By Phoebe Starr
Washington, DC—Odanacatib, an investigational agent, was effective in building bone mass in women with postmenopausal osteoporosis who did not respond to 3 years of treatment with alendronate (Fosamax). Odanacatib treatment significantly improved bone mineral density (BMD) at the femoral neck, hip, trochanter, and lumbar spine compared with placebo in this group of women, and it had acceptable safety and tolerability.
The results of this phase 3 clinical trial were presented during the 2012 meeting of the American College of Rheumatology. The study was halted prematurely by an independent data and safety monitoring committee because of the robust effectiveness of odanacatib versus placebo.
“Odanacatib inhibits bone resorption while maintaining bone formation, unlike bisphosphonates that reduce bone resorption and bone formation,” stated lead author Roland Chapurlat, MD, Hôpital Edouard Herriot, Lyon, France. “The treatment was safe and well tolerated, with no evidence of excess bone formation or abnormal stress fracture.”
The goal of the study was to determine if odanacatib would be effective in women who had previously received alendronate for postmenopausal osteoporosis. This randomized, double-blind, placebo-controlled, 24-month trial was conducted at 42 sites in 12 countries and included 246 women aged ≥60 years (mean age, 71.3 years) with osteoporosis. The patients were randomized to receive odanacatib 50 mg once weekly or placebo. All of the patients received vitamin D and calcium supplementation.
Baseline demographic and disease characteristics were similar between the 2 treatment arms. Most women were Caucasian, 73.7% had a history of any fracture, and 68.3% had sustained a postmenopausal fracture. The patients had taken alendronate for a mean of 5.5 years, and ≥50% had used that drug for 3 to 5 years.
Dr Chapurlat noted that, typically, patients using alendronate over the long-term continue to have a residual effect on bone turnover, even after they stop treatment. This effect probably accounted for an approximately 6-month lag until the effect of the novel agent became evident.
Odanacatib was significantly superior to placebo in building BMD at the femoral neck (the primary end point) and the hip. After 24 months of treatment, a 2.67% difference in femoral neck BMD was observed in favor of odanacatib (P <.001). Total hip BMD had a 2.7% difference favoring odanacatib (P <.001). For both end points, the effect of odanacatib was not seen until about 6 months after treatment was initiated, presumably because of the residual effect of alendronate, Dr Chapurlat noted.
At 24 months, BMD was significantly improved at the trochanter (3.18% difference vs placebo) and the lumbar spine (2.57% difference vs placebo; P <.001 for both comparisons). At 24 months, odanacatib significantly reduced the markers of bone resorption and significantly increased markers of bone formation compared with placebo (P <.001 and P = .011, respectively).
The rate of discontinuation because of adverse events (AEs) was 9% in the odanacatib group versus 3% in the placebo group. No significant differences in AEs were observed between the 2 treatment arms.
Although the study was not designed to assess fracture as the primary end point, the fracture rate was 4.9% in the odanacatib group versus 13.2% for placebo. The results of an ongoing phase 3 clinical trial that is investigating the effect of odanacatib on bone fractures in 16,000 women are expected next year.
Financial analysts forecast odanacatib as a blockbuster drug if it is approved by the US Food and Drug Administration, which is poised to replace alendronate, but some rheumatologists believe that this will not happen soon. The consensus is that bisphosphonates are quite inexpensive, very effective, and have a long track record. The challenge is to determine the optimal length of treatment to avoid the rare cases of atypical fracture that are reported with bisphosphonates. n