Plenary Poster 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

A pooled analysis of fall incidence from placebo-controlled trials of denosumab (#89)

Eugene McCloskey 1 , Richard Eastell 1 , Michael McClung 2 , Nico Pannacciulli 3 , Christine Wang 3 , Susan Yue 3 , Steven R Cummings 4 , Jeffrey Hassall 5
  1. The University of Sheffield, Sheffield, UK
  2. Oregon Osteoporosis Center, Portland, OR, USA
  3. Amgen Inc., Thousand Oaks, CA, USA
  4. San Francisco Coordinating Center, San Francisco, CA, USA
  5. Amgen Australia, North Ryde, NSW, Australia

Purpose: In the pivotal fracture trial of denosumab in postmenopausal women with osteoporosis (FREEDOM), treatment with denosumab, a RANK ligand (RANKL) inhibitor, resulted in a lower subject incidence of falls not associated with fracture (log rank P‑value = 0.02) compared with placebo [1]. In addition to its role in osteoporosis, the RANK/RANKL pathway has also been shown to play a role in muscle strength in a murine model [2]. In an ad hoc exploratory analysis, we pooled data from additional placebo-controlled trials of denosumab to determine the consistency across trials of the reduction in the incidence of falls.

 

Methods: Five placebo-controlled trials that contributed data to the FDA approval of denosumab for the bone loss indication were analyzed. These included: trials in postmenopausal women with osteoporosis (FREEDOM, Trial 1, NCT00089791, [1]) and low bone mass (Trial 2, NCT00091793, [3]), men with osteoporosis (Trial 3, NCT00980174, [4]), women receiving adjuvant aromatase inhibitors for breast cancer (Trial 4, NCT00089661, [5]), and men receiving androgen deprivation therapy for prostate cancer (Trial 5, NCT00089674, [6]). The analysis was stratified by trial and only included data from the placebo-controlled period of each trial. A time-to-event analysis of first fall and exposure‑adjusted subject incidence rates of falls (data not shown) were analyzed. Falls were reported as adverse events and not prospectively collected.

 

Results: Kaplan-Meier estimates showed that falls occurred in 6.5% of subjects in the placebo groups (N = 5006), compared to 5.2% in denosumab-treated subjects (N = 5030), with an HR (95% CI) of 0.78 (0.66, 0.93), P-value 0.0053. The forest plot of time-to-first occurrence of fall is shown for both the individual studies and overall (Figure).

 

Conclusions: Denosumab may reduce the risk of falls in postmenopausal women with osteoporosis, in addition to the established fracture risk reduction in these patients.

5d1bf8daf12f3-Figure+falls.jpg