title: The combination therapy with alfacalcidol and risedronate improves the mechanical property in lumbar spine by affecting the material properties in an ovariectomized rat model of osteoporosis.
abstract: BACKGROUND
  We conducted the present study to investigate the therapeutic effects of a combination treatment of alfacalcidol (ALF) and risedronate (RIS) on the bone mechanical properties of bone and calcium (Ca) metabolism using an ovariectomized (OVX) rat model of osteoporosis.
  
  
  METHODS
  Female Wistar rats were OVX- or sham-operated at 40 weeks of age. Twelve weeks post-surgery, rats were randomized into seven groups: 1) sham + vehicle, 2) OVX + vehicle, 3) OVX + ALF 0.025 microg/kg/day, 4) OVX + ALF 0.05 microg, 5) OVX + RIS 0.3 mg, 6) OVX + RIS 3.0 mg, 7) OVX + ALF 0.025 microg + RIS 0.3 mg. Each drug was administered orally five times a week for 12 weeks. After treatment, we evaluated the mechanical properties of the lumbar vertebra and femoral midshaft. In the lumbar vertebra, structural and material analyses were performed using micro-computed tomography (micro-CT) and microbeam X-ray diffraction (micro-XRD), respectively. Biochemical markers in serum and urine were also determined.
  
  
  RESULTS
  (1) With respect to improvement in the mechanical strength of the lumbar spine and the femoral midshaft, the combination treatment of ALF and RIS at their sub-therapeutic doses was more effective than each administered as a monotherapy; (2) In the suppression of bone resorption and the amelioration of microstructural parameters, the effects of ALF and RIS were considered to be independent and additive; (3) The improvement of material properties, such as microstructural parameters and the biological apatite (Bap) c-axis orientation, contributed to the reinforcement of spinal strength; and (4) The combination treatment of ALF and RIS normalized urinary Ca excretion, suggesting that this treatment ameliorated the changes in Ca metabolism.
  
  
  CONCLUSIONS
  These results demonstrate that the combination treatment of ALF and RIS at their sub-therapeutic doses can improve the mechanical properties of the spine as well as the femur and ameliorate changes in Ca metabolism in an animal model of osteoporosis, suggesting that the combination treatment of ALF and RIS has a therapeutic advantage over each monotherapy for the treatment of osteoporosis.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co, Ltd,, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan. shiraishiayk@chugai-pharm.co.jp
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraishi
authors.forename: Sayaka
authors.initials: S
authors.lastname: Miyabe
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Nakano
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Umakoshi
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000652:urine; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000502:physiology; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017886:Durapatite / Q000032:analysis / Q000378:metabolism; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006887:Hydroxycholecalciferols / Q000494:pharmacology* / Q000627:therapeutic use; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D000068296:Risedronic Acid; D013314:Stress, Mechanical; D016896:Treatment Outcome; D016474:Weight-Bearing / Q000502:physiology; D014961:X-Ray Diffraction; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D006887:Hydroxycholecalciferols; D017886:Durapatite; D000068296:Risedronic Acid; D012968:Etidronic Acid; C008088:alfacalcidol