Short-term effects of bisphosphonates on the biomechanical properties of canine bone.

Periprosthetic osteolysis and aseptic loosening of total joint replacements are believed to be initiated often by abnormal bone resorption induced by prosthetic wear debris. Bisphosphonates can inhibit bone resorption and have been successfully used clinically to treat osteoporosis and Paget's disease. In a recent study it also was shown that a third generation bisphosphonate (alendronate) is effective in preventing wear debris-induced periprosthetic osteolysis. Since inhibition of bone resorption by alendronate may disrupt the delicate balance between bone resorption and formation in normal bone remodeling, it is possible that continuous alendronate therapy may have an adverse effect on the biomechanical properties of bone. Thus the purpose of the present study was to examine the effects of systemic alendronate administration on the biomechanical properties of normal bone using a canine total hip arthroplasty model. We evaluated the biomechanical properties of femora from canines that had received total hip replacements on one side and had been given oral alendronate daily for 23 weeks. The biomechanical properties assessed were fracture toughness, elastic modulus, tensile strength, microhardness, porosity, and weight fractions of the mineral and organic phases of bone. Also, bone microstructure was examined using optical microscopy. Our results indicate that in the short term alendronate therapy does not have any adverse effects on the intrinsic biomechanical properties of canine bone. However, the long-term effects of alendronate therapy still need to be investigated.Copyright 1999 John Wiley & Sons, Inc.     

Combined treatment with vitamin k2 and bisphosphonate in postmenopausal women with osteoporosis

Vitamin K2, as well as bisphosphonates, such as etidronate, alendronate, and risedronate, is widely used in the treatment with osteoporosis in Japan. Etidronate increases the lumbar bone mineral density (BMD), and prevents new vertebral fractures, in patients with osteoporosis, while alendronate and risedronate increase the lumbar and femoral neck BMDs, and prevent new vertebral and femoral neck fractures. Vitamin K2 enhances gamma-carboxylation of bone glutamic acid residues and the secretion of osteocalcin, sustains the lumbar BMD, and prevents osteoporotic fractures in patients with osteoporosis. Bisphosphonates, such as alendronate and risedronate, rather than vitamin K2, should be initially chosen for the treatment of osteoporosis, because they are more efficacious than vitamin K2. Available evidence suggest that risedronate prevents deterioration of the connectivity of the trabeculae in ovariectomized rats, whereas vitamin K2 increase the trabecular thickness, and that a combination of risedronate and vitamin K2 has a synergistic effect on preventing the deterioration of trabecular bone architecture induced by estrogen deficiency. Some studies have shown that combined treatment with etidronate and vitamin K2 appears to be more effective than etidronate alone in the prevention of new osteoporotic vertebral fractures. Based on these findings, combined treatment with vitamin K2 and bisphosphonates may be more efficacious in the prevention new vertebral fractures than a single treatment with bisphosphonate in postmenopausal women with osteoporosis. Thus, this combined treatment should be recommended for the treatment of postmenopausal osteoporosis. It is proposed that the role of vitamin K2 should be emphasized, when used in combination with bisphosphonates, especially in patients with vitamin K deficiency.     

局部应用阿伦膦酸钠对非负荷期种植体骨结合影响的X射线观察*

背景：阿伦膦酸钠作为第3代二膦酸盐,具有很强的抑制骨吸收的能力。 目的：研究阿伦膦酸钠对非负荷期种植体周围骨结合的影响。 方法：取健康成年Beagle犬6只,随机等分为实验组和对照组,选取每犬的双侧下颌第二、四前磨牙共计24牙位,于实验第1,29,43,50天分别行即刻种植手术。实验组于种植体周围局部注射阿伦膦酸钠,对照组注射生理盐水,每周2次。 结果与结论：于实验第57天进行X射线显示种植体骨结合情况良好,实验组2周时即可见到种植体周围骨小梁的形成,明显早于对照组。提示阿伦膦酸钠可促进种植体周围骨组织中骨小梁的早期形成,从而影响种植体周围骨改建,提高非负荷期种植体周围骨结合。     

Synergistic Antiosteoporotic Effect of Lepidium Sativum and Alendronate in Glucocorticoid-Induced Osteoporosis in Wistar Rats

Alendronate belongs to a class of drugs called bisphosphonates. Bisphosphonates (BP) therapy is a vital option to reduce the risk of bone fracture in people who suffer from osteoporosis. Yet, bisphosphonate have displayed several side effects. Lepidium sativum (LS) seeds have been used in traditional folk medicine to heal fractured bones. However, there is a dearth of information on the impact of LS on bone metabolism especially in cases of glucocorticoids induced osteoporosis. Therefore, the aim of the study was to compare the biochemical bone markers and histological responses of LS alone (6 g of LS seeds in diet daily, n=8), ALD (alendronate, 70 mg/kg s.c.; n=8) alone, or LS and ALD combined in a rat model of glucocorticoid-induced osteoporosis (GIO) by injecting rats with methylprednisolone 3.5 mg/kg per day for 4 weeks. Serum calcium (Ca), albumin, phosphorus (P), bone-specific alkaline phosphatase (b-ALP), and tartrate-resistant acid phosphatase (TRAP) were measured 4 weeks after induction of GIO. GIO-group showed significantly increased serum TRAP and decreased b-ALP. GIO-group also showed significantly decreased serum P and unaltered Ca concentrations. Histological examination of GIO-group tibia bones indicated an osteoporotic change and a concomitant decrease in percentage of trabecular area or bone marrow area (PTB) in the proximal femoral epiphysis. Treatment with either LS and/or ALD ameliorated the above mentioned changes with variable degrees, with a net results of enhanced serum calcium, bone architecture, PTB, b-ALP and decreased TRAP in LS and LS+ALD groups compared to that of animals treated with alendronate alone. In conclusion, our findings present evidence supporting the potential benefits of LS in reducing the burden of GCs on bone health.     

Anabolic effects of bisphosphonates on peri-implant bone stock

The long-term durability of total joint replacements is critically dependent on adequate peri-implant bone stock, which can be compromised by wear debris-mediated osteolysis. This study investigated the effects of bisphosphonates on enhancing peri-implant bone in the presence of clinically relevant ultra-high molecular weight polyethylene (UHMWPE) wear debris. Fiber-mesh coated titanium-alloy plugs were implanted bilaterally in the femoral condyles of 36 New Zealand white rabbits. Implants in the left femora were covered with submicron UHMWPE particles during surgery. Rabbits were administered either no drug, subcutaneous alendronate weekly (1.0mg/kg/week) or a single dose of intravenous zoledronate (0.015mg/kg). A total of 6/12 rabbits in each group were sacrificed at 6 weeks and the remainder at 12 weeks postoperatively. Peri-implant bone stock was analyzed radiographically and histomorphometrically. Radiographically, both bisphosphonates significantly increased periprosthetic cortical thickness at 6 weeks (p<0.0001; alendronate: +18%; zoledronate: +11%) and at 12 weeks (p=0.001; alendronate: +17%; zoledronate:+19%). Histomorphometrically, alendronate and zoledronate raised peri-implant bone volume (BV/TV) up to 2-fold after 6 weeks without added wear debris and more than 3-fold when wear debris was present. Furthermore a 6-week bisphosphonate treatment increased osteoid thickness in the absence of wear debris (alendronate: +132%, p=0.007; zoledronate: +67%, p=0.51) and in the presence of wear debris (alendronate: +134%, p=0.023; zoledronate: +138%, p=0.016). In summary, alendronate and zoledronate treatment increased periprosthetic bone stock in a rabbit femoral model, particularly in the presence of UHMWPE wear debris. These new findings suggest that bisphosphonates may more than compensate for the well-documented negative effects of wear debris on peri-implant bone stock. The combined antiresorptive and osteoanabolic effects of bisphosphonates on periprosthetic bone stock may have an important role for critically improving the biological fixation and ultimate durability of total joint arthroplasty.     

The effect of a bisphosphonate on bone volume and eggshell structure in the hen

Bisphosphonates, used in the prevention and treatment of osteoporosis, in man, can prevent bone loss in experimental models of osteoporosis in mammals. In egg-laying hens there is a high incidence of bone fractures which are due to osteoporosis. Alendronate, a bisphosphonate, was given to three groups of hens in mid-lay. Different doses of alendronate were given to each group and group 4 was a control. The birds were killed after 2 weeks of treatment. The hens receiving the highest dosage of alendronate (1 mg/kg every 2nd day) ceased laying and had reduced serum calcium concentrations. Lower dosages of alendronate (0.1 and 0.01 mg/kg every 2nd day) resulted in normal egg production and serum calcium concentrations. Egg shells with ultra-structural features indicative of reduced shell quality were produced by hens on the two higher dosages, but the egg shells from the controls and from the hens on the lowest dosage were considered normal. When alendronate was administered to hens in mid-lay there was no effect on trabecular bone volumes, but there was a reduction in mean medullary bone volume in some groups. In a second experiment, pullets were treated with alendronate (0.01 mg/kg twice a week) before the onset of lay. The pullets were killed after laying their first egg. In the pullets treated with alendronate, this protocol resulted in a significantly greater volume of trabecular (structural) bone at the onset of lay.     

Effect of Y2 Receptor Deletion on Whole Bone Structural Behavior in Mice

Recent evidence has shown that mice deficient in the NPY Y2 receptor have an increase in trabecular bone volume as well as cortical bone mass due to increased osteoblast activity. However, the mechanical phenotype of Y2 ?/? bone has not yet been assessed. Thus, the aim of the present study was to examine the effect of Y2 deletion on murine cortical bone structural behavior, as well as to assess the material and geometric contributions to that behavior. The results of this study indicate that Y2 ?/? mice on a 129 SV × Balb/c background strain are smaller in body mass and have smaller bones than wild‐type controls. As expected based on smaller bone cross‐sectional properties, cortical bone structural strength was lower in ?/? animals. Surprisingly, the structural stiffness of ?/? bones was comparable to that of +/+ bones despite their smaller cross‐sectional geometry. Comparable structural stiffness appeared to be achieved by means of an elevated effective shear modulus, which was associated with a small, but statistically significant, higher ash content in Y2 ?/? bones. These data represent the first comprehensive characterization of the effect of Y2 deletion on cortical bone structural and material behavior to date. Anat Rec, 291:14–18, 2007. © 2007 Wiley‐Liss, Inc.     

Response to alendronate in osteoporotic women previously treated with pamidronate

INTRODUCTION: Different bisphosphonates have been shown to increase bone mineral density (BMD) and reduce the risk of fracture in osteoporotic patients. It is unclear how shifting from a treatment with one bisphosphonate to another will influence the evolution of BMD and bone turnover. METHODS: In the present study, we followed BMD (DXA, Hologic QDR1000) of the lumbar spine (BMDL) and of the total hip (BMDH), bone alkaline phosphatase (Ostase, Hibritech), and urinary collagen cross links (pyridinoline, deoxypyridinoline, Biorad) in 39 patients treated with IV pamidronate (60 mg/3 months) since at least 2 years and who were shifted to oral alendronate (10 mg/day, n=18) or left to IV pamidronate (n=21) for 2 more years. RESULTS: BMD increased similarly and significantly in both groups after 2 additional years of treatment as compared to baseline (P<0.05, sign test). BMDL: +3.8% in the alendronate group vs +4.1% in the pamidronate group; BMDH: +4.3% in alendronate group vs +3.6% in pamidronate group, There was no significant change in the biological parameters of bone turnover in any group. CONCLUSION: The increase of BMD with both bisphosphonates in these previously treated patients was as expected after a 2 more years of treatment. Alendronate administration did not induce a larger gain in BMD as compared to cyclic pamidronate. Bone turnover was no longer affected by switching the bisphosphonate treatment.     

二膦酸盐防治骨质疏松症的进展

骨质疏松症是一种骨量减少和骨微结构破坏为特征，骨脆性增加，易导致骨折的全身性疾病。其主要病理生理机制是破骨细胞所介导的骨吸收增加。二膦酸盐在体内能抑制破骨细胞的骨吸收，因此被用于骨质疏松的治疗。二膦酸盐是焦磷酸盐的类似物，是碳（Ｃ）原子替代了焦磷酸盐...     

不同角度载荷下股骨头骨小梁的生物力学特性

目的 探讨不同角度载荷对股骨头骨小梁形态学与力学性能的影响,为研究股骨头坏死、塌陷的生物力学机制提供理论依据。方法 利用12月龄羊股骨头和人尸体股骨头分别制作羊股骨头骨小梁试件94个和人股骨头骨小梁试件43个。按照受力方向与骨小梁主压力方向之间的不同夹角,将骨小梁以10°间隔分为内翻10°、0°和外翻10°、20°、30°共计5组,模拟股骨颈骨折内固定术后不同戈登（Garden）对线指数下的复位情况。通过分别对羊股骨头骨小梁进行micro-CT扫描、计算与压缩破坏试验以及对人尸体股骨头骨小梁进行循环压缩试验,分析不同受力方向下股骨头骨小梁的骨体积分数（BV/TV）、骨表面积/骨体积（BS/BV）、骨小梁平均厚度（Tb.Th）、骨小梁数量（Tb.N）、骨小梁间距（Tb.Sp）等形态学指标以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数等力学指标。结果 加载方向与骨小梁的主压力方向之间夹角为0°时,BV/TV、Tb.Th以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数均为最大,而BS/BV与Tb.N为最小,并随着夹角增大前者呈递减而后者呈递增趋势。结论 12月龄羊股骨头骨小梁BV/TV与极限强度随受力方向与骨小梁主压力方向之间夹角变化的趋势与人股骨头骨小梁一致;加载方向与主压力骨小梁之间夹角增大时,股骨头骨小梁形态学与力学性能均下降;Garden指数偏离160°越大时,股骨头内骨小梁越易发生损伤。     

Alendronate-hydroxyapatite nanocomposites and their interaction with osteoclasts and osteoblast-like cells

The direct synthesis of hydroxyapatite in the presence of bisphosphonates is quite difficult due to the great affinity for calcium of these compounds, which are widely used in the treatment of pathologies related to bone loss. We recently developed a new method which allowed to synthesize alendronate-hydroxyapatite composite nanocrystals with a bisphosphonate content up to about 7 wt%. Herein we report the results of an in vitro study aimed to investigate the effects of alendronate incorporation into hydroxyapatite on bone cells response. Osteoblast-like MG63 cells and human osteoclasts were cultured on nanocrystals at different alendronate content (3.9, 6.2, 7.1 wt%). MG63 cells cultured on the composite nanocrystals display normal morphology, good proliferation and increased values of the differentiation parameters. In particular, when cultured on composites at relatively high alendronate contents, osteoblasts display increased values of alkaline phosphatase activity (ALP), collagen type I, and osteocalcin production, as well as significant decrease of matrix metalloproteinases (MMP-1 and MMP-13) production, with respect both to the control and to pure hydroxyapatite nanocrystals. It follows that the presence of alendronate enhances osteoblast activation and extracellular matrix mineralization processes, without any abnormal collagen degradation. The osteoclast number on the composite nanocrystals decrease indicating that the bisphosphonate exerts its inhibitory effect on osteoclast proliferation even when incorporated into hydroxyapatite.     

Postcranial skeletal pneumaticity: a case study in the use of quantitative microCT to assess vertebral structure in birds

Limb elements in birds have been characterized as exhibiting a reduction in trabecular bone, thinner cortices and decreased bending strength when pneumatized, yet it is unclear if these characteristics generalize to the axial skeleton. Thin section techniques, the traditional gold standard for bone structure studies, have most commonly been applied to the study of avian bone. This destructive technique, however, makes it subsequently impossible to use the same samples in experimental testing systems that allow researchers to correlate structure with the mechanical properties of the bone. Micro-computed tomography (microCT), a non-destructive X-ray imaging technique, can be used to assess the effect of pneumatization on vertebral cortical and trabecular bone through virtual extraction and structural quantification of each tissue type. We conducted a preliminary investigation of the application of microCT methods to the study of cortical and trabecular bone structure in a small sample of pneumatic and apneumatic thoracic vertebrae. The sample consisted of two similar-sized anatids, Aix sponsa (n = 7) and Oxyura jamaicensis (n = 5). Volumes of interest were created that contoured (outlined) the boundaries of the ventral cortical bone shell, the trabecular compartment and the whole centrum (cortical bone + trabecular bone), and allowed independent structural analysis of each volume of interest. Results indicated that bone volume fraction of the whole centrum was significantly higher in the apneumatic O. jamaicensis than in the pneumatized A. sponsa (A. sponsa = 36%, O. jamaicensis = 48%, P < 0.05). In contrast, trabecular bone volume fraction was similar between the two species. The ventral cortical bone shell was approximately 23% thinner (P < 0.05) in A. sponsa (0.133 mm) compared with apneumatic O. jamaicensis (0.172 mm). This case study demonstrates that microCT is a powerful non-destructive imaging technique that may be applied to the three-dimensional study of avian bone. The preliminary results suggest that pneumatic and apneumatic vertebrae of comparably sized avian species differ in relative bone volume, with the largest difference apparent at the level of the cortex, and not within trabecular bone. The presence of relatively thin cortices in pneumatic vertebrae is consistent with previous studies contrasting diaphyseal cortical bone between pneumatic and apneumatic long bones. Methodological issues related to this and any comparative microCT study of bone structure are discussed.     

不同角度载荷下股骨头骨小梁的生物力学特性

目的探讨不同角度载荷对股骨头骨小梁形态学与力学性能的影响,为研究股骨头坏死、塌陷的生物力学机制提供理论依据。方法利用12月龄羊股骨头和人尸体股骨头分别制作羊股骨头骨小梁试件94个和人股骨头骨小梁试件43个。按照受力方向与骨小梁主压力方向之间的不同夹角,将骨小梁以10°间隔分为内翻10°、0°和外翻10°、20°、30°共计5组,模拟股骨颈骨折内固定术后不同戈登(Garden)对线指数下的复位情况。通过分别对羊股骨头骨小梁进行micro-CT扫描、计算与压缩破坏试验以及对人尸体股骨头骨小梁进行循环压缩试验,分析不同受力方向下股骨头骨小梁的骨体积分数(BV/TV)、骨表面积/骨体积(BS/BV)、骨小梁平均厚度(Tb.Th)、骨小梁数量(Tb.N)、骨小梁间距(Tb.Sp)等形态学指标以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数等力学指标。结果加载方向与骨小梁的主压力方向之间夹角为0°时,BV/TV、Tb.Th以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数均为最大,而BS/BV与Tb.N为最小,并随着夹角增大前者呈递减而后者呈递增趋势。结论 12月龄羊股骨头骨小梁BV/TV与极限强度随受力方向与骨小梁主压力方向之间夹角变化的趋势与人股骨头骨小梁一致;加载方向与主压力骨小梁之间夹角增大时,股骨头骨小梁形态学与力学性能均下降;Garden指数偏离160°越大时,股骨头内骨小梁越易发生损伤。     

不同角度载荷下股骨头骨小梁的生物力学特性

目的 探讨不同角度载荷对股骨头骨小梁形态学与力学性能的影响,为研究股骨头坏死、塌陷的生物力学机制提供理论依据。方法 利用12月龄羊股骨头和人尸体股骨头分别制作羊股骨头骨小梁试件94个和人股骨头骨小梁试件43个。按照受力方向与骨小梁主压力方向之间的不同夹角,将骨小梁以10°间隔分为内翻10°、0°和外翻10°、20°、30°共计5组,模拟股骨颈骨折内固定术后不同戈登（Garden）对线指数下的复位情况。通过分别对羊股骨头骨小梁进行micro-CT扫描、计算与压缩破坏试验以及对人尸体股骨头骨小梁进行循环压缩试验,分析不同受力方向下股骨头骨小梁的骨体积分数（BV/TV）、骨表面积/骨体积（BS/BV）、骨小梁平均厚度（Tb.Th）、骨小梁数量（Tb.N）、骨小梁间距（Tb.Sp）等形态学指标以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数等力学指标。结果 加载方向与骨小梁的主压力方向之间夹角为0°时,BV/TV、Tb.Th以及弹性模量、极限强度、屈服强度、初始弹性模量、循环次数均为最大,而BS/BV与Tb.N为最小,并随着夹角增大前者呈递减而后者呈递增趋势。结论 12月龄羊股骨头骨小梁BV/TV与极限强度随受力方向与骨小梁主压力方向之间夹角变化的趋势与人股骨头骨小梁一致;加载方向与主压力骨小梁之间夹角增大时,股骨头骨小梁形态学与力学性能均下降;Garden指数偏离160°越大时,股骨头内骨小梁越易发生损伤。     

股骨头坏死中松质骨微观力学特性的演变规律

目的采用结合显微CT和显微有限元分析方法,即基于显微CT图像建立三维有限元模型并进行数值模拟仿真分析,无创研究不同分期的坏死股骨头松质骨的微结构和微观力学性能,以期了解在股骨头坏死的发展过程中,松质骨微结构和微观力学特性的变化规律,为临床预测股骨头坏死提供理论基础。方法采集10例股骨头坏死患者的股骨头标本的显微CT图像,按照国际骨循环研究学会分期标准分为Ⅱ期样本3例,Ⅲ期3例,Ⅳ期4例。将图像中骨组织进行阈值分割,分区域建立坏死区、侧向区、硬化区和远端区的松质骨块三维有限元模型(边长8 mm),并根据CT值赋予非均匀材料属性。利用ImageJ软件中的BoneJ插件通过识别显微CT组图像,计算测量各区域松质骨的微结构参数,包括骨体积分数、骨小梁厚度、骨小梁间隙、结构模型指数。对松质骨块施加表观应变为1%的压缩载荷,计算骨组织应力和松质骨表观刚度等参数,对比分析各分期、各分区结果。结果在松质骨微结构方面,Ⅳ期较Ⅱ期的股骨头内部硬化区和坏死区的变化最为明显,硬化区的骨体积分数不断上升,骨小梁间隙下降,结构模型指数减小,而坏死区域与之相反;在骨组织微观受力方面,Ⅱ期到Ⅲ期坏死区域的应力并没有明显变化,而硬化区域随着分期增加应力不断上升,侧向区的应力不断下降。表观刚度变化与应力变化一致。结论随着股骨头坏死程度的加剧,硬化区的松质骨微结构和力学性能变化最大,应作为临床早期诊断中重点关注的区域。此外,微结构参数并不能准确体现松质骨的力学行为,而股骨头塌陷最终取决于其力学特性,因此结合有限元分析方法可更加全面了解股骨头坏死的微观力学演变规律。     

Bisphosphonate-laden acrylic bone cement: mechanical properties, elution performance, and in vivo activity

Cemented total hip replacements generally fail after 10-20 years, often due to implant loosening from bone resorption. Bisphosphonates such as zoledronic acid (ZA) and pamidronate (PAM) are potent inhibitors of bone resorption. The local delivery of bisphosphonates via acrylic bone cement could decrease osteolysis and prolong implant lifespan. Conflicting studies suggest that bisphosphonate loading may or may not reduce the mechanical properties of acrylic bone cement. We assayed acrylic bone cement laden with ZA or PAM at different concentrations and diluent volumes. Four-point bend testing and compressive testing indicated that high volumes of diluent (with or without bisphosphonate) significantly reduced bending modulus and compressive strength. Radiography and electron microscopy indicated that high diluent volumes generated abnormal acrylic bone cement structure. After 6 weeks of incubation in saline, only 0.9% w/w of the total bisphosphonate incorporated in acrylic bone cement eluted in vitro, indicating a slow elution rate. In vivo testing was performed using a rat model. Cement cylinders were inserted into incisions in rat distal femora and ZA delivered locally (via elution from acrylic bone cement) or systemically (via injection). At 4 weeks postoperatively, dual energy X-ray absorptiometry demonstrated no significant increase in local bone mineral density (BMD) adjacent to ZA-laden implants. In contrast, systemic ZA delivery (0.1 mg/kg) led to a large (48.6%) and significant increase in BMD. Thus, systemic delivery appears more effective than local delivery.     

Mechanical strength of trabecular bone at the knee

Interest in the biomechanical properties of trabecular bone has expanded in response to the problems related to total and partial joint replacement with the knee joint constituting a main focus of attention. This relatively recent development has left a number of fundamental problems unanswered, especially related to the machining, storage and testing of trabecular bone specimens. Nevertheless, these studies have contributed to the understanding of the mechanical function of trabecular bone. Regarding the role of trabecular bone at the knee joint, the following conclusions may be emphasized (conclusions drawn from the author's previous studies (I-X) are shown in italics): (1) Trabecular bone is almost exclusively responsible for the transmission of load at the proximal tibial epiphysis from the knee joint to the metaphysis. The peripheral shell surrounding the epiphysis is not composed of cortical bone and plays a negligible role in load transmission. (2) The compressive strength and stiffness of trabecular bone is primarily dependent upon the apparent density, trabecular architecture and the strength of the bone material. Direct and indirect sources suggest that the true material strength of trabecular bone is less than that of cortical bone. The epiphyseal trabecular architecture, featuring a marked polarity with alignment of primary trabeculae at right angles to the joint surface, is responsible for functional anisotropy which points to the axial compressive properties as the more important mechanical parameters. (3) Tensile and shear properties are of special relevance to mechanical loosening of implants. These properties may be derived from the apparent density, and a close empirical relation to the axial compressive strength and stiffness is suggested. (4) The foam-like structure of trabecular bone is the basis for the large energy absorptive capacity. (5) The pattern of axial compressive stiffness and strength at the normal proximal tibia differs little among individuals. Supporting the medial tibial plateau is a large high strength area with maximal strength centrally and slightly anteriorly, while laterally there is a restricted area of relatively high strength posteriorly with a lower maximal value than medially. Bone strength is significantly reduced within ten millimeters of the subchondral bone plate, and this reduction continues distally at the lateral condyle. At both condyles strength is reduced towards the periphery with very low values being obtained at the margins of the condyles and at the intercondylar region. Absolute bone strength values are influenced by the level of physical activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells

Bisphosphonates are well known potent inhibitors of osteoclast activity and are widely used to treat metabolic bone diseases. Recent evidence from in vitro and in vivo studies indicates that bisphosphonates may additionally promote osteoblastic bone formation. In this study, we evaluated the effects of three FDA-approved and clinically utilized bisphosphonates, on the proliferation and osteogenic differentiation of human bone marrow stromal cells (BMSC). BMSC were obtained from patients undergoing primary total hip arthroplasty for end-stage degenerative joint disease. Cells were treated with or without a bisphosphonate (alendronate, risedronate, or zoledronate) and analyzed over 21 days of culture. Cell proliferation was determined by direct cell counting. Osteogenic differentiation of BMSC was assessed with alkaline phosphatase bioassay and gene expression analyses using conventional RT-PCR as well as real-time quantitative RT-PCR. All bisphosphonates tested enhanced the proliferation of BMSC after 7 and 14 days of culture. Steady-state mRNA levels of key genes involved in osteogenic differentiation such as bone morphogenetic protein-2 (BMP-2), bone sialoprotein-II, core-binding factor alpha subunit 1 (cbfa1) and type 1 collagen, were generally increased by bisphosphonate treatment in a type- and time-dependent manner. Gene expression levels varied among the different donors. Enhancement of osteogenic differentiation was most pronounced after 14 days of culture, particularly following zoledronate treatment (p < 0.05 for BMP-2). In conclusion, using a clinically relevant in vitro model we have demonstrated that bisphosphonates enhance proliferation of BMSC and initiate osteoblastic differentiation. When administered around joint replacements, bisphosphonates may potentially compensate for the deleterious effects of particulate wear debris at the bone-implant interface, by encouraging increased numbers of cells committed to the osteoblastic phenotype, and thus improve the longevity of joint replacements.     

Oral bisphosphonates improve Bone Mineral Density in adults with cystic fibrosis

In adults with Cystic Fibrosis (CF) we sought to establish the effect of oral bisphosphonate therapy. Bone densitometry measured by dual energy X-ray absorptiometry (DXA), and clinical patient data, were reviewed retrospectively. Eighty-one patients (median age 27 years) had baseline and follow-up DXA, with an interval of 19.2 +/- 7.1 months. Thirty-six patients were treated with bisphosphonates (alendronate=23 and risedronate=13). Median follow-up Bone Mineral Density in the bisphosphonate group was 3.7% greater at the lumbar spine (95%CI 1.9 to 5.7%, P<0.0005) and 2.4% greater at the femur (95%CI 0.8 to 3.9%, P<0.005) than the group not treated with bisphosphonates. Oral bisphosphonate therapy had a beneficial effect on BMD in adults with CF.