Travis A. Burgers

Regulation of Wnt/β-catenin signaling within and from osteocytes.

Bone has long been known to be responsive to mechanical loading. For at least 25 years it has been known that osteocytes sense mechanical load, and because of their response to mechanical loading, osteocytes are believed to be the mechanosensory cell. The Wnt/β-catenin signaling pathway has been shown to be crucial in bone development. Mutations in LRP5 and SOST, which cause high bone mass, have increased interest in the Wnt pathway as a potential target for osteoporosis therapy and have helped link Wnt/β-catenin signaling to bones response to mechanical loading. Because of its specificity to osteocytes, the Wnt inhibitor sclerostin is a target for anabolic bone therapies. The response of bone to mechanical loading is critically regulated by osteocytes secreting sclerostin, which binds to Lrp5.

Compressive properties of trabecular bone in the distal femur.

Early loosening and implant migration are two problems that lead to failures in cementless (press-fit) femoral knee components of total knee replacements. To begin to address these early failures, this study determined the anterior-posterior mechanical properties from four locations in the human distal femur. Thirty-three cylindrical specimens were removed perpendicular to the press-fit surface after the surgical cuts on 10 human cadaveric femurs (age 71.5+/-14.2 years) had been made. Compression testing was performed that utilized methods to reduce the effects of end-artifacts. The bone mineral apparent density (BMAD), apparent modulus of elasticity, yield and ultimate stress, and yield and ultimate strain were measured for 28 cylindrical specimens. The apparent modulus, yield and ultimate stress, and yield and ultimate strain each significantly differed (p<0.05) in the superior and inferior locations. Linear and power law relationships between superior and inferior mechanical properties and BMAD were determined. The inferior apparent modulus and stresses were higher than those in the superior locations. These results show that the press-fit fixation characteristics of the femoral knee component differ on the anterior shield and posterior condyles. This information will be useful in the assignment of mechanical properties in finite element models for further investigations of femoral knee components. The property-density relations also have applications for implant design and preoperative assessment of bone strength using clinically available tools.

Biomechanical evaluation of fracture fixation constructs using a variable-angle locked periprosthetic femur plate system

BACKGROUND In the United States there are more than 230,000 total hip replacements annually, and periprosthetic femoral fractures occur in 0.1-4.5% of those patients. The majority of these fractures occur at the tip of the stem (Vancouver type B1). The purpose of this study was to compare the biomechanically stability and strength of three fixation constructs and identify the most desirable construct. METHODS Fifteen medium adult synthetic femurs were implanted with a hip prosthesis and were osteotomized in an oblique plane at the level of the implant tip to simulate a Vancouver type B1 periprosthetic fracture. Fractures were fixed with a non-contact bridging periprosthetic proximal femur plate (Zimmer Inc., Warsaw, IN). Three proximal fixation methods were used: Group 1, bicortical screws; Group 2, unicortical screws and one cerclage cable; and Group 3, three cerclage cables. Distally, all groups had bicortical screws. Biomechanical testing was performed using an axial-torsional testing machine in three different loading modalities (axial compression, lateral bending, and torsional/sagittal bending), next in axial cyclic loading to 10,000 cycles, again in the three loading modalities, and finally to failure in torsional/sagittal bending. RESULTS Group 1 had significantly greater load to failure and was significantly stiffer in torsional/sagittal bending than Groups 2 and 3. After cyclic loading, Group 2 had significantly greater axial stiffness than Groups 1 and 3. There was no difference between the three groups in lateral bending stiffness. The average energy absorbed during cyclic loading was significantly lower in Group 2 than in Groups 1 and 3. CONCLUSIONS Bicortical screw placement achieved the highest load to failure and the highest torsional/sagittal bending stiffness. Additional unicortical screws improved axial stiffness when using cable fixation. Lateral bending was not influenced by differences in proximal fixation. CLINICAL RELEVANCE To treat periprosthetic fractures, bicortical screw placement should be attempted to maximize load to failure and torsional/sagittal bending stiffness.

Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing.

The failure of an osseous fracture to heal (development of a non-union) is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cretg/+;Ptenflox/flox). Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cretg/+;Ptenflox/flox mice were studied via micro-computed tomography (µCT) scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn-cretg/+;Ptenflox/flox mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF) and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing.

Initial fixation of a femoral knee component: an in vitro and finite element study

Loosening is the primary cause of total knee arthroplasty implant failure; therefore, to investigate this failure mode, femoral knee components were implanted in vitro on three cadaveric femurs. Bone-implant finite element (FE) models were created to predict the initial fixation of the interface of each femur. Initial fixation of the femoral knee component was successfully measured with the strain-gauged implants. Specimen-specific FE models were calibrated using the in vitro strain measurements and used to assess initial fixation. Initial fixation was shown to increase with bone density. The geometry of the implant causes the distal femur to deform plastically. It also causes higher stresses in the lateral side and higher pressures on the lateral surfaces. The implementation of plasticity in the bone material model in the FE model decreased these strains and pressures considerably from a purely elastic model, which demonstrated the importance of including plasticity.

Time-dependent fixation and implantation forces for a femoral knee component—An in vitro study

Implant survival rate is a primary concern for individuals receiving a primary total knee arthroplasty. Loosening is the primary reason for revision surgery and was therefore the focus of the current study. To better understand the mechanics of implant fixation, the time-dependent fixation of a femoral knee component was measured in vitro on three cadaveric femurs. The fixation of each femoral knee component was measured with strain gauged implants for at least 10min on each femoral component. Additionally, impaction forces were measured during the implantation of each component. These forces were 2-6 times less than previously reported. The implantation impact forces were higher for the bones with higher bone density. Power law regressions were fit to the absolute value of the principal strains measured on the components over time to quantify the relaxation of the bone. The average power coefficient value for the three bones was lower for the bones with higher bone density. The average power coefficient value for the maximum principal strains was significantly higher than that of the minimum principal strains in each bone. The results were extrapolated to approximate the fixation strength at 9 months after implantation. In this time period the strain was predicted to decrease to between 78 and 91% of the strain 1s after implantation where those with lower bone density will have decreased fixation strength.

Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur

In the United States, approximately eight million osseous fractures are reported annually, of which 5-10% fail to create a bony union. Osteoblast-specific deletion of the gene Pten in mice has been found to stimulate bone growth and accelerate fracture healing. Healing rates at four weeks increased in femurs from Pten osteoblast conditional knock-out mice (Pten-CKO) compared to wild-type mice (WT) of the same genetic strain as measured by an increase in mechanical stiffness and failure load in four-point bending tests. Preceding mechanical testing, each femur was imaged using a Skyscan 1172 micro-computed tomography (μCT) scanner (Skyscan, Kontich, Belgium). The present study used µCT image-based analysis to test the hypothesis that the increased femoral fracture force and stiffness in Pten-CKO were due to greater section properties with the same effective material properties as that of the WT. The second moment of area and section modulus were computed in ImageJ 1.46 (National Institutes of Health) and used to predict the effective flexural modulus and the stress at failure for fourteen pairs of intact and callus WT and twelve pairs of intact and callus Pten-CKO femurs. For callus and intact femurs, the failure stress and tissue mineral density of the Pten-CKO and WT were not different; however, the section properties of the Pten-CKO were more than twice as large 28 days post-fracture. It was therefore concluded, when the gene Pten was conditionally knocked-out in osteoblasts, the resulting increased bending stiffness and force to fracture were due to increased section properties.

Estimating the density of femoral head trabecular bone from hip fracture patients using computed tomography scan data

The purpose of this study was to compare computed tomography density (ρCT) obtained using typical clinical computed tomography scan parameters to ash density (ρash), for the prediction of densities of femoral head trabecular bone from hip fracture patients. An experimental study was conducted to investigate the relationships between ρash and ρCT and between each of these densities and ρbulk and ρdry. Seven human femoral heads from hip fracture patients were computed tomography–scanned ex vivo, and 76 cylindrical trabecular bone specimens were collected. Computed tomography density was computed from computed tomography images by using a calibration Hounsfield units–based equation, whereas ρbulk, ρdry and ρash were determined experimentally. A large variation was found in the mean Hounsfield units of the bone cores (HUcore) with a constant bias from ρCT to ρash of 42.5 mg/cm3. Computed tomography and ash densities were linearly correlated (R2 = 0.55, p < 0.001). It was demonstrated that ρash provided a good estimate of ρbulk (R2 = 0.78, p < 0.001) and is a strong predictor of ρdry (R2 = 0.99, p < 0.001). In addition, the ρCT was linearly related to ρbulk (R2 = 0.43, p < 0.001) and ρdry (R2 = 0.56, p < 0.001). In conclusion, mineral density was an appropriate predictor of ρbulk and ρdry, and ρCT was not a surrogate for ρash. There were linear relationships between ρCT and physical densities; however, following the experimental protocols of this study to determine ρCT, considerable scatter was present in the ρCT relationships.

Post-yield relaxation behavior of bovine cancellous bone

Relaxation studies were conducted on specimens of bovine cancellous bone at post-yield strains. Stress and strain were measured for 1000s and the relaxation modulus was determined. Fifteen cylindrical, cancellous bone specimens were removed from one bovine femur in the anterior-posterior direction. The relaxation modulus was found to be a function of strain. Therefore cancellous bone is non-linearly viscoelastic/viscoplastic in the plastic region. A power law regression was fit to the relaxation modulus data. The multiplicative constant was found to be statistically related through a power law relationship to both strain (p<0.0005) and apparent density (p<0.0005) while the power coefficient was found to be related through a power law relationship, E(t, epsilon)=A(epsilon)t(-n(epsilon)), to strain (p<0.0005), but not apparent density.

Mice with a heterozygous Lrp6 deletion have impaired fracture healing

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 +/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 +/− mice and wild-type controls (Lrp6 +/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 +/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.