Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Abstract

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double‐blind, placebo‐controlled, event‐driven, Phase 3, Long‐term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double‐blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN‐treated versus placebo‐treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN‐treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

“…In a preclinical model, in ovariectomized rhesus monkeys treated for 21 months, histomorphometric analysis indicate that both osteoclast number and osteoclast surface increased approximately 4‐fold by odanacatib treatment compared to vehicle . Similarly, in the bone biopsy substudy of LOFT, osteoclast surface area at Month 36 was approximately doubled in patients receiving 50 mg weekly odanacatib relative to patients receiving placebo in the histomorphometric analysis of transilial bone biopsies …”

Effects of Parathyroid Hormone, Alendronate and Odanacatib on the mineralisation process in intracortical and endocortical Haversian bone of ovariectomized rabbits

“…without blocking bone formation [7][8][9], a finding partially upheld by the present study, where histomorphometry showed no significant reduction in EcMAR or PsMAR. Previous work in OVX monkeys has reported increased bone formation on both periosteal and endocortical surfaces in the central femur [40], but we did not see this, suggesting a species difference in the effect of ODN on periosteal bone formation.…”

Osteoblast-Osteoclast Communication and Bone Homeostasis

“…Odanacatib has received a lot of attention as a potential osteoporosis drug since it inhibits osteoclast activity and function, rather than osteoclast generation, resulting in prevention of bone resorption with more modest overall effects on the ability of osteoblasts to form bone than most other anti-resorptive agents. It still remains unclear whether these effects reflect functional blockade of osteoclast-driven coupling processes or whether CTSK inhibition may have direct effects on CTSK-expressing periosteal mesenchymal progenitors [ 90 , 91 ]. Although odanacatib was highly effective in reducing fractures of postmenopausal women in clinical phase-3, its further development was discontinued due to concerns regarding risk of cerebrovascular events [ 92 ].…”