Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

Abstract

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased boneresorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between À2.0 and À3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n ¼ 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (À50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. ß

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

“…A similar pattern was also observed with odanacatib, a selective cathepsin K inhibitor, in a 2-year study in which a transient rise in BTMs above baseline after treatment discontinuation was seen. (76) The implication of this rebound effect on the clinical outcomes is not clear.…”

Discontinuation of odanacatib and other osteoporosis treatments: Here today and gone tomorrow?

“…The odanacatib resolution-of-effect study reported by Eisman and colleagues (6) is well designed, and the results are interesting, but several important limitations are worth noting. The most important shortcomings of the study are the small sample size and short duration.…”

“…(6) Odanacatib inhibits cathepsin K, a cysteine protease produced by osteoclasts that degrades type 1 collagen. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development, and preclinical studies have demonstrated that odanacatib has profound effects on bone resorption with few off-target effects.…”

“…(7) Odanacatib is currently being examined in a large trial with fracture endpoints, with the eventual goal of Food COMMENTARY J JBMR and Drug Administration (FDA) approval for use in individuals with osteoporosis, but smaller trials have found that odanacatib treatment is associated with significant reductions in bone turnover and increases in axial BMD. (8,9) In the current odanacatib study, (6) Eisman and colleagues describe the results of an extension of a published phase II (doseranging) trial. In the parent study, (9) 399 postmenopausal women with low bone mass were randomized to placebo or one of four doses of weekly odanacatib and followed for 2 years.…”

“…These comparisons should be interpreted with caution: The studies are not head-to-head examinations, and therefore the populations studied, severity of disease, and analytical approach may differ substantially. Nonetheless, the available evidence suggests that standard doses of alendronate, risedronate, denosumab, and odanacatib have similar effects on (n ¼ 437) (13) Risedronate, 5 mg/day (n ¼ 398) (14) Denosumab, 60 mg/6 month (n ¼ 128) (15) Odanacatib, 50 mg/week (n ¼ 20) (6) Effects on bone mass c 0-to 24-month change on active treatment bone turnover and BMD after 2 years of treatment, but discontinuation of treatment results in substantially greater 1-year axial bone loss among denosumab-and odanacatib-treated women compared with the bisphosphonate-treated women ( Table 1). Discontinuation of odanacatib in particular appears to increase bone markers substantially, a potentially worrisome scenario if one accepts the current paradigm that rapid bone loss and sustained increases in bone turnover are independently associated with increased fracture risk, at least among older untreated women.…”