The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study

Abstract

The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile.

Introduction: This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis.

Methods: Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively.

Results: Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed.

Conclusions: Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

Keywords: Bone mineral density; Clinical trial; Denosumab; Fracture; Osteoporosis; Safety.

Fig. 1

Disposition of all participants through year 5 of the FREEDOM Extension. All women who completed FREEDOM (i.e., completed their 3-year visit, did not discontinue investigation product, and did not miss more than one dose) were eligible to participate in the Extension. ^aTwo women who discontinued denosumab also entered the Extension in the long-term denosumab group [2]

Fig. 2

Serum bone turnover markers during FREEDOM and the FREEDOM Extension. Concentrations of predose CTx (a) and P1NP (b) are shown. Dashed lines represent the premenopausal reference ranges: 0.20–0.90 ng/mL for CTx and 17.4–61.6 μg/L for P1NP. Data are median (interquartile range). n = number of women with observed data. Time points shown include baseline, month 1, and years 0.5, 1, 2, 3, 3 (day 10), 3.5, 4, 5, 6, 7, and 8. CTx serum C-terminal telopeptide of type 1 collagen, P1NP serum procollagen type 1 N-terminal propeptide

Fig. 3

Percentage change from FREEDOM baseline in BMD during FREEDOM and the FREEDOM Extension. Percentage change in BMD at the lumbar spine (a), total hip (b), femoral neck (c), and 1/3 radius (d) is shown. Data are least squares means (95 % CI). *p < 0.05 compared with the FREEDOM baseline; ^† p < 0.05 compared with the Extension baseline. BMD bone mineral density, CI confidence interval

Fig. 4

Incidence of nonvertebral and new vertebral fractures during FREEDOM and the FREEDOM Extension. The yearly incidence of new vertebral and nonvertebral fractures in the long-term (a, b) and cross-over (c, d) groups are shown. For new vertebral fractures, percentages are crude incidence; lateral radiographs (lumbar and thoracic) were not obtained at Extension years 1 and 4 (long-term denosumab treatment years 4 and 7); n = number of women with ≥1 fracture; N = number of women with a spine X-ray evaluation during the time period of interest. ^aAnnualized incidence (2-year incidence/2). For nonvertebral fractures, percentages are Kaplan-Meier estimates; n = number of women with ≥1 fracture; N = number of women who were still on study at the beginning of each period