Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension

Abstract

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.

Trial registration: ClinicalTrials.gov NCT00523341.

Fig. 1

Study design showing the 3-year FREEDOM study and the 7-year extension. The data reported here are for the first 2 years of the extension study. SC = subcutaneous; Q6M = every 6 months.

Fig. 2

Disposition of all participants. All women who completed FREEDOM (ie, completed their 3-year visit, did not discontinue investigational product [IP], and did not miss >1 dose) were eligible to participate in the FREEDOM extension. ^aTwo women who discontinued denosumab also entered the extension in the long-term denosumab group.

Fig. 3

Percent change in bone turnover markers during FREEDOM and the extension. Changes in serum C-terminal telopeptide of type 1 collagen (CTX; panel A) and serum procollagen type I N-terminal propeptide (P1NP; panel B) are shown for 101 subjects (36 cross-over, 65 long-term) who were included in a substudy of bone turnover markers. Data are median (interquartile range).

Fig. 4

Percent change in bone mineral density (BMD) during FREEDOM and the extension. Changes in BMD at the lumbar spine (A), total hip (B), femoral neck (C), and 1/3 radius (D) are shown. Data are least squares means (95% CI). ^ap < 0.05 compared with FREEDOM baseline; ^bp < 0.05 compared with FREEDOM baseline and extension baseline. ^cp < 0.05 compared with year 4.

Fig. 5

Yearly incidence of new vertebral fractures (A and C) and nonvertebral fractures (B and D) during FREEDOM and the extension. n = number of subjects with ≥1 fracture. N = number of subjects in the primary efficacy analysis set who were still on study at the beginning of each period. *Annualized rate: (2-year rate/2).