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.

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

“…These important techniques were not performed in the present work and are limitations of this study. Incorporation of these approaches would provide better insight on skeletal changes during cancer cachexia, such as cortical bone characteristics, which is particularly relevant because a majority of non-vertebral fractures occur at cortical sites, age-related deterioration of appendicular bone is mostly cortical, and much of this bone loss arises from intracortical remodeling leading to porosity [32,33]. Such technical approaches would also help to evaluate the efficacy of exercise therapies.…”

Osteoporosis drug effects on cortical and trabecular bone microstructure: a review of HR-pQCT analyses

“…The decline in these parameters was prevented in the ALN group, and the parameters were either stable or, in particular total and cortical BMD, increased with DMAB. 21 In a post hoc analysis of the head to head analysis of DMAB vs ALN, a detailed study of the compact-appearing cortex porosity has been done 39 A greater reduction in cortical porosity by DMAB vs ALN was observed, this finding was associated with earlier and more complete inhibition of remodeling by DMAB vs ALN 39 Contrasting treatment-specific effects were observed between two different PTH agents (that is, PTH 1-34 and PTH1-84) and zoledronate ( Table 2). Once again, the limited sample size and the design of the protocol cannot lead to definitive and clear conclusions from this latter study.…”

The clinical contribution of cortical porosity to fragility fractures

“…25,26 Increasing porosity increases odds for fracture, 14,24,25 and treatment reduces porosity at the distal radius and at the proximal femoral shaft in postmenopausal women. [27][28][29] It is therefore reasonable to conclude that porosity is a substantial determinant of the bone fragility that underlies risk of fractures.…”