Effects of alendronate on particle-induced osteolysis in a rat model

BACKGROUND: Particle-induced osteolysis is currently a major problem affecting the long-term survivorship of total joint replacements. Alendronate is a third-generation bisphosphonate that blocks osteoclastic bone resorption. The objective of this study was to determine whether alendronate could prevent particle-induced osteolysis or restore (reverse) bone loss in established osteolysis. METHODS: A rat model of particle-induced osteolysis was used. A specially designed polyethylene implant was placed in the proximal part of the right tibia of seventy-two animals. Following four weeks of healing, the animals were randomized into control groups, a prevention group, or a treatment group. In the prevention group, animals received intra-articular injections of high-density polyethylene particles (mean size, 2 m; all <10 m) at four, six, and eight weeks postoperatively. Alendronate (0.01 mg/kg/day) was administered concomitantly through an implantable pump from the fourth week through the tenth week. In the treatment group, animals were also exposed to polyethylene particles at four, six, and eight weeks, to establish bone loss, but they received alendronate subsequently, from the tenth week through the sixteenth week, to treat the bone loss. Positive (particle-only) and negative (saline-solution-only) control groups were assessed as well. Tissues were harvested at ten weeks in the prevention group and at sixteen weeks in the treatment group. Histological analyses and histomorphometric determinations of the periprosthetic bone volume were carried out. RESULTS: Histological examination showed a rim of new bone (neocortex) around the implant in the untreated and saline-solution-treated control animals (no polyethylene particles). Treatment with saline solution (no polyethylene particles) did not affect periprosthetic bone. Animals exposed to polyethylene particles had bone loss. In those that received alendronate, the bone loss was either prevented or reversed, and the quantity of neocortical and trabecular bone was increased compared with that of the controls. Alendronate effectively preserved periprosthetic bone in both the prevention and treatment groups. In the prevention arm, the mean periprosthetic bone volume of the neocortex and the surrounding trabecular bone, as determined with histomorphometry, was 21.5% +/- 6.5% in the saline-solution-treated controls (no particles), 13.1% +/- 5.9% in the particle-treated animals, and 32.6% +/- 6.4% in the alendronate-treated animals (p < 0.001). In the treatment arm, the mean periprosthetic bone volume was 27.2% +/- 5.6% in the saline-solution-treated controls, 17.7% +/- 6.2% in the particle-treated animals, and 30.2% +/- 5.9% in the alendronate-treated animals (p = 0.002). CONCLUSIONS: In our model, the intra-articular injection of polyethylene particles caused substantial bone loss around a loaded implant. Alendronate effectively prevented and treated the particle-induced periprosthetic bone loss.     

Erythromycin inhibits wear debris-induced inflammatory osteolysis in a murine model.

Up to 20% of patients with total joint arthroplasty will develop radiographic evidence of aseptic loosening (AL), which most likely results from an inflammatory response to billions of wear debris shed from the implant. Our previous work has demonstrated that erythromycin (EM), a macrolide antibiotic, inhibits wear debris-induced inflammatory osteoclastogenesis through the reduction of cytokine production and osteoclast differentiation, both of which involve the NF-kappaB pathway. The aim of the current study was to determine whether EM inhibits wear debris-induced inflammatory osteolysis in a murine osteolysis model. Ultrahigh molecular-weight polyethylene (UHMWPE) debris was introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM (2 mg/kg/day) was given to mice intraperitoneally 2 days before UHMWPE introduction and maintained until the sacrifice of the mice. Mice with and without EM treatment, as well as control mice injected with saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Our findings indicate that: (1) EM reduced UHMWPE-induced tissue inflammation, including the diminished pouch membrane thickness, reduced inflammatory cellular infiltration, and lowered IL-1beta and TNF-alpha expression (mRNA and protein); (2) EM inhibited UHMWPE-induced osteoclastogenesis, with reduced gene activation of RANK, RANKL, and CPK, and diminished RANKL expression in UHMWPE stimulated pouches, and (3) EM markedly reduced the number of TRAP(+) cells in pouch tissues, and protected against bone collagen depletion. In conclusion, this study provides the evidence that EM inhibits the UHMWPE particles-induced inflammatory osteolysis in a murine model, and represents a promising therapeutic candidate for the prevention and treatment of AL.     

载阿仑膦酸钠骨水泥抑制钛磨屑诱导的假体周围骨溶解

目的 比较载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠抑制钛磨眉诱导的骨溶解的效果.方法 48只成年雄性新西兰兔随机均分为无钛磨屑且无阿仑膦酸钠组(A组),有钛磨屑注射且无阿仑膦酸钠组(B组),钛磨屑分别注射0.1%、0.5%、1.0%载阿仑膦酸钠丙烯酸骨水泥组(C、I)、E组),钛磨屑注射且皮下手射阿仑膦酸钠组(F组),每组8只.将载阿仑膦酸钠骨水泥植入兔股骨远端.制备磨屑诱导骨溶解动物模型.术后8周对股骨行组织形态学分析、骨密度(bone mineral density,BMD)测定及界面力学测试结果 B组假体周围可见明显的骨溶解,而C、D、E、F组骨溶解明显少于B组.B组假体周围BMD和骨-骨水泥界面抗剪强度分别较A组下降17%和56%;D组假体周围BMD和界面抗剪强度较B组分别增加29%和62%;E组假体周围BMD和界画抗剪强度较B组分别增加37%和29%;F组假体周围BMD和界面抗剪强度较B组分别增加51%和69%;C组、D组、E组分别与F组比较,假体周围BMD和界面抗剪强度的差异均无统计学意义.结论 载阿仑瞵酸钠丙烯酸骨水泥与皮下注射阿仑瞵酸钠均可在一定程度上抑制磨屑诱导的骨吸收,增强界画抗剪强度.     

Efficacy of etanercept for wear debris-induced osteolysis.

A major limitation of total joint arthroplasty is that up to 20% of patients require revision surgery to correct prosthetic loosening. Aseptic loosening is believed to result from the phagocytosis of wear debris particles by macrophages, which secrete proinflammatory cytokines that stimulate osteolysis. Tumor necrosis factor alpha (TNF-alpha) has been shown to be one of the prominent cytokines in this cascade and to be involved critically in the generation of particle-induced osteolysis. Etanercept is a soluble inhibitor of TNF-alpha, which is widely used for the treatment of rheumatoid arthritis. Here, we show this agent's ability to prevent wear debris-induced osteolysis. In vitro we show that Etanercept can inhibit directly osteoclastic bone resorption in a bone wafer pit assay, as well as cytokine production from titanium (Ti)-stimulated macrophages. Using a quantitative in vivo model of wear debris-induced osteolysis, we show that Etanercept prevents bone resorption and osteoclastogenesis. In mice treated with Etanercept at the time of osteolysis induction, bone resorption and osteoclast numbers were reduced to background levels in both normal and human TNF-alpha (hTNF-alpha) transgenic mice. In an effort to evaluate its effect on established osteolysis, Etanercept was administered 5 days after Ti implantation, and we observed that further osteolysis was prevented. These data support the concept that TNF-alpha is involved critically in osteoclastogenesis and bone resorption during periprosthetic osteolysis and suggest that soluble TNF-alpha inhibitors may be useful as therapeutic agents for the treatment of prosthetic loosening in humans.     

Mechanism and clinical significance of wear debris-induced osteolysis.

Loosening of joint replacement components is often multifactorial. The quality of initial fixation is very important to the outcome of the arthroplasty and is often a factor in short-term and long-term failure. This paper discusses another important factor of implant loosening, namely wear debris induced osteolysis. Macrophages activated by the phagocytosis of particulate wear debris are the key cells in this process, which can potentially occur in any implant system regardless of implant design or fixation mode. This is because each implant system creates wear debris from the articulating surfaces and the interfaces. The clinical consequences of wear debris cover a broad spectrum from radiolucencies to massive osteolysis and implant failure. For this reason, the reduction of wear debris should be a primary goal of orthopedic research in the future.     

Pressure-induced periprosthetic osteolysis: a rat model.

Recent animal experiments have indicated that oscillating fluid pressure at the interface of bone and implant can lead to osteolysis. However, external nonphysiologic saline solutions were used to generate the pressure in these studies. In the present study on 15 Sprague-Dawley rats, hydrostatic pressure fluctuations were applied to bone through body fluids, by compressing a soft-tissue membrane adjacent to the proximal tibia. A titanium plate was fixed to the bone surface. After 28 days of osseointegration of the plate, a 1-mm-wide gap was created between it and the cortical bone and 5 days were given for fibrous tissue to form. Load was transmitted to this soft tissue by applying force on a piston mounted in the plate. In six rats, a cyclic pressure of 0.6 MPa was then applied to this tissue by 20 cycles twice a day with a frequency of 0.17 Hz for 5 days. The remaining rats served as controls, with the piston left untouched in its upper position. All of the rats were killed 10 days after creation of the gap. Histological sections were produced at a right angle to the loaded surface. In the pressurized specimens, osteoclastic bone resorption was dramatic. In all specimens, the original cortex was almost entirely resorbed but new woven bone had formed deeper in the marrow and walled off a cystic lesion. When necrotic remnants of the cortex were still in place, new woven bone was seen on the side away from the piston. This "lee effect" may indicate that bone formation was inhibited by fluid flow away from the pressurized tissue. The specimens with a nonloaded piston showed no signs of resorption. This new experimental model shows again that a moderate rise of hydrostatic pressure at the interface of bone and implant leads to considerable bone resorption. This could be a mechanism of prosthetic loosening.     

Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis.

Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1-/- mice. COX-2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis.     

红霉素和阿伦磷酸钠防治人工关节松动动物实验研究

[目的]应用植骨气囊模型观察红霉素和阿伦磷酸钠防治人工关节松动的效果.[方法]应用8～10周大的BALB/c小鼠建立气囊模型,气囊成熟后在气囊内植入同基因小鼠颅骨,同时在气囊内注入超高分子聚乙烯颗粒.实验分4组:空白组气囊和腹腔均注射生理盐水(阴性对照);颗粒刺激组气囊注射聚乙烯颗粒,腹腔注射生理盐水(阳性对照);红霉素组气囊注射聚乙烯颗粒,腹腔注射红霉素;阿伦磷酸钠组气囊注射聚乙烯颗粒,腹腔注射阿伦磷酸钠.14 d后处死,取囊壁和植入颅骨组织进行组织形态学和分子生物学检测.[结果]红霉素和阿伦磷酸钠组破骨细胞激活均受抑制,两者无显著差别.但红霉素组IL-1、TNF和VEGF含量明显下降,气囊炎性反应减轻,而阿伦磷酸钠无此抗炎作用.[结论]本试验证明红霉素和阿伦磷酸钠均有可能成为延缓和治疗人工关节松动的药物.     

依那西普对磨屑诱导骨溶解影响的实验研究

[目的]检测依那西普（Etanercept，Enbrel）对钛颗粒刺激巨噬细胞（macrophages，MФ）分泌肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）、白介素1（interleukin-1，IL-1）、白介素6（interleukin-6，IL-6）的影响，探讨依那西普防治人工关节无菌性松动的可能性。[方法]分离、培养小鼠腹腔巨噬细胞，24h后分为5组。A组：仅为MФ；B组：MФ＋钛颗粒；C组：MФ＋钛颗粒＋依那西普（10ng／m1）；D组：MФ＋钛颗粒＋依那西普（100ng／ml）；E组：MФ＋钛颗粒＋依那西普（1000ng／ml）。培养18h后，用酶联免疫法（ELISA）检测细胞培养上清液中TNF-α、IL-1、IL-6的含量。[结果]B组TNF-α、IL-1、IL-6含量明显高于A、D、E组（P〈0．001），E组TNF-α、IL-1、IL-6的含量明显低于B组、C组（P〈0．001，E组和D组间无统计学意义（P〉0．05）。[结论]钛颗粒可以刺激MФ分泌大量的TNF-α、IL-1、IL-6，依那西普能够呈剂量依赖型地有效抑制钛颗粒诱导的MФ分泌TNF-α、IL-1、IL-6，有望成为预防人工关节无菌性松动的药物。     

Quantitative small-animal surrogate to evaluate drug efficacy in preventing wear debris-induced osteolysis.

Individuals who suffer from severe joint destruction caused by the various arthritidies often undergo total joint arthroplasty. A major limitation of this treatment is the development of aseptic loosening of the prosthesis in as many as 20% of patients. The current paradigm to explain aseptic loosening proposes that wear debris generated from the prosthesis initiates a macrophage-mediated inflammatory response by resident macrophages, leading to osteoclast activation and bone resorption at the implant interface. No therapeutic interventions have been proved to prevent or inhibit aseptic loosening. The development of therapeutic strategies is limited due to the absence of a quantitative surrogate in which drugs can be screened rapidly in large numbers of animals. We have previously described a model in which titanium particles implanted on mouse calvaria induce an inflammatory response with osteolysis similar to that observed in clinical aseptic loosening. Here, we present new methods by which the osteolysis in this model can be quantified. We determined that 6-8-week-old mice in normal health have a sagittal suture area of 50 (+/-6) microm2, which contains approximately five osteoclasts. As a result of the titanium-induced inflammation and osteolysis, the sagittal suture area increases to 197 (+/-27) microm2, with approximately 30 osteoclasts, after 10 days of treatment. The sagittal suture area and the number of osteoclasts in the calvaria of sham-treated mice remained unchanged during the 10 days. We also determined the effects of pentoxifylline, a drug that blocks the responses of tumor necrosis factor-alpha to wear debris, and the osteoclast inhibitor alendronate. We found that both drugs effectively block wear debris-induced osteolysis but not osteoclastogenesis. In conclusion, we found the measurements made with this model to be reproducible and to permit quantitative analysis of agents that are to be screened for their potential to prevent aseptic loosening.     

Effect of anti-tumor necrosis factor-alpha gene therapy on wear debris-induced osteolysis.

BACKGROUND: Particle phagocytosis by macrophages induces the secretion of tumor necrosis factor-alpha, which is involved in the development of an osteolytic response. Therefore, we aimed to determine whether gene delivery of a soluble inhibitor of tumor necrosis factor-alpha (sTNFR:Fc) could prevent wear debris-induced osteolysis in a mouse model. sTNFR:Fc is a fusion protein containing the extracellular domain of the human type-I tumor necrosis factor receptor fused to the Fc region of mouse immunoglobulin. It acts by binding to tumor necrosis factor-alpha and preventing signaling through the membrane-bound tumor necrosis factor receptors. METHODS: An adenoviral vector encoding the LacZ gene (Ad.CMV-NlacZ) was propagated and was tested for its ability to transduce calvarial tissue. Ad.CMV-TNFR:Fc (encoding sTNFR:Fc) or Ad.CMV-NlacZ was administered to CBAxB6 mice in the presence or absence of titanium particles implanted onto the calvaria. Serum levels of sTNFR:Fc were measured with enzyme-linked immunosorbent assay, and the mice were killed on the tenth postoperative day for histological analysis. The experiments were repeated in athymic nude mice to avoid complications associated with the adenovirus-specific immune response. RESULTS: Administration of the control virus (Ad.CMV-NlacZ) transduced 10% of the cells in the periosteum. Ad.CMV-NlacZ treatment of sham-treated or titanium-treated animals induced significant bone resorption and osteoclastogenesis above control levels (that is, those in animals not treated with a virus). Treatment with the sTNFR:Fc virus did not reduce bone resorption or osteoclast numbers below control levels in CBAxB6 mice. In the athymic mice, no increase in the midline sagittal suture area or osteoclastogenesis was observed after treatment with the control vector and sTNFR:Fc gene therapy reduced the suture area to background levels. CONCLUSIONS: An immunologic response to Ad.CMV-NlacZ was most likely responsible for the increase in bone resorption and osteoclastogenesis in the animals treated with the control vector alone. In the athymic mice, in the absence of this immune response, sTNFR:Fc gene therapy reduced bone resorption in the midline sagittal suture area but had no effect on osteoclastogenesis.     

Polyethylene debris-induced osteolysis and loosening in uncemented total hip arthroplasty. A cause of late failure.

Uncemented total hip arthroplasty has proven to be an acceptable alternative to cemented total hip arthroplasty with good short-term results. With the elimination of the use of polymethyl methacrylate for component fixation, failure at the bone-cement interface, with resultant osteolysis and progressive loosening, was thought to be preventable. Unfortunately the ultra-high-molecular-weight polyethylene acetabular insert can wear and produce particulate debris. This debris can stimulate an osteolytic reaction and lead to late aseptic loosening in a cementless total hip arthroplasty.     

塞来昔布抑制大鼠颅骨内钛微粒引起骨溶解的实验研究

目的 探讨塞来昔布对关节磨损颗粒诱导的大鼠颅骨骨溶解的影响.方法 取健康雌性大鼠行颅骨手术,实验分为植入钛颗粒组、钛颗粒结合塞来昔布处理组和空白对照组,HE染色后通过测定骨小梁面积比计算骨吸收情况,并用实时荧光定量PCR,Western Blot检测COX-2、TNF-α的表达,ELISA法检测血清IL-1、IL-6、PGE2水平.结果 与对照组比较,钛颗粒组、钛颗粒结合塞来昔布处理组骨吸收明显,而钛颗粒结合塞来昔布处理组骨吸收较钛颗粒组改善;塞来昔布可明显下调钛颗粒植入大鼠颅骨后PGE2、TNF-α、IL-1和IL-6的表达.结论 塞来昔布可抑制钛颗粒诱导的大鼠颅骨骨溶解,有望成为防治人工关节无菌性松动的药物.     

阿仑膦酸钠预防磨损颗粒诱导假体周围骨溶解的作用机制

目的 目的是利用阿仑膦酸钠来研究其对人工关节假体周围骨溶解的影响及其作用机制。方法 体重300～350g的雄性SD大鼠24只，经膝关节将特制的钛合金假体及混合磨损颗粒植入胫骨近端（双侧），随机分为实验组和对照组，每组12只，术后分别每日空腹阿仑膦酸钠（0.1mg／kg体重）灌胃和生理盐水2ml灌胃，共6周。术后12周处死取材，进行组织学观察及组织形态计量学测定，并采用ELISA法及半定量RT—PCR检测假体周围组织中TNF-α的的含量及OPGL／OPG含量的比率。结果 组织学观察发现，对照组假体柄周围纤维界膜厚、细胞成分多。可分3层：紧贴假体处为疏松结缔组织，稍外为致密纤维结缔组织。最外层含有单核细胞、巨噬细胞及异物巨细胞。与纤维界膜连接处新生骨边缘呈虫蚀状，新生骨与假体接触少。对假体的支撑作用差。实验组假体周围纤维界膜较薄、细胞成分少，多为成纤维细胞。新生骨与假体间呈点状接触。对假体有明显的支撑作用。形态计量学检测发现，两组间假体周围界膜厚度及面积差异有统计学意义；ELISA和半定量RT—PCR检测假体周围组织中TNF-α及OPGL／OPG发现。两组间差异有统计学意义。结论 阿仑膦酸钠不仅可直接作用于假体周围组织的中破骨细胞。同时可通过调节假体周围组织分泌TNF-α、OPGL、OPG等的含量来调节破骨细胞的分化、成熟及增殖。     

阿仑膦酸钠不同给药时间间隔对磨损颗粒诱导的假体周围骨溶解影响

目的 观察阿仑膦酸钠不同给药时间间隔对磨损颗粒诱导假体周围骨溶解的影响,为临床应用阿仑膦酸钠预防人工关节假体周围骨溶解提供理论依据。方法 雄性SD大鼠12只,经膝关节将钛合金假体及混合磨损颗粒植入胫骨近端（双侧）,随机分成实验Ⅰ组和实验Ⅱ组,每组6只,术后分别每日1次空腹阿仑膦酸钠（0．1m∥kg）灌胃和每周1次空腹阿仑膦酸钠（0．7mg／kg）灌胃,持续6周。术后12周处死取材,进行组织学观察及组织形态计量学测定。结果 实验Ⅰ组和实验Ⅱ组假体柄周围纤维界膜均较薄,细胞成分少,假体周围新生骨与假体间可见有直接接触,对假体支撑作用良好。假体周围界膜厚度及面积的形态计量学检测发现,两组间差异无显著性。结论阿仑膦酸钠预防磨损颗粒诱导的假体周围骨溶解时,每周给药1次与每日给药1次可产生同样的效果。     

Collagen crosslinked N-telopeptides as markers for evaluating particulate osteolysis: a preliminary study.

The purpose of this study was to determine whether a marker of bone resorption could be used noninvasively to diagnose and assess treatment of periprosthetic osteolysis. The crosslinked N-telopeptide marker of osteoclast-mediated bone resorption potentially has the sensitivity to detect periprosthetic osteolysis. Second-morning urine specimens were obtained from (a) seven age-matched controls, (b) eight patients who had a hip arthroplasty, hybrid implants at least 1 year after surgery, and no osteolysis, (c) 11 patients who had a hip arthroplasty and osteolysis, and (d) 10 patients who had a hip arthroplasty and with osteolysis before and after 6 weeks of oral Fosamax (alendronate) treatment. The Fosamax treatment consisted of one 10-mg dose per day for 6 weeks. Men and young women (less than 40 years old) were chosen for this study to avoid bone resorption enhanced after menopause as a possible confounder. An enzyme-linked immunosorbent assay technique for quantifying crosslinked N-telopeptides of type-I collagen was performed on all specimens. The patients with osteolysis had significantly elevated levels of N-telopeptide compared with the implant control group. In addition, levels of N-telopeptide were significantly lowered after Fosamax treatment. These findings indicate that a systemic bone-resorption marker (N-telopeptide) can be used to evaluate local particulate-induced osteolysis and its treatment. The study also provides clinical evidence that osteolysis is associated with increased osteoclast-mediated bone resorption and that this locally induced bone resorption can be suppressed by certain bisphosphonates (Fosamax). These insights have potential value in the understanding and clinical management of aseptic loosening.     

Inhibition of AAA in a rat model by treatment with ACEI perindopril

Background

The purpose of the present study was to evaluate the effect of a new angiotensin converting enzyme inhibitor perindopril on the formation of experimental abdominal aortic aneurysms (AAAs) in a rat model induced by intraluminal elastase infusion and extraluminal calcium chloride (CaCl₂) application.

Materials and methods

Thirty-six male Sprague–Dawley rats were randomly distributed into three groups (n = 12 per group): model (A), sham (B), and perindopril (C). Rats in model and perindopril groups underwent intra-aortic elastase perfusion and extraluminal CaCl₂ application to induce AAAs. Rats in the sham group received aortic perfusion and extraluminal application of saline. A dose of 3 mg/kg/d of perindopril was fed orally in the perindopril group. The maximum abdominal aortic diameter was measured in vivo on days 0 and 28 and by ultrasound on days 7, 14, and 21. The arterial blood pressure was measured directly using a pressure transducer after cannulation in surgery and before death. AAA tissue samples were harvested at day 28 and evaluated using normal hematoxylin and eosin stain, Verhoeff-van Gieson stain for elastin, and image analysis technique.

Results

Aortic diameters of rats in the model group consistently increased within 28 d, coinciding with the development of a transmural inflammatory response, thickening of intima, and destruction of the elastic media. Without alteration in blood pressure, the AAA formation rate and mean maximal diameter of aorta at day 28 were significantly lower in the perindopril group compared with the control group (1.71 ± 0.20 versus 2.70 ± 0.69 mm, P < 0.001; 0% versus 90.91%, P < 0.001) and were similar to those in the sham group (1.79 ± 0.29 mm, P = 0.175; 0%, P = 1). The thickness of intima in the perindopril group was lower than that in the model group (20.68 ± 9.96 versus 58.49 ± 32.01 μm, P = 0.001), but higher than that in the sham group (7.23 ± 2.68 μm, P = 0.005). The intensity of elastin fiber showed the opposite trend (0.8541 ± 0.0495 in sham group versus 0.7376 ± 0.1024 in perindopril group versus 0.5413 ± 0.0912 in model group, P < 0.001).

Conclusions

Perindopril inhibited the aortic degeneration and AAA formation in the experimental AAA model induced by elastase and CaCl₂. This effect, which was independent of its influence on hemodynamics, appeared to be induced by the suppression of the inflammatory cell influx and intimal thickening and the preservation of aortic medial elastin.     

不同剂量阿仑膦酸钠对磨损颗粒诱导假体周围骨溶解的影响

目的观察不同剂量阿仑膦酸钠对磨损颗粒诱导假体周围骨溶解的影响,确定其合适剂量.方法雄性SD大鼠24只,经膝关节将钛合金假体及混合磨损颗粒植入胫骨近端（双侧）,随机分为对照组和实验Ⅰ、Ⅱ、Ⅲ组,每组6只,术后对照组每日空腹生理盐水2ml灌胃;实验Ⅰ、Ⅱ、Ⅲ组每日空腹阿仑膦酸钠灌胃,剂量分别为0．01、0．1、1mg／（kg·d）,持续6周.术后12周处死取材,进行组织学观察及组织形态计量学测定.结果对照组和实验Ⅰ组假体柄周围纤维界膜厚,细胞成分多,与纤维界膜连接处新生骨边缘呈虫蚀状,新生骨对假体的支撑作用较差;实验Ⅱ、Ⅲ组假体柄周围纤维界膜较薄,新生骨与假体间可见有直接接触,对假体有良好的支撑作用.假体周围界膜厚度及面积的形态计量学检测并经统计学分析显示：对照组与实验Ⅰ组、实验Ⅱ与Ⅲ组间差异无显著性（P〉0．05）,对照组和实验Ⅰ组分别与实验Ⅱ组和实验Ⅲ组间差异有显著性（P〈0．05）.结论以阿仑膦酸钠预防磨损颗粒诱导的假体周围骨溶解时,最适合剂量为0．1mg／（kg·d）.