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

Abstract

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/ PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness.

Dynamic expression of SMAD3 is critical in�osteoblast differentiation of PDMCs

“…Osteoporosis is a disease of the bones, in which the rate of bone resorption by osteoclasts exceeds the rate of bone formation by osteoblasts (41). The therapeutic strategy for treating patients with osteoporosis is straightforward: Either decrease the activity of osteoclasts with bisphosphonates and estrogen-associated compounds or increase the activity of osteoblasts with parathyroid hormones (42). Therefore, the agent alendronate acid is widely used to increase bone marrow density in clinics (43,44).…”

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

“…Here it is of interest that ovariectomized skeletally mature New Zealand rabbits displayed reduced ductility and enhanced brittleness of the central femur after 14 weeks of odanacatib treatment. [158] Other antiresorptive therapies such as bisphosphonate treatment have also been demonstrated to contribute to osteopetrosis-like symptoms in humans. A case of osteopetrosis was described for a 12 year-old child who had received a bisphosphonate treatment for 5 years [159] and numerous bisphosphonateinduced jaw osteonecrosis cases in adults have been discussed as a specific form of chemically induced osteopetrosis.…”

From disease to treatment: from rare skeletal disorders to treatments for osteoporosis

“…Furthermore, odanacatib did not impair callus formation or its biomechanical integrity in a rabbit model of fracture healing [ 41 ]. A recent study reported that while odanacatib restored trabecular BMD, microstructure and biomechanical properties, and increased bone formation and cortical thickness of the central femur in osteopenic rabbits, it also led to loss of crystal heterogeneity that appeared to contribute to cortical brittleness [ 42 ]. The latter report, that contrasts all other observations, needs to be confirmed in further studies.…”