title: Comparison of proximal femur and vertebral body strength improvements in the FREEDOM trial using an alternative finite element methodology.
abstract: Denosumab reduced the incidence of new fractures in postmenopausal women with osteoporosis by 68% at the spine and 40% at the hip over 36 months compared with placebo in the FREEDOM study. This efficacy was supported by improvements from baseline in vertebral (18.2%) strength in axial compression and femoral (8.6%) strength in sideways fall configuration at 36 months, estimated in Newtons by an established voxel-based finite element (FE) methodology. Since FE analyses rely on the choice of meshes, material properties, and boundary conditions, the aim of this study was to independently confirm and compare the effects of denosumab on vertebral and femoral strength during the FREEDOM trial using an alternative smooth FE methodology. Unlike the previous FE study, effects on femoral strength in physiological stance configuration were also examined. QCT data for the proximal femur and two lumbar vertebrae were analyzed by smooth FE methodology at baseline, 12, 24, and 36 months for 51 treated (denosumab) and 47 control (placebo) subjects. QCT images were segmented and converted into smooth FE models to compute bone strength. L1 and L2 vertebral bodies were virtually loaded in axial compression and the proximal femora in both fall and stance configurations. Denosumab increased vertebral body strength by 10.8%, 14.0%, and 17.4% from baseline at 12, 24, and 36 months, respectively (p<0.0001). Denosumab also increased femoral strength in the fall configuration by 4.3%, 5.1%, and 7.2% from baseline at 12, 24, and 36 months, respectively (p<0.0001). Similar improvements were observed in the stance configuration with increases of 4.2%, 5.2%, and 5.2% from baseline (p≤0.0007). Differences between the increasing strengths with denosumab and the decreasing strengths with placebo were significant starting at 12 months (vertebral and femoral fall) or 24 months (femoral stance). Using an alternative smooth FE methodology, we confirmed the significant improvements in vertebral body and proximal femur strength previously observed with denosumab. Estimated increases in strength with denosumab and decreases with placebo were highly consistent between both FE techniques.
authors.affiliation: University of Bern, Bern, Switzerland. Electronic address: philippe.zysset@istb.unibe.ch.
authors.forename: Philippe
authors.initials: P
authors.lastname: Zysset
authors.affiliation: Vienna University of Technology, Vienna, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Pahr
authors.affiliation: University of Erlangen, Erlangen, Germany and Synarc Germany, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Engelke
authors.affiliation: UCSF and Synarc, San Francisco, CA, USA.
authors.forename: Harry K
authors.initials: HK
authors.lastname: Genant
authors.affiliation: Oregon Osteoporosis Center, Portland, OR, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: McClung
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Kendler
authors.affiliation: United Osteoporosis Centers, Gainesville, GA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Recknor
authors.affiliation: Vienna University of Technology, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Kinzl
authors.affiliation: University of Bern, Bern, Switzerland.
authors.forename: Jakob
authors.initials: J
authors.lastname: Schwiedrzik
authors.affiliation: University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Museyko
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Libanati
mesh_terms: D000368:Aged; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D000069448:Denosumab / Q000627:therapeutic use*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D020342:Finite Element Analysis; D006801:Humans; D021621:Imaging, Three-Dimensional; D015663:Osteoporosis, Postmenopausal / Q000150:complications; D058866:Osteoporotic Fractures / Q000517:prevention & control*; D011857:Radiographic Image Interpretation, Computer-Assisted / Q000379:methods*; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab
keywords: Denosumab; FEA; Proximal femur strength; QCT; Vertebral body strength