• Metabolic Bone Disease
• Diabetes & Endocrinology Clinical Trials

Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM; NCT00089791) was a randomized, placebo-controlled, Phase 3 trial designed to test the effect of denosumab on risk of fracture in postmenopausal women during a 3-year follow-up period [Cummings SR et al. N Engl J Med 2009]. Henry G. Bone, MD, Michigan Bone and Mineral Center, Grosse Pointe, Michigan, USA, presented findings from the first 2 years of the FREEDOM trial extension.

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density.

A total of 7808 women aged between 60 and 90 years with osteoporosis were enrolled at 213 study sites worldwide. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary endpoint was new verterbral fractures. Secondary endpoints included nonvertebral and hip fractures.

The cumulative incidence of new radiographic vertebral fractures in the denosumab group was 2.3% versus 7.2% in the placebo group (p<0.001). The cumulative incidence of hip fractures was 0.7% in the denosumab group versus 1.3% in the placebo group (p=0.04). The relative decrease in nonvertebral fractures in the treatment group was 20% (p=0.01), with no increase in the risk of adverse events

The extension study monitored crossover and safety data for up to 10 years in 4550 subjects who completed the FREEDOM trial; 2207 crossover and 2343 long-term subjects received 60 mg of denosumab every 6 months. The placebo group data reflect up to 4 doses of denosumab (2 years; crossover). The treatment group data reflect up to 10 doses over 5 years (long-term group).

During the first 2 years of treatment, the crossover group showed significant gains of 7.9% in lumbar spine BMD and 4.1% in total hip BMD (p<0.0001). The long-term group had further significant BMD increases of 13.7% in the lumbar spine and 7.0% in the total hip over the cumulative 5-year period (p<0.0001). Serum c-telopeptide of type 1 collagen was rapidly and similarly reduced after the first (crossover) or seventh (long-term) administration of denosumab.

The crossover group had lower yearly incidences of new vertebral and nonvertebral fractures than the control group. The rate of fractures in the long-term group remained low. Adverse events (AEs) and serious AEs (SAEs) in the crossover group were similar to or lower than in the placebo and denosumab FREEDOM groups. Neither AEs nor SAEs increased over time with long-term administration of denosumab.

Infection rates in Years 4 and 5 in the denosumab group were similar to or lower than yearly rates in the FREEDOM placebo group. This was also the case for individual SAEs of infection, including pneumonia, urinary tract infection, diverticulitis, gastroenteritis, cellulitis/erysipelas, and bronchopneumonia. Two oral AEs were adjudicated to osteonecrosis of the jaw in the crossover group; both healed completely, and 1 woman continued taking denosumab. No oral AEs occurred in the long-term group, and there were no atypical fractures. These outcomes are consistent with the original FREEDOM study observations.

• © 2011 MD Conference Express