ECTS Abstracts (2015) 1 P356

Denosumab (DMab) restores cortical bone loss at the 1/3 radius associated with ageing and reduces wrist fracture risk: analyses from the FREEDOM Extension Cross-over Group

John Bilezkian1, Claude Laurent Benhamou2, Celia Lin3, Jacques Brown4, Nadia Daizadeh3, Peter Ebeling5, Astrid Fahrleitner-Pammer6, Edward Franek7, Nigel Gilchrist8, Paul Miller9, James Simon10, Ivo Valter11, Cristiano Zerbini12 & Cesar Libanati3

1College of Physicians and Surgeons, Columbia University, New York, NY, USA; 2CHR d’Orléans, Orléans, France; 3Amgen Inc., Thousand Oaks, CA, USA; 4CHU de Québec Research Centre and Laval University, Quebec City, Canada; 5Monash University, Clayton, Australia; 6Medical University, Graz, Austria; 7Medical Research Center, Polish Academy of Sciences, Warsaw, Poland; 8The Princess Margaret Hospital, Christchurch, New Zealand; 9Colorado Center for Bone Research, Lakewood, CO, USA; 10George Washington University, Washington, DC, USA; 11Center for Clinical and Basic Research, Tallinn, Estonia; 12Centro Paulista de Investigação Clinica, São Paulo, Brazil.

Cortical bone loss contributes importantly to increased fracture risk. DMAb increases BMD at sites of cortical bone, including the 1/3 radius, a site not responsive to most osteoporosis treatments. We evaluated changes over time in 1/3 radius BMD and wrist fracture incidence in women with postmenopausal osteoporosis during placebo and subsequent DMAb treatment. Wrist fractures were evaluated in 2207 women who enrolled in the FREEDOM Extension and received placebo during FREEDOM (3 years) and DMAb 60 mg Q6M during the Extension (6 years; cross-over group). All women received daily calcium and vitamin D. A subset (n=115) participated in a radius DXA substudy. Mean percentage changes in BMD over time were analysed using a repeated measures model and wrist fracture rates computed. At FREEDOM baseline, mean (SD) 1/3 radius T-score was –2.53 (1.18). While on placebo for 3 years, a significant loss of BMD at the 1/3 distal radius was observed (–1.2% at Year 3; p < 0.05 vs FREEDOM baseline), with a wrist fracture rate of 1.02 (95% CI=0.80─1.29) per 100 subject-years. Upon DMAb initiation, this bone loss was reversed, resulting in BMD gains at the 1/3 distal radius of 1.5% at Extension Year 2 (p < 0.05 vs Extension baseline). During the 3 years following DMAb initiation (Extension Years 1─3), the BMD deficit recovered to the original baseline levels and the wrist fracture rate stabilised. Over a further 2 years of DMAb treatment (Extension Years 4─5), BMD increased above the original FREEDOM baseline and significantly fewer wrist fractures occurred (rate ratio=0.57, 95% CI=0.34-0.95; p=0.03 vs FREEDOM placebo rate). This significant decline in the wrist fracture rate corresponded to the 1/3 radius cortical BMD improvement over baseline and continued until extension year 6 (rate ratio for Extension Years 4─6=0.61 vs FREEDOM placebo, 95% CI=0.39-0.94, p=0.025). These data provide additional evidence of a relevant clinical endpoint of reversing cortical bone loss in patients with osteoporosis.

Disclosure: CL, ND, AW, CL - Amgen employees; JB, JBr, PE, AF, EF, PM, CB, JS received research grants, consulting fees &/or speaker bureau from one or more- AbbVie, Actavis, Amgen, Apotex, Ascend Therapeutics, Depomed, Eisai, Everett, Lupin, TherapeuticsMD, Meda Pharmaceuticals, Merck, Novartis, Noven Pharmaceuticals, NovoNordisk, Pfizer, Shionogi, Shippan, Sprout, Teva. Amgen Inc provided funding for this study.