Background/Purpose: During the first 3 years of denosumab treatment in FREEDOM, there were continued increases in bone mineral density (BMD) and a robust reduction in fracture risk (Cummings et al., NEJM 2009). The changes in total hip BMD explained a considerable proportion of the reduction in new or worsening vertebral and nonvertebral fracture risk (Austin et al., JBMR 2011). Here, we conducted a BMD responder analysis and explored if the progressive BMD gains with 6 years of denosumab therapy continued to relate to the observed fracture incidence.

Methods: The long-term efficacy and safety of denosumab for up to 10 years is being investigated in the open-label extension of the 3-year FREEDOM trial. During the extension, all participants receive 60 mg denosumab every 6 months. For the analyses presented here, women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years. The percentages of women treated with denosumab who achieved BMD increases from FREEDOM baseline at the lumbar spine, total hip, and femoral neck were determined. A logistic regression model was used to examine the relationship between change in total hip BMD and new or worsening vertebral fracture. A comparable approach was employed for nonvertebral fracture using the Cox proportional hazards model.

Results: For women who received 3 additional years of denosumab treatment (N=2343 enrolled), further significant increases in BMD occurred for cumulative 6‑year mean gains of 15.2% (lumbar spine), 7.5% (total hip), and 6.7% (femoral neck). At year 6, almost all women treated with denosumab had gains in BMD at the lumbar spine (98%), total hip (96%), and femoral neck (91%). Additionally, 99% of women had gains in BMD at any of these sites, and of these, the gains were >3% in 98% of women and >6% in 95% of women. Fracture incidence remained low during the extension. The relationships between total hip BMD gains and new or worsening vertebral and nonvertebral fractures with 6 years of denosumab treatment are shown in Figures 1 and 2, respectively.

Conclusion: Almost all women who received 6 years of denosumab treatment had gains in BMD at the lumbar spine, total hip, or femoral neck; and those gains were >6% in 95% of them. While on denosumab treatment, the risk of new or worsening vertebral fracture and nonvertebral fracture decreased with increasing percentage change in total hip BMD over 6 years. This association provides clinical relevance to the progressive and continued BMD gains reported with denosumab over time.