title: Differing effects of denosumab and alendronate on cortical and trabecular bone.
abstract: Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70mg weekly (n=82), or denosumab 60mg every 6months (n=83) for 12months. Porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6months, more so by 12months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) versus -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) versus -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) versus -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6months relative to baseline and controls but further decreased porosity of only the ITZ at 12months. By 12months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p=0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.
authors.affiliation: Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: zebaze@unimelb.edu.au.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Zebaze
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA. Electronic address: cesarl@amgen.com.
authors.forename: Cesar
authors.initials: C
authors.lastname: Libanati
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA. Electronic address: maustin@amgen.com.
authors.forename: Matthew
authors.initials: M
authors.lastname: Austin
authors.affiliation: Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: alig@unimelb.edu.au.
authors.forename: Ali
authors.initials: A
authors.lastname: Ghasem-Zadeh
authors.affiliation: University of Calgary, Calgary, Canada. Electronic address: dahanley@ucalgary.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Hanley
authors.affiliation: Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina. Electronic address: jrz@idim.com.ar.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Zanchetta
authors.affiliation: INSERM U1059, University Hospital of St-Etienne, St-Etienne, France. Electronic address: thierry.thomas@univ-st-etienne.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Thomas
authors.affiliation: INSERM U1033, Université de Lyon, Lyon, France. Electronic address: Stephanie.boutroy@inserm.fr.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boutroy
authors.affiliation: Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina. Electronic address: bogadoc@idim.com.ar.
authors.forename: Cesar E
authors.initials: CE
authors.lastname: Bogado
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: jpb2@columbia.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Bilezikian
authors.affiliation: Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: egos@unimelb.edu.au.
authors.forename: Ego
authors.initials: E
authors.lastname: Seeman
mesh_terms: D000368:Aged; D019386:Alendronate / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D016022:Case-Control Studies; D024042:Collagen Type I / Q000097:blood; D000069448:Denosumab; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008875:Middle Aged; D010455:Peptides / Q000097:blood; D011859:Radiography
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D024042:Collagen Type I; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D019386:Alendronate
keywords: Alendronate; Bone quality; Denosumab; Intracortical porosity; Structure