title: Effects of 18-month treatment with bazedoxifene on enzymatic immature and mature cross-links and non-enzymatic advanced glycation end products, mineralization, and trabecular microarchitecture of vertebra in ovariectomized monkeys.
abstract: Bazedoxifene (BZA) is used for the treatment of post-menopausal osteoporosis. To elucidate changes in collagen, mineralization, and structural properties and their relationship to bone strength after treatment with BZA in ovariectomized (OVX) monkeys, the levels of collagen and enzymatic immature, mature, and non-enzymatic cross-links were simultaneously examined, as well as trabecular architecture and mineralization of vertebrae. Adult female cynomolgus monkeys were divided into 4 groups (n=18 each) as follows: Sham group, OVX group, and OVX monkeys given either 0.2 or 0.5mg/kg BZA for 18 months. Collagen concentration, enzymatic and non-enzymatic pentosidine cross-links, whole fluorescent advanced glycation end products (AGEs), trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. The levels of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness (Tb.Th) in BZA-treated groups were significantly higher than those in the OVX control group. In contrast, the trabecular bone pattern factor (TBPf), the structure model index (SMI), the enzymatic cross-link ratio, and the levels of pentosidine and whole AGEs in BZA-treated groups were significantly lower than those in the OVX control group. Stepwise logistic regression analysis revealed that BV/TV, Tb.Th, TbPf, and pentosidine or whole AGEs independently affected ultimate load (model R(2)=0.748, p<0.001) and breaking energy (model R(2)=0.702). Stiffness was affected by Tb.Th, enzymatic immature cross-link levels and their ratio (model R(2)=0.400). Treatment with BZA prevented OVX-induced deterioration in the total levels of immature enzymatic cross-links and AGEs accumulation and structural properties such as BV/TV, Tb.Th, and TbPf, which contribute significantly to vertebral cancellous bone strength.
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nishizawa
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Arakawa
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Hinako
authors.initials: H
authors.lastname: Okabe
authors.affiliation: Tsukuba Research Center, HAMRI Co., Ltd., Ibaraki, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Seki
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Marumo
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008252:Macaca fascicularis; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D010052:Ovariectomy; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; D003094:Collagen; D001120:Arginine; C062187:pentosidine; D008239:Lysine; C447119:bazedoxifene
keywords: Advanced glycation end products; Bazedoxifene; Cancellous bone; Collagen cross-links; OVX monkeys; Pentosidine