Background Glucocorticoid (GC)-induced osteoporosis (GIOP) remains the most common secondary cause of osteoporosis. Despite approved therapies, many subjects do not receive GIOP prevention or treatment. There is increased RANKL and decreased osteoprotegerin (OPG) expression in patients with GIOP. Denosumab (DMAb) is a monoclonal antibody to RANKL. This study was designed to assess the safety and efficacy of DMAb compared with risedronate (RIS) in GC-treated individuals, in whom treatment guidelines advocate a GIOP intervention.
Objectives The primary objective was to demonstrate, in separate GC-continuing (GC-C) and GC-initiating (GC-I) subpopulations, that DMAb was not inferior to RIS with respect to percentage change from baseline (%Δ) in lumbar spine (LS) bone mineral density (BMD) at 12 months. Secondary objectives were to assess superiority of DMAb over RIS with respect to %Δ in LS and total hip (TH) BMD at 12 months.
Methods This was a phase 3, randomized, double-blind, double-dummy, active-controlled study to evaluate DMAb vs. RIS in GC-treated individuals for 24 months. Eligible subjects were women and men ≥18 yrs receiving GC therapy at a dose ≥7.5 mg prednisone daily or its equivalent for ≥3 months or <3 months prior to screening (GC-C and GC-I, respectively). All subjects <50 yrs were required to have a history of osteoporotic fracture. GC-C subjects ≥50 yrs were required to have a LS, TH, or femoral neck BMD T-score ≤-2.0; or a T-score ≤-1.0 with a history of osteoporotic fracture. Subjects were randomized 1:1 to SC DMAb 60 mg every 6 months or oral RIS 5 mg daily for 24 months. Subjects were to receive daily calcium (≥1000 mg) and vitamin D (≥800 IU) supplementation. Primary outcome was %Δ in LS BMD at 12 months (non-inferiority in GC-C and GC-I). Secondary outcomes included %Δ in LS and TH BMD at 12 months (superiority). The study remains blinded and is ongoing.
Results A total of 795 subjects (505 GC-C and 290 GC-I) enrolled in the study. Baseline characteristics were balanced between treatment groups (Table). Non-inferiority and superiority with DMAb were demonstrated for both the GC-C and GC-I subpopulations, as indicated by significantly greater BMD gains compared with RIS at the LS and TH in both subpopulations (Figure). The incidences of adverse events (AEs) and serious AEs, including serious AEs of infection, as well as fracture, were similar between treatment groups and consistent with the known safety profile of DMAb.
Conclusions DMAb significantly increased BMD more than RIS at the spine and hip at 12 months. The overall safety profile was similar between treatment groups. DMAb has the potential to become another treatment option for patients newly initiating or continuing GC who are at risk for fracture.
Acknowledgements The study was funded by Amgen. C Desborough (Amgen [Europe] GmbH) provided editorial support.
Disclosure of Interest K. Saag Grant/research support from: Amgen, Merck, Consultant for: Amgen, Merck, Radius, R. B. Wagman Shareholder of: Amgen, Employee of: Amgen, P. Geusens Grant/research support from: Pfizer, Abbott, Lilly, Amgen, MSD, Will, Roche, UCB, BMS, Novartis, J. Adachi Grant/research support from: Amgen, Eli Lilly, Merck, Pfizer, Consultant for: Amgen, Eli Lilly, Merck, International Osteoporosis Foundation, Speakers bureau: Amgen, Eli Lilly, O. Messina Grant/research support from: Amgen, GSK, R. Emkey Speakers bureau: Amgen, R. Chapurlat Grant/research support from: Amgen, Merck, Chugai, Consultant for: Amgen, Eli Lilly, BMS, AbbVie, Pfizer, Chugai, UCB, N. Daizadeh Shareholder of: Amgen, Employee of: Amgen, N. Pannacciulli Shareholder of: Amgen, Employee of: Amgen, W. Lems Grant/research support from: Eli Lilly, Amgen, MSD, Novartis.