Background/Purpose: Odanacatib is a selective and reversible inhibitor of cathepsin K; a collagenase secreted by osteoclasts, and is currently being evaluated for the treatment of osteoporosis. In a Phase 2 study of postmenopausal women with low BMD, oral odanacatib 50 mg once-weekly increased BMD progressively over 5 years by 11.9% at the lumbar spine and 9.8% at the femoral neck.

Methods: A randomized, double-blind, Phase 3 trial designed to examine osteoporotic fracture reduction and safety enrolled 16,227 postmenopausal osteoporotic women to receive odanacatib 50 mg or placebo once weekly (without regard to food). All participants also received vitamin D3 5600 IU weekly, and calcium supplements as needed. This event-driven trial was designed to be completed after 237 hip fractures had accrued, but allowed for early termination based on the results of 2 pre-planned interim analyses. The trial has three primary endpoints: morphometric vertebral fracture, non-vertebral fracture, and hip fracture. Controls are employed for elevation of the false-positive error rate due to multiple primary endpoints. Clinical fractures are adjudicated centrally via clinical history, radiology reports, and/or x-rays. Secondary endpoints include clinical vertebral fractures, BMD, height, bone turnover markers, and safety and tolerability. Collection of extensive baseline clinical information, pharmacogenomic data, archived serum and urine samples for all participants and trans-iliac bone biopsies from some participants will provide additional information.

Results: Postmenopausal women with (n=7,470) or without a prior radiographic vertebral fracture (n=8,757) were enrolled at 383 centers worldwide. At baseline they had a mean age of 73 years, were 57% Caucasian, and had mean BMD T-scores at lumbar spine -2.7, total hip -2.4, femoral neck -2.7, and trochanter -2.3.

Conclusion: This trial was designed to provide information on the efficacy and safety of once-weekly odanacatib 50 mg in reducing the risk of osteoporotic fractures in postmenopausal women with osteoporosis. A pre-planned interim analysis demonstrated anti-fracture efficacy and a favorable benefit/risk profile. Some safety findings were identified that will be followed in the pre-planned extension of the study. The trial is being extended as a placebo-controlled study with the same design for a minimum total period of observation of 5 years for each participant, in order to collect additional safety and efficacy data.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-3-fracture-trial-of-odanacatib-for-osteoporosis-baseline-characteristics-and-study-design/