Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study

Abstract

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores À2.0 to À3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D 3 and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n ¼ 41) or ODN 50 mg (n ¼ 100) had similar baseline characteristics. For women who received ODN (10-50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n ¼ 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus À0.4% (À3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n ¼ 14). In pooled results of women receiving continuous ODN (10-50 mg, n ¼ 26-29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and crosslinked C-telopeptide (CTX) were approximately À55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n ¼ 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10-50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated. ß

An overview on the treatment of postmenopausal osteoporosis

“…Discontinuation of ODN resulted in reversal on these effects, with fast bone loss. Treatment with ODN for up to 5 years was generally well-tolerated (59).…”

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

“…Odanacatib is an oral, selective cathepsin K inhibitor that is in development as a treatment for osteoporosis (Langdahl et al, 2012). The pharmacokinetics (PK) of odanacatib have been investigated in phase 1 single-dose (Stoch et al, 2013) and multiple-dose (Stoch et al, 2009;Anderson et al, 2014) studies.…”

Role of osteoclasts in regulating hematopoietic stem and progenitor cells

“…Increased osteoblastogenesis reportedly increases the HSC pool, while degradation of Cxcl12 or surrounding extracellular matrix protein is required for HSPC mobilization to the periphery [9,10,20] . Since osteoclasts express high levels of matrix-degrading enzymes, such as matrix metalloprotenase 9 (MMP9) and Cathepsin K [99][100][101][102][103][104][105] , and osteoclast activity increases following G-CSF injection [48] , osteoclasts were predicted to be critical for HPSC mobilization through degradation of Cxcl12 and matrix protein [62] . In our study, we found that HSPC mobilization to the periphery was induced at comparable or even higher rates than that seen in controls following serial G-CSF injection of three independent osteoclast-less and therefore BM-less mice, phenotypes also seen in wild-type mice treated with two independent osteoclast inhibiting agents [75] .…”