Background/Purpose: Odanacatib
(ODN), a selective oral inhibitor of cathepsin K, is in development for the
treatment of osteoporosis. In the Phase 3, Long-Term Odanacatib Fracture Trial
(LOFT; NCT00529373) of postmenopausal women with osteoporosis, ODN
significantly reduced fracture risk and led to progressive increases in BMD at
the lumbar spine (LS) and total hip (TH) vs. placebo. The incidence of AEs and
serious AEs has been previously presented. Major cardiovascular events overall
were generally balanced but there were numerically more adjudicated strokes in
the ODN group. Final blinded, independent adjudication of all major
cardiovascular events is ongoing. Pre-specified analyses evaluated the efficacy
of ODN in different patient subgroups.

Methods: Women
aged ≥65 years without a baseline radiographic vertebral fracture (VFx)
and a TH or femoral neck (FN) BMD T-score between -2.5 and -4.0 or with a prior
VFx and a TH or FN T-score between -1.5 and -4.0 were randomized (1:1) to ODN
50 mg/week or placebo. All patients received vitamin D3 (5600 IU/week) and
calcium as required to achieve ~1200 mg/day. Treatment effects on primary
endpoints (new and worsening morphometric vertebral, incident hip, non-VFx)
were investigated in patient subgroups, including baseline age, race,
bisphosphonate intolerance, prior radiographic VFx, and baseline BMD.

Results:
16,713 women were randomized (16,071
included in analyses) at 387 centers in 40 countries. Baseline mean age was
72.8 years, 57% Caucasian, 46.5% with prior VFx. Mean BMD T-scores were: LS
-2.7, TH -2.4, and FN -2.7. The risk reduction of ODN vs. placebo for primary
fracture endpoints was generally consistent across all subgroups. For
morphometric VFx, the relative risk reductions (RRR) for participants with or
without prior VFx were 51% and 60%, respectively; for age groups <70 and
≥70 years, the RRRs were 57% and 53%, respectively (Table). RRR for
morphometric VFx based on baseline LS BMD T-score tertiles (≥-2.22;
-3.25< to <-2.22; ≤-3.25) were 54%, 47% and 58%, respectively. In
bisphosphonate-intolerant patients, the RRR for morphometric VFx, hip and
non-VFx were 52%, 48% and 17% respectively consistent with the overall study
population.

Conclusion:
In postmenopausal women with osteoporosis, the effect of ODN vs. placebo was
generally consistent among various predefined subgroups in reducing the risk of
new and worsening morphometric vertebral, hip and non-VFx.

Table.
Interval-censored
analysis of time to first morphometric vertebral fracture and time to first
adjudicated osteoporotic fracture (hip and non-vertebral): subgroup analyses
(Full-Analysis-Set population; base study)

^aAnalyses
based on generalized linear model for binary data with cloglog link and terms
for time interval, treatment, stratum, geographic region, subgroup and
treatment by subgroup interaction.

^bAnalyses were based on Cox proportional hazards model with terms
for treatment, stratum and geographic region.