LOFT (NCT00529373) is a randomised, double-blind, placebo-controlled, event-driven trial of odanacatib (ODN), an oral selective inhibitor of cathepsin K Postmenopausal women ≥65 years with bone mineral density (BMD) T-score ≤−2.5 at total hip (TH) or femoral neck (FN), or with prior radiographic vertebral fracture (VFx) and T-score ≤−1.5 at TH or FN, were randomised to ODN 50 mg/week or placebo. Patients received vitamin D (5600 IU/week), plus calcium to achieve intake of 1200 mg/day. Primary endpoints were: new/worsening morphometric VFx; hip fractures; non-vertebral fractures. Secondary endpoints included clinical VFx; BMD; bone turnover markers. Safety/tolerability measures included adjudicated adverse events (AEs) of interest. 16 713 women were randomised; 16 071 were included in analysis. Mean age was 72.8 years; 46.5% had prior radiographic VFx. Mean BMD T-scores were: lumbar spine (LS) −2.7; TH −2.4; FN −2.7. Mean follow-up was 34.5 months. Versus placebo, ODN treatment resulted in relative risk reductions of: 54% for new/worsening morphometric VFx; 47% for hip fractures; 23% for non-vertebral fractures; 72% for clinical VFx (P<0.001). ODN treatment led to progressive increases over 5 years in BMD at LS and TH: 11.2 and 9.5%, respectively, versus placebo. The incidence of AEs and serious AEs overall did not differ meaningfully between groups. There were 271 deaths reported in the ODN group and 242 on placebo (hazard ratio 1.13 (95% CI: 0.95, 1.35)); this numeric imbalance in mortality did not appear related to a particular reported cause of death. Adjudicated morphea-like skin lesions and femoral shaft fractures (including those with atypical features) occurred in small numbers of patients, more commonly with ODN than placebo. No cases of osteonecrosis of the jaw were reported. Major cardiovascular events overall were generally balanced; however, there were numerically more adjudicated strokes with ODN than with placebo. Final blinded adjudication of major cardiovascular events is ongoing.
Disclosure: Authors conflicts of interest for Merck include: consulting fees (M R McClung, B Langdahl, S Papapoulos, K Saag, H Bone); grants (M R McClung, B Langdahl, K Saag, H Bone); royalties (M R McClung); participation in speakers bureaux (M R McClung, B Langdahl); employee (A Rybak-Feiglin, D Cohn, C A DaSilva, D Cohn, C A DaSilva, R Massaad, A C Santora, B B Scott, K D Kaufman, N Verbruggen, A Lombardi); former employee (A Leung). This study was sponsored by Merck & Co., Inc.