The evaluation of a rat model for the analysis of densitometric and biomechanical properties of tumor-induced osteolysis.

Pathologic fractures from a reduction in bone mass and strength are a debilitating complication affecting the quality of life of individuals with metastatic lesions. There are a number of existing animal models for studying the effects of bone metastases experimentally, but these models are unsuitable for measuring structural changes in metastatic bone. Our goal was to present an in vivo model for directly investigating the densitometric and structural consequences of tumor-induced osteolysis in long bones. One femur from female Sprague Dawley rats was implanted with Walker Carcinosarcoma 256 malignant breast cancer cells or with a Sham implant. After 28 days, the animals were killed, and both femora of each animal evaluated using histomorphometry, densitometry, and mechanical testing. Compared to Sham-operated controls, we found an 11% decrease in bone mineral content, a 9% decrease in bone mineral density using dual energy X-ray absorptiometry, and a 16% decrease in bone density using peripheral quantitative computed tomography in the group with tumor cell implants. In addition, failure torque was decreased by 35% compared to the contralateral controls and by 41% compared to the Sham-operated controls. Torsional stiffness in the tumor cell-implanted femora was decreased by 35% compared to contralateral controls and by 39% compared to Sham-operated controls. Bone density was only weakly to moderately associated with bone strength in our model. By creating reproducible localized tumor-induced osteolytic lesions in a long bone, this model provides the most direct evaluation of the structural consequences of bone metastases. In the future, this model may provide a method for determining the effects of new therapeutic approaches on the preservation of bone mass and bone strength in the presence of metastatic bone disease.

The threshold trip duration for which recovery is no longer possible is associated with strength and reaction time.

The recovery of young adults from trips of increasing severity was studied. Our null hypothesis was that lower extremity strength, and reaction time, step time, step distance and step velocity measured in a volitional stepping task would not explain a significant portion of the variance in the magnitude of the threshold trip duration for which recovery is no longer possible. Ten males and 11 females (average age 26.8 and 28.4 years old, respectively) were subjected to trips of increasing duration until recovery was no longer possible with a single step. The average threshold trip duration for which subjects were no longer able to recover with a single step was 681+/-169ms. The threshold trip duration significantly increased as lower extremity strength increased and volitional reaction time decreased (multiple stepwise linear regression: R(2)=0.52, p=0.001). The other volitional step parameters and the subject characteristics were not significantly associated with the magnitude of the threshold trip duration. These results suggest that some trip-related falls may be due to slower reaction times and/or reduced lower extremity strengths.

Disturbance type and gait speed affect fall direction and impact location.

Since falling to the side and impacting on or near the hip increase hip fracture risk, we examined the fall direction and pelvis impact location resulting from four disturbances (faint, slip, step down, trip) at three gait speeds (fast, normal, slow) in 14 young adults instructed not to attempt recovery. We hypothesized that certain disturbances such as faints and slips and slow walking speed were more likely to result in an impact on the hip. For each trial, the fall direction, impact location and pelvis impact velocity were measured. The results showed that both disturbance type and gait speed significantly affected fall direction and impact location (analysis of covariance with repeated measures, p< or =0.0001) with a significant interaction (p<0.05). Trips and steps down usually resulted in forward falls, with frontal impacts regardless of gait speed. At fast gait speed, slips and faints also usually resulted in forward falls, with frontal impacts. As gait speed decreased, however, slips usually resulted in sideways or backward falls, with impact on the hip or buttocks, and faints resulted in a greater number of sideways falls, with impact near the hip. Therefore, compared to other disturbances and gait speeds, slipping or fainting while walking slowly was more likely to result in an impact on the hip, suggesting a greater risk for hip fracture. Furthermore, 56% of the impact velocities generated were within one standard deviation of the estimate of the mean impact velocity needed to fracture an elderly femur.

Functional mobility discriminates nonfallers from one-time and frequent fallers.

BACKGROUND: Given that 90% of hip fractures result from a fall, individuals who fall frequently are more likely to be at greater risk for fracture than one-time fallers. Our aim was to determine whether performance variables associated with injurious falls could be used to distinguish frequent fallers from both one-time fallers and nonfallers. METHODS: A total of 157 men and women (77.4-5.4 years) were recruited and categorized into one of the following three groups based on falls status over the previous 12 months: nonfallers (n = 48), one-time fallers (n = 56), and frequent fallers (more than one fall) (n = 53). All subjects were evaluated on functional mobility and lower extremity strength and power. RESULTS: Using multivariate analysis of covariance with height as a covariate, nonfallers were significantly faster than both one-time and frequent fallers during the Get Up and Go (a test involving lower extremity strength and power, and mobility) and faster than one-time fallers on the Tandem Gait (p < .01). There were no significant differences between groups for other mobility variables or for laboratory measures of strength and power. Because one-time and frequent fallers were similar on all measures. they were grouped as "fallers" in discriminant analysis. The Get Up and Go discriminated between the fallers and nonfallers with a final Wilks's Lambda of .900 (p < .001) and correctly classified 72.4% of fallers and nonfallers before crossvalidation and 71.2% of the cases after validation. CONCLUSIONS: Given that the Get Up and Go discriminates between fallers and nonfallers and is associated with lower extremity strength and power, fall prevention strategies should focus on improving both functional mobility and lower extremity strength and power.

Postfracture instability of vertebrae with simulated defects can be predicted from computed tomography data.

STUDY DESIGN: Structural properties of vertebrae with simulated defects were measured from computed tomography data. Relations between structural properties and postfracture stability were tested using linear regressions. OBJECTIVES: To determine whether the postfracture stability of lumbar and thoracic vertebrae can be predicted from noninvasive, prefracture measurements of structural properties. SUMMARY OF BACKGROUND DATA: Sensitive and specific guidelines are needed that can predict fracture risk and spinal stability after pathologic fractures. Such guidelines may help determine whether treatment is needed to prevent neurologic complications. Simple measurements made from computed tomography data can predict the load-bearing capacity of intact vertebrae and vertebrae with simulated and actual metastatic defects. It is not known whether these same measurements can also predict postfracture stability. METHOD: Simulated metastatic defects were created in human three-vertebrae segments from the lumbar and thoracic spine. Axial rigidity was calculated from quantitative computed tomography data, and failure load and postfracture stability were measured. RESULTS: Postfracture stability was linearly correlated with both failure load (r2 = 0.3-0.6) and axial rigidity (r2 = 0.3-0.6). CONCLUSIONS: The postfracture stability of three-vertebrae segments with simulated defects was modestly related to noninvasively measured, prefracture structural properties.

Sequential labelling of microdamage in bone using chelating agents.

Basic fuchsin labels microcracks, but a series of stains is required to differentiate between preexisting and test-induced microcracks and to label their growth in vitro. Basic fuchsin and five chelating agents-alizarin complexone, calcein, calcein blue, oxytetracycline, and xylenol orange-were randomly assigned to label microcracks in sequential rib sections from 10 donors. The density, length, and location of the microcracks did not differ significantly between the six stains, suggesting that each was equally effective in detecting microcracks. Paired specimens of trabecular bone were machined from bovine tibiae, stained with oxytetracycline, and fatigued in compression. One specimen from each pair was then stained with xylenol orange. Preexisting microdamage was stained with oxytetracycline, propagating microcracks with both stains and new, test-initiated damage with xylenol orange. Chelating agents are site-specific markers of the initiation and growth of microcracks.

Effect of augmentation on the mechanics of vertebral wedge fractures.

STUDY DESIGN: The effect of cement augmentation of wedge-fractured vertebral bodies on spine segment compliance was studied in 16 cadaver specimens. OBJECTIVES: 1) To assess the mechanical effects of cement augmentation of vertebral wedge fractures. 2) To determine whether a new reduction/injection procedure has the same mechanical effects as the established direct injection procedure. SUMMARY OF BACKGROUND DATA: Although wedge fractures cause pain and disability in hundreds of thousands of people, few effective treatments are available. Clinical studies have shown that cement augmentation, a new procedure, effectively relieves pain and restores mobility in patients suffering from weak or fractured vertebrae. However, only a few studies have examined the mechanics of vertebral augmentation. METHODS: A wedge fracture was created in the middle vertebra of 16 three-vertebra cadaver spine segments. Neutral and full-load compliance of each fractured spine segment in flexion/extension and lateral bending were assessed by measuring the relative rotation of the vertebral bodies in response to applied moments. Eight of the fractured vertebral bodies were then augmented using direct injection, while the remaining eight fractured vertebral bodies were augmented using a combined reduction/injection procedure. Compliance of the augmented segments was then assessed. RESULTS: Augmentation significantly reduced the neutral compliance (reduction of 25% +/- 23%) (mean +/- standard deviation) and the full-load compliance (reduction of 23% +/- 20%) in flexion/extension (P < 0.005). Augmentation also significantly reduced the neutral compliance (reduction of 34% +/- 20%) and the full-load compliance (reduction of 26% +/- 17%) in lateral bending (P < 0.0001). No significant difference was found between the two procedures for compliance reduction. CONCLUSIONS: Augmentation of wedge fractures using both direct injection and reduction/injection reduces spine segment compliance significantly.

Phenotypical characterization of c-kit receptor deficient mouse femora using non-destructive high-resolution imaging techniques and biomechanical testing.

OBJECTIVE: Pathological processes in bone can lead to fatal health consequences. Therefore, it is important to study factors that possibly influence the activity of bone cells. The mast cell is a normal component of bone, storing and producing many potent bioactive substances. One of the most important factors to influence mast cell number, function, and phenotype is the c-kit ligand. A defect of the c-kit receptor leads to mast cell deficiency. In literature oversight, evidence for the importance of mast cells in skeletal homeostasis is compiled. METHODS: To investigate the influence of c-kit receptor deficiency on bone mass, geometry, microstructure, and strength, 30 femora of profoundly c-kit receptor deficient mouse mutants and 30 control group animals aged 8-20 weeks were phenotypically characterized using peripheral quantitative computed tomography (pQCT), micro-computed tomography (microCT) and 3-point-bending. RESULTS: The femora of the c-kit receptor and therefore mast cell deficient animals were significantly altered in bone mass and geometry but not in bone density and microstructure. The mutants had a lighter femur with a thinner shape. The lower load bearing capacity of the femora of mast cell deficient mouse mutants is more likely explained by the smaller amount of bone material than due to a change in intrinsic material properties. TECHNICAL CONSIDERATIONS: With the little dimensions of mouse bones, it is of prime importance to have precise methods to phenotypically characterize the bone. The pQCT allows the separate assessment and analysis of trabecular and cortical bone density, as well as a statement about bone geometry. Beyond it, the microCT-technique delivers a 3-D analysis of bone microstructure, which so far was only achieved with 2-D histomorphometry. microCT is an efficient alternative to destructive histological preparations allowing further biomechanical testing of the same specimens to also deliver measures for bone strength.

In vivo evaluation of coralline hydroxyapatite and direct current electrical stimulation in lumbar spinal fusion.

STUDY DESIGN: An animal model of posterolateral intertransverse process lumbar spinal fusion using autologous bone, coralline hydroxyapatite, and/or direct current electrical stimulation. OBJECTIVES: To evaluate the effect of an osteoconductive bone graft substitute and direct-current electrical stimulation on the rate of pseudarthrosis in a rabbit spinal fusion model. SUMMARY OF BACKGROUND DATA: Conventional techniques for the surgical treatment of degenerative conditions in the lumbar spine have a substantial failure rate and associated morbidity. Bone graft substitutes and electrical stimulation are alternative techniques to enhance fusion rates and limit the morbidity associated with posterolateral intertransverse process fusion using autologous iliac crest bone graft. METHODS: Fifty-three adult female New Zealand White rabbits underwent single-level lumbar posterolateral intertransverse process fusion. Animals were assigned to one of four groups using either autologous bone (Group I), coralline hydroxyapatite with autologous bone marrow aspirate (Group II), coralline hydroxyapatite with a 40-microA implantable direct current electrical stimulator and bone marrow aspirate (Group III), or coralline hydroxyapatite with a 100-microA implantable direct current electrical stimulator and bone marrow aspirate (Group IV). Animals were killed at 8 weeks, and fused motion segments were subjected to manual palpation, mechanical testing, and radiographic and histologic analysis to assess the fusion mass. RESULTS: Successful fusion was achieved in 57% (8/14) of animals in Group I, 25% (3/12) in Group II, 50% (6/12) in Group III, and 87% (13/15) in Group IV. Mean stiffness and ultimate load to failure were significantly higher in Group IV than in all other groups (P < 0.05). Histologic analysis demonstrated a qualitative increase in fusion mass in Group IV versus all other groups. CONCLUSIONS: Direct-current electrical stimulation increased fusion rates in a dose-dependent manner in a rabbit spinal fusion model. Coralline hydroxyapatite is an osteoconductive bone graft substitute, and thus requires an osteoinductive stimulus to ensure reliable fusion rates. Furthermore, coralline hydroxyapatite and direct current electrical stimulation can be used together to increase fusion rates in a rabbit spinal fusion model while avoiding the morbidity associated with harvesting iliac crest bone.

Hamstring tendon grafts for reconstruction of the anterior cruciate ligament: biomechanical evaluation of the use of multiple strands and tensioning techniques.

BACKGROUND: Our hypothesis that multiple, equally tensioned strands of hamstring graft used for reconstruction of the anterior cruciate ligament are stronger and stiffer than ten-millimeter patellar ligament grafts was tested biomechanically with use of tendons from cadavera. METHODS: In the first part of the study, we measured the strength and stiffness of one, two, and four-strand hamstring grafts, from fresh-frozen cadaveric knees, that had been tensioned equally when clamped. In the second part of the study, we compared four-strand grafts to which tension had been applied by hand and then clamped with similar grafts to which tension had been applied with weights and then clamped. The grafts for the two experiments were obtained from thirty-four paired and ten unpaired knees. We also studied the effects of cooling on the biomechanical properties of grafts by comparing patellar ligament grafts tested at 13 degrees Celsius with those tested at room temperature. RESULTS: Two equally tensioned gracilis strands had 185 percent of the strength and 210 percent of the stiffness (1550+/-428 newtons and 336+/-141 newtons per millimeter, respectively) of one gracilis strand (837+/- 138 newtons and 160+/-44 newtons per millimeter, respectively). Two equally tensioned semitendinosus strands had 220 percent of the strength and 220 percent of the stiffness (2330+/-452 newtons and 469+/-185 newtons per millimeter, respectively) of one semitendinosus strand (1060+/-227 newtons and 213+/-44 newtons per millimeter, respectively). Four combined strands (two gracilis strands and two semitendinosus strands) that were equally tensioned with weights and clamped had the additive tensile properties of the individual strands. With the numbers available, four combined strands that were manually tensioned and clamped were not found to be significantly stronger or stiffer than two semitendinosus strands that were equally tensioned with weights (p>0.07). CONCLUSIONS: Four combined strands that were equally tensioned with weights and clamped were stronger and stiffer than all ten-millimeter patellar ligament grafts that have been described in previous reports. All strands of a hamstring graft must be equally tensioned for the composite to have its optimum biomechanical properties. CLINICAL RELEVANCE: Because of the well recognized donor-site morbidity associated with the use of patellar ligament grafts for reconstruction of the anterior cruciate ligament, multiple-strand hamstring-tendon grafts have become an increasingly popular choice. Our data demonstrate that equally tensioned four-strand hamstring-tendon grafts have initial tensile properties that are higher than those reported for ten-millimeter patellar-ligament grafts; thus, from a biomechanical point of view, they seem to be a reasonable alternative.

Critically sized osteo-periosteal femoral defects: a dog model.

A 21-mm defect was created in 1 femoral diaphysis each of 15 dogs. Periosteum as well as a cylinder of bone was removed, and the defect was stabilized with a bone plate. Twelve of the defects were filled with an equal volume of autogenous cancellous bone harvested from the ipsilateral ilium. Three defects were left untreated. Cranial to caudal radiographs were taken postoperatively and every 4 weeks for 16 weeks. The radiographs were evaluated for healing using two ordinal scales. At 16 weeks, the dogs were euthanized and the femurs harvested for biomechanical testing and histologic evaluation. Both operated and contralateral not operated femurs were mechanically tested to failure in torsion, and load at failure and stiffness were calculated. All dogs tolerated the procedure well, and were using the operated limb within 1 or 2 days postoperatively. There were no complications noted during the 16 weeks of the study. Unfilled defects did not heal and became atrophic nonunions. The defects filled with autogenous cancellous bone healed in a consistent pattern of consolidation, incorporation, and remodeling, with uniform increases of both ordinal scales used. The femoral cortex opposite the bone plate demonstrated most mature remodeling, evident both radiographically as well as histologically. Unoperated femurs failed at 13.61 +/- 3.88 N-m and grafted femurs failed at 2.96 +/- 1.3 N-m, which was 23% of the measurement of the unoperated femur. Relative stiffness of the unoperated femurs was 5974 +/- 4316 N-m2/radian, and grafted femurs had a relative stiffness of 642 +/- 561 N-m2/radian, which was 10.4% of the measurement of unoperated femur. This model proved to be a critically sized defect, which when left unfilled resulted in an atrophic nonunion, and when filled with cancellous bone resulted in a consistent healing pattern.

Results from demineralized bone creep tests suggest that collagen is responsible for the creep behavior of bone.

Cortical and trabecular bone have similar creep behaviors that have been described by power-law relationships, with increases in temperature resulting in faster creep damage accumulation according to the usual Arrhenius (damage rate approximately exp (-Temp.-1)) relationship. In an attempt to determine the phase (collagen or hydroxyapatite) responsible for these similar creep behaviors, we investigated the creep behavior of demineralized cortical bone, recognizing that the organic (i.e., demineralized) matrix of both cortical and trabecular bone is composed primarily of type I collagen. We prepared waisted specimens of bovine cortical bone and demineralized them according to an established protocol. Creep tests were conducted on 18 specimens at various normalized stresses sigma/E0 and temperatures using a noninvasive optical technique to measure strain. Denaturation tests were also conducted to investigate the effect of temperature on the structure of demineralized bone. The creep behavior was characterized by the three classical stages of decreasing, constant, and increasing creep rates at all applied normalized stresses and temperatures. Strong (r2 > 0.79) and significant (p < 0.01) power-law relationships were found between the damage accumulation parameters (steady-state creep rate d epsilon/dt and time-to-failure tf) and the applied normalized stress sigma/E0. The creep behavior was also a function of temperature, following an Arrhenius creep relationship with an activation energy Q = 113 kJ/mole, within the range of activation energies for cortical (44 kJ/mole) and trabecular (136 kJ/mole) bone. The denaturation behavior was characterized by axial shrinkage at temperatures greater than approximately 56 degrees C. Lastly an analysis of covariance (ANCOVA) of our demineralized cortical bone regressions with those found in the literature for cortical and trabecular bone indicates than all three tissues creep with the same power-law exponents. These similar creep activation energies and exponents suggest that collagen is the phase responsible for creep in bone.

Density predicts the activity-dependent failure load of proximal femora with defects.

OBJECTIVE: To determine whether the load-bearing capacity of human proximal femora with metastatic defects can be predicted from the bone mineral content. DESIGN: The bone mineral content (BMC) of the total proximal femur was measured by dual-energy X-ray absorptiometry (DXA). The femurs were loaded so as to simulate stair ascent or external rotation. PATIENTS: Simulated lytic defects were created using specialized cutting tools in the intertrochanteric region of 32 human cadaveric femora. Bone density measurements were made before and after creating defects. RESULTS: A linear relation could be used to predict failure load from BMC or bone mineral density. The slope of the linear relation was greater for loads representing external rotation than for loads representing stair ascent. The linear relations suggest that the BMC measurements account for both the density of the host bone and the amount of bone removed by the defect. CONCLUSIONS: The data suggest that between 70% and 80% of the variation in failure load of human femora with lytic metastatic defects can be predicted from the BMC and that relations between BMC and failure load are sensitive to the type of loading. Combined with information on the loads associated with the activities of daily living, these data may be used to help identify patients in whom prophylactic stabilization might prevent a pathologic fracture.

Preclinical evidence of normal bone with alendronate.

This review summarises the results of preclinical studies aimed at elucidating the mode of action of alendronate and assessing its effects on bone quality. Alendronate preferentially localises at bone resorption sites, where the drug inhibits osteoclastic activity. In a variety of estrogen-deficient animal models, alendronate normalised bone turnover, promoted normal mineralisation and increased bone mass and strength. In these studies, bone formed during alendronate therapy was histologically normal and was not associated with spontaneous fractures. Therefore, preclinical studies have established that the antiresorptive activity of alendronate results in the prevention of bone loss and the accretion of normal-quality bone.

A comparison of the Synthes 4.5-mm cannulated screw and the Synthes 4.5-mm standard cortex screw systems in equine bone.

OBJECTIVE: To determine risk of failure of the Synthes 4.5-mm cannulated screw system instrumentation in equine bone and to compare its application with the Synthes 4.5-mm standard cortex screw system. STUDY DESIGN: The maximum insertion torque of the cannulated and standard cortex screw systems were compared with the ultimate torsional strengths of the equipment. Pullout strength and ultimate tensile load of cannulated and standard cortex screws were also determined. SAMPLE POPULATION: Paired equine cadaver third metacarpal and third carpal bones. METHODS: Maximum insertion torque and ultimate torsional strengths were determined by using an axial-torsional, servohydraulic materials testing system and a hand-held torquometer. Pullout tests were performed by using a servohydraulic materials testing system. RESULTS: Maximum insertion torque of all cannulated instrumentation was less than ultimate torsional strength at all locations (P < .05). Maximum insertion torques of cannulated taps and screws were greater than for standard taps and screws in the third carpal bone (P < .002). Pullout strength of the cannulated screws was less than the standard cortex screws at all sites (P < .001). Cannulated screws broke before bone failure in all but one bone specimen. CONCLUSIONS: The risk of cannulated instrument or screw failure during insertion into bone is theoretically low. The relatively low pullout strength of the cannulated screws implies that the interfragmentary compression achievable is likely to be less than with standard cortex screws. CLINICAL RELEVANCE: The relatively low pullout strength of the cannulated screw suggests that its risk of failure during fracture repair is greater than with the standard cortex screw.

Fluorescence-aided detection of microdamage in compact bone.

En bloc staining with basic fuchsin is an established method for demonstrating microdamage in bone. Using transmitted light microscopy, variations in light intensity, depth of focus and magnification are necessary to distinguish fully-stained microcracks generated in vivo, from partially-stained or unstained artefactual cracks due to cutting and machining. This process is both difficult and time-consuming. In this study, 2 methods were used to examine fuchsin-stained microcracks in human rib sections, transmitted light and epifluorescence microscopy. No differences were found in crack number, density or length between the 2 methods indicating comparable accuracy. Using green epifluorescence, only microcracks containing fuchsin fluoresced orange against the darkfield background, enabling unstained, artefactual cracks to be screened out. Under UV epifluorescence, microcracks stained through the full 100 microm depth of the section fluoresced purple. Partially-stained artefactual cracks failed to fluoresce and were screened out. Epifluorescence is a simple, rapid and accurate screening method for differentiating fully-stained from artefactual microcracks in bone.

Fall direction, bone mineral density, and function: risk factors for hip fracture in frail nursing home elderly.

PURPOSE: To determine the importance of fall characteristics, body habitus, function, and hip bone mineral density as independent risk factors for hip fracture in frail nursing home residents. SUBJECTS AND METHODS: In this prospective, case-control study of a single, long-term care facility, we enrolled 132 ambulatory residents (95 women and 37 men) aged 65 and older, including 32 cases (fallers with hip fracture) and 100 controls (fallers with no hip fracture). Principal risk factors included fall characteristics, body habitus, measures of functional assessment, and hip bone mineral density by dual-energy X-ray absorptiometry. RESULTS: In multivariate analysis, including only those with knowledge of the fall direction (n=100), those who fell and suffered a hip fracture were more likely to have fallen sideways (odds ratio 5.7, 95% confidence interval [CI] 1.7 to 18, P= 0.004) and have a low hip bone mineral density (odds ratio 1.9, 95% CI 0.97 to 3.7, P=0.06) than those who fell and did not fracture. When all participants were included (n=132) and subjects who did not know fall direction were coded as not having fallen to the side, a fall to the side (odds ratio 3.9, 95% CI 1.3 to 11, P=0.01), low hip bone density (odds ratio 1.8, 95% CI 1.03 to 3, P=0.04), and impaired mobility (odds ratios 6.4, 95% CI 1.9 to 21, P=0.002) were independently associated with hip fracture. Sixty-seven percent of subjects (87% with and 62% without hip fracture) had a total hip bone mineral density greater than 2.5 SD below adult peak bone mass and were therefore classified as having osteoporosis using World Health Organization criteria. CONCLUSIONS: Among frail elderly nursing home fallers, the preponderance of whom are osteoporotic, a fall to the side, a low hip bone density, and impairment in mobility are all important and independent risk factors for hip fracture. These data suggest that, among the frailest elderly, measures to reduce the severity of a sideways fall and improve mobility touch on new domains of risk, independent of bone mineral density, that need to be targeted for hip fracture prevention in this high-risk group.

Computed tomography-based finite element analysis predicts failure loads and fracture patterns for vertebral sections.

Computed tomography-based finite element analysis represents a powerful research tool for investigating the mechanics of skeletal fractures. To provide evidence that this technique can be used to predict failure loads and fracture patterns for bone structures, we compared the observed and predicted failure behaviors of 18 midsagittal sections, 10 mm thick, cut from human vertebral bodies. The specimens were scanned by computed tomography, and finite element models were generated with use of empirically determined density-property relations to assign element-specific material properties. The specimens were loaded to failure in uniaxial compression, and the models were analyzed under matching conditions. The models provided predictions of yield load that were strongly correlated with experimentally measured values (r2 > 0.86) and were typically within 25% of measured values. Predicted stiffness values were moderately correlated with measured values, but large absolute differences existed between them. Comparisons between regions of observed fracture and of high predicted strain indicated that strain was an accurate indicator of the pattern of local fracture in more than two-thirds of the bone specimens. In addition, strain contour plots provided better indicators of local fracture than did stress plots in these heterogeneous bone structures. We conclude that computed tomography-based finite element analysis can be used successfully to predict both global and local failure behavior of simplified skeletal structures.

Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells.

Bone marrow contains a population of rare progenitor cells capable of differentiating into bone, cartilage, tendon, and other connective tissues. These cells, referred to as mesenchymal stem cells, can be purified and culture-expanded from animals and humans and have been shown to regenerate functional tissue when delivered to the site of musculoskeletal defects in experimental animals. To test the ability of purified human mesenchymal stem cells to heal a clinically significant bone defect, mesenchymal stem cells isolated from normal human bone marrow were culture-expanded, loaded onto a ceramic carrier, and implanted into critical-sized segmental defects in the femurs of adult athymic rats. For comparison, cell-free ceramics were implanted in the contralateral limb. The animals were euthanized at 4, 8, or 12 weeks, and healing bone defects were compared by high-resolution radiography, immunohistochemistry, quantitative histomorphometry, and biomechanical testing. In mesenchymal stem cell-loaded samples, radiographic and histologic evidence of new bone was apparent by 8 weeks and histomorphometry demonstrated increasing bone formation through 12 weeks. Biomechanical evaluation confirmed that femurs implanted with mesenchymal stem cell-loaded ceramics were significantly stronger than those that received cell-free ceramics. These studies demonstrate that human mesenchymal stem cells can regenerate bone in a clinically significant osseous defect and may therefore provide an alternative to autogenous bone grafts.