During FREEDOM, 438 placebo- and 272 denosumab-treated subjects received at least two doses of investigational product, had an osteoporotic fracture, and remained on study post-fracture. The mean ages at first on-treatment fracture were 74.1 and 74.5 years for the placebo- and denosumab-treated subjects, respectively. Subject characteristics were generally balanced between the placebo- and denosumab-treated groups in the FREEDOM 3-year analysis.
After 3 years in FREEDOM, 23 of 3702 subjects (0.6%) in the denosumab group had multiple new vertebral fractures compared with 59 of 3691 subjects (1.6%) in the placebo group. The risk ratio (95% confidence interval) for this reduction in multiple vertebral fractures is 0.39 (0.24, 0.63). When all subjects on denosumab from FREEDOM and the Extension for up to 10 years were combined (the combined denosumab group), 794 had an incident osteoporotic fracture while on denosumab, with a mean age at first incident fracture of 76.5 years. Other baseline characteristics for these subjects were similar to those observed in the FREEDOM 3-year analysis, except the expected longer treatment duration prior to first fracture and follow-up duration after the first fracture (Table 1).
Of the placebo- and denosumab-treated subjects with an incident osteoporotic fracture in FREEDOM, 54 (12.3%) and 24 (8.8%) subjects, respectively, had one or more subsequent fractures in these groups. The exposure-adjusted subsequent fracture rate was 10.1 per 100 subject-years for placebo-treated subjects vs 6.7 per 100 subject-years for denosumab-treated subjects (Table 2; hazard ratio, HR [95% confidence interval, CI]: 0.65 [0.41–1.03]; P = 0.0685; Fig. 2). Of the subjects in the combined denosumab group, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted subsequent fracture rate of 5.8 per 100 subject-years, similar to the rate observed in the FREEDOM denosumab group (Table 2). The risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group than in the FREEDOM placebo group (HR 0.59 [95% CI 0.43–0.81]; P = 0.0012; Fig. 2).
The median time to subsequent fracture since the first incident fracture was 1.0 year for the FREEDOM placebo group, 0.8 years for the FREEDOM denosumab group, and 1.9 years for the combined denosumab group. The difference between the time to first subsequent fracture between the combined denosumab vs placebo group subjects was significant with a log rank P value = 0.0045; Fig. 3).
A majority of subjects who had subsequent osteoporotic fractures had only one subsequent fracture: 90.7% (49 of 54 subjects) in the FREEDOM placebo group, 91.7% (22 of 24 subjects) in the FREEDOM denosumab group, and 89.6% (129 of 144 subjects) in the combined denosumab group. Vertebral fracture was the most common subsequent fracture across groups; a greater proportion of subjects in the FREEDOM placebo group (72.2%; 39 of 54) experienced these fractures compared with the FREEDOM denosumab (29.2%; 7 of 24) group and the combined denosumab (48.6%; 70 of 144) group. The second most common subsequent fracture location was the forearm, sustained by 4 of 54 (7.4%) subjects in the FREEDOM placebo group, 5 of 24 (20.8%) subjects in the FREEDOM denosumab group, and 29 of 144 (20.1%) subjects in the combined denosumab group (Table 3).
The effect of denosumab treatment on the reduction of subsequent fracture risk after an on-study fracture was significantly greater in subjects with baseline vertebral fractures compared with subjects without baseline vertebral fracture (P value = 0.0347). The refracture rate in subjects with baseline vertebral fracture in the FREEDOM placebo group was 17.4 per 100 subject-years vs 7.8 per 100 subject-years in the combined denosumab group (HR [95% CI]: 0.41 [0.26–0.65]; p < 0.0001). The refracture rate in subjects without baseline vertebral fracture in the FREEDOM placebo group was 6.8 per 100 subject-years vs 4.9 per 100 subject-years in the combined denosumab group from the Extension (HR [95% CI]: 0.81 [0.50–1.30]; P = 0.373; Fig. 4).
Subjects with at least one on-study osteoporotic fracture event were further analyzed to determine whether there were any differences in baseline characteristics between subjects with and without subsequent fractures. Baseline age and age at first incident fracture were similar between these groups. Overall, among the subjects who suffered an incident fracture, those with a subsequent fracture were more likely to have had a baseline vertebral or osteoporotic fracture than were those who did not suffer a subsequent fracture (Table 4).
The rates of subsequent vertebral and nonvertebral fractures were also determined for subjects with subsequent fractures. For subjects with subsequent osteoporotic fractures in the FREEDOM placebo group, 31.5% had both initial and subsequent vertebral fractures, 7.4% had an initial vertebral fracture followed by a subsequent nonvertebral fracture, 40.7% had an initial nonvertebral fracture followed by a subsequent vertebral fracture, and 20.4% had both initial and subsequent nonvertebral fractures. For subjects with subsequent osteoporotic fractures in the combined denosumab group, 21.5% had both initial and subsequent vertebral fractures, 10.4% had an initial vertebral fracture followed by a subsequent nonvertebral fracture, 27.1% had an initial nonvertebral fracture followed by a subsequent vertebral fracture, and 41.0% had both initial and subsequent nonvertebral fractures (Table 5).