title: Combination therapy with eldecalcitol and alendronate has therapeutic advantages over monotherapy by improving bone strength.
abstract: Eldecalcitol (ED-71), a 2β-hydroxypropyloxy derivative of 1α,25(OH)(2)D(3), inhibits bone resorption more potently than does alfacalcidol while maintaining osteoblastic function in an estrogen-deficient, high-turnover osteoporosis rat model. Alendronate (ALN) has been reported to increase bone mass by suppressing bone resorption mainly by inducing apoptosis of osteoclasts. The aim of this study was to clarify the combination effect of ED-71 and ALN on bone loss in ovariectomized rats. Wistar-Imamichi rats (32weeks old) were ovariectomized and randomly assigned to 10 groups (n=9-11); 11 rats were sham-operated. Rats were orally administered either vehicle alone, ALN (0.05, 0.2mg/kg), ED-71 (0.015, 0.03μg/kg), or a combination of ALN and ED-71. The treatment started 2weeks after surgery and continued for 12weeks. ED-71 significantly increased calcium and phosphorus in serum and urine; however, the mean values were within the normal range. Bone mineral density (BMD) and maximum load in both the lumbar spine and femur significantly increased with ED-71 monotherapy, and showed a tendency to increase with ALN monotherapy. Compared with ALN monotherapy, the combination of ALN and ED-71 significantly increased BMD and maximum load in both the lumbar spine and femur, suggesting that the combination therapy is more beneficial than ALN monotherapy in this protocol. The combination treatment had an additive suppressive effect on eroded surface and osteoclast number, with the suppressive effect more potent than either ALN or ED-71 monotherapy. Moreover, the combination therapy partially counteracted the suppressive effects of ALN on bone formation and on the histomorphometric indices of osteoblast number and activity. Interestingly, ALN had no effect on the anabolic action of ED-71. In conclusion, the combination therapy of ALN and ED-71 has therapeutic advantages over ALN monotherapy in terms of improving bone mechanical strength without excessive suppression of bone turnover.
authors.affiliation: Product Research Department, Fuji-Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Sadaoki
authors.initials: S
authors.lastname: Sakai
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraishi
mesh_terms: D015502:Absorptiometry, Photon; D019386:Alendronate / Q000494:pharmacology*; D000596:Amino Acids / Q000652:urine; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D004359:Drug Therapy, Combination; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D010521:Periosteum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D051381:Rats; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D055114:X-Ray Microtomography
chemical_list: D000596:Amino Acids; D050071:Bone Density Conservation Agents; D014807:Vitamin D; C036020:deoxypyridinoline; C547512:eldecalcitol; D019386:Alendronate