阿伦膦酸钠防治人工关节松动的实验研究

目的：评价二膦酸盐阿伦膦酸钠在防治人工关节松动中的作用。方法：36只SD大鼠右膝置入自制人工关节假体,建立人工关节松动的动物模型,分成3组：阴性对照组,阳性对照组和实验组。阴性对照组关节腔内注射磷酸缓冲液与鼠血清混合液,阳性对照组关节腔内注射10^10/ml关节磨屑（超高分子聚乙烯颗粒）,实验组关节腔内注射10^10/ml关节磨屑同时用阿伦膦酸钠灌胃（每日1mg/kg）。术后12周,处死各组动物行组织切片对比观察假体周围骨溶解情况。体外分离培养人外周血单个核细胞并分成5组,A组为单核细胞组,B组为单核细胞和关节磨屑混合培养组,C组为单核细胞和关节磨屑混合培养加入10^-4mol/L阿伦膦酸钠,D组单核细胞和关节磨屑混合培养加入10^-5mol/L阿伦膦酸钠,E组为单核细胞和关节磨屑混合培养加入10^-6mol/L阿伦膦酸钠,检测各组单个核细胞分泌溶骨因子的情况。结果：关节磨屑可引起假体周围骨溶解,刺激单个核细胞分泌溶骨因子,阿伦膦酸钠可阻止这种作用。结论：阿伦膦酸钠可有效防止关节磨屑诱导的人工关节松动,有望用于临床。     

Inhibition of particulate debris-induced osteolysis by alendronate in a rat model.

A rat model was used to study the efficacy of alendronate therapy in inhibition of particle-induced periprosthetic osteolysis. A prosthesis was simulated by inserting a cylindrical polymethylmethacrylate plug into the distal femur of 24 rats allowing the plug to communicate with the joint space. Intra-articular injections of irregularly-shaped ultra-high molecular weight polyethylene particles of 20-200 pm in diameter were administered at 2-week intervals. The rats were randomized into two groups (n=12 each). Group A rats received twice weekly subcutaneous injections of alendronate sodium while group B rats received injections of saline vehicle only. At 10 weeks all rats were sacrificed. The distal femurs were harvested and axial sections were prepared for histologic analysis. Each section was graded on a scale of 1-4, quantifying the degree of osteolysis surrounding the polymethylmethacrylate plug. Microscopic examination showed a significant (P<.0001) difference in the amount of periprosthetic bone. Femurs from group A treated with alendronate demonstrated mostly normal or near-normal periprosthetic trabeculations, whereas femurs from group B treated with saline showed extensive bone resorption. There was no qualitative difference in the inflammatory cellular response between the groups. This study established the ability of alendronate to inhibit the osteoclastic-mediated osteolysis around joint implants.     

Alendronate reduces periprosthetic bone loss after uncemented primary total hip arthroplasty: a prospective randomized study.

Periprosthetic bone loss, especially in the proximal part of the femur, is common after cemented and uncemented total hip arthroplasty (THA). Bone loss can be progressive and, in the extreme, may threaten survival of the prosthesis. To study whether alendronate therapy can reduce bone loss adjacent to prostheses, 13 uncemented primary THA patients were randomized to the study. They received 10 mg alendronate + 500 mg calcium (n = 8) or 500 mg calcium only (n = 5) daily for 6 months follow-up after THA. Periprosthetic bone mineral density (BMD) was measured with dual energy X-ray absorptiometry (DXA). Decreases in periprosthetic BMD in the alendronate-treated group were lower compared with the changes in the calcium-only group in the same regions of interest at the same follow-up time. In the proximal femur, the mean BMD decrease was 17.1% in the calcium-only group, whereas in the alendronate-treated group the decrease was only 0.9% (p = 0.019). The mean periprosthetic BMD change was also significantly different in the total periprosthetic area between the study groups at the end of the follow-up (calcium-only group -9.9% vs. alendronate-treated group -2.6%; p = 0.019). Alendronate therapy led to a significant reduction in periprosthetic bone loss after primary uncemented THA compared with the changes found in patients without therapy. This kind of bone response may improve the support of the prosthesis and may result in better survival of the prosthesis. However, in this study the follow-up time was too short and the study population was too small to make any long-term conclusions as to the prognosis for THA patients treated with alendronate.     

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.     

The effects of local and systemic alendronate delivery on wear debris‐induced osteolysis in vivo

We investigated the effects of locally and systemically administered alendronate on wear debris‐induced osteolysis in vivo. Endotoxin‐free titanium particles were injected into rabbit femurs, prior to insertion of a nonweight‐bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee 2, 4, and 6 weeks after the implantation. Alendronate was incorporated at three different concentrations (0.1, 0.5, and 1.0 wt %) into bone cement for local delivery. For systemic delivery, alendronate was subcutaneously injected (1.0 mg/kg/week) 1 week after the implantation and then once a week until sacrifice. Eight weeks postoperatively, there was significant evidence of osteolysis surrounding the plug in the control group compared with markedly blocked osteolysis in the 0.5 wt % and the 1.0 wt % groups, and the systemic group. There was a concentration‐dependent effect of alendronate‐loaded bone cement on the improvement of peri‐prosthetic bone stock. Notably, no significant differences were found between the 0.5 wt % and the systemic group in peri‐prosthetic bone stock and implant fixation. Collectively, although the biological efficacy after the systemic delivery of alendronate was slightly higher than that in the local treatment groups, alendronate‐loaded bone cement may be therapeutically effective in inhibiting titanium particle‐induced osteolysis in vivo. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:893–899, 2010     

Alendronate did not inhibit instability-induced bone resorption. A study in rats

Alendronate is a bisphosphonate that can decrease osteoclastic activity. It has been suggested as treatment for periprosthetic osteolysis. We used 48 rats, of which 32 had a plate implant on one tibia, to study the effect of alendronate on bone resorption at an unstable implant-bone interface. The plate has a handle on top, which can be grasped through the skin and turned, to create a sliding motion of a titanium surface against the underlying bone. This is known to result in bone resorption, which was studied by histomorphometry. Osmotic minipumps were used to administer alendronate at 0.063 mg/kg/day or saline. The systemic effect of the treatment was assessed by ashing the proximal metaphyses of the tibia of the contralateral unoperated leg. The ash-weight was increased in the alendronate-treated group by 43% (p = 0.0001), corresponding to histological changes in the metaphyseal bone. There was no inhibition of the instability-induced bone resorption at the test surface by alendronate: bone was being resorbed and replaced by a tissue similar to a loosening membrane.     

Alendronate did not inhibit instability-induced bone resorption : A study in rats

Alendronate is a bisphosphonate that can decrease osteoclastic activity. It has been suggested as treatment for periprosthetic osteolysis. We used 48 rats, of which 32 had a plate implant on one tibia, to study the effect of alendronate on bone resorption at an unstable implant-bone interface. The plate has a handle on top, which can be grasped through the skin and turned, to create a sliding motion of a titanium surface against the underlying bone. This is known to result in bone resorption, which was studied by histomorphometry. Osmotic minipumps were used to administer alendronate at 0.063 mg/kg/day or saline. The systemic effect of the treatment was assessed by ashing the proximal metaphyses of the tibia of the contralateral unoperated leg. The ash-weight was increased in the alendronate-treated group by 43% (p = 0.0001), corresponding to histological changes in the metaphyseal bone. There was no inhibition of the instability-induced bone resorption at the test surface by alendronate: bone was being resorbed and replaced by a tissue similar to a loosening membrane.     

The effectiveness of polyethylene versus titanium particles in inducing osteolysis in vivo.

Bearing surface wear and periprosthetic osteolysis due to wear particles are among the most common reasons for joint replacement failure. A murine calvarial model of wear particle-induced osteolysis has been used to identify different biologic factors associated with this problem and to test nonsurgical methods of modulating the host response to particulate debris. This model has utilized titanium particles, however, in clinical practice the most common source of particulate debris is polyethylene particles from bearing surface wear. We now report a calvarial model of wear particle-induced osteolysis based on commercially available polyethylene particles. We found that compared to sham surgery osteoclast recruitment and bone resorption can be induced by introduction of the titanium particles or polyethylene particles. However, bone resorption was significantly higher with polyethylene particles compared to titanium particles (p=0.02). We consider the polyethylene based murine calvarial model of wear particle-induced osteolysis a reliable and clinically relevant tool to understand the host factors and potential pharmacologic interventions that can influence wear debris generated osteolysis. This model might serve as an extension of the well-established titanium based bone resorption model.     

Effects of short-term alendronate treatment on the three-dimensional microstructural,physical, and mechanical properties of dog trabecular bone

The bisphosphonate, alendronate, is well known for its potent inhibition of osteoclast-mediated bone resorption. It has been used clinically for the treatment of osteoporosis and has also recently been used to reduce osteolysis around prostheses in a canine revision model of implant loosening (femoral condyle). In this study, the effects of alendronate on trabecular bone properties were assessed in dogs at an oral dose of 0.5 mg/kg per day over a 12 week period, and compared with control dogs. Cubic cancellous bone specimens were produced from lumbar vertebrae (L-1 and L-2) and bilateral proximal humeri. These specimens were scanned using a high-resolution microcomputed tomography (micro-CT) system. From accurate data sets, three-dimensional microstructural properties were calculated and physical and mechanical properties were determined. Treatment with alendronate increased bone volume fraction by 9.5%, 7.7%, 7.4%, and 18.4%, respectively, in L-1, L-2, humeral greater tuberosity, and humeral head trabecular bone. In the lumbar vertebrae, the alendronate-treated trabeculae were thicker and lower in bone surface-to-volume ratio. In the greater tuberosity, the alendronate-treated trabeculae were thicker, lower in bone surface-to-volume ratio, and less anisotropic. In the humeral head, the alendronate-treated trabeculae were thicker, less anisotropic, lower in surface density, and showed decreased trabecular separation. Alendronate significantly increased apparent density and collagen density in the lumbar vertebrae and humeral heads, and significantly decreased collagen concentration in the vertebrae. In the lumbar vertebrae, Young's modulus in the cephalocaudal direction, ultimate stress, and failure energy were significantly increased in the alendronate-treated group. The changes in mechanical properties in the humeral head trabecular bone were similar to those seen in the lumbar vertebrae. Our results demonstrate that alendronate increases the mechanical properties of healthy canine trabecular bone after short-term treatment. The physical and microstructural changes of trabecular bone are consistent with the significantly increased mechanical properties.     

大颗粒聚乙烯对人工关节假体周围组织影响的实验研究

目的　制作松动人工关节的动物模型 ,了解大颗粒聚乙烯对实验动物人工关节假体周围骨组织的影响 ,并初步探讨其作用机制。　方法　选用健康新西兰白兔 2 0只 ,雌雄各半 ,体重 2 .3～ 2 .7kg。从两侧膝关节向股骨置入钴 -铬 -钼棒 ,分别于术后 2、4、6、8及 10周向一侧膝关节腔内注射聚乙烯微粒 (直径 10 0 μm)悬液 1.5 ml(实验侧 ) ,向另一侧膝关节腔内注射生理盐水 1.5 ml(对照侧 )。术后第 10周摄双下肢 X线片 ,了解假体周围是否有骨溶解和假体松动。术后第 12周处死动物。取 13只兔检查聚乙烯颗粒在关节囊分布情况 ,假体有否松动 ,周围有无新骨及界膜形成 ;取5只兔双侧股骨、膝关节囊作组织学检查 (实验过程中有 2只动物死亡 )。　结果　 1肉眼观察 :实验侧有 4侧金属假体被新生骨组织覆盖 ,9侧被纤维膜覆盖 ;对照侧有 11侧金属假体被新生骨组织覆盖 ,2侧被纤维膜覆盖 ,差异有统计学意义(P<0 .0 5 )。2 X线片观察 :假体位于股骨髓腔远端 ,其周围未见明显新生骨组织和骨溶解征像。3组织学观察 :实验侧关节囊见大量异物颗粒被成纤维细胞和多核巨细胞包绕 ,假体近端髓腔周围见成纤维细胞和纤维组织或新生骨组织形成 ,未见异物颗粒和多核巨细胞 ,靠近关节面部分见异物颗粒被成纤维细胞和多核巨细胞包绕     

Effects of the systemic administration of alendronate on bone formation in a porous hydroxyapatite/collagen composite and resorption by osteoclasts in a bone defect model in rabbits

Several bisphosphonates are now available for the treatment of osteoporosis. Porous hydroxyapatite/collagen (HA/Col) composite is an osteoconductive bone substitute which is resorbed by osteoclasts. The effects of the bisphosphonate alendronate on the formation of bone in porous HA/Col and its resorption by osteoclasts were evaluated using a rabbit model. Porous HA/Col cylinders measuring 6 mm in diameter and 8 mm in length, with a pore size of 100 μm to 500 μm and 95% porosity, were inserted into a defect produced in the lateral femoral condyles of 72 rabbits. The rabbits were divided into four groups based on the protocol of alendronate administration: the control group did not receive any alendronate, the pre group had alendronate treatment for three weeks prior to the implantation of the HA/Col, the post group had alendronate treatment following implantation until euthanasia, and the pre+post group had continuous alendronate treatment from three weeks prior to surgery until euthanasia. All rabbits were injected intravenously with either saline or alendronate (7.5 μg/kg) once a week. Each group had 18 rabbits, six in each group being killed at three, six and 12 weeks post-operatively. Alendronate administration suppressed the resorption of the implants. Additionally, the mineral densities of newly formed bone in the alendronate-treated groups were lower than those in the control group at 12 weeks post-operatively. Interestingly, the number of osteoclasts attached to the implant correlated with the extent of bone formation at three weeks. In conclusion, the systemic administration of alendronate in our rabbit model at a dose-for-weight equivalent to the clinical dose used in the treatment of osteoporosis in Japan affected the mineral density and remodelling of bone tissue in implanted porous HA/Col composites.     

Prevention of distortion of vascular deprivation-induced osteonecrosis of the rat femoral head by treatment with alendronate

Introduction  In animals with a disrupted blood supply and drainage of the femoral head, the dead epiphyseal bone undergoes osteoclastic osteolysis and is replaced by newly synthesized, immature, and weak bone, which cannot withstand the daily loads and, therefore, the articular surface caves in. Methods  Female Sprague–Dawley rats with interrupted blood circulation of the femoral head were treated with alendronate and compared to controls. Results  There was no distortion of the femoral heads in the alendronate-treated animals. Interpretation  Alendronate medication interferes with osteoclastic activities, slowing down bone turnover. These observations verify our hypothesis that osteoclastic activity is detrimental to the conservation of a hemispherical femoral head because of the rapidly occurring replacement of the dead by living tissues. Hence, halting the activities of the osteoclasts by alendronate stops the hasty new bone formation which is responsible for early femoral capital disfigurement. Jochanan H. Boss is deceased.     

Particle-Induced Osteolysis in Three-Dimensional Micro-Computed Tomography

Small-animal models are useful for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening after total joint replacement. Microstructural changes associated with particle-induced osteolysis have been extensively explored using two-dimensional (2D) techniques. However, relatively little is known regarding the 3D dynamic microstructure of particle-induced osteolysis. Therefore, we tested micro-computed tomography (micro-CT) as a novel tool for 3D analysis of wear debris-mediated osteolysis in a small-animal model of particle-induced osteolysis. The murine calvarial model based on polyethylene particles was utilized in 14 C57BL/J6 mice randomly divided into two groups. Group 1 received sham surgery, and group 2 was treated with polyethylene particles. We performed 3D micro-CT analysis and histological assessment. Various bone morphometric parameters were assessed. Regression was used to examine the relation between the results achieved by the two methods. Micro-CT analysis provides a fully automated means to quantify bone destruction in a mouse model of particle-induced osteolysis. This method revealed that the osteolytic lesions in calvaria in the experimental group were affected irregularly compared to the rather even distribution of osteolysis in the control group. This is an observation which would have been missed if histomorphometric analysis only had been performed, leading to false assessment of the actual situation. These irregularities seen by micro-CT analysis provide new insight into individual bone changes which might otherwise be overlooked by histological analysis and can be used as baseline information on which future studies can be designed.     

Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies.

Effects of alendronate (ALN) on bone quality and turnover were assessed in 88 patients (52 women and 36 men aged 22-75 years) who received long-term oral glucocorticoid exposure. Patients were randomized to receive oral placebo or alendronate 2.5, 5, or 10 mg/day for 1 year and stratified according to the duration of their prior glucocorticoid treatment. Transiliac bone biopsies were obtained for qualitative and quantitative analysis after tetracycline double-labeling at the end of 1 year of treatment. As previously reported in glucocorticoid-induced osteoporosis, low cancellous bone volume and wall thickness were noted in the placebo group as compared with normal values. Alendronate treatment was not associated with any qualitative abnormalities. Quantitative comparisons among the four treatment groups were performed after adjustment for age, gender, and steroid exposure. Alendronate did not impair mineralization at any dose as assessed by mineralization rate. Osteoid thickness (O.Th) and volume (OV/BV) were significantly lower in alendronate-treated patients, irrespective of the dose (P = 0.0003 and 0.01, respectively, for O.Th and OV/BV); however, mineral apposition rate was not altered. As anticipated, significant decreases of mineralizing surfaces (76% pooled alendronate group; P = 0.006), activation frequency (-72%; P = 0.004), and bone formation rate (-71%; P = 0.005) were also noted with alendronate treatment. No significant difference was noted between the changes observed with each dose. Absence of tetracycline label in trabecular bone was noted in approximately 4% of biopsies in placebo and alendronate-treated groups. Trabecular bone volume, parameters of microarchitecture, and resorption did not differ significantly between groups. In conclusion, alendronate treatment in patients on glucocorticoids decreased the rate of bone turnover, but did not completely suppress bone remodeling and maintained normal mineralization at all alendronate doses studied. Alendronate treatment did not influence the osteoblastic activity, which is already low in glucocorticoid-induced osteoporosis.     

Pharmacological treatment of osteopenia induced by gastrectomy or ovariectomy in young female rats

BACKGROUND: Both gastrectomy (GX) and ovariectomy (OVX) induce osteopenia in man and experimental animals. The present study addresses the question--can alendronate, estrogen or parathyroid hormone (PTH) be used to treat established GX- or OVX -evoked osteopenia? METHODS: Rats were GX-, OVX- or SHAM-operated 8 weeks before starting the treatment with drugs. Each group was then treated for 8 weeks with 50 microg/kg/day alendronate, 10 microg/kg/day estrogen or 75 microg/kg/day PTH(1-84); n = 8 rats/group. Peripheral Quantitative Computed Tomography (pQCT) was used to measure trabecular bone mineral density (BMD) and various cortical bone parameters. RESULTS: At killing, 16 weeks after surgery, GX and OVX rats had a greatly reduced trabecular BMD in the metaphysis of the distal femur (GX -44% and OVX -55%). Alendronate increased the trabecular BMD by 44% in GX rats and by 64% in OVX rats, while PTH increased it by 51% and 115%, respectively. However, estrogen increased the trabecular BMD in GX rats (35%), but not in OVX rats (15%, not significant). Cortical bone parameters were adversely (but moderately) affected by GX, but not by OVX or by treatment with the three drugs. INTERPRETATION: Alendronate, estrogen and PTH restored the trabecular bone loss in rats with an established GX-evoked osteopenia. In contrast, alendronate and PTH, but not estrogen, restored the trabecular bone loss after OVX. Hence, the mechanism underlying GX-evoked bone loss differs from that underlying OVX-evoked bone loss. The ability of alendronate, estrogen and PTH to reverse the GX-evoked osteopenia in the rat may be of clinical interest when dealing with bone loss in humans after GX.     

Polyethylene particle-induced bone resorption in alpha-calcitonin gene-related peptide-deficient mice.

This study investigates the impact of alpha-CGRP on bone metabolism after implantation of polyethylene particles. alpha-CGRP knockout mice showed less osteolysis compared with wildtype mice. The local neurogenic microenvironment might be a crucial factor in particle-induced osteolysis. INTRODUCTION: Periprosthetic osteolysis is the major reason for aseptic loosening in joint arthroplasty. This study aimed to investigate the potential impact of alpha-calcitonin gene-related peptide (alpha-CGRP) deficiency on bone metabolism under conditions of polyethylene particle-induced osteolysis. MATERIALS AND METHODS: We used the murine calvarial osteolysis model based on polyethylene particles in 14 C57BL 6 mice and 14 alpha-CGRP-deficient mice divided into four groups of 7 mice each. Groups 1 (C57BL/J 6) and 3 (alpha-CGRP knockout) received sham surgery, and groups 2 (C57BL/J 6) and 4 (alpha-CGRP knockout) were treated with polyethylene particles. Qualitative and quantitative 3D analyses were performed using microCT. In addition, bone resorption was measured within the midline suture by histological examination. The number of osteoclasts was determined by counting the TRACP(+) cells. Calvarial bone was tested for RANKL expression by RT-PCR and immunocytochemistry. RESULTS: Bone resorption was significantly reduced in alpha-CGRP-deficient mice compared with their corresponding wildtype C57BL 6 mice as confirmed by histomorphometric data (p < 0.001) and microCT (p < 0.01). Osteoclast numbers were significantly reduced in group 3 and the particle subgroup compared with group 1 (p < 0.001). We observed a >3-fold increase of basal RANKL mRNA levels within group 1 compared with group 3. Additional low RANKL immunochemistry staining was noted in groups 3 and 4. CONCLUSIONS: In conclusion, alpha-CGRP knockout mice did not show the expected extended osteolysis compared with wildtype mice expressing alpha-CGRP. One of the most reasonable explanations for the observed decrease in osteolysis could be linked to the osteoprotegerin (OPG)/RANK/RANKL system in alpha-CGRP-deficient animals. As a consequence, the fine tuning of osteoclasts mediating resorption in alpha-CGRP-null mice may be deregulated.     

A Controlled Study of the Effects of Alendronate in a Growing Mouse Model of Osteogenesis Imperfecta

Recent studies have reported that bisphosphonates reduce fracture incidence and improve bone density in children with osteogenesis imperfecta (OI). However, questions still persist concerning the effect of these drugs on bone properties such as ultrastructure and quality, particularly in the growing patient. To address these issues, the third-generation bisphosphonate alendronate was evaluated in the growing oim/oim mouse, an animal model of moderate-to-severe OI. Alendronate was administered to 6-week-old mice during a period of active growth at a dosage of 73 microg alendronate/kg/day for the first 4 weeks and 26 microg alendronate/kg/day for the next 4 weeks. Positive treatment effects included a reduction in the number of fractures sustained by the alendronate-treated oim/oim mice compared with untreated oim/oim mice (2.1+/-2.0 vs 3.2+/-1.6 fractures per mouse), increased femoral metaphyseal density (0.111+/-0.02 vs 0.034+/-0.04 g/cm2), a tendency towards reduced tibial bowing (4.0+/-3.7 vs 6.1+/-5.8 degrees), and towards increased femoral diameter (1.22+/-0.12 vs 1.15+/-0.11 mm). Potential negative effects included a persistence of calcified cartilage in the treated oim/oim metaphyses compared with treated wildtype (+/+) (33.8+/-11.1 vs 22.1+/-10.2%), and significantly shorter femora compared with nontreated oim/oim mice (14.8+/-0.67 vs 15.3+/-0.37 mm). This preclinical study demonstrates that alendronate is effective in reducing fractures in a growing mouse model of OI, and is also an important indicator of potential positive and negative outcomes of third-generation bisphosphonate therapy in children with OI.     

Dose-dependent prevention of early periprosthetic bone loss by alendronate

AIM: Periprosthetic bone loss occurs in the first six months after total hip arthroplasty (THA) and is felt to be largely the result of initial operative irritation, immobilization, and stress shielding. This study (a prospective, randomized, open, blinded endpoint evaluation) aims at preventing bone loss around the stem with an oral bisphosphonate. METHOD: 66 healthy subjects with uncemented THA and low lumbar bone mass density (BMD) (negative T score) were treated post-operatively with alendronate as follows: n = 21 with 10 mg/d for 10 weeks (A), n = 21 20 mg/d for 5 weeks (B), n = 24 no treatment for controls (C). The periprosthetic BMD in the Gruen zones (ROI) was measured after the 2nd, 4th, 6th, and 12th month by DEXA as a percentage of the value measured one week after surgery. RESULTS: In C, there was significant bone loss in all ROI during the first months and a deficit of 29 % in ROI 7 following one year. In B, bone loss was completely prevented up to the second month, in ROI 7, a significant difference in comparison to C was registered for the entire year. In A, significant bone loss reduction during 12 months was seen. CONCLUSION: Alendronate, therefore, is capable of preventing initial periprosthetic bone loss. A dosage of 20 mg/d is required initially with daily treatment lasting at least 10 weeks.     

Alendronate prevents further bone loss in renal transplant recipients.

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 +/- 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 +/- 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b-ALP) and urinary type I collagen cross-linked N-telopeptide (u-NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (-2.4 +/- 1.0), total femur (-2.0 +/- 0.7), and femoral neck (-2.2 +/- 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (-2.6 +/- 5.7%;p < 0.01), total femur (-1.4 +/- 4.2%; p < 0.05), and femoral neck (-2.0 +/- 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A-10 mg/day of alendronate, 0.50 microg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B-0.50 microg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12-month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b-ALP and u-NTX decreased significantly in alendronate-treated patients. Bone density of the spine (+5.0 +/- 4.4%), femoral neck (+4.5 +/- 4.9%), and total femur (+3.9 +/- 2.8%) increased significantly only in the alendronate-treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug-related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long-term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.     

Polyethylene Particle-Induced Bone Resorption in Substance P-Deficient Mice

Aseptic loosening is the major cause of total joint replacement failure. Substance P (SP) is a neurotransmitter richly distributed in sensory nerve fibers, bone, and bone-related tissue. The purpose of this study was to investigate the potential impact of SP on bone metabolism in polyethylene particle-induced osteolysis. We utilized the murine calvarial osteolysis model based on ultrahigh molecular weight polyethylene (UHMWPE) particles in 14 wild-type mice (C57BL/J6) and 14 SP-deficient mice. Group 1 (C57BL/J 6) and group 3 (SP-knockout) received sham surgery, and group 2 (C57BL/J6) and group 4 (SP-knockout) were treated with polyethylene particles. Analytical methods included three-dimensional micro-computed tomographic (micro-CT) analysis and histomorphometry. Bone resorption was measured within the midline suture. The number of osteoclasts was determined by counting the tartrate-resistant acid phosphatase-positive cells. UHMWPE-particle treated SP-deficient mice showed significantly reduced osteolysis compared to wild-type mice, as confirmed by histomorphometry (P < 0.001) and micro-CT (P = 0.035). Osteoclast numbers were significantly reduced in groups 3 and 4 compared to groups 1 and 2 (P < 0.001). Unexpectedly, SP-deficient mice (group 3) showed a significantly increased absolute bone mass compared to wild-type mice (group 1) (P = 0.02). The findings of our murine calvaria model lead to the assumption that SP is a promoter in particle-induced osteolysis. The pathophysiology of aseptic loosening is complex, and neuropeptides are not solely responsible for the progress of implant loosening; however, we conclude that there could be coherence between neurotransmitters and particle-induced osteolysis in patients with aseptic loosening.