Treatment with the combination of ibandronate plus eldecalcitol has a synergistic effect on inhibition of bone resorption without suppressing bone formation in ovariectomized rats.
Bisphosphonates are widely used in the treatment of osteoporosis and contribute to the reduction of bone fractures. Ibandronate (IBN) is a highly potent, nitrogen-containing bisphosphonate, which is administered orally or intravenously at extended dosing intervals. Vitamin D or active vitamin D3 derivatives are also used in the treatment of osteoporosis, and are often used in combination with other drugs. In this study, we investigated the effect of treatment with the combination of once-monthly s.c. dosing of IBN plus once-daily oral eldecalcitol (ELD), an active vitamin D3 derivative, using aged ovariectomized (OVX) rats. Treatment was started the day after OVX, and analyses were performed 4, 8, and 12 weeks thereafter by determination of bone markers, bone mineral density, biomechanical properties, and histomorphometry. The combination treatment showed a synergistic effect in increasing both lumbar and femoral BMD, and resulted in a significant increase in bone ultimate load. The combination of IBN plus ELD acted synergistically to reduce bone resorption, whereas bone formation did not decrease any more than with monotherapy with either IBN or ELD. Bone formation independent of bone resorption (a process known as 'minimodeling') was not changed in vehicle treated OVX rats despite the increase in bone turnover. ELD upregulated minimodeling, which was however not diminished in the combination treatment. In conclusion, treatment with the combination of IBN plus ELD was beneficial in the treatment of osteoporosis in aged OVX rats. It exhibited a synergistic inhibitory effect on bone resorption and keeps bone formation at the level of sham controls. This uncoupling of bone resorption/bone formation was affected, to some extent, by minimodeling-based bone formation which is independent of bone resorption. This combination regimen which showed synergistic effect on BMD and bone ultimate load without inhibition of bone formation may be beneficial in long-term osteoporosis treatment to prevent bone fractures.
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: sakaisdo@chugai-pharm.co.jp.
Sadaoki
S
Sakai
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: takedasts@chugai-pharm.co.jp.
Satoshi
S
Takeda
Pharmacology 3, Pharmacology Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530 Japan. Electronic address: m-sugimoto@so.taisho.co.jp.
Masanori
M
Sugimoto
Discovery Pharmacology Dept. 1, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: shimizumsr@chugai-pharm.co.jp.
Masaru
M
Shimizu
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: shimonakayss@chugai-pharm.co.jp.
Yasushi
Y
Shimonaka
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: yogoknj@chugai-pharm.co.jp.
Kenji
K
Yogo
Primary Lifecycle Management Dept., Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihombashi Muromachi, Chuo-ku, Tokyo 103-8324, Japan. Electronic address: hashimotojnk@chugai-pharm.co.jp.
Junko
J
Hashimoto
Roche Pharmaceutical Research and Early Development, Discovery Oncology, Roche Innovation Center Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany. Electronic address: frieder.bauss@roche.com.
Frieder
F
Bauss
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513 Japan. Electronic address: endokui@chugai-pharm.co.jp.
Koichi
K
Endo
D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D000077557:Ibandronic Acid; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D010758:Phosphorus / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives*
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D014807:Vitamin D; D010758:Phosphorus; C547512:eldecalcitol; D002118:Calcium; D000077557:Ibandronic Acid
Combination therapy; Eldecalcitol; Ibandronate; Osteoporosis treatment; Ovariectomized (OVX) rats