【作者】 陈治宇；

【导师】 裴福兴；

【作者基本信息】 四川大学 ， 外科学， 2007， 硕士

【摘要】 【背景】骨质疏松症是一种以低骨量和骨组织微结构破坏为特征，导致骨脆性和骨折风险度升高的全身性骨代谢疾病。其严重影响人们生理、社会心理和经济后果的健康问题，已成为全世界关注的老年性疾病之一。长期应用糖皮质激素所造成的骨质疏松症(GIO)的发病率居继发性骨质疏松的首位。GIO的主要致病因素之一是骨形成减少，然而迄今为止，已有的抗骨质疏松药物以抗骨吸收为主。因此，如今骨质疏松研究领域最大的挑战之一就是寻找一种能刺激成骨细胞活性增加骨量的药物。肾上腺髓质素(ADM)是一种有效的促成骨细胞有丝分裂剂，肾上腺髓质素(27-52)是ADM的多肽片段，其在失去ADM对心血管系统，肺，血小板，胃酸分泌等的作用的同时，保留了促成骨细胞增殖分裂的活性。因此，肾上腺髓质素(27-52)有潜力成为有效的促骨形成剂。【目的】在建立激素性骨质疏松性大鼠模型的基础上，给予肾上腺髓质素(27-52)治疗，并通过影象学，骨密度，组织学，骨显微形态计量学及生物力学的检测，研究肾上腺髓质素(27-52)对激素性骨质疏松症的治疗作用。【材料与方法】将6月龄的雌性Wistar大鼠48只随机分为四组：①正常对照组；②激素(地塞米松)组；③肾上腺髓质素(27-52)治疗组；④维生素D治疗组。后三组建立激素性骨质疏松性大鼠模型后，分别给予生理盐水，肾上腺髓质素(27-52)和维生素D治疗，8周后进行影象学，骨密度，组织学，骨显微形态计量学及生物力学的检测。【结果】①骨密度肾上腺髓质素(27-52)治疗组腰椎、股骨BMD较地塞米松组均显著升高(P＜0.01)；与正常对照组比BMD无显著差异。而维生素D组与地塞米松组相比第三腰椎BMD明显升高(P＜0.05)，而股骨BMD则无显著变化；与正常对照组相比，第三腰椎BMD仍有明显下降。②股骨的几何参数指标与地塞米松组相比：肾上腺髓质素(27-52)治疗组直径(P＜0.05)和抗弯截面模量(P＜0.01)均显著性增高。维生素D治疗组各参数虽然表现出上升趋势，但未出现显著性差异。③股骨的结构力学指标与地塞米松组相比：肾上腺髓质素(27-52)治疗组最大桡度(P＜0.01)、最大载荷均显著性增高(P＜0.01)。维生素D治疗组最大载荷显著性增高(P＜0.05)，最大桡度表现出上升趋势，但未出现显著性差异。④股骨的材料力学与地塞米松组相比：维生素D治疗组最大应力、最大应变和弹性模量表现出上升趋势，但未出现显著性差异。肾上腺髓质素(27-52)治疗组最大应力(P＜0.01)、最大应变(P＜0.05)和弹性模量(P＜0.01)均显著性增高。⑤股骨的形态计量学与地塞米松组相比，维生素D治疗组静态参数骨小梁面积百分率(％Tb.Ar)显著增加(P＜0.05)，骨小梁间隙(Tb.Sp)明显减少(P＜0.05)，骨小梁数目(Tb.N)和骨小梁厚度(Tb.Th)有增加的趋势，但是均无显著差异；肾上腺髓质素(27-52)治疗组静态参数骨小梁面积百分率(％Tb.Ar)和骨小梁数目(Tb.N)显著增加(P＜0.01)，骨小梁间隙(Tb.Sp)明显减少(P＜0.01)，骨小梁厚度(Tb.Th)有增加的趋势，但无显著差异。⑥影象学从各组的X光片分析可知，肾上腺髓质素(27-52)组比地塞米松组股骨骨皮质更厚，松质骨透光度更低。⑦组织学显示正常对照组和肾上腺髓质素(27-52)组骨小梁排列密集，小梁厚度宽、间距小，骨小梁之间的连接较多；而地塞米松组骨小梁排列稀疏，数目减少，小梁明显变细、间距加宽，骨小梁结构出现较大的空白区域。【结论】①肾上腺髓质素(27-52)能明显增加激素性骨质疏松大鼠的股骨，腰椎的骨密度，增加骨量，且其效用要明显高于维生素D。②肾上腺髓质素(27-52)能改善骨显微形态结构，显著增加单位体积骨小梁数目，明显减少骨小梁间隙，同时增加骨小梁的厚度，有利于提高骨质量。③肾上腺髓质素(27-52)能显著改善激素性骨质疏松大鼠的股骨的生物力学性能，且结构力学、材料力学均有改善，这将增加激素性骨质疏松大鼠抵抗骨质疏松性骨折的能力，提高骨质量。④肾上腺髓质素(27-52)有明确的促骨形成的作用，能干预激素诱导的骨质疏松症的发生和发展，治疗激素诱导的骨质疏松症，是有广阔应用前景的促骨形成的抗骨质疏松药物。更多还原

【Abstract】 【Background】Osteoporosis（OP） is a disease characterized by low bone mass anddeterioration of bone microarchitecture, which lead to an increase bonefragility and tendency of fractures. The incidence ofGlucocorticoid-induced osteoporosis（GIOP） takes the first place of theprevalence of secondary osteoporosis. The main cause for GIOP is thedecrease of bone formation, however, the regular drugs for osteoporosismostly belong to antiresorptives. Therefore, the most challenge of theresearch area of osteoporosis is to seek for a bone-forming drugs.Adrenomedullin（ADM） is a potent stimulator which can effectively stimulatethe differentiation of osteoblast. Adrenomedullin （27-52）is a polypeptide thatis a part of adrenomedullin. Comparing with adrenomedullin,Adrenomedullin （27-52） has the same effect on bone but without any effecton lung, platelet, stomach and cardiovascular system. Thus, Adrenomedullin（27-52） have a potential for becoming a effective and selectivebone-forming drug. 【Objective】To investigate the effects of adrenomedullin（27-52） on bone minernaldensity and histology of bone tissue, biomechanical property of the femur,radiography of femur, as well as histomorphometric parameters inglucocorticoid-induced osteoporosis rats.【Material and method】48 adult female Wistar rats were randomly divided into four groups:①normal control;②DXM,③DXM+ADM（27-52）;④DXM+Vitamin D₃.By intramuscular injection of dexamethasone （DXM） 1mg/kg twice a weekduring the first 8 weeks, the animal model of Glucocorticoid inducedosteopoprosis was established. After DXM, DXM+ADM（27-52） and DXM+Vitamin D₃ were applied normal saline（NS）, ADM（27-52） and Vitamin D₃respectively for 8 weeks, bone minemal density and histology of bonetissue, biomechanical property of the femur, radiography of femur, as well ashistomorphometric parameters were measured.【Results】1.bone minernal densityBMD of vertebrae body and femur in ADM（27-52） group wassignificantly higher than those in dexamethasone （DXM） group, while onlyBMD of vertebrae body in Vitamin D₃ group was higher than the DXM group.There were no differences between the BMD of vertebrae body and femur inADM（27-52） group and those in normal control.2. femoral geometrical parameters Comparing with the DXM group, the diameter（P＜0.05） and sectionmodulus under torsion（P＜0.01） were significantly increased inADM（27-52） group, however, these parameters were increased withoutsignificant difference in Vitamin D₃ group.3.Parameters in structural mechanicsComparing with the DXM group, the displacement（P＜0.01） and peakload（P＜0.01） were significantly increased in ADM（27-52） group, however,only peak load （P＜0.05） was significantly increased in Vitamin D₃ group.4. material mechanical parametersComparing with the DXM group, the max-strain（P＜0.01） andmax-stress（P＜0.01） were significantly increased in ADM（27-52） group,however, these parameters were increased without significant difference inVitamin D₃ group.5. histomorphometric parameters of femurComparing with the DXM group, %Tb. Ar and Tb. N significantlyincreased（P＜0.01）, while Tb. Sp decreased significantly（P＜0.01） inADM（27-52） group. As to Vitamin D₃ group, %Tb. Ar significantlyincreased（P＜0.05） and Tb. Sp decreased significantly（P＜0.05）.6. radiologyAccording to the X-ray film, cortex of femur in ADM（27-52） group ismuch thicker than those in DXM group, and transmittance of Cancellousbone decreased comparing with the DXM group.7.histologyThe trabecular bone was more compact, thicker, less sparse inADM（27-52） group comparing with the DXM group. 【Conclusion】1. ADM（27-52） could significantly increase the bone minernal densityof glucocorticoid-induced osteoporosis rats, and had better effects thanVitamin D₃.2. ADM（27-52） could significantly elevate biomechanical property ofthe femur of glucocorticoid-induced osteoporosis rats. Parameters instructural mechanics, histomorphometry and material mechanics were allimproved, which led to better resistance to fracture.3. ADM（27-52） could improve the microstructure of bone, significantlyincreased %Tb. Ar and Tb. N, moreover, significantly decreased Tb. Sp.Thus,the bone quality was improved.4. ADM（27-52） had a prominent bone-forming effect, and couldinterfere the development of glucocorticoids-induced osteoporosis,ADM（27-52） was a promising bone-forming anti-osteoporosis drug.更多还原