NEW YORK (Reuters Health) – In postmenopausal women with low bone mass, continuous treatment with denosumab -- 2 doses per year for up to 6 years -- is well tolerated and results in progressive gains in bone mineral density (BMD), results of an extension study indicate.

Denosumab (Prolia, Amgen) is a fully human monoclonal antibody designed to target receptor activator of nuclear factor-kappa-B ligand (RANKL), a protein that acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density.

Denosumab is approved by the U.S. Food and Drug Administration for treatment of osteoporosis and in some countries as a therapy for bone loss associated with hormone ablation therapy.

In the pivotal FREEDOM trial, three years' treatment with denosumab substantially reduced the incidence of vertebral and nonvertebral fractures, including fractures of the hip, in postmenopausal women with osteoporosis.

The new findings stem from a 2-year interim analysis of an ongoing 4-year, open-label, single-arm extension study of a dose-ranging phase 2 trial. The analysis appears in the February 2011 issue of the Journal of Clinical Endocrinology and Metabolism, available online now.

Of the 262 women aged 80 or younger who completed the parent study (years 1-4), 200 enrolled in the extension study and 178 completed the first 2 years (years 5-6). They received denosumab 60 milligrams subcutaneously every 6 months. Inclusion criteria for the parent study included a BMD T-score between -1.8 and -4.0 for the lumbar spine or between -1.8 and -3.5 for either the total hip or femoral neck.

According to the investigators, 2 years into the 4-year extension study, the response to denosumab has been “durable” -- regardless of past treatment and whether or not subjects were previously discontinued the drug for a period of time, as some did in the parent study.

With continued treatment, the reduction in bone resorption seen in the parent study was sustained and further gains in BMD were noted, Dr. Paul D. Miller of the Colorado Center for Bone Research in Lakewood and colleagues report.

From the extension study baseline, mean BMD increased at the lumbar spine by 2.9%, total hip by 1.1%, one third radius by 1.0% and femoral neck by 1.2%.

Six years of continuous treatment was associated with mean BMD changes from parent study baseline of 13.3% for lumbar spine, 6.1% for total hip, 1.9% for one third radius, and 5.6% for femoral neck.

These benefits were achieved with a no change in the safety profile of the drug. Reported adverse events were generally mild and consistent with those seen in the first 4 years of treatment, the investigators say. “We didn't see any increase incidence of any infections or side effects and the fracture rates continue to stay down,” Dr. Miller noted in an interview with Reuters Health.

Denosumab has a “great anti-fracture profile,” he said, adding: “The fracture reduction data to date are compelling for vertebral, non-vertebral and hip fracture prevention.”

“When it comes to parenteral osteoporosis drugs,” Dr. Miller said, “denosumab and Reclast (zolodronic acid) are going to be the players. Now, it's going to come down to the war between bisphosphonates and denosumab, which is not a bisphosphonate and has completely different pharmacokinetics.”

Asked about the cost of longer-term treatment with denosumab, Dr. Miller said: “We'd have to see how pricing would play out across the country. The adjusted average wholesale price of the drug in most places is about $1,600 for the two shots per year.” Medicare and private insurance will pick up a portion of the cost.

The study was supported by denosumab maker, Amgen Inc., of Thousand Oaks, California. Several of the authors are Amgen employees; others disclose financial relationships with the company and other pharmaceutical companies.

Effect of Denosumab on Bone Mineral Density and Biochemical Markers of Bone Turnover: Six-Year Results of a Phase 2 Clinical Trial
J Clin Endocrin Metab 2010. Published online December 15, 2010.