本文選題：成骨不全癥 + 雙膦酸鹽　； 參考：《北京協(xié)和醫(yī)學(xué)院》2015年碩士論文

【摘要】：第一部分成骨不全癥基因型-表現(xiàn)型的關(guān)聯(lián)研究研究背景：成骨不全癥是一組以骨強度下降、骨折風(fēng)險增加為特點的遺傳異質(zhì)性骨病,最常見的致病基因為編碼Ⅰ型膠原的COL1A1、COL1A2。此外還有約15種基因可引起成骨不全癥。通過傳統(tǒng)Sanger測序的方式對成骨不全癥進行基因診斷費時費力。研究目的：探究二代測序平臺診斷成骨不全癥的敏感性、特異性,同時對明確基因診斷的成骨不全癥進行基因型-表現(xiàn)型關(guān)聯(lián)的分析。研究方法：我們設(shè)計了包含12種成骨不全癥致病基因在內(nèi)的二代測序平臺,檢測臨床診斷為成骨不全癥的患者,通過Sanger測序?qū)z測結(jié)果進行驗證,并對COL1A1、COL1A2所致成骨不全癥的基因型表現(xiàn)型進行進一步分析。研究結(jié)果：二代測序的平均測序深度為每個堿基200X。經(jīng)Sanger測序驗證,二代測序平臺檢測成骨不全癥的敏感性約為90.2%,特異性為100%,檢測到46個新突變位點。在COL1A1、 COL1A2基因所致OI中,COL1A1單倍劑量不足所致的OI表型比a三螺旋結(jié)構(gòu)改變所致的表型較輕,其中身高Z值的改變有顯著差異(單倍劑量不足組為-0.6±1.1,COL1A1 a三螺旋結(jié)構(gòu)改變者為-6.5±6.1,COL1A2 a三螺旋結(jié)構(gòu)改變者為-5.5±4.6,P=0.007)。未發(fā)現(xiàn)氨基酸替換、a三螺旋結(jié)構(gòu)位置與表現(xiàn)型之間的關(guān)系。研究結(jié)論：二代測序平臺是診斷成骨不全癥的有效手段。COL1A1單倍劑量不足引起的成骨不全癥較其他類型COLIA1?COL1A2改變臨床表現(xiàn)更輕。第二部分阿侖膦酸鈉、唑來膦酸鹽治療成骨不全癥的療效對比摘要研究背景：成骨不全癥是一種以骨密度、骨強度下降,骨折風(fēng)險增高為主要表現(xiàn)的遺傳代謝性骨病。目前,雙膦酸鹽為最常用的治療成骨不全癥的藥物,其中阿侖膦酸鈉、唑來膦酸是較常見的強有效的雙膦酸鹽類藥物。研究目的：評估阿侖膦酸鈉、唑來膦酸治療成骨不全癥的療效及安全性。研究方法：在這一單中心、隨機、對照臨床試驗中,2-16歲成骨不全癥患者按照2：1的比例進行分組,分別接受口服阿侖膦酸鈉70mg/周或者靜脈注射唑來膦酸5mg/年的治療。每隔6月對患者進行骨密度(Bone mineral density, BMD)、X線、血清學(xué)檢測、藥物不良反應(yīng)的評估。主要研究終點為腰椎骨密度(]Lumbar spine BMD, LS BMD)變化率,次要研究終點為LS BMD Z值、股骨頸B MD(Femoral neck BMD,FN BMD)變化率、FN BMDZ值、骨轉(zhuǎn)換指標變化率、再次發(fā)生骨折率。主要研究終點采用協(xié)方差方法計算,固定因子為治療方式,協(xié)變量為年齡及基線水平。分析基于意向性分析人群。研究結(jié)果：共有161例患者納入研究,其中隨機分配至阿侖膦酸鈉組107例,唑來膦酸組54例。136例患者完成了2年的治療與隨訪。經(jīng)過2年治療,阿侖膦酸鈉組LS BMD的變化率為60.01%±7.08%,唑來膦酸組變化率為62.04%±5.9%,兩組之間無顯著性差異(0.951)。唑來膦酸組能夠顯著降低骨折發(fā)生率(危險比0.23,95%置信區(qū)間0.118-0.431,P0.001)。隨訪6月時,唑來膦酸組的FN BMD增長率(32.23%±4.43%)及FN BMD Z值(0.631±0.065)均顯著高于阿侖膦酸鈉組(22.64%±3.69%,P=0.025)(0.436±0.054,P=0.025)。隨訪24個月時,唑來膦酸組的LSBMD Z值(0.706±0.006)顯著高于阿侖膦酸鈉組(0.499±0.051)的LS BMD Z值(P=0.013)。兩組均能顯著降低骨轉(zhuǎn)換指標堿性磷酸酶及Ⅰ型膠原羧基肽,但組間無顯著性差異。研究結(jié)論：口服阿侖膦酸鈉及靜脈輸注唑來膦酸均能顯著提高成骨不全癥患者的骨密度。在降低骨折風(fēng)險方面,唑來膦酸優(yōu)于阿侖膦酸鈉。兩種藥物的耐受性均較好。第三部分Gorham-Stout綜合征的臨床分析摘要研究背景：Gorham-Stout綜合征(Gorham-Stout syndrome,GSS)又稱為大塊骨溶解癥,是一種極為罕見的以骨溶解性破壞為主要表現(xiàn)的疾病。研究目的：探究GSS可能的發(fā)病機制,探索雙膦酸鹽(Bisphosphonates, BPs)對GSS的療效。研究方法：分析在北京協(xié)和醫(yī)院就診的GSS患者的臨床、影像學(xué)、病理學(xué)表現(xiàn)。對取了骨組織活檢的患者進行淋巴管特異標記物D2-40、血管標記物CD 31、CD 34及血管內(nèi)皮生長因子(Vascular endothelial growth factor, VEGF),血管內(nèi)皮生長因子受體Vascular endothelial growth factor receptor, VEGF-R)等染色。通過影像學(xué)、骨密度等指標評估BPs對于GSS的療效。研究結(jié)果：在12例就診的GSS患者中,11例為多發(fā)骨骼受累,1例為單一骨骼受累。4例患者合并其他部位的淋巴管瘤。4例合并乳糜胸3的患者出現(xiàn)反復(fù)呼吸困難。骨骼活檢顯示病變部位的內(nèi)皮細胞有CD31、CD34及D2-40的陽性表達。此外,還發(fā)現(xiàn)有VEGF、VEGF-R的弱陽性表達。研究結(jié)論：GSS是一種極為罕見的淋巴管來源的疾病。合并乳糜胸時提示預(yù)后較差。
[Abstract]:The first part of the genotype - phenotype association study background: osteogenesis imperfecta is a group of genetic heterozygous bone diseases characterized by decreased bone strength and increased fracture risk. The most common pathogenetic gene is COL1A1 encoding type I collagen, and COL1A2. in addition to about 15 genes can cause osteogenesis imperfecta. Through traditional San Ger sequencing is time-consuming for gene diagnosis of osteogenesis imperfecta. Objective: To explore the sensitivity and specificity of the two generation sequencing platform to diagnose osteogenesis imperfecta, and to analyze the genotype phenotype association of osteogenesis imperfecta in the diagnosis of gene diagnosis. Research methods: we designed to include 12 types of osteogenesis imperfecta. The two generation sequencing platform, which was diagnosed as osteogenesis imperfecta, tested the results by Sanger sequencing, and further analyzed the genotype phenotype of COL1A1, COL1A2 induced osteogenesis imperfecta. The results showed that the average sequencing depth of the two generation sequencing was verified by Sanger sequencing for each base base 200X., The sensitivity of the two generation sequencing platform to detect osteogenesis imperfecta was about 90.2%, the specificity was 100%, and 46 new mutation sites were detected. In the COL1A1, the COL1A2 gene induced OI, the OI phenotype caused by the inadequacy of COL1A1 double dose was lighter than the a three spiral structure change, and there was a significant difference in the height Z value of the phenotype. 0.6 + 1.1, COL1A1 a three spiral structural changes were -6.5 + 6.1, COL1A2 a three spiral structure was -5.5 4.6, P=0.007). No amino acid replacement, the relationship between the position of the spiral structure of a three and the relationship between the phenotype. The study concluded that the two generation sequencing platform was an effective means to diagnose osteogenesis imperfecta caused by the lack of single dose of.COL1A1. Total disease is lighter than other types of COLIA1? COL1A2 changes. Second alendronate, zoledronate in the treatment of osteogenesis imperfecta: a summary of the summary of the effect of osteogenesis: osteogenesis imperfecta is a genetic metabolic bone disease characterized by bone density, reduced bone strength, and increased fracture risk. Drugs for the treatment of osteogenesis imperfecta, of which alendronate and zoledronic acid are the most common potent bisphosphonates. Purpose: To evaluate the efficacy and safety of alendronate and zoledronic acid in the treatment of osteogenesis imperfecta. Methods: 2-16 year old osteogenesis imperfecta in this single center, random, controlled clinical trial. The patients were divided into groups according to the proportion of 2:1, receiving oral alendronate 70mg/ weeks or intravenous zoledronic acid for 5mg/ years. Every June, the patients were treated with bone mineral density (Bone mineral density, BMD), X-ray, serological examination, and evaluation of adverse drug reactions. The main research end was lumbar bone mineral density (]Lumbar spine BMD, LS BM). D) rate of change, the secondary end point was LS BMD Z, B MD (Femoral neck BMD, FN BMD), FN depreciation, bone conversion index, and fracture rate. The main endpoint was calculated by covariance method, the fixation factor was the treatment method, the covariance was age and baseline level. Analysis based on intentional analysis population. Results: a total of 161 patients were randomly assigned to 107 cases of alendronate group and 54 cases of zoledronic acid group (.136) were treated and followed up for 2 years. After 2 years of treatment, the change rate of LS BMD in alendronate group was 60.01% + 7.08%, and the change rate of zoledronic acid group was 62.04% + 5.9%, and there was no significant difference between the two groups (0.951). Zoledronic acid group could significantly reduce the incidence of fracture (0.23,95% confidence interval 0.118-0.431, P0.001). In June, the FN BMD growth rate (32.23% + 4.43%) and FN BMD Z (0.631 + 0.065) in the zoledronic acid group were significantly higher than that in the alendronate group (22.64% + 3.69%, P=0.025) (0.436 + 0.054, P=0.025). The follow-up was 24 months, zoledronic acid The LSBMD Z value of the group (0.706 + 0.006) was significantly higher than the LS BMD Z value (P=0.013) of the alendronate group (0.499 + 0.051). The two groups could significantly reduce the bone conversion index alkaline phosphatase and type I collagen carboxyl peptide, but there was no significant difference between the groups. Bone mineral density. Zoledronic acid is better than alendronate in reducing fracture risk. The two drugs are well tolerated. The clinical analysis of the third part of the Gorham-Stout syndrome is a summary of the clinical summary: the Gorham-Stout syndrome (Gorham-Stout syndrome, GSS), also known as massive osteolysis, is an extremely rare osteolysis The purpose of the study is to explore the possible pathogenesis of GSS and explore the effect of bisphosphonates (Bisphosphonates, BPs) on GSS. Methods: to analyze the clinical, imaging, and pathological manifestations of GSS patients in Peking Union Medical College Hospital, and to perform lymphatic specific marker D2-4 for patients who have taken bone tissue biopsy. 0, vascular markers CD 31, CD 34 and vascular endothelial growth factor (Vascular endothelial growth factor, VEGF), vascular endothelial growth factor receptor Vascular endothelial growth factor receptor, and other staining. The case was multiple skeletal involvement. 1 cases of.4 patients with single bone involvement were combined with other parts of the lymphangioma.4 cases with chylothorax and 3 of the patients with recurrent dyspnea. The bone biopsy showed that the endothelial cells in the lesion site had CD31, CD34 and D2-40 positive expression. Furthermore, the weak positive expression of VEGF and VEGF-R was found. Conclusion: GSS It is a rare disease of lymphatic origin. When combined with chylothorax, the prognosis is poor.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R681.1

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2 劉怡;1、成骨不全癥基因型—表現(xiàn)型的關(guān)聯(lián)研究 2、阿侖膦酸鈉、唑來膦酸治療成骨不全癥的療效對比 3、Gorham-Stout綜合征的臨床分析[D];北京協(xié)和醫(yī)學(xué)院;2015年

3 吳樹鑫;補腎活血法聯(lián)合阿侖膦酸鈉對絕經(jīng)后骨質(zhì)疏松癥的療效觀察[D];福建中醫(yī)藥大學(xué);2012年

4 邵紅芳;激素替代治療與阿侖膦酸鈉治療絕經(jīng)后骨質(zhì)疏松癥的臨床療效研究[D];蘇州大學(xué);2011年

5 婁方勇;阿侖膦酸鈉對去卵巢大鼠關(guān)節(jié)軟骨的影響[D];山西醫(yī)科大學(xué);2009年

6 劉曉民;載阿侖膦酸鈉超高分子量聚乙烯的研究[D];西南交通大學(xué);2010年

7 李征宇;阿侖膦酸鈉不同給藥方案治療絕經(jīng)后婦女骨質(zhì)疏松癥效果研究[D];第四軍醫(yī)大學(xué);2012年

8 駱陽;阿侖膦酸鈉對卵巢切除大鼠股骨骨折愈合影響的實驗研究[D];華北煤炭醫(yī)學(xué)院;2010年

9 邊志穎;阿侖膦酸鈉腸溶片治療和預(yù)防絕經(jīng)后婦女骨質(zhì)疏松的相關(guān)研究[D];河北醫(yī)科大學(xué);2010年

10 賈鵬;阿侖膦酸鈉對大鼠主動脈鈣化血管組織骨橋蛋白表達的影響[D];華中科技大學(xué);2010年

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