Pojchong Chotiyarnwong MD PhD,1,2* Eugene McCloskey MD,2* Richard Eastell MD,2 Michael R. McClung MD,3 Evelien Gielen MD PhD,4 John Gostage MRes,2 Michele McDermott MD,5 Arkadi Chines MD,5 Shuang Huang PhD,5 Steven R. Cummings MD6
Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo-controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non-fracture-related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo-controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. 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 were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5,030 received denosumab 60 mg subcutaneously once every 6 months for 12-36 months and 5,006 received placebo. KaplanMeier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio [95% CI]: 0.79 [0.66, 0.93]; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome.