Vertebral Fracture Incidence after Discontinuation of Denosumab Treatment: Analysis from Freedom and Its Extension

Presentation Number: OR08-3
Date of Presentation: April 1st, 2017

Serge Ferrari*1, Jacques P Brown2, Nico Pannacciulli3, Nigel Gilchrist4, Christian Roux5, Ove Törring6, Ivo Valter7, Rachel B Wagman3, Andrea T Wang3 and Steven R Cummings8
1Geneva University Hospital, Geneva, Switzerland, 2Laval University and CHU de Québec (CHUL), Québec City, QC, Canada, 3Amgen Inc., Thousand Oaks, CA, 4The Princess Margaret Hospital, Christchurch, New Zealand, 5Paris Descartes University, Paris, France, 6Karolinska Institutet, Södersjukhuset, Stockholm, Sweden, 7Center for Clinical and Basic Research, Tallinn, Estonia, 8San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA


Purpose: Discontinuation of denosumab (DMAb), a reversible RANKL inhibitor, is associated with increases in bone turnover markers and decreases in lumbar spine and total hip bone mineral density (BMD) to baseline levels, and increases in vertebral Fx (VFx) incidence to rates comparable with placebo (PBO). Isolated cases of multiple VFx (MVF) after DMAb cessation have recently been reported (1). Furthermore, we previously observed that (a) subjects who sustained new VFx after DMAb cessation had a greater incidence of MVF than after PBO cessation and (b) prior VFx was the major determinant of off-treatment (Tx) VFx (2). This analysis further characterizes off-Tx VFx, including MVF, and associated factors in subjects who discontinued DMAb.

Methods: Subjects who discontinued investigational product (IP; PBO or DMAb 60 mg SC Q6M) from the 3-year FREEDOM trial and its 7-year Extension (Ext) were included in this analysis. Subjects receiving DMAb from FREEDOM or Ext were analyzed together. Off-Tx period was defined as 7 mo after last dose of IP through the end of study. Analyses assessed off-Tx new or worsening VFx; MVF were defined as ≥ 2 off-Tx new and/or worsening VFx.

Results: This analysis included 470 PBO and 1001 DMAb subjects. VFx were sustained by 6.6% subjects off PBO and 5.6% off DMAb, with 2.6% PBO and 3.4% DMAb sustaining MVF (including 0.9 and 1.6% with clinical MVF). Median follow-up time was 1.4/1.4 years (PBO/DMAb) and 0.5/0.3 years (PBO/DMAb) for those who did and did not sustain off-Tx VFx, respectively. More subjects who discontinued PBO (43%) than DMAb (15%) initiated alternative OP therapy. Subjects who initiated OP therapy before single VFx or MVF began OP therapy a median 4.4 or 6.3 months after last dose of PBO and 6.3 or 10.2 months after DMAb, respectively. Among those who initiated OP therapy, 5.0 and 4.0% from PBO and 4.1 and 9.0% from DMAb sustained a single VFx and MVF, respectively. Among subjects with available off-Tx BMD data (N = 297 PBO, N = 466 DMAb), mean annualized percent change in total hip BMD was +0.6% and –1.9% after stopping PBO and DMAb, respectively, for those with no off-Tx VFx; –1.3% and –2.2% for single VFx; and –1.2% and –3.5% for MVF.

Conclusion: This analysis confirms and expands previous results showing discontinuation of DMAb is associated with an increase in VFx rate, particularly clinical and morphometric MVF, whose incidence remained low and comparable to that of PBO. Fewer subjects who discontinued DMAb than PBO transitioned to alternative OP treatment, and transitioned later, suggesting that delaying a substitute therapy after DMAb may be detrimental. This is further corroborated by off-Tx BMD loss, which was greatest among subjects who sustained MVF and greater among those who sustained single VFx than those with no off-Tx VFx. Those who discontinue DMAb should transition to another OP therapy after the 6-mo dosing interval.


Disclosure: SF: Speaker, Eli Lilly & Company, Consultant, Eli Lilly & Company, Speaker, MSD, Consultant, MSD, Principal Investigator, MSD, Speaker, UCB, Consultant, UCB, Consultant, Amgen, Speaker, Amgen, Principal Investigator, Amgen. JPB: Scientific Board Member, Merck & Co., Speaker Bureau Member, Eli Lilly & Company, Scientific Board Member, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker Bureau Member, Amgen, Principal Investigator, Amgen, Scientific Board Member, Amgen. NP: Employee, Amgen, Employee, Amgen. CR: Board Member, Alexion, Speaker, Eli Lilly & Company, Board Member, UCB, Board Member, MSD, Board Member, Amgen. RBW: Employee, Amgen, Employee, Amgen. ATW: Employee, Amgen, Employee, Amgen. SRC: Consultant, Radius, Consultant, Amgen. Nothing to Disclose: NG, OT, IV