Cathepsin K inhibitors, such as
ONO-5334, are being developed for the treatment of
postmenopausal osteoporosis. However, their relative effects on
bone resorption and formation, and how quickly the effects resolve
after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with
ONO-5334 and to assess the effect of
treatment cessation over 2 months. We studied 197 postmenopausal women with
osteoporosis or
osteopenia with one fragility fracture. Patients were randomized to
ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily,
alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all
ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001).
ONO-5334 300 mg significantly suppressed the
bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as
alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for
ONO-5334 to close to baseline levels by 12 to 24 months. On
treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns.
Cathepsin K inhibition with
ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on
biochemical markers was rapidly reversible on
treatment cessation.