Denosumab Increases Bone Density, No Atypical Fracture Risk

Debra Gordon

November 10, 2011

November 10, 2011 (Chicago, Illinois) — Long-term use of the antiresorptive agent denosumab in postmenopausal women with osteoporosis continues to increase bone density and reduce markers of bone turnover, with no increased risk for the atypical fractures seen with long-term use of another class of antiresporptive agents, bisphosphonates.

The research, from the first 3 years of an open-label extension of the pivotal phase 3 Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial, was presented here at the American College of Rheumatology (ACR) 2011 Annual Meeting as a late-breaking abstract.

FREEDOM was an international, randomized, placebo-controlled trial involving 7868 women 60 to 90 years of age with a bone mineral density (BMD) T score below ?2.5 at the lumbar spine or total hip. Approximately 70% of the original participants continued in the follow-up study. Of these, 2343 continued to receive denosumab and 2207 crossed over from placebo to denosumab. The women continue to receive denosumab, 60 mg every 6 months, and take supplemental calcium and vitamin D daily. They will be followed for a total of 10 years.

Women in the long-term group continue to demonstrate BMD gains: 5.1% improvement at the lumbar spine and 1.8% in the total hip, for cumulative gains of 15.2% at the lumbar spine and 7.5% total hip compared with baseline (P < .05). Women in the crossover group demonstrated BMD gains similar to those seen in the original study: 9.4% in the lumbar spine and 4.8% in the total hip (P < .05).

In addition, serum collagen type 1 crosslinked C-telopeptide, a marker of bone turnover, was rapidly and similarly reduced after the first dose in the crossover group or after the seventh dose in the long-term follow-up group, with the characteristic attenuation observed at the end of the dosing period.

Four women developed osteonecrosis of the jaw during the follow-up study (2 in the long-term group and 2 in the crossover group). No cases of osteonecrosis occurred during the original FREEDOM trial. The condition resolved in both women from the crossover group, 1 of whom resumed the study drug. The 2 women in the long-term group are still being followed. No other serious adverse events occurred.

In addition, annual incidence of new vertebral and nonvertebral fractures in the crossover group was lower than in the FREEDOM placebo group, whereas fracture incidence remained low in the long-term group.

The fracture rate was not highlighted in the presentation, said lead author Jacques Brown, MD, from CHUQ-CHUL Research Centre at Laval University in Quebec, Canada, because the follow-up study was not powered to assess fracture rates. "Seeing that you have a stable and low incidence of fracture that is maintained in the extension is a good signal," he said.

The continued increase in BMD was unexpected, he said. "We tend to see a plateau of BMD increase between 3 and 5 years with bisphosphonates, so seeing the continued increase in BMD is somewhat marvelous." It will be important, he added, to understand the biological underpinnings of the continue BMD increase.

However, Eric L. Matteson, MD, who chairs the Rheumatology Department at the Mayo Clinic in Rochester, Minnesota, noted that the osteonecrosis seen in the follow-up study "is a concern." Still, he said, "it was a low event rate. The important thing is to put it in perspective in terms of the severity of the osteoporosis in patients to determine whether patients ought to receive the drug."

Dr. Matteson also noted the importance of the continued BMD increase, but said it would need to put into perspective with the fracture rate to determine whether the side effects are acceptable.

"It seems to be clear that [denosumab] works in terms of gain in bone density and even after the first three years, there is continued gain," Dr. Matteson said. "There are grounds for being optimistic here regarding the impact of the drug on patients."

Dr. Brown reports relationships with Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, sanofi-aventis, Servier, and Warner Chilcott.

American College of Rheumatology Annual Meeting 2011; Abstract L8. Presented November 8, 2011.

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