Comparison of proximal femur and vertebral body strength improvements in the FREEDOM trial using an alternative finite element methodology

Zysset, Philippe; Pahr, Dieter H.; Engelke, Klaus; Genant, Harry K.; McClung, Michael R.; Kendler, David L.; Recknor, Christopher; Kinzl, Michael; Schwiedrzik, Jakob; Museyko, Oleg; Wang, Andrea; Libanati, Cesar

doi:10.1016/j.bone.2015.06.025

Cited by 51 publications

(20 citation statements)

References 88 publications

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“…That study found a relatively large (for humans) strengthening effect for denosumab versus placebo of 22.4% over 3 years (31) -a result that was replicated by an independent analysis of the same cohort but using a slightly different continuum-type FEA implementation. (34) If the capability of FEA to quantify treatment effects as demonstrated in this cynos study does indeed extrapolate to humans, those clinical FEA studies should provide a reasonable estimate of the likely effect sizes in humans-but that will be difficult to confirm without direct experiments on humans. Another generality issue pertains to the nature of the study outcomes.…”

Section: Discussionmentioning

confidence: 90%

“…They have been tested in cadaver studies against direct mechanical testing for hip and spine strength (R 2 ranged from 0.74 to 0.96) (7,9,10) and validated clinically in fracture-outcome studies for prevalent vertebral, (11)(12)(13)(14)(15) incident vertebral, (9,16) incident hip (16)(17)(18) and prevalent general osteoporotic (19) fractures, in women and men. Whereas this general technique has also been utilized in many clinical studies to elucidate changes in hip and spine strength resulting from various osteoporosis therapeutic agents, (14,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) such changes in strength have not yet been directly compared with destructive ex vivo biomechanical testing. Addressing this issue, we assessed the ability of a clinically available implementation of this type of FEA to quantify treatment effects on vertebral strength in mature cynomolgus monkeys treated with denosumab.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Finite Element Analysis of Denosumab Treatment Effects on Vertebral Strength in Ovariectomized Cynomolgus Monkeys

Lee

Varela²,

Kostenuik

et al. 2016

Journal of Bone and Mineral Research

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Finite element analysis has not yet been validated for measuring changes in whole-bone strength at the hip or spine in people after treatment with an osteoporosis agent. Toward that end, we assessed the ability of a clinically approved implementation of finite element analysis to correctly quantify treatment effects on vertebral strength, comparing against direct mechanical testing, in cynomolgus monkeys randomly assigned to one of three 16-month-long treatments: sham surgery with vehicle (Sham-Vehicle), ovariectomy with vehicle (OVX-Vehicle), or ovariectomy with denosumab (OVX-DMAb). After treatment, T12 vertebrae were retrieved, scanned with micro-CT, and mechanically tested to measure compressive strength. Blinded to the strength data and treatment codes, the micro-CT images were coarsened and homogenized to create continuum-type finite element models, without explicit porosity. With clinical translation in mind, these models were then analyzed for strength using the U.S. Food and Drug Administration (FDA)-cleared VirtuOst software application (O.N. Diagnostics, Berkeley, CA, USA), developed for analysis of human bones. We found that vertebral strength by finite element analysis was highly correlated (R 2 ¼ 0.97; n ¼ 52) with mechanical testing, independent of treatment (p ¼ 0.12). Further, the size of the treatment effect on strength (ratio of mean OVX-DMAb to mean OVX-Vehicle, as a percentage) was large and did not differ (p ¼ 0.79) between mechanical testing (þ57%; 95% CI [26%, 95%]) and finite element analysis (þ51% [20%, 88%]). The micro-CT analysis revealed increases in cortical thickness (þ45% [19%, 73%]) and trabecular bone volume fraction (þ24% [8%, 42%]). These results show that a preestablished clinical finite element analysis implementation-developed for human bone and clinically validated in fracture-outcome studies-correctly quantified the observed treatment effects of denosumab on vertebral strength in cynomolgus monkeys. One implication is that the treatment effects in this study are well explained by the features contained within these finite element models, namely, the bone geometry and mass and the spatial distribution of bone mass.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Finite Element Analysis of Denosumab Treatment Effects on Vertebral Strength in Ovariectomized Cynomolgus Monkeys

Lee

Varela²,

Kostenuik

et al. 2016

Journal of Bone and Mineral Research

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“…Subject specific finite element (FE) models can estimate the bone strength in simulated loading scenarios by accounting for geometry and BMD distribution. This method has been recently applied to DXA [7][8][9][10][11], to 2D projections from QCT scans [12], and to QCT images [13][14][15][16] in order to estimate the risk of fracture or the effect of anti-osteoporotic drug treatments. Validation studies that compare the FE outcomes to bone strength measurements performed on cadaveric femora have shown that QCT based FE can predict 80-90% of femoral strength in simulated fall [17][18][19][20][21][22] and 80-94% of femoral strength in simulated one legged stance [21,[23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Experimental validation of DXA-based finite element models for prediction of femoral strength

Dall’Ara

Eastell

Viceconti

et al. 2016

Journal of the Mechanical Behavior of Biomedical Materials

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Osteoporotic fractures are a major clinical problem and current diagnostic tools have an accuracy of only 50%. The aim of this study was to validate dual energy X-rays absorptiometry (DXA)-based finite element (FE) models to predict femoral strength in two loading configurations. Thirty-six pairs of fresh frozen human proximal femora were scanned with DXA and quantitative computed tomography (QCT). For each pair one femur was tested until failure in a one-legged standing configuration (STANCE) and one by replicating the position of the femur in a fall onto the greater trochanter (SIDE). Subject-specific 2D DXA-based linear FE models and 3D QCT-based nonlinear FE models were generated for each specimen and used to predict the measured femoral strength. The outcomes of the models were compared to standard DXA-based areal bone mineral density (aBMD) measurements. For the STANCE configuration the DXA-based FE models (R(2)=0.74, SEE=1473N) outperformed the best densitometric predictor (Neck_aBMD, R(2)=0.66, SEE=1687N) but not the QCT-based FE models (R(2)=0.80, SEE=1314N). For the SIDE configuration both QCT-based FE models (R(2)=0.85, SEE=455N) and DXA neck aBMD (R(2)=0.80, SEE=502N) outperformed DXA-based FE models (R(2)=0.77, SEE=529N). In both configurations the DXA-based FE model provided a good 1:1 agreement with the experimental data (CC=0.87 for SIDE and CC=0.86 for STANCE), with proper optimization of the failure criteria. In conclusion we found that the DXA-based FE models are a good predictor of femoral strength as compared with experimental data ex vivo. However, it remains to be investigated whether this novel approach can provide good predictions of the risk of fracture in vivo.

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“…Thus, all BCT is not the same and different implementations of BCT by different groups may produce different values of strength, requiring, for example, different classification cut-points. That said, one study reported different absolute measurements from two different implementations of BCT but similar measurements of treatment-induced percent changes [118], suggesting that BCT is more robust across different implementations for assessing temporal changes than absolute values. Related, the clinical term "BCT" is intended only to apply to finite element analysis of clinical-resolution CT scans and does not apply to finite element analysis of other types of medical images.…”

Section: Summary and Discussionmentioning

confidence: 99%

Biomechanical Computed Tomography analysis (BCT) for clinical assessment of osteoporosis

et al. 2020

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The surgeon general of the USA defines osteoporosis as "a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture." Measuring bone strength, Biomechanical Computed Tomography analysis (BCT), namely, finite element analysis of a patient's clinical-resolution computed tomography (CT) scan, is now available in the USA as a Medicare screening benefit for osteoporosis diagnostic testing. Helping to address under-diagnosis of osteoporosis, BCT can be applied "opportunistically" to most existing CT scans that include the spine or hip regions and were previously obtained for an unrelated medical indication. For the BCT test, no modifications are required to standard clinical CT imaging protocols. The analysis provides measurements of bone strength as well as a dual-energy X-ray absorptiometry (DXA)equivalent bone mineral density (BMD) T-score at the hip and a volumetric BMD of trabecular bone at the spine. Based on both the bone strength and BMD measurements, a physician can identify osteoporosis and assess fracture risk (high, increased, not increased), without needing confirmation by DXA. To help introduce BCT to clinicians and health care professionals, we describe in this review the currently available clinical implementation of the test (VirtuOst), its application for managing patients, and the underlying supporting evidence; we also discuss its main limitations and how its results can be interpreted clinically. Together, this body of evidence supports BCT as an accurate and convenient diagnostic test for osteoporosis in both sexes, particularly when used opportunistically for patients already with CT.

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Comparison of proximal femur and vertebral body strength improvements in the FREEDOM trial using an alternative finite element methodology

Cited by 51 publications

References 88 publications

Finite Element Analysis of Denosumab Treatment Effects on Vertebral Strength in Ovariectomized Cynomolgus Monkeys

Finite Element Analysis of Denosumab Treatment Effects on Vertebral Strength in Ovariectomized Cynomolgus Monkeys

Experimental validation of DXA-based finite element models for prediction of femoral strength

Biomechanical Computed Tomography analysis (BCT) for clinical assessment of osteoporosis

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