Inhibition of Cathepsin K Increases Modeling-Based Bone Formation, and Improves Cortical Dimension and Strength in Adult Ovariectomized Monkeys

Abstract

Treatment with the cathepsin K (CatK) inhibitor odanacatib (ODN) protects against bone loss and maintains normal biomechanical properties in the spine and hip of ovariectomized (OVX) preclinical models. Here, we characterized the effects of ODN on the dynamics of cortical modeling and remodeling, and dimension and strength of the central femur in adult OVX-rhesus monkeys. Animals were treated with vehicle or ODN (6 or 30 mg/kg, once per day [q.d., p.o.]) in prevention mode for 21 months. Calcein and tetracycline double-labeling were given at 12 and 21 months, and the femoral cross-sections were subjected to dynamic histomorphometric and cement line analyses. ODN treatment significantly increased periosteal and endocortical bone formation (BFR/BS), accompanied with an increase in endocortical mineralizing surface (102%, p < 0.01) with the 6 mg/kg dose. ODN at both doses reduced remodeling hemiosteon numbers by 51% and 66% (p < 0.05), respectively, and ODN 30 mg/kg numerically reduced activation frequency without affecting wall thickness. On the same endocortical surface, ODN increased all modeling-based parameters, while reducing intracortical remodeling, consistent with the observed no treatment effects on cortical porosity. ODN 30 mg/kg markedly increased cortical thickness (CtTh, p < 0.001) and reduced marrow area (p < 0.01). Lastly, ODN treatment increased femoral structural strength (p < 0.001). Peak load was positively correlated with the increases in bone mineral content (BMC) (r 2 ¼ 0.9057, p < 0.0001) and CtTh (r 2 ¼ 0.6866, p < 0.0001). Taken together, by reducing cortical remodeling-based and stimulating modeling-based bone formation, ODN significantly improved cortical dimension and strength in OVX monkeys. This novel mechanism of CatK inhibition in stimulating cortical formation suggests that ODN represents a novel therapeutic approach for the treatment of osteoporosis.

Development of an in vivo rabbit ulnar loading model

“…Basal periosteal MS/BS and MAR have been measured to be ≤ 10% and ≤ 1 μm/day, respectively, at multiple cortical bone sites within nonhuman primates [39][40][41], as well as in human iliac crest biopsies [46], similar to measurements in this study. Rabbits are also well-suited for preclinical investigations of osteopenia and pharmaceutical interventions as rabbits experience cortical bone loss after ovariectomy [29], and respond to PTH [25,26], bisphosphonates [28,29], and cathepsin K inhibitors [29].…”

Pharmacological diversity among drugs that inhibit bone resorption

“…There had therefore been an expectation that the responses to a cathepsin K inhibitor might be different from other anti-resorptive drugs, based on the notion that inhibition of cathepsin K may partially uncouple the link between reduction in bone resorption and bone formation, allowing bone formation to continue while bone resorption is reduced [90,91]. This has been borne out with results from both preclinical and clinical studies with odanacatib showing that the extent of reduction in biochemical markers of bone resorption was dose-dependent, but the effects on bone formation biomarkers were less than with other drugs such as bisphosphonates or denosumab.…”

Long-term safety of antiresorptive treatment: bone material, matrix and mineralization aspects

“…16 Denosumab, a fully human monoclonal antibody, inhibits bone resorption by binding to RANKL, an essential mediator of bone resorption. 16 Although the actions of these agents on bone cells may be different (as for instance, odanacatib was observed to promote periosteal bone formation 17 ), all considered agents (bisphosphonates, odanancatib, denosumab) have the ability to reduce the number of remodeling sites, thus leading to a reduction in bone resorption and/or turnover in common. In case of unbalanced bone remodeling, this leads to a deceleration or even eradication (dependent on reduction magnitude) of bone loss.…”

“…24 Considering the action of odanacatib, there is experimental evidence for an increase in periosteal bone formation, additionally to a general reduction of bone turnover, resulting in a thickening of the femoral cortical bone in treated monkeys. 17 Most of the information of antiresorptives' effect is available for cancellous bone, as this compartment has been considered to be most important to osteoporosis and its therapy. Histomorphometric analysis reveals increases in cancellous bone volume by antiresorptives, 7,17 in the case of bisphosphonate treatment owing to the aforementioned filling of remodeling space.…”

“…17 Most of the information of antiresorptives' effect is available for cancellous bone, as this compartment has been considered to be most important to osteoporosis and its therapy. Histomorphometric analysis reveals increases in cancellous bone volume by antiresorptives, 7,17 in the case of bisphosphonate treatment owing to the aforementioned filling of remodeling space. 7 Although this is observed in short-term use, an additional increase that plateaus over long-term use was predicted by theoretical models.…”