睾酮对去势与非去势小鼠前列腺增生影响的实验研究

目的:探讨睾酮(T)对去势和非去势小鼠前列腺增生影响的各自特点及差异。方法:选用48只BALB/c小鼠,随机分为去势对照组(A)、非去势对照组(B)、去势小剂量T组(C)、非去势小剂量T组(D)、去势大剂量T组(E)、非去势大剂量T组(F),每组8只。C、D组和E、F组分别采用12.5mg/(kg.d)和125mg/(kg.d)丙酸睾酮连续腹腔内注射20d,A、B组则注射生理盐水。第21d所有小鼠摘眼法采血后处死,观察前列腺并称重,对比分析其各自病理学特点。结果:A组可见前列腺萎缩及部分脂肪组织替代,B组是正常前列腺。C、D组小鼠前列腺均出现增生,以腹侧叶为主,背侧叶增生不明显,但D组前列腺增生较C组更明显(P<0.05),呈单侧腹侧叶结节状非对称局限性增生。E、F组前列腺增生的程度稍高于C、D组,但并不与T增加的剂量成正比,且伴有腺体局部糜烂坏死和轻度异型。T治疗后小鼠血清T和血管内皮生长因子升高,雌二醇下降,以非去势大剂量T组更明显。结论:去势与非去势小鼠经不同剂量T短期治疗后均可出现前列腺增生,但增生程度和特点存在差别,有助于我们进一步研究睾丸去势、雄激素与前列腺疾病之间的关系。     

探讨综合治疗对去势家兔骨质疏松模型股骨上端骨折愈合？…

目的 探讨应用雌激素、降钙素、维生素Ｄ３和钙剂对去热家兔骨质疏松模型股骨上端骨折愈合的作用。方法 １６只雌性青紫兰家兔支势复制骨质疏松模型,行股骨上端骨折克氏针内固定。术后随机分为两组,实验组给予益钙宁、尼尔雌醇、维生素Ｄ３及钙剂观察对骨折愈合的影响。结果 Ｘ射线片示实验组较对照组外骨痂生成量多,骨折愈合时间缩短。股骨的极限扭矩和最大刚度增加。ＱＣＴ检测腰２～４椎体松质骨骨密度皆增加。结论 骨质疏     

高能震波治疗骨折延迟愈合或不愈合

高能震波治疗骨折延迟愈合或不愈合已有近20年历史,具有非侵入性和并发症少的优点,疗效明显.它应成为治疗骨折延迟愈合和不愈合的首选疗法.该文回顾近年高能震波促进骨折愈合的文献,对治疗骨折延迟愈合和骨折不愈合的基本原理、作用机制、使用仪器及参数、临床效果进行简要描述和分析,提出影响因素、安全性及今后应注重的方向.     

骨折不愈合与延迟愈合的成因与治疗

目的探讨骨折不愈合与延迟愈合的成因、报肯治疗的方法与设果。方法对1990年7月～2004年12月间收治的107例骨折不愈台、54例骨折延迟愈合2例先天性胫骨骨不连进行回顾性研究，分析原因，随访治疗结果。18例延迟愈合行保守治疗，本组其他145例行手术治疗，结果除2例先天性胫骨骨不连外，其余161例的成因中均有医源性因素。10例失去随访，153例平均随访17（6-28）个月，骨折均获骨性连接，愈合时间平均10（6-14）个月，肢体功能恢复良好，结论医源性技术缺陷是骨折不愈合与延迟愈合的主要原因，针对各种不同因素进行合理治疗可获得满意效果。     

三叉髓内针治疗股骨干骨折不愈合延迟愈合

目的：探讨运用三叉弹性髓内针治疗股骨干骨折不愈合延迟愈合,观察其疗效。方法：运用三叉髓内针（专利号2296218964.2天津津大医疗器械厂提供）,按股骨髓内逆行固定方法,进行髓内固定,对萎缩型骨不愈合或骨折端缺损大,行骨折端周围植骨。结果：31例手术切口均一期愈合,29例半年以上随访,骨折全部愈合,平均愈合时间5.8个月,3例遗留部分膝关节功能障碍,与本次手术前外固定时间长有关。结论：三叉弹性髓内针具有抗旋转,抗弯力强,应力集中小,遮挡效应小,内固定牢固,可早期行膝关节功能活动。骨愈合后取出简便,较加压钢板创伤小,梅花针内固定稳定,Crosse-Kempf针操作简单,是治疗股骨干骨折不愈合延迟愈合的一种较好方法。     

探讨综合治疗对去势家兔骨质疏松模型股骨上端骨折愈合的影响

目的　探讨应用雌激素、降钙素、维生素 D3和钙剂对去势家兔骨质疏松模型股骨上端骨折愈合的作用。方法　 16只雌性青紫兰家兔去势复制骨质疏松模型 ,行股骨上端骨折克氏针内固定。术后随机分为两组 ,实验组给予益钙宁、尼尔雌醇、维生素 D3及钙剂观察对骨折愈合的影响。结果　X射线片示实验组较对照组外骨痂生成量多 ,骨折愈合时间缩短。股骨的极限扭矩和最大刚度增加。QCT检测腰 2～ 4椎体松质骨骨密度皆增加。结论　骨质疏松并骨折除内固定外 ,还要联合应用抑制骨吸收 ,并促进骨形成的药物 ,加速了骨折的愈合     

骨折愈合刺激素治疗骨折延迟愈合8例

我科从1995～1997年采用骨折端局部注射骨折愈合刺激素,治疗骨折延迟愈合10例,其中8例得到随访并摄Ｘ线片复查,临床效果满意,现报告如下。1　临床资料本组8例中男6例,女2例;年龄18～54岁。交通事故撞伤7例,砸压伤1例。胫骨中下段5例(粉碎性2例,开放性3例),尺桡骨双骨折2例(1例为粉碎性),肱骨中上段骨折1例。原治疗方法:胫骨骨折切开复位内固定3例,手法复位外固定2例。尺桡骨双骨折2例采用切开复位桡板尺针内固定。肱骨中上段骨折采用夹板外固定。受伤距注射骨折愈合刺激素时间56～300天,平均148天。注射前均摄Ｘ线片,骨折线清晰,没有骨痂或…     

骨折延迟愈合与不愈合的冲击波治疗

目的 探讨应用体外冲击渡治疗骨折延迟愈合与不愈合的方法 、适应证、禁忌证及治疗效果.方法 使用冲击波骨科治疗机,根据骨折部位和骨的形状大小选择能量和冲击次数.基准点一般选在距骨折端0.5cm处或硬化骨端,每次选4～6个基准点,每个基准点冲击800次左右,能量16～17.5 kV,频率60～80次/min,每个治疗期2800～3400次,每期间隔1～2 d,每个疗程3～5个治疗期.结果 42例获随访,35例愈合,骨折愈合时间11～26周,平均15周,治愈率为83.3%,7例无效改行植骨术治疗.无血管神经损伤及其他并发症发生.结论 冲击波治疗骨折延迟愈合与不愈合方法 简便、疗效确切、经济安全,应作为首选,但是要注意选择好适应证.     

经皮注射自体骨髓治疗骨折延迟愈合与不愈合

目的 探讨经皮注射注入自体骨髓移植治疗骨折延迟愈合与不愈合的治疗效果。方法 21例患者抽取自体红骨髓离心后在C臂X线机透视下经皮注射至骨折延迟愈合与不愈合部位,定期随访观察骨折愈合进展情况。结果 20例获随访,骨折愈合18例,2例未愈合,愈合率90％,愈合时间4-11个月,平均8个月。21例患者经注射后无局部及全身感染并发症,未见异位骨化。结论 经皮注射自体骨髓移植治疗骨折延迟愈合与不愈合具有安全、有效、创伤小等优点,是临床上可供选择的治疗方法,值得深入研究及推广。     

Sildenafil accelerates fracture healing in mice

Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873     

Delayed fracture healing in tetranectin-deficient mice

Tetranectin is a plasminogen-binding protein that enhances plasminogen activation, which has been suggested to play a role in tissue remodeling. Recently, we showed that tetranectin has a role in the wound-healing process. In this study, we investigated whether tetranectin plays a role in fracture healing. The fracture-healing process was studied using a femoral osteotomy model in tetranectin-null mice, previously generated by the authors. Radiographic imaging, micro-computed tomography (μCT), and histological analysis were used to evaluate osteotomy healing. In wild-type mice, a callus was apparent from 7 days, and most samples showed marked callus formation and rebridging of the cortices at the osteotomy site at 21 days. In contrast, in the tetranectin-null mice there was no callus formation at 7 days and much less callus formation and no bridging of cortices were observed at 21 days. At 35 days, all osteotomy sites showed clear rebridging, and secondary bone formation was achieved in wild-type mice by 42 days. In contrast, no clear rebridging or secondary bone formation was observed at 42 days in the tetranectin-null mice. Analysis using μCT at 21 days after osteotomy revealed that the callus area in tetranectin-null mice was smaller than that in wild-type mice. Histological analysis also showed that soft tissue and callus formation were smaller in the tetranectin-null mice at the early stage of the healing process after drill-hole injury. These results suggested that tetranectin could have a role in the positive regulation at the early stage of the fracture-healing process, which was reflected in the delayed fracture healing in tetranectin-deficient mice.     

Simvastatin improves fracture healing in mice.

Recently, several articles have been published dealing with the anabolic effects on bone by statins. Mundy and associates discovered that several statins were able to activate the promotor of bone morphogenetic protein (BMP) 2. Additionally, oral simvastatin and lovastatin increased the cancellous bone volume in rats, presumably an effect of the increase of BMP-2. Other studies have followed, with conflicting results; some have found a positive bone metabolic effect of statins and others have not. Studies published so far have focused on osteoporosis. In this study, femur fractures were produced in 81 mature male BALB/c mice and stabilized with marrow-nailing. Forty-one mice were given a diet prepared with simvastatin, so that each mouse received an approximate dose of 120 mg/kg of body weight per day. The remaining mice received the same diet with the exception of the simvastatin. Bilateral femurs were harvested at 8, 14, and 21 days postoperatively (po), the marrow-nail was extracted, and diameters were measured. Biomechanical tests were performed on 42 mice, by way of three-point bending. Histological specimens were prepared using standard techniques. For statistical analysis, ANOVA with Scheffés post hoc test was used. At 8 days, the fracture callus was too soft for meaningful biomechanical testing. At 14 days, the callus of the simvastatin-treated mice had a 53% larger transverse area than controls (p = 0.001), the force required to break the bone was 63% greater (p = 0.001), and the energy uptake was increased by 150% (p = 0.0008). Stiffness and modulus of elasticity were not significantly affected. At 21 days, the fractures were histologically healed and the mechanical differences had disappeared. The contralateral unbroken bone showed a slight increase in transverse area because of the simvastatin treatment, but there was no significant effect on the force required to break the bone or on energy uptake. These results point to a new possibility in the treatment of fractures.     

Locally applied Simvastatin improves fracture healing in mice

Background  

HMG-CoA reductase inhibitors, statins, are widely prescribed to lower cholesterol. High doses of orally administered simvastatin has previously been shown to improve fracture healing in a mouse femur fracture model. In this study, simvastatin was administered either subcutaneously or directly to the fracture area, with the goal of stimulating fracture repair at acceptable doses.     

The SERM raloxifene improves diaphyseal fracture healing in mice

Although several studies reported that raloxifene treatment improves postmenopausal osteoporotic bone structure and reduces fracture risk, only a few animal and no human studies have examined its effects on the fracture healing process. Thus the aim of the present study was to determine, whether systemic application of the selective estrogen receptor modulator raloxifene promotes fracture healing compared to untreated control-, estrogen-deficient-, as well as estrogen-treated mice using a standardized femoral osteotomy model (n = 60 mice). Ten days after surgery, contact radiography and undecalcified histomorphometric analysis revealed that raloxifene administration significantly improved the early stage of fracture healing compared to all other groups. At day 20, raloxifene and estrogen treatment led to a significant increase in callus mineralization and trabecular thickness compared to control mice. μCT analyses revealed no evidence of complete bony bridging of the fracture site in any control-, nor estrogen-deficient mouse after 20 days, while all femoral fractures in the raloxifene and estrogen group already healed adequately at this time. These data indicate that raloxifene treatment significantly improves all phases of fracture healing at least in mice. Therefore, raloxifene could be a possible pharmaceutical to enhance fracture healing in women, without the known side effects of estrogen.     

Impaired fracture healing in macrophage migration inhibitory factor-deficient mice

Summary  

This study investigated the role of macrophage migration inhibitory factor (MIF) in fracture repair using MIF gene-deficient mice (MIF KO). Fracture healing was delayed in MIF KO, and this was mainly due to the delay in the mineralization of osteoid within the fracture callus.     

Osteoclast depletion with clodronate liposomes delays fracture healing in mice

Osteoclasts are abundant within the fracture callus and also localize at the chondro‐osseous junction. However, osteoclast functions during fracture healing are not well defined. Inhibition of osteoclast formation or resorptive activity impairs callus remodeling but does not prevent callus formation. Interestingly, though anti‐osteoclast therapies differentially affect resolution of callus cartilage into bone. Treatments that inhibit osteoclast formation or viability tend to impair callus cartilage resolution, while treatments that target inhibition of bone resorption generally do not affect callus cartilage resolution. Here, we tested whether depletion of osteoclasts by systemic treatment with clodronate liposomes would similarly impair callus cartilage resolution. ICR mice were treated by intraperitoneal injections of clodronate‐laden liposomes or control liposomes and subjected to closed femur fracture. Femurs were resected at multiple times after fracture and analyzed by radiography, histology, and mechanical testing to determine effects on healing. Clodronate liposome treatment did not prevent callus formation. However, radiographic scoring indicated that clodronate liposome treatment impaired healing. Clodronate liposome treatment significantly reduced callus osteoclast populations and delayed resolution of callus cartilage. Consistent with continued presence of callus cartilage, torsional mechanical testing found significant decreases in callus material properties after 28 days of healing. The results support a role for osteoclasts in the resolution of callus cartilage into bone. Whether the cartilage resolution role for osteoclasts is limited to simply resorbing cartilage at the chondro‐osseous junction or in promoting bone formation at the chondro‐osseous junction through another mechanism, perhaps similar to the reversal process in bone remodeling, will require further experimentation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1699–1706, 2017.

     

Stimulation of angiogenesis by cilostazol accelerates fracture healing in mice

Cilostazol, a selective phosphodiesterase‐3 inhibitor, is known to control cyclic adenosine monophosphate (c‐AMP) and to stimulate angiogenesis through upregulation of pro‐angiogenic factors. There is no information, however, whether cilostazol affects fracture healing. We, therefore, studied the effect of cilostazol on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine femur fracture stabilized with an intramedullary screw. Radiological, biomechanical, histomorphometric, histochemical, and protein biochemical analyses were performed at 2 and 5 weeks after fracture. Twenty‐five mice received 30 mg/kg body weight cilostazol p.o. daily. Controls (n = 24) received equivalent amounts of vehicle. In cilostazol‐treated animals radiological analysis at 2 weeks showed an improved healing with an accelerated osseous bridging compared to controls. This was associated with a significantly higher amount of bony tissue and a smaller amount of cartilage tissue within the callus. Western blot analysis showed a higher expression of cysteine‐rich protein 61 (CYR61), bone morphogenetic protein (BMP)‐4, and receptor activator of NF‐kappaB ligand (RANKL). At 5 weeks, improved fracture healing after cilostazol treatment was indicated by biomechanical analyses, demonstrating a significant higher bending stiffness compared to controls. Thus, cilostazol improves fracture healing by accelerating both bone formation and callus remodeling. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1880–1887, 2015.     

Bone loss and impaired fracture healing in spinal cord injured mice

Summary

Spinal cord injury (SCI) results in impaired fracture healing in mice while leading to significant bone loss. Poor fracture healing following SCI is consistent with significant bone loss.

Introduction

SCI leads to significant bone loss in sublesional limbs, but there is few data concerning the relationship between fracture healing and bone loss following SCI. This study was undertaken to investigate the effect of SCI on fracture healing using a mouse femur fracture model.

Methods

One hundred twenty male C57BL/6J mice were randomly divided into SCI and control groups (n?=?60, respectively). A femoral shaft fracture was generated and fixed with intramedullary pins 3?weeks after SCI. Fracture healing was evaluated by micro-computed tomography (micro-CT) for callus formation and mineralization and neovascularization, and bone mineral density (BMD) was measured by DXA at 1, 2, and 4?weeks after fracture. Serum vascular endothelial growth factor (VEGF), osteocalcin, and alkaline phosphatase (ALP) were assessed using ELISA at each time point. Biomechanical testing was performed at 2 and 4?weeks.

Results

BMD in SCI mice was significantly lower compared to control mice at each time point, with callus volume and all vessel parameters reduced as measured by micro-CT. Ultimate stress of the femora was significantly lower in SCI mice than in control mice at 2 and 4?weeks after fracture, whereas Young's modulus between the SCI and control mice turned to be significantly different at 4?weeks. Serum VEGF was lower in SCI mice than in the control group at 2 and 4?weeks, whereas serum osteocalcin and ALP were lower in SCI mice than in control ones at each time point.

Conclusion

Significant bone loss and fracture healing impairment was noted in SCI mice. Decreased angiogenesis is consistent with the changes of microarchitecture and biomechanical properties during fracture healing.