脂联素与骨钙素正相关（R=0.258，p=0.003），与β-CTX正相关（R=0.181，P=0.043）,内脂素与β-CTX 负相关（R=-0.199，p=0.024），瘦素与PINP正相关（r=0.184，p=0.038），调整年龄、性别后，脂联素、内脂素相关仍存，瘦素则消失，提示脂联素参与骨形成与骨吸收过程，影响骨代谢，内脂素可能与骨转化水平有关。

广州医科大学硕士学位论文（4）逻辑回归分析显示：进行二分类变量分析骨质疏松有哪些影响因素，以骨质疏松为应变量，年龄、性别、脂联素、TC、LDL、HDL、BMI、体重、内脂素为协变量，进入logistic二元回归方程结果显示：胆固醇（B=0.444，OR=1.559，95%CI 1.013-2.401 ，P=0.044），脂联素（B=0.188，OR=1.207，95%CI 1.078-1.351 ，P=0.004）是骨质疏松的危险因素，体重指数（B=-0.151，OR=0.860，95%CI 0.764—0.968 ，P=0.013）是骨质疏松的保护因素。

结论：（1）脂联素在骨质疏松组显著高于正常组，与BMD负相关，提示高水平脂联素在骨质疏松发病中可能取一定作用；与BMI、血脂不相关，不受肥胖因素影响，与空腹血糖负相关，提示脂联素与糖尿病骨质疏松的发生有一定相关性，糖脂代谢异常与骨质疏松的发病有一定相关性。

（2）瘦素对骨负性调节，受ＢＭＩ影响，可能与肥胖有关；内脂素仅在2型糖尿病（T2DM）中与BMD正相关，与血糖正相关，提示内脂素可能参与糖尿病性骨质疏松的发病。

瘦素、内脂素对骨密度影响，可能与肥胖、胰岛功能有关，但作用机制尚不明确；仍需要结合相关因素进一步研究。

（3）脂联素与骨转化指标变化有一定相关性，推测其作为炎症因子诱导破骨细胞作用骨质疏松发病。

内脂素可能参与骨代谢调节，但不是关键因素。

瘦素与骨代谢指标无关联。

（4）肥胖介导相关性代谢与骨质疏松密切相关，进一步证实脂肪因子参与骨质疏松的发病。

关键词：骨质疏松肥胖脂联素、瘦素、内脂素、骨密度英文摘要Correction between serum leptin , adiponectin,visfatinand osteoporosisMaster Candidate: Lei ShulingSupervisor: Prof. Lou HuilingAbstractBackgroundAt present,Obesity and osteoporosis are two normal chronic diseases with increasing prevalences in the overword. With the obesity and aging population developing, the incidence of osteoporosis has been increasing year by year. The most of patients ususlly appear short stature, bone pain and humpbacked ,and even fractures in clinical manifestations.Otherwise the exact pathogenesis of osteoporosis have been unclear. Traditionally,ob -esity have regarded as being beneficial to bone health. Further,they think that obesity would increase bone mineral content (BMC) , and decrease the risk of fracture. However, the protective effect of obesity on osteosteoporosis has been questioned. In some recent studies, obesity is regarded as defined by percentage body fat, and a risk factor for osteoporosis . They suggest that postmenopausal women easily to becmoe obesity, bacause of the estrogen levels decreasing and body fat redistribution.The most of body fat mainly concentrats in the abdominal organs and parts of the subcutaneous tissue.One of them accumulate in the abdominal organs called visceral fat, and the others subcutaneous tissue accumulation called subcutaneous fat. Obesity not only affect the weight-bearing bones such as the spine and hip,but also can produce large amounts of fat cytokines and pro-inflammatory cytokines by adipose tissuesaid. Normally,obesity is often accompanied by a low inflammatory responsion,which make adipokines (leptin, adiponectin, visfatin) and inflammatory cytokines (TNF-a, IL-1, IL-2, IL-6 etc.)广州医科大学硕士学位论文changed.As a result of that , make the imbalance between the formation of osteoblasts and absorb of osteoclasts according to RANKL / OPG pathway,so that decreased bone mass and further more development of osteoporosis. As the abord reported , there is related between adipokines and obesity. It is in some extent significance of the adipokines such as adiponectin、leptin and visfatin with the osteoporosis in clinical .Otherwhise, the association of adipokines in osteoporosis patients is still lack of appropriate research and the mechanism is unclear.Objective(1)The present study investigated that how the serum adipokines distribute in obesity-related metabolic osteoporosis population level.(2)The purpose of this study was to investigate whether these serum adipocytokines levels are associated with BMD in obesity-related metabolic osteoporosis and bone turnover markers. Furthermore，we would like understanding the mechanis about adipokine how to work between obesity osteoporosis and clinical significance.METHODSThe study was designed as a cross-sectional investigation, in which a sample of 128 participants (57 men and 71 women) were measured by dual-energy X-ray absorptiometry from June 2013 to December 2013 in Guangzhou First People's Hospital. The mean age of men was the average aged （73.30±8.98）years old and the women was（71.55±9.14）years old. We used to collect basic information and the detection index (such as height, weight, BMI, gender, age, bone density, fasting blood glucose, glycated hemoglobin, lipids, β-CTX, PINP, osteocalcin). We also make use of ELISA to measured lipid adiponectin, leptin and visfatin levels. Laste we determined to making groups according to gender, body mass index, bone density and so on. We use 19.0 statistical software for data analysis.英文摘要RESULTS(1)Comparison with the non-osteoporosis group, Fasting levels of plasma adiponectin were significantly increased P <0.001 in osteoporosis group .We used to study osteoporosis as sample,a result,fasting levels of plasma adiponectin had a significant negative correlation with BMD of the lumbar spine both in the obesity group (r = -0.488, P = 0.001) and in the non-obesity group (r = -0.313, P = 0.018) ,but not inconclusive with BMI（r=-0.248，P=0.088 VS r=-0.255，P=0.094）.After adjust sex and age,the relation between obesity and non-obesity is still significant negative.Secondly, fasting levels of plasma adiponectin had a significant negative correlation with BMD of the lumbar spine both in the dyslipidemia group (r = -0.645, P = 0.000) andt in the non-dyslipidemia group (r = -0.353, P = 0.004), after adjust sex and age,the relation between dyslipidemia and non- dyslipidemia is still significant negative.Thirdly, fasting levels of plasma adiponectin had a significant negative correlation with BMD of the lumbar spine both in the DM group (r = -0.392, P = 0.012) andt in the non-DM group (r = -0.430, P = 0.001), after adjust sex and age,the relation between DM a and non- DM is still significant negative.Furthers,it sugests that fasting levels of plasma adiponectin were related with osteoporosis and depending without obesity and lipids.(2) We used to study osteoporosis as a sample,a result ,fasting plasma levels of leptin were significantly correlated only with neck BMD in the obsityand Ward triangle BMD in DM group(r = -0.391 P = 0.011 vs r = -0.387, P = 0.014). After adjust sex and age,the relation between obesity and diabetesis still significant negative. Otherwise,it is not significantly correlated with BMD in non-obesity and non- diabetes groups. So,we think that leptin may bea principal fator between obesity and osteoporosis.The others, fasting plasmalevels of visfatin were significantlyposity posity correlated only with lumbar spine BMD in DM group(r = 0.315 P = 0.047). After adjust sex and age, therelation still significant posity（R=0.447，P=0.005）. For the reason that,we consider visfatin play a centin effect on BMD about diabetes.广州医科大学硕士学位论文(3) Correlation analysis showed: we had found that adiponectin was significant positive correlation both osteocalcin (r=0.258,p=0.003),and correlat ion β-CTX (R=0.181, P=0.043). Visfatin have a significant negative correlation with β-CTX (R=-0.199, p=0.024). Leptin have a positive correlation with PINP (r =0.209, p =0.018), after adjusted for age and BMI, we also found that both adiponectin and visfatin were still relevant, but not leptin.(4) In the multiple linear stepwise regression analysis: we take osteoporosis into two categorical variables to analyzed what factors to dependent variables, age, gender, adiponectin, TG, LDL, HDL, BMI, body weight, visfatin as covariates into the logistic binary regression equation in osteoporosis. The results showed that adiponectin（B=0.188，OR=1.207，95%CI 1.078-1.351，P=0.004）and TG （B=0.444，OR=1.559，95%CI 1.013-2.401 ，P=0.044）were risk factors for osteoporosis,but weight（B=-0.151，OR=0.860，95%CI 0.764—0.968，P=0.013）was a protective factor for osteoporosis.CONCLUSIONS:(1) Adiponectin was significantly higher than the non-osteoporosis group, and also play a negative correlation with BMD.It is suggested that adiponectin with high levels had played a certain effect in the pathogenesis of osteoporosis. Furthermore, fasting adiponectin haven’t relationship between BMI and lipids ,when it is compared in obesity group.Simply , fasting adiponectin have negatively correlated with glucose, of course,suggesting that it play a certain role in diabetes osteoporosis.In a word ,t there is a certain relationship between lipid metabolism and the pathogenesis of osteoporosis.(2) We found that it is negative regulator of leptin on boneaccording toBMI, maybe it is associated with obesity. Otherwise visfatin have only positively associated with BMD in type of 2 diabetes with osteoporosis,and take positively associated with glucose .So we think that it may be involved in the pathogenesis of diabetic英文摘要osteoporosis . Leptin and visfatin not only play a effect on bone density, but also have associated with obesity and islet dysfunction.However,it is not still clear with the mechanism about them, we should still collect a combination of factors for further study.(3) It is centin related for adiponectin to play a role on bone turnover index change.Weconsider adiponectin as inflammatory making osteoclast into steoporosis. Visfatin may be involved in regulating bone metabolism, but not the key factor. There is not association between leptin and bone metabolism .(4)There is closly related between mediated metabolic obesity an osteoporosis .Furthermore,it is proved that adipocytokines would play a tole in the pathogenesis of osteoporosis.Key words：osteoporosis obesity adiponectin leptin visfatin BMD广州医科大学硕士学位论文前言骨质疏松症（Osteoporosis,OP）是骨骼的一种全身性疾病,在骨组织中以低骨量和骨骼微细结构破坏，致使骨脆性增加而骨折危险增加为特征慢性骨病。