Association between transitory increase in PTH following denosumab administration and reduced intracortical porosity is a distinctive attribute of denosumab therapy

Abstract

Two processes largely determine the impact of an antiresorptive on bone mass and structure: its direct and indirect effects on the volumes of bone resorbed and deposited by each bone remodeling unit (BMU) and the numberof BMUs inhibited in both the trabecular and cortical compartments. Denosumab (DMAb) markedly inhibits the birth rate of new BMUs and rapidly reduces bone resorption by existing BMUs following administration. This acute reduction in remodeling is accompanied bya transitory increase in circulating endogenous PTH, which has the theoretical potential to increase osteoblast longevity and/or activity. We tested the hypothesis that the direct effect of DMAb on inhibition of resorption, and the possible indirect effect on bone formationmediated by an increase in PTH in the face of inhibited osteoclast activity by the BMU,would be associated with a reduction in cortical porosity in postmenopausal women. In this double-blind, double-dummy trial, 247 postmenopausal women with mean (SD) age 60.6 (5.4) yrs and low BMD were randomly assigned to DMAb 60 mg Q6M (N=83), alendronate (ALN) 70 mg QW (N=82) or placebo (Pbo; N=82). PTH was measured at baseline (BL), week 1 and months 1, 3, 6, 6.25, 7, 9 and 12. Area under the curve (AUC) for PTH was derived from the change from BL for each subject. Porosity was evaluated in the compact-appearing cortex of the distal radius at BL and mo 12 by HR-pQCT. Associations between PTH AUC and change in porosity were evaluated. Transitory increases in PTHwere seen in the DMAb and ALN, but not Pbo, groups. The increase in PTH was larger following DMAb than ALN (Pb0.05) and was observed after each DMAb dose. By 12 mo, porosity in the radius increased in the Pbo group (+5.2%), increased less in the ALN group (+2.9%) and was reduced by DMAb (−3.0%). In the Pbo andALN groups, porosity increasedwith increasing PTH,whilewith DMAb, it decreased as PTH increased. These relationships were maintained after adjusting for BL remodeling. Thus, DMAb partly reverses microarchitectural deterioration. The predominant mechanism is the direct major reduction of bone remodeling intensity, with perhaps an indirect effect of transiently increasing PTH with an associated increase in bone formation positively influencing BMU balance. This is a distinct attribute of DMAb administration since the increase in endogenous PTH, expected to be catabolic to bone, occurs when osteoclastic resorption is fully inhibited by DMAb.