Cathepsin K inhibitors increase distal femoral bone mineral density in rapidly growing rabbits

Abstract

BackgroundSelective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; thus the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption.MethodsIn this study, the efficacy of the selective inhibitors L-833905, L-006235, L-873724, and L-1037536 (ODN) of human CatK in the rapidly growing rabbit ‘Schenk’ model (age seven weeks) was compared to vehicle, using the bisphosphonate, alendronate (ALN), as a positive control, to assess inhibition of bone resorption. An enzyme inhibition assay (EIA) and an in vitro bone resorption assay using rabbit osteoclasts on bovine cortical bone slices were performed to evaluate the potency of these CatK inhibitors. Bone mineral density of the distal femur (DFBMD) was measured after ten days of treatment using ex vivo DXA densitometry.ResultsResults of the EIA using rabbit CatK and the rabbit bone resorption assay showed that three of the four compounds (L-006235, L-873724, and ODN) had similar potencies in the reduction of collagen degradation. L-833905 appeared to be a weaker inhibitor of CatK. Taking into account the respective in vitro potencies and pharmacokinetic profiles via oral administration, the efficacy of these four CatK inhibitors was demonstrated in a dose-related manner in the growing rabbit. Significant increases in DFBMD in animals dosed with the CatK inhibitors compared to vehicle were seen.ConclusionsEfficacy of the CatK inhibitors in the Schenk rabbit correlated well with that in the in vitro rabbit bone resorption assay and in the ovariectomized rabbit model as previously published. Hence, these studies validated the rabbit Schenk assay as a rapid and reliable in vivo model for prioritizing human CatK inhibitors as potential therapeutic agents.

Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH, Estrogen, and Alendronate

“…(11) Bone formation is a dominant event during skeletal growth, and ODN increased distal femoral BMD in growing rabbits. (12) Adult mice in which CK gene has been deleted displayed higher mineral apposition and bone formation rates in addition to having higher trabecular and cortical bone mass than their wild-type counterparts. (13) In human bone biopsy samples, CK immunoreactivity was demonstrated in osteoblasts, osteocytes, and lining cells, and CK activity was shown in cultured osteoblasts.…”

“…Five years of continued ODN therapy in a phase 2 study on postmenopausal women with low BMD showed a trend of elevation of procollagen type 1 N‐terminal propeptide (P1NP; a serum marker of bone formation) over the baseline values . Bone formation is a dominant event during skeletal growth, and ODN increased distal femoral BMD in growing rabbits . Adult mice in which CK gene has been deleted displayed higher mineral apposition and bone formation rates in addition to having higher trabecular and cortical bone mass than their wild‐type counterparts .…”

Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model

“…The human CatK inhibitor ODN is significantly less potent against the rodent enzyme due to the differences between human versus rodent enzymatic sites . Meanwhile, rabbit CatK shares high sequence identity to its human counterpart . Thus, the inhibitors developed against the human enzyme, including ODN, have similar efficacy in blocking the recombinant rabbit CatK and effectively preventing bone loss in the rabbit model of estrogen‐deficiency osteopenia .…”

“…Meanwhile, rabbit CatK shares high sequence identity to its human counterpart . Thus, the inhibitors developed against the human enzyme, including ODN, have similar efficacy in blocking the recombinant rabbit CatK and effectively preventing bone loss in the rabbit model of estrogen‐deficiency osteopenia . Previously, the rabbit mid‐ulnar osteotomy fracture model has been used to evaluate the therapeutic agent, recombinant human bone morphogenic protein .…”

“…15 Thus, the inhibitors developed against the human enzyme, including ODN, have similar efficacy in blocking the recombinant rabbit CatK and effectively preventing bone loss in the rabbit model of estrogen-deficiency osteopenia. 15,16 Previously, the rabbit mid-ulnar osteotomy fracture model has been used to evaluate the therapeutic agent, recombinant human bone morphogenic protein. 17,18 Using the same fracture repair model, two different studies were conducted to evaluate the effects of ODN compared to alendronate (ALN) treatment on the early phase ($6-weeks) of callus development (Study 1) and the late phase (15-weeks) of callus remodeling (Study 2).…”