Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Abstract

Odanacatib is a cathepsin K inhibitor developed for the treatment of postmenopausal osteoporosis. It is a bone resorption inhibitor, but which preserves bone formation to some extent. It can be administered once a week, in tablets also containing vitamin D. In a large clinical development program, it has been shown that odanacatib reduces bone resorption, with a reduction of about 60-70% in biochemical markers of resorption, while bone formation decreases to a lesser magnitude. Odanacatib continuously increases bone mineral density (BMD) at the hip and lumbar spine over 5 years. Once it is stopped, a complete resolution of effect is observed, with declining BMD and increased bone turnover. Bone microarchitecture and bone strength have also been improved in clinical trials using quantitative computed tomography (QCT) at the lumbar spine and hip, and high resolution peripheral QCT at the distal radius and tibia. In a phase III trial involving 16,713 postmenopausal women ⩾65 years of age with low BMD, the risk of fragility fracture was significantly reduced at the spine, hip and other nonvertebral sites compared with the placebo group. Odanacatib has been generally well tolerated, with no observation of osteonecrosis of the jaw so far, but with exceptional observations of subtrochanteric atypical fracture and morphea-like lesions. Odanacatib appears a useful new option in the treatment of postmenopausal osteoporosis.

Small molecule nAS‐E targeting cAMP response element binding protein (CREB) and CREB‐binding protein interaction inhibits breast cancer bone metastasis

“…Therefore, novel agents have been pursued to mitigate osteolysis induced by breast cancer metastasis. Cathepsin K inhibitor odanacatib has been reported to be an agent against osteoporosis and breast cancer‐induced bone metastasis . However, odanacatib was withdrawn from the clinical trials for safety reasons.…”

“…Cathepsin K inhibitor odanacatib has been reported to be an agent against osteoporosis and breast cancer-induced bone metastasis. 22,23 However, odanacatib was withdrawn from the clinical trials for safety reasons. In addition, clinical studies of c-Src inhibitors have been initiated in patients with bone metastases, since c-Src plays multiple roles in the bone resorption and in the proliferation, survival, metastasis of breast cancer cells.…”

Inhibition of cathepsin K promotes osseointegration of titanium implants in ovariectomised rats

“…A previous study showed that the treatment-related responses of bone resorption markers were similar for CatKI and the typical bisphosphonate alendronate (ALN); however, the reduction in the levels of bone-formation markers was less with CatKI than with ALN26. Moreover, CatKI was generally well tolerated without bone necrosis27. Thus, CatK is considered an important target for the treatment of postmenopausal osteoporosis28.…”

An Ectosteric Inhibitor of Cathepsin K Inhibits Bone Resorption in Ovariectomized Mice

“…The pros for this decision were the relatively selective expression of CatK in osteoclasts, its proven role as the therapeutically relevant bone collagen‐degrading protease without affecting osteoclast viability when inhibited, and acting as the final executioner in the bone resorption pathway with the promise of fewer side effects than expected when targeting upstream, more complex regulatory proteins such as tumor necrosis factor‐α (TNF‐α) or receptor activator of NF‐κB ligand (RANKL). However, despite the successful generation of potent, selective, and preclinically active CatK inhibitors, and despite the fact that human osteoporosis trials showed impressive bone‐preserving efficacies of CatK inhibitors and keeping bone formation mostly unaffected, none of these compounds were ever approved. Relacatib, balicatib, odanacatib (ODN), and ONO‐5334 were all terminated because of increased side effects or for marketing reasons .…”