Of the 7808 women enrolled in the FREEDOM study, 5928 (76 %) were eligible for enrollment in the Extension, and of these, 4550 (77 %) enrolled (2343 long-term, 2207 cross-over) (Fig. 1). Of the women who entered the Extension, 66 % in each group completed year 5 totaling 3004 participants. The percentage of women who discontinued the study and the reasons for discontinuation were similar between the two groups (Fig. 1). The demographics of the two groups were balanced at the start of the Extension [2]; Online Resource Table S1 summarizes characteristics for the long-term and cross-over groups at both the FREEDOM and Extension baselines. The mean (standard deviation) age for the women who completed year 5 of the Extension was 79.0 (4.7) years. Since these two groups have different durations of exposure to denosumab, the results from each group are described separately below.
Long-term group
BTMs and BMD
Following administration of denosumab at the beginning of the Extension, prompt decreases in serum CTx and P1NP concentrations were observed at month 1, followed by a characteristic attenuation in the degree of reduction of remodeling through month 6, consistent with the FREEDOM parent study (Fig. 2). Through year 5 of the Extension, representing up to 8 years of therapy, denosumab treatment resulted in sustained reduction of serum CTx and P1NP levels.
During the Extension, mean percentage changes from FREEDOM baseline in lumbar spine, total hip, and femoral neck BMD at each time point were significantly greater than those observed at the previous time point (Online Resource Table S2). Mean percentage changes in BMD from FREEDOM through Extension year 5, totaling up to 8 years of treatment, were increases of 18.4 % at the lumbar spine, 8.3 % at the total hip, 7.8 % at the femoral neck, and 3.5 % at the 1/3 radius (all p < 0.05) (Fig. 3).
Fractures
Among subjects who entered the Extension and had at least one subsequent X-ray assessment for new vertebral fracture, 116 women (5.5 %) in the long-term group had at least one new vertebral fracture by Extension year 5. Throughout the Extension, the annualized subject incidence of new vertebral fractures remained low (1.5, 1.3, and 1.3 % during years 4/5, 6, and 7/8 of denosumab treatment, respectively) (Fig. 4a and Online Resource Fig. S2). By Extension year 5, 133 women (6.6 %) had at least one nonvertebral fracture, and the yearly subject incidence remained low (1.5, 1.2, 1.8, 1.6, and 0.7 % during years 4, 5, 6, 7, and 8 of denosumab treatment, respectively) (Fig. 4b and Online Resource Fig. S2). Through year 5 of the Extension, the most common nonvertebral fracture sites in the long-term group were wrist (n = 57), rib (n = 17), hip (femoral neck or intertrochanteric) (n = 13), and ankle (n = 12) (n is the number of affected women). The cumulative subject incidence of hip fractures during years 1 through 5 of the Extension was 0.7 %; the annualized incidence of hip fractures during Extension year 5 (totaling up to 8 years of denosumab treatment), when the mean age of the group was 79.0 years, was 0.2 %.
AEs and SAEs
The yearly exposure-adjusted subject incidence for all AEs during the Extension in the long-term group was similar to or lower than in the active treatment group during FREEDOM (Table 1). The yearly rates for malignancy and serious infections as well as for other AEs of interest per 100 subject-years showed no trend toward increase over time (Table 1). For AEs and SAEs where events were <0.1 per 100 subjects-years, yearly rates expressed per 10,000 subject-years are shown in Table 2. The cumulative exposure-adjusted subject incidence rates for all AEs, SAEs, and fatal AEs in the long-term group during the Extension were 100.8, 10.7, and 0.8 per 100 subject-years, respectively (Online Resource Tables S3 and S4).
Table 1 Yearly exposure-adjusted subject incidence of adverse events per 100 subject-years for long-term denosumab participants
Table 2 Yearly exposure-adjusted subject incidence of adverse events per 10,000 subject-years for long-term denosumab participants where events of interest were <0.1 per 100 subject-years
During 8 years of denosumab treatment, four subtrochanteric/diaphyseal femoral fractures occurred in the long-term group; of these, one was adjudicated as consistent with atypical diaphyseal femoral fracture. It occurred in Extension year 4 after the participant received her 14th dose of denosumab. Initial treatment included internal fixation with an intramedullary nail. The participant developed hardware failure in the form of broken distal locking screws, which was detected 6 weeks after intramedullary rod placement. Union was delayed but progressed after surgical revision was performed, approximately 20 months after detection of the broken screws. The participant has continued denosumab treatment and remained in the study. There were no cases of AFF in the long-term group during year 5.
Through year 5 of the Extension, five oral events have been adjudicated as consistent with ONJ in the long-term group. Of the four previously reported cases [3], one event previously reported as resolved is ongoing at the time of this report. The fifth event occurred in the fourth year of the Extension, after the participant received her 13th dose of denosumab; denosumab was discontinued and the event has resolved. No additional ONJ events were reported during year 5.
Cross-over group
BTMs and BMD
In the cross-over group, the median concentrations of serum CTx and P1NP were rapidly reduced after the initial administration of denosumab (day 10 and month 6 of the Extension, respectively) and were similar to those observed in the denosumab group in the FREEDOM parent study (Fig. 2). The reductions in both markers were also sustained through 5 years of denosumab treatment and, over time, the bone turnover profiles were consistent with the long-term group during their first 5 years of denosumab exposure.
BMD increased rapidly in the cross-over group during the first year of denosumab treatment, and measurements at the lumbar spine, total hip, and femoral neck continued to increase significantly at each time point measured compared to the previous time point through 5 years of treatment (Online Resource Table S2). The mean percentage changes in BMD from Extension baseline were 13.1 % at the lumbar spine, 6.2 % at the total hip, 5.7 % at the femoral neck, and 1.5 % at the 1/3 radius (all p < 0.05) (Fig. 3). These values largely replicated those observed in the long-term group after 5 years of denosumab exposure, which were 13.7 % at the lumbar spine, 7.0 % at the total hip, 6.1 % at the femoral neck, and 2.3 % at the 1/3 radius (all p < 0.05) [2].
Fractures
During the fifth year of the Extension, totaling up to 5 years of denosumab treatment, fracture rates remained low in the cross-over group; 110 women in the cross-over group (5.5 %) had at least one new vertebral fracture. These low rates are similar to those observed during the first 5 years of denosumab treatment in the long-term group (4.0 %). In addition, the annualized subject incidence of new vertebral fracture remained low after the initiation of denosumab (0.9, 1.6, and 1.8 % during years 1/2, 3, and 4/5 of denosumab treatment, respectively) (Fig. 4c and Online Resource Fig. S2). One hundred and seventy-five women (9.2 %) had at least one nonvertebral fracture through year 5 of the Extension, consistent with the cumulative subject incidence observed over the first 5 years of denosumab treatment in the long-term group (7.9 %). Likewise, the yearly subject incidence remained low (2.5, 2.0, 2.6, 1.2, and 1.4 % during years 1, 2, 3, 4, and 5 of denosumab treatment, respectively) (Fig. 4d and Online Resource Fig. S2). Through year 5 of the Extension, the most common nonvertebral fracture sites in the cross-over group were wrist (n = 76), hip (femoral neck or intertrochanteric) (n = 22), ankle (n = 19), humerus (n = 15), and rib (n = 14) (n is the number of affected women). The cumulative subject incidence of hip fractures during years 1 through 5 of the Extension was 1.1 %.
AEs and SAEs
Overall, the AE rates in the cross-over group confirmed those previously reported for the corresponding time period in the long-term group [2]. The yearly exposure-adjusted subject incidence for all AEs in the cross-over group during the Extension was similar to or lower than that of the placebo group during FREEDOM (Table 3). The yearly rates per 100 subject-years showed no increase over time. For AEs and SAEs where events were <0.1 per 100 subjects-years, yearly rates expressed per 10,000 subject-years are shown in Table 4. The cumulative exposure-adjusted subject incidence rates of all AEs, SAEs, and fatal AEs in the cross-over group during the Extension were 99.7, 10.2, and 0.7 per 100 subject-years, respectively (Online Resource Tables S3 and S4).
Table 3 Yearly exposure-adjusted subject incidence of adverse events per 100 subject-years for cross-over denosumab participants
Table 4 Yearly exposure-adjusted subject incidence of adverse events per 10,000 subject-years for cross-over denosumab participants where events of interest were <0.1 per 100 subject-years
During 5 years of denosumab treatment, three diaphyseal femoral fractures occurred in the cross-over group. Of these, one fracture was adjudicated as consistent with AFF, as previously reported [3]. There were no reports of AFF during year 5 of the Extension in the cross-over group.
Through year 5 of the Extension, three oral events have been adjudicated as consistent with ONJ in the cross-over group. Two of these events resolved as previously reported [3]. The third event occurred in year 4 of the Extension, after the participant received her eighth dose of denosumab. The participant discontinued the study. Hence, the outcome of the case is unknown. There were no ONJ cases during Extension year 5.