odanacatib and Bone-Diseases--Metabolic

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.

Topics: Alendronate; Animals; Biomechanical Phenomena; Biphenyl Compounds; Bone Density; Bone Diseases, Metabolic; Calcification, Physiologic; Cancellous Bone; Cortical Bone; Crystallization; Diaphyses; Drugs, Investigational; Estrogens; Female; Femur; Lumbar Vertebrae; Osteoblasts; Osteoclasts; Osteoporosis; Parathyroid Hormone; Rabbits

Topics: Absorptiometry, Photon; Animals; Biomarkers; Biomechanical Phenomena; Biphenyl Compounds; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Cancellous Bone; Cortical Bone; Disease Models, Animal; Female; Femur; Lumbar Vertebrae; Organ Size; Ovariectomy; Rabbits; Regression Analysis; Tomography, X-Ray Computed; Withholding Treatment

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13-weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L-006235 (L-235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX-vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L-235 had no effect. Similarly, endocortical bone-formation rate and the number of double-labeled Haversian canals in the femoral diaphysis were not affected by L-235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady-state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX-vehicle control to levels comparable with sham or ALN. ODN also dose-dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L-235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption.

Topics: Alendronate; Animals; Biphenyl Compounds; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Cathepsin K; Densitometry; Dose-Response Relationship, Drug; Estradiol; Female; Femur; Haversian System; Rabbits