Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate

Abstract

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (-2.1% to -0.8%) at the distal radius after 12 months. Alendronate prevented the decline (-0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p < or = .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.

Trial registration: ClinicalTrials.gov NCT00293813.

Figures

Figure 1

Subject disposition. Although the placebo and alendronate groups had 82 patients each, the safety analyses in these groups included 83 and 81 patients, respectively, because 1 subject in the alendronate group received placebo injection but no oral alendronate treatment; this subject was evaluated for safety in the placebo group. Q6M = every 6 months; QW = every week.

Figure 2

Percent changes by HR‐pQCT at the distal radius: total vBMD (A), cortical vBMD (B), trabecular vBMD (C), and cortical thickness (D). Least‐squares means with 95% CIs based on an ANCOVA model adjusting for baseline, age group, and treatment. Between‐group p values at months 6 and 12 are shown. DMAb = denosumab; ALN = alendronate.

Figure 3

Percent changes by HR‐pQCT at the distal tibia: total vBMD (A), cortical vBMD (B), trabecular vBMD (C), and cortical thickness (D). Least‐squares means with 95% CIs based on an ANCOVA model adjusting for baseline, age group, and treatment. Between‐group p values at months 6 and 12 are shown. DMAb = denosumab; ALN = alendronate.

Figure 4

Percent change in total vBMD by QCT (A) and calculated PMI (B) at the distal radius. Least‐squares means with 95% CIs based on an ANCOVA model adjusting for baseline, age group, and treatment. Between‐group p values at months 6 and 12 are shown.

Figure 5

Median percent change in bone turnover markers. (A) Serum C‐telopeptide of type 1 collagen cross‐links (CTX). (B) Procollagen type 1 N‐terminal propeptide (P1NP). aSignificantly different from alendronate (p < .05).