The Risk of Subsequent Osteoporotic Fractures Is Decreased in Patients Experiencing Fracture While on Denosumab: Results from the Freedom and Freedom Extension Studies

Presentation Number: OR08-4
Date of Presentation: April 1st, 2017

David L Kendler*1, A Chines2, M L Brandi3, S Papapoulos4, E M Lewiecki5, J-Y Reginster6, C Roux7, M Munoz Torres8, A Wang2 and H G Bone9
1University of British Columbia, Vancouver, BC, Canada, 2Amgen Inc., Thousand Oaks, CA, 3University of Florence, Florence, Italy, 4Leiden University Medical Center, Leiden, Netherlands, 5New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, 6University of Liège, Liège, Belgium, 7Paris Descartes University, Paris, France, 8Hospital Universitario San Cecilio, Granada, Spain, 9Michigan Bone and Mineral Clinic, Detroit, MI


Osteoporosis is a common, progressive condition leading to increased bone fragility and susceptibility to fracture (fx). Although osteoporosis therapy decreases fx risk, fx while on treatment can occur and does not necessarily represent treatment failure. It is therefore of interest to assess whether patients who fx on denosumab (DMAb; FREEDOM and FREEDOM Extension) experience a lower risk of subsequent fx continuing on therapy than those on placebo (Pbo) who have fx.

During FREEDOM, postmenopausal women with osteoporosis were randomized to Pbo or DMAb for 3 years. During the 7-year Extension, all participants were allocated to receive DMAb. In this analysis, we report subsequent osteoporotic fx (new vertebral or nonvertebral) in subjects who received ≥ 2 doses of DMAb during FREEDOM or the Extension, had an osteoporotic fx while on treatment, and continued treatment post-fx, compared with subsequent fx in FREEDOM Pbo subjects. These subsequent fx were analyzed as recurrent events using the stratified Cox model with the robust variance estimation adjusting for prior fx. The analysis was repeated in subgroups of subjects with or without prevalent vertebral fx, defined at treatment baseline, without adjusting for prior fx.

During FREEDOM, 438 Pbo and 272 DMAb subjects had an osteoporotic fx (mean age at first on-study fx: 74.1 and 74.5 years, respectively). Of these, there were 54 (12.3%) and 24 (8.8%) subjects who had ≥ 1 subsequent fx in the Pbo and DMAb groups, respectively. Adjusted subject incidence per 100 patient-years was lower for DMAb (6.7) vs Pbo (10.1). Combining all subjects on DMAb from FREEDOM and the Extension for up to 10 years (Combined-DMAb), 794 (13.7%) subjects had an osteoporotic fx while on DMAb (mean age at first on-study fx: 76.5 years); of these, one or more subsequent fx occurred in 144 (18.1%) subjects, with an adjusted subject incidence of 5.8 per 100 patient-years, similar to FREEDOM DMAb (6.7 per 100 patient-years). Among subjects with ≥ 1 subsequent fx, 90% had only 1 fx; vertebral fx was the most frequent. The risk of having subsequent on-study osteoporotic fx was lower in the Combined-DMAb group vs Pbo (HR 0.59 [95% CI: 0.43–0.81]; p = 0.0012), adjusting for prior fx. In this analysis, 33% of subjects had prevalent vertebral fx at treatment baseline. The effect of DMAb treatment on reduction of subsequent on-study fx was statistically greater in subjects with prevalent vertebral fx (Pbo = 17.4 vs Combined-DMAb = 7.8 per 100 patient-years; HR 0.41 [95% CI: 0.26–0.65]; p < 0.0001) compared with subjects without prevalent vertebral fx (Pbo = 6.8 vs Combined-DMAb = 4.9 per 100 patient-years; HR 0.81 [95% CI: 0.50, 1.30]; p = 0.3728), with an interaction p = 0.0347. In both subgroups, spine fx was the most frequent subsequent fx. These data demonstrate that DMAb decreases the risk of subsequent fx and a fx sustained while on DMAb is not necessarily indicative of treatment failure.


Disclosure: DLK: Principal Investigator, Amgen, Speaker, Amgen, Consultant, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker, Eli Lilly & Company, Principal Investigator, Astellas, Principal Investigator, Astra Zeneca, Data Safety Advisory Board, Merck & Co., Consultant, Amgen. AC: Employee, Amgen, Employee, Amgen. MLB: Speaker, Amgen, Principal Investigator, Amgen, Speaker, Abiogen, Principal Investigator, Abiogen, Speaker, Eli Lilly & Company, Principal Investigator, Eli Lilly & Company, Speaker, Alexion, Principal Investigator, Alexion, Speaker, Shire, Principal Investigator, Shire. SP: Ad Hoc Consultant, UCB, Speaker, Amgen, Advisory Group Member, Merck & Co., Speaker, Merck & Co., Ad Hoc Consultant, Axsome, Advisory Group Member, Mereo Biopharma, Advisory Group Member, Amgen. EML: Study Investigator, Amgen, Medical Advisory Board Member, Merck & Co., Study Investigator, Merck & Co., Medical Advisory Board Member, Eli Lilly & Company, Study Investigator, Eli Lilly & Company, Medical Advisory Board Member, Radius, Medical Advisory Board Member, Amgen. JYR: Speaker, IBSA-Genevrier, Speaker, Cniel, Speaker, Meda, Speaker, Danone, Speaker, Servier, Speaker, Merck Sharp & Dohme, Investigator, IBSA-Genevrier, Investigator, Cniel, Investigator, Meda, Investigator, Danone, Investigator, Pfizer, Inc., Investigator, Servier, Investigator, Lilly, Investigator, Amgen, Investigator, Merck Sharp & Dohme, Speaker, Pharmevo, Speaker, Dairy Research Council, Consultant, Servier, Consultant, IBSA-Genevrier, Consultant, UCB, Consultant, Asahi, Consultant, Radius Health, Consultant, Meda, Consultant, Pierre Fabre. CR: Board Member, MSD, Board Member, UCB, Speaker, Eli Lilly & Company, Board Member, Alexion, Board Member, Amgen. MM: Medical Advisory Board Member, Amgen, Study Investigator, Eli Lilly & Company. AW: Employee, Amgen, Employee, Amgen. HGB: Consultant, Sucampo, Speaker, Shire, Consultant, Shire, Consultant, Radius, Investigator, Merck & Co., Consultant, Merck & Co., Data and Safety Monitoring Board, Grunenthal, Investigator, Amgen, Speaker, Amgen, Consultant, Amgen.