Twice-yearly denosumab reduced risk for postmenopausal fractures

Postmenopausal women with osteoporosis assigned to twice-yearly denosumab experienced a 68% reduction in risk for vertebral fracture, 40% reduction in risk for hip fracture and 20% reduction in risk for nonvertebral fracture after three years of treatment compared with placebo, according to results of the FREEDOM study.

“These results suggest that denosumab offers a new approach to prevention of fractures in women with postmenopausal osteoporosis,” Steven Cummings, MD, researcher and director of the San Francisco Coordinating Center of the California Pacific Medical Center Research Institute, said in a press release. “It reduces the risk of all major types of fractures and, because it is given as an injection twice a year, it also has the potential to help compliance to treatment.”

Denosumab (Prolia, Amgen) is an investigational fully human monoclonal antibody that specifically targets RANK Ligand, an essential regulator of osteoclasts. Denosumab is being studied in a range of bone loss conditions, including postmenopausal osteoporosis and bone loss in patients undergoing hormone ablation for prostate and breast cancer.

The FREEDOM study included 7,868 women aged 60 and 90 years who had a bone mineral density T-score of <–25 but not <–4.0 at the lumbar spine or total hip. Women were assigned to 60 mg denosumab or placebo, given subcutaneously every six months for 36 months.

Reduced risk for fracture at multiple sites

Denosumab reduced the risk for new radiographic vertebral fracture — the primary endpoint — compared with placebo; the cumulative incidence was 2.3% in the denosumab group vs. 7.2% in the placebo group (RR=0.32; 95% CI, 0.26-0.41). A similar finding was reported for nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group vs. 8.0% in the placebo group (HR=0.80; 95% CI, 0.67-0.95).

The cumulative incidence of hip fracture was 0.7% in the denosumab group vs. 1.2% in the placebo group (HR=0.60; 95% CI, 0.37-0.97).

Over the three-year study period, women assigned to denosumab also experienced significant increases in BMD — 8.8% at the lumbar spine and 6.4% at the total hip.

Rates of adverse events (93%) and serious adverse events (about 25%) were similar between the two groups (93%). Serious adverse events of skin infections, particularly cellulitis, were more common in the denosumab group (0.4% vs. 0.1%). The most commonly reported adverse events in both treatment arms were arthralgia, back pain, hypertension and nasopharyngitis. Researchers reported no increased in risk for cancer, cardiovascular disease, delayed fracture healing, hypocalcemia or osteonecrosis of the jaw.

In February 2009, the FDA accepted the Biologics License Application submitted by Amgen for denosumab for the treatment and prevention of osteoporosis in postmenopausal women and cancer treatment-induced bone loss in women and men receiving hormone therapy for either breast or prostate cancer.

Cummings SR. N Engl J Med. 2009;doi:10.1056/NEJMoa0809493.

Click here to read perspective on this article from an EndocrineToday.com blogger.

This was a 36-month study that looked at postmenopausal women with osteoporosis T-score of <-2.5 but not <-4.0. Fracture risk reduction in the spine was similar to that seen with zoledronic acid and better than that reported for oral bisphosphonates. Nonvertebral fracture risk reduction was similar to that reported in both the oral and IV bisphosphonates. Risk for hip fracture, specifically, was reduced by 40% but the number of fractures in the treated and placebo groups was small. There was a 9.2% relative increase in spine density and a 6% increase in hip density. Adverse reactions included severe cellulitis requiring hospitalization, eczema and flatulence. There was no osteonecrosis of the jaw during the time of the study. Th major limitation is that in this study most women with osteopenia and women who were immediately postmenopausal were not studied, nor were men. Most fractures occur in women with osteopenia. This group will need to be looked at along with men. However, reducing fracture risk by reducing recruitment of osteoclasts rather than impairing their structure and function is a step in the right direction.

– Donald A. Bergman, MD

Endocrine Today Editorial Board member