title: 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.
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Mohd Parvez
authors.initials: MP
authors.lastname: Khan
authors.affiliation: Centre for Research in Nanotechnology and Science, Indian Institute of Technology-Bombay, Mumbai, India.
authors.forename: Atul Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Centre for Research in Nanotechnology and Science, Indian Institute of Technology-Bombay, Mumbai, India.
authors.forename: Pragya
authors.initials: P
authors.lastname: Shrivastava
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Mahesh Chandra
authors.initials: MC
authors.lastname: Tiwari
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Geet Kumar
authors.initials: GK
authors.lastname: Nagar
authors.affiliation: Department of Laboratory Animal, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Himangshu Kousik
authors.initials: HK
authors.lastname: Bora
authors.affiliation: Mechanical Engineering Department, Indian Institute of Technology-Kanpur, Kanpur, India.
authors.forename: Venkitanarayanan
authors.initials: V
authors.lastname: Parameswaran
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Centre for Research in Nanotechnology and Science, Indian Institute of Technology-Bombay, Mumbai, India.|Department of Chemical Engineering, Indian Institute of Technology-Bombay, Mumbai, India.
authors.forename: Jayesh R
authors.initials: JR
authors.lastname: Bellare
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
mesh_terms: D019386:Alendronate / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000187:drug effects; D000071556:Cancellous Bone / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D000071538:Cortical Bone / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D003460:Crystallization; D018483:Diaphyses / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000473:pathology / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D001713:Biphenyl Compounds; D015507:Drugs, Investigational; D004967:Estrogens; D010281:Parathyroid Hormone; C527128:odanacatib; D019386:Alendronate
keywords: CATHEPSIN K; CRYSTALLINITY; ODANACATIB; STROMAL CELLS; TISSUE MINERALIZATION