Zoledronic acid after spinal cord injury mitigates losses in proximal femoral strength independent of ambulation ability.

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI. INTRODUCTION: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes. METHODS: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment. RESULTS: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength. CONCLUSION: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.

Bone Mineral Loss at the Distal Femur and Proximal Tibia Following Spinal Cord Injury in Men and Women.

PURPOSE: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI. METHODS: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI. RESULTS: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences. CONCLUSIONS: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men.

A continuum damage model of fatigue and failure in whole bone.

Predicting the fatigue failure of whole bone may provide insight into the etiology of stress fractures and lead to new methods for preventing and rehabilitating these injuries. Although finite element (FE) models of whole bone have been used to predict fatigue failure, they often do not consider the cumulative and nonlinear effect of fatigue damage, which causes stress redistribution over many loading cycles. The purpose of this study was to develop and validate a continuum damage mechanics FE model for the prediction of fatigue damage and failure. Sixteen whole rabbit-tibiae were imaged using computed tomography (CT) and then cyclically loaded in uniaxial compression until failure. CT images were used to generate specimen-specific FE models and a custom program was developed to iteratively simulate cyclic loading and progressive modulus degradation associated with mechanical fatigue. Four tibiae from the experimental tests were used to develop a suitable damage model and define a failure criterion; the remaining twelve tibiae were used to test the validity of the continuum damage mechanics model. Fatigue-life predictions explained 71% of the variation in experimental fatigue-life measurements with a directional bias towards over-predicting fatigue-life in the low-cycle regime. These findings demonstrate the efficacy of using FE modeling with continuum damage mechanics to predict damage evolution and fatigue failure of whole bone. Through further refinement and validation, this model may be used to investigate different mechanical factors that influence the risk of stress fractures in humans.

Twelve Months of Denosumab and/or Alendronate Is Associated With Improved Bone Fatigue Life, Microarchitecture, and Density in Ovariectomized Cynomolgus Monkeys.

Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 µg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). A total of 240 cortical beam samples were cyclically tested in four-point bending at 80, 100, 120, or 140 MPa peak stress. High-resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p = 0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, and DMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

The probability of whole-bone fatigue fracture can be accurately predicted using specimen-specific finite element analysis incorporating a stochastic failure model.

A better understanding of the mechanisms of mechanical fatigue in bone could help improve understanding of the etiology of stress fractures. Investigations of small material samples of bone have identified a nonlinear relationship between strain magnitude, strained volume, and fatigue life, but it is non-trivial to extend these principles to predict the fatigue-life of whole bones which experience complex loading and non-uniform strain distribution. The purpose of this investigation was to experimentally validate a specimen-specific finite element (FE) model that predicts whole-bone fatigue failure using a stochastic model based on strain magnitude and volume. Thirty-four rabbit tibiae were previously tested to failure under cyclic compression, torsion, or both. Strain distribution during the test was estimated from computed-tomography based specimen-specific FE models, and a stochastic failure model based on strain magnitude and volume was used to predict the probability of failure as a function of loading cycles. Model predicted fracture risk matched experimental observations. Respectively, for the 25%, 50%, 75%, and 95% probabilistic predictions, we observed experimental failure ≤ model predicted values in 41%, 53%, 76%, and 80% of the tested specimens. A Brier scoring rule further demonstrated that this model, using strain magnitude and volume, more accurately predicted failure probability compared to two reference models that considered strain magnitude only. In conclusion, the stochastic model may be a powerful tool in future studies to assess mechanical factors that influence stress fracture risk.

Denosumab treatment is associated with decreased cortical porosity and increased bone density and strength at the proximal humerus of ovariectomized cynomolgus monkeys.

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (µCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 µg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and µCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, µCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via µCT; no effects on trabecular morphology were observed. FE estimated strength based on µCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.

Tibial-fibular geometry and density variations associated with elevated bone strain and sex disparities in young active adults.

Tibial stress fracture is a common injury in runners and military personnel. Elevated bone strain is believed to be associated with the development of stress fractures and is influenced by bone geometry and density. The purpose of this study was to characterize tibial-fibular geometry and density variations in young active adults, and to quantify the influence of these variations on finite element-predicted bone strain. A statistical appearance model characterising tibial-fibular geometry and density was developed from computed tomography scans of 48 young physically active adults. The model was perturbed ±1 and 2 standard deviations along each of the first five principal components to create finite element models. Average male and female finite element models, controlled for scale, were also generated. Muscle and joint forces in running, calculated using inverse dynamics-based static optimization, were applied to the finite element models. The resulting 95th percentile pressure-modified von Mises strain (peak strain) and strained volume (volume of elements above 4000 µÎµ) were quantified. Geometry and density variations described by principal components resulted in up to 12.0% differences in peak strain and 95.4% differences in strained volume when compared to the average tibia-fibula model. The average female illustrated 5.5% and 41.3% larger peak strain and strained volume, respectively, when compared to the average male, suggesting that sexual dimorphism in bone geometry may indeed contribute to greater stress fracture risk in females. Our findings identified important features in subject-specific geometry and density associated with elevated bone strain that may have implications for stress fracture risk.

Are subject-specific models necessary to predict patellar tendon fatigue life? A finite element modelling study.

Patellar tendinopathy is an overuse injury that occurs from repetitive loading of the patellar tendon in a scenario resembling that of mechanical fatigue. As such, fatigue-life estimates provide a quantifiable approach to assess tendinopathy risk and may be tabulated using nominal strain (NS) or finite element (FE) models with varied subject-specificity. We compared patellar tendon fatigue-life estimates from NS and FE models of twenty-nine athletes performing countermovement jumps with subject-specific versus generic geometry and material properties. Subject-specific patellar tendon material properties and geometry were obtained using a data collection protocol of dynamometry, ultrasound, and magnetic resonance imaging. Three FE models were created for each subject, with: subject-specific (hyperelastic) material properties and geometry, subject-specific material properties and generic geometry, and generic material properties and subject-specific geometry. Four NS models were created for each subject, with: subject-specific (linear elastic) material properties and moment arm, generic material properties and subject-specific moment arm, subject-specific material properties and generic moment arm, and generic material properties and moment arm. NS- and FE-modelled fatigue-life estimates with generic material properties were poorly correlated with their subject-specific counterparts (r2≤0.073), while all NS models overestimated fatigue life compared to the subject-specific FE model (r2≤0.223). Furthermore, FE models with generic tendon geometry were unable to accurately represent the heterogeneous strain distributions found in the subject-specific FE models or those with generic material properties. These findings illustrate the importance of incorporating subject-specific material properties and FE-modelled strain distributions into fatigue-life estimations.

Durability and delayed treatment effects of zoledronic acid on bone loss after spinal cord injury: a randomized, controlled trial.

A single infusion of zoledronic acid (ZOL) after acute spinal cord injury (SCI) attenuates bone loss at the hip (proximal femur) and knee (distal femur and proximal tibia) for at least 6 months. The objective of this study was to examine the effects of timing and frequency of ZOL over 2 years. In this double-blind, placebo-controlled trial, we randomized 60 individuals with acute SCI (<120 days of injury) to receive either ZOL 5-mg infusion (n = 30) or placebo (n = 30). After 12 months, groups were again randomized to receive ZOL or placebo, resulting in four treatment groups for year 2: (i) ZOL both years; (ii) ZOL year 1, placebo year 2; (iii) placebo year 1, ZOL year 2; and (iv) placebo both years. Our primary outcome was bone loss at 12 months; compared to placebo, a single infusion of ZOL attenuated bone loss at the proximal femur, where median changes relative to baseline were -1.7% to -2.2% for ZOL versus -11.3% to -12.8% for placebo (p < 0.001). Similarly, the distal femur and proximal tibia showed changes of -4.7% to -9.6% for ZOL versus -8.9% to -23.0% for placebo (p ≤ 0.042). After 24 months, differences were significant at the proximal femur only (-3.2% to -6.0% for ZOL vs. -16.8% to -21.8% for placebo; p ≤ 0.018). Although not statistically significant, median bone density losses suggested some benefit from two annual infusions compared to a single baseline infusion, as well as from a single infusion 12 months after baseline compared to 2 years of placebo; therefore, further investigation in the 12-month to 24-month treatment window is warranted. No unanticipated adverse events associated with drug treatment were observed. In summary, ZOL 5-mg infusion after acute SCI was well-tolerated and may provide an effective therapeutic approach to prevent bone loss in the first few years following SCI. © 2021 American Society for Bone and Mineral Research (ASBMR).

Mechanical fatigue of whole rabbit-tibiae under combined compression-torsional loading is better explained by strained volume than peak strain magnitude.

The mechanical fatigue behavior of whole bone is poorly defined, particularly for the combined loading modes that occur in vivo. The purpose of this study was to quantify the fatigue life of whole rabbit-tibiae under cyclic uniaxial compression and biaxial (compression and torsion) loading, and to explore the relationship between fatigue life and specimen-specific finite element (FE) predictions of stress/strain. Twelve tibiae were tested cyclically until failure across a range of uniaxial-compressive loads. Another twenty-two tibiae were separated into three groups and loaded biaxially; peak compressive load was constant in all three groups (50% ultimate force) but torsion was varied (0%, 25%, or 50% of ultimate torque). FE models with heterogeneous linear-elastic material properties were developed from computed tomography. We assessed peak stress/strain and stressed/strained volume based on principal stress/strain, as well as von Mises and pressure modified von Mises criteria. A logarithmic (r2 = 0.68; p < 0.001) relationship was observed between uniaxial-compressive load and fatigue life. Biaxial tests demonstrated that fatigue life decreased with superposed torsion (p = 0.034). Strained volume, based on a maximum principal strain or pressure modified von Mises strain criteria, were strong predictors of fatigue life under both uniaxial (r2 = 0.73-0.82) and biaxial (r2 = 0.59-0.60) loads, and these outperformed equivalent peak stress- and strain-based measures. Our findings highlight the importance of evaluating strain distributions, rather than peak stress or strain, to predict the fatigue behavior or whole bone, which has important implications for the study of stress fracture.

Stiffness and Strength Predictions From Finite Element Models of the Knee are Associated with Lower-Limb Fractures After Spinal Cord Injury.

Spinal cord injury (SCI) is associated with bone fragility and fractures around the knee. The purpose of this investigation was to validate a computed tomography (CT) based finite element (FE) model of the proximal tibia and distal femur under biaxial loading, and to retrospectively quantify the relationship between model predictions and fracture incidence. Twenty-six cadaveric tibiae and femora (n = 13 each) were loaded to 300 N of compression, then internally rotated until failure. FE predictions of torsional stiffness (K) and strength (Tult) explained 74% (n = 26) and 93% (n = 7) of the variation in experimental measurements, respectively. Univariate analysis and logistic regression were subsequently used to determine if FE predictions and radiographic measurements from CT and dual energy X-ray absorptiometry (DXA) were associated with prevalent lower-limb fracture in 50 individuals with SCI (n = 14 fractures). FE and CT measures, but not DXA, were lower in individuals with fracture. FE predictions of Tult at the tibia demonstrated the highest odds ratio (4.98; p = 0.006) and receiver operating characteristic (0.84; p = 0.008) but did not significantly outperform other metrics. In conclusion, CT-based FE model predictions were associated with prevalent fracture risk after SCI; this technique could be a powerful tool in future clinical research.

Association between intracortical microarchitecture and the compressive fatigue life of human bone: A pilot study.

Many mechanical properties of cortical bone are largely governed by the underlying microarchitecture; however, the influence of microarchitecture on the fatigue life of bone is poorly understood. Furthermore, imaging-based studies investigating intracortical microarchitecture may expose bone samples to large doses of radiation that may compromise fatigue resistance. The purpose of this pilot study was to 1) investigate the relationship between intracortical microarchitecture and the fatigue life of human bone in compression and 2) examine the effects of synchrotron irradiation on fatigue life measurements. Cortical samples were prepared from the femoral and tibial shafts of three cadaveric donors. A subset of samples was imaged using synchrotron X-ray microCT to quantify microarchitecture, including porosity, canal diameter, lacunar density, lacunar volume, and lacunar orientation. A second group of control samples was not imaged and used only for mechanical testing. Fatigue life was quantified by cyclically loading both groups in zero-compression until failure. Increased porosity and larger canal diameter were both logarithmically related to a shorter fatigue life, whereas lacunar density demonstrated a positive linear relationship with fatigue life (r2 = 45-73%, depending on measure). Irradiation from microCT scanning reduced fatigue life measurements by 91%, but relationships with microarchitecture measurements remained. Additional research is needed to support the findings of this pilot study and fully establish the relationship between intracortical microarchitecture and the compressive fatigue life of bone.

Subject-Specific Finite Element Models of the Tibia With Realistic Boundary Conditions Predict Bending Deformations Consistent With In Vivo Measurement.

Understanding the structural response of bone during locomotion may help understand the etiology of stress fracture. This can be done in a subject-specific manner using finite element (FE) modeling, but care is needed to ensure that modeling assumptions reflect the in vivo environment. Here, we explored the influence of loading and boundary conditions (BC), and compared predictions to previous in vivo measurements. Data were collected from a female participant who walked/ran on an instrumented treadmill while motion data were captured. Inverse dynamics of the leg (foot, shank, and thigh segments) was combined with a musculoskeletal (MSK) model to estimate muscle and joint contact forces. These forces were applied to an FE model of the tibia, generated from computed tomography (CT). Eight conditions varying loading/BCs were investigated. We found that modeling the fibula was necessary to predict realistic tibia bending. Applying joint moments from the MSK model to the FE model was also needed to predict torsional deformation. During walking, the most complex model predicted deformation of 0.5 deg posterior, 0.8 deg medial, and 1.4 deg internal rotation, comparable to in vivo measurements of 0.5-1 deg, 0.15-0.7 deg, and 0.75-2.2 deg, respectively. During running, predicted deformations of 0.3 deg posterior, 0.3 deg medial, and 0.5 deg internal rotation somewhat underestimated in vivo measures of 0.85-1.9 deg, 0.3-0.9 deg, 0.65-1.72 deg, respectively. Overall, these models may be sufficiently realistic to be used in future investigations of tibial stress fracture.

The Role of Lower-Limb Geometry in the Pathophysiology of Atypical Femoral Fracture.

PURPOSEOF REVIEW: The etiology of atypical femoral fracture (AFF) is likely multifactorial. In this review, we examined the recent literature investigating the role of lower-limb geometry in the pathophysiology of AFF. RECENT FINDINGS: Increased femoral bowing was associated with prevalent AFF and a greater likelihood of a diaphyseal versus a subtrochanteric AFF location. Femoral neck geometry or hip alignment may also be related to AFF, but findings remain equivocal. Differences in femoral geometry may, in part, be responsible for the high rate of AFF in Asian compared with Caucasian populations. Finally, simulation studies suggest that lower-limb geometry influences AFF risk via its effects on mechanical strain of the lateral femoral cortex. Femoral geometry, and bowing in particular, is related to prevalent AFF, but more prospective investigation is needed to determine whether measurements of geometry can be used for clinical risk stratification.

Open-label clinical trial of alendronate after teriparatide therapy in people with spinal cord injury and low bone mineral density.

STUDY DESIGN: Non-randomized open-label clinical trial of oral alendronate after teriparatide therapy in people with spinal cord injury (SCI) and low bone mineral density (BMD). OBJECTIVES: To determine if alendronate would prevent bone loss after discontinuation of teriparatide. SETTING: Outpatient research clinic at Northwestern University Feinberg School of Medicine. METHODS: Seventeen participants with chronic SCI who recently completed 12-24 months of teriparatide treatment received oral alendronate 70 mg once weekly for 12 months. Participants were evaluated at baseline, 6 months and 12 months. Bone was assessed by: DXA at the spine and hip, CT at the distal femur/proximal tibia, serum collected for bone markers, and bone strength determined by finite element (FE) analysis of the proximal tibia. RESULTS: Areal BMD showed no significant change from baseline at the total hip or femoral neck, where mean change (SD) was 1.3% (4.7) and 0.54% (5.0), respectively. However, areal BMD increased significantly at the spine by 2.5% (4.6). CT demonstrated significant increases in bone mineral content at the femoral epiphysis, metaphysis, and diaphysis, 15% (18), 7.7% (12), and 3.0% (3.5), respectively. Measurements at the tibia illustrated improvements and reductions, but no changes to FE-predicted strength were observed. Biomarkers illustrated inhibition of bone formation and resorption, with P1NP and CTX decreasing by 52% (82) and 62% (74), respectively. CONCLUSION: Twelve months of alendronate after discontinuation of teriparatide in people with SCI can prevent bone loss and may increase bone mass and preserve bone strength at the spine, hip, and some sites of the knee.

Previous Damage Accumulation Can Influence Femoral Fracture Strength: A Finite Element Study.

To manage osteoporotic hip fracture risk, it is necessary to understand failure mechanisms of bone at both the material and organ level. The structural response of bone is dependent on load history. Repeated loading causes progressive microstructural cracking, resulting in reduced apparent-level stiffness and, if damage is significant, reductions to peak load bearing capability. However, the effect of previous damage accumulation has not been well explored at the organ level. It was hypothesized that femoral fracture load and fracture pattern may be sensitive to damage accumulation from previous loading events. Six cadaveric specimens were used to develop patient specific finite element (FE) models from quantitative tomographic (qCT) scans. Material properties were assigned from qCT intensity at each element location, and damage evolution was predicted using a previously validated quasi-brittle FE model. Three scenarios were investigated: stumble followed by another stumble (S-S), fall followed by another fall (F-F), and stumble followed by a fall (S-F). Fracture load and pattern were compared to FE predictions for a single stumble (S) or single fall (F) loading event. Most specimens were resilient to accumulated damage, showing little (<5%) change in fracture load from the multiple-load scenarios (S-S, F-F, and S-F) compared to an equivalent single load scenario (S or F). Only one specimen demonstrated moderate (5-15%) reductions in strength from all three multiple-load scenarios. However, two specimens experienced moderate (20-30%) increase in fracture load in some load cases. In these cases, initial damage caused the load to be more evenly distributed upon subsequent loading events. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2197-2203, 2019.

Effects of Teriparatide and Vibration on Bone Mass and Bone Strength in People with Bone Loss and Spinal Cord Injury: A Randomized, Controlled Trial.

Spinal cord injury (SCI) is associated with marked bone loss and an increased risk of fracture. We randomized 61 individuals with chronic SCI and low bone mass to receive either teriparatide 20 µg/d plus sham vibration 10 min/d (n = 20), placebo plus vibration 10 min/d (n = 20), or teriparatide 20 µg/d plus vibration 10 min/d (n = 21). Patients were evaluated for 12 months; those who completed were given the opportunity to participate in an open-label extension where all participants (n = 25) received teriparatide 20 µg/d for an additional 12 months and had the optional use of vibration (10 min/d). At the end of the initial 12 months, both groups treated with teriparatide demonstrated a significant increase in areal bone mineral density (aBMD) at the spine (4.8% to 5.5%). The increase in spine aBMD was consistent with a marked response in serum markers of bone metabolism (ie, CTX, P1NP, BSAP), but no treatment effect was observed at the hip. A small but significant increase (2.2% to 4.2%) in computed tomography measurements of cortical bone at the knee was observed in all groups after 12 months; however, the magnitude of response was not different amongst treatment groups and improvements to finite element-predicted bone strength were not observed. Teriparatide treatment after the 12-month extension resulted in further increases to spine aBMD (total increase from baseline 7.1% to 14.4%), which was greater in patients initially randomized to teriparatide. Those initially randomized to teriparatide also demonstrated 4.4% to 6.7% improvements in hip aBMD after the 12-month extension, while all groups displayed increases in cortical bone measurements at the knee. To summarize, teriparatide exhibited skeletal activity in individuals with chronic SCI that was not augmented by vibration stimulation. Without additional confirmatory data, the location-specific responses to teriparatide would not be expected to provide clinical benefit in this population. © 2018 American Society for Bone and Mineral Research.

Femoral fracture load and fracture pattern is accurately predicted using a gradient-enhanced quasi-brittle finite element model.

Nonlinear finite element (FE) modeling can be a powerful tool for studying femoral fracture. However, there remains little consensus in the literature regarding the choice of material model and failure criterion. Quasi-brittle models recently have been used with some success, but spurious mesh sensitivity remains a concern. The purpose of this study was to implement and validate a new model using a custom finite element designed to mitigate mesh sensitivity problems. Six specimen-specific FE models of the proximal femur were generated from quantitative tomographic (qCT) scans of cadaveric specimens. Material properties were assigned a-priori based on average qCT intensities at element locations. Specimens were experimentally tested to failure in a stumbling load configuration, and the results were compared to FE model predictions. There was a strong linear relationship between FE predicted and experimentally measured fracture load (R2 = 0.79), and error was less than 14% over all cases. In all six specimens, surface damage was observed at sites predicted by the FE model. Comparison of qCT scans before and after experimental failure showed damage to underlying trabecular bone, also consistent with FE predictions. In summary, the model accurately predicted fracture load and pattern, and may be a powerful tool in future studies.

Influence of geometry on proximal femoral shaft strains: Implications for atypical femoral fracture.

INTRODUCTION: Atypical femoral fractures (AFF) are characterized as low-energy fractures of the femoral shaft or subtrochanteric region. Femoral geometry is known to play a role in AFF risk; it is hypothesized that high-risk geometries are associated with elevated femoral shaft strain. However, it is not well known which geometric parameters have the greatest effect on strain, or whether interaction between parameters is significant. The purpose of this study was to thoroughly quantify the relationship between femoral geometry and diaphyseal strain, using patient specific finite element (FE) modelling in concert with parametric mesh morphing. METHODS: Ten FE models were generated from computed tomography (CT) images of cadaveric femora. Heterogeneous material properties were assigned based on average CT intensities at element locations and models were subject to loads and boundary conditions representing the stance phase of gait. Mesh morphing was used to manipulate 8 geometric parameters: neck shaft angle (NSA), neck version angle (NV), neck length (NL), femoral length (FL), lateral bowing angle (L.Bow), anterior bowing angle (A.Bow), shaft diameter (S.Dia), and cortical bone thickness (C·Th). A 2-Level full factorial analysis was used to explore the effect of different combinations of physiologically realistic minimum and maximum values for each parameter. Statistical analysis (Generalized Estimating Equations) was used to assess main effects and first order interactions of each parameter. RESULTS: Six independent parameters and seven interaction terms had statistically significant (p<0.05) effects on peak strain and strained volume. For both measures, the greatest changes were caused by S.Dia, L.Bow, and A.Bow, and/or first order interactions involving two of these variables. CONCLUSIONS: As hypothesized, a large number of geometric measures (six) and first order interactions (seven) are associated with changes in femoral shaft strain. These measures can be evaluated radiographically, which may have important implications for future studies investigating AFF risk in clinical populations.