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
Mohd. Parvez Khan M.Sc., Atul Kumar Singh M.Tech., Abhishek Kumar Singh M.Sc., Pragya Shrivastava M.Sc., Mahesh Chandra Tiwari M.Sc., Geet Kumar Nagar B.Sc., Himangshu Kousik Bora M.V.Sc., Venkitanarayanan Parameswaran PhD, Sabyasachi Sanyal PhD, Jayesh R. Bellare PhD, and Naibedya Chattopadhyay PhD
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 anti-resorptive, 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 OVX and following induction of bone loss were given a steady-state exposure of ODN (9μM/day) for 14 weeks. Sham operated and OVX rabbits treated with alendronate (ALD), 17β-estradiol (E2) or PTH served as various controls. Efficacy was evaluated by assessing BMD, bone microarchitecture (using microcomputed 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 BMD, area and thickness, and periosteal deposition) and serum P1NP were largely comparable. Skeletal improvements in ALD 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, increases crystallinity and tissue mineralization thus leading to increased cortical bone brittleness.