Differing effects of denosumab and alendronate on cortical and trabecular bone

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 61. years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70. mg weekly (n=82), or denosumab 60. mg every 6. months (n=83) for 12. months. 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 6. months, more so by 12. months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12. months 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 6. months relative to baseline and controls but further decreased porosity of only the ITZ at 12. months. By 12. months, 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 6. months, 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.