Background In the FREEDOM pivotal phase 3 fracture trial, denosumab 60 mg every 6 months decreased the risk of new vertebral, nonvertebral and hip fractures at 3 years versus placebo.1 As osteoporosis is a chronic disease, continued treatment is required to provide antifracture efficacy. Discontinuation of denosumab is associated with transient increases in bone remodelling and declines in bone mineral density (BMD),2,3 but the effect on fracture risk is not as well characterized.
Objectives To understand fracture incidence in an osteoporotic population after cessation of denosumab treatment.
Methods We evaluated subjects in FREEDOM who received 2–5 doses of investigational product (IP), either denosumab or placebo, and discontinued treatment while continuing study participation for ≥6 months since the last dose + 1-month study visit window (≥7 months). The off-treatment observation period began 7 months after last IP dose and lasted approximately 6–24 months (for subjects who received 5 to 2 doses, respectively).
Results Among subjects eligible for this analysis, age, prevalent fracture, and lumbar spine and total hip BMD T-scores were similar at baseline in placebo (N=470) and denosumab groups (N=327). During the treatment period, more subjects treated with placebo than denosumab sustained a fracture (19% vs 11%) and had significant decreases in BMD (17% vs 1%). Alternative therapy after last IP dose was initiated by 42% of placebo-treated vs 28% of denosumab-treated subjects. After treatment cessation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate/100 subject-years of 13.5 and 9.7, respectively (Hazard Ratio 0.82; 95% Confidence Iinterval: 0.49, 1.38), adjusted for age and total hip BMD T-score at baseline. Fracture occurrence during the off-treatment period was not apparently different between the treatment groups.
Conclusions This analysis indicated that there was no excess fracture risk after treatment cessation with denosumab when compared with placebo during the off-treatment period (≤24 months).
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Disclosure of Interest O. Törring Consultant for: Takeda Nycomed, Amgen, Speakers Bureau: Takeda Nycomed, Amgen, J. Brown Grant/Research support from: Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, sanofi-aventis, Servier and Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Novartis, sanofi-aventis, Warner Chilcott, Speakers Bureau: Amgen, Eli Lilly, Novartis, J.-E. B. Jensen Consultant for: Eli Lilly,Takeda Nycomed, Amgen, Novartis, MSD, Speakers Bureau: Eli Lilly,Takeda Nycomed, Amgen, Novartis, MSD, N. Gilchrist Grant/Research support from: Merck Sharpe & Dohme, Amgen, Consultant for: Eli Lilly, Merck Sharpe & Dohme, Amgen, Speakers Bureau: Eli Lilly, Merck Sharpe & Dohme, Amgen, C. Recknor Consultant for: Zelos, Takeda, Dramatic Health, Novartis, Eli Lilly, Paid Instructor for: Amgen, Novartis, Publicis Meetings, C. Roux Grant/Research support from: Amgen, Novartis, Consultant for: Amgen, Novartis, MSD, M. Austin Shareholder of: Amgen, Employee of: Amgen, A. Wang Shareholder of: Amgen, Employee of: Amgen, A. Grauer Shareholder of: Amgen, Employee of: Amgen, P.-R. Ho Shareholder of: Amgen, Employee of: Amgen, R. Wagman Shareholder of: Amgen, Employee of: Amgen