title: Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone.
abstract: Eldecalcitol (ED-71) is a new vitamin D₃ derivative recently approved for the treatment of osteoporosis in Japan. Previous studies have shown that the daily administration of ED-71 increases bone mineral density (BMD) by suppressing bone resorption in various animal models. In this study, we examined how ED-71 suppresses bone resorption in vivo, by analyzing bone histomorphometry and ex vivo osteoclastogenesis assays. Daily administration of ED-71 (50 ng/kg body weight) to 8-week-old male mice for 2 and 4 weeks increased BMD in the femoral metaphysis without causing hypercalcemia. Bone and serum analyses revealed that ED-71 inhibited bone resorption and formation, indicating that the increase in BMD is the result of the suppression of bone resorption. This suppression was associated with a decrease in the number of osteoclasts in trabecular bone. We previously identified cell cycle-arrested receptor activator of NF-κB (RANK)-positive bone marrow cells as quiescent osteoclast precursors (QOPs) in vivo. Daily administration of ED-71 affected neither the number of RANK-positive cells in vivo nor the number of osteoclasts formed from QOPs in ex vivo cultures. In contrast, ED-71 suppressed the expression of RANK ligand (RANKL) mRNA in femurs. Immunohistochemical experiments also showed that the perimeter of the RANKL-positive cell surface around the trabecular bone was significantly reduced in ED-71-treated mice than in the control mice. ED-71 administration also increased BMD in 12-week-old ovariectomized mice, through the suppression of RANKL expression in the trabecular bone. These results suggest that the daily administration of ED-71 increases BMD by suppressing RANKL expression in trabecular bone in vivo.
authors: Institute for Oral Science, Matsumoto Dental University, Shiojiri-shi, Nagano, Japan.
authors: Suguru
authors: S
authors: Harada
authors: Toshihide
authors: T
authors: Mizoguchi
authors: Yasuhiro
authors: Y
authors: Kobayashi
authors: Yuko
authors: Y
authors: Nakamichi
authors: Satoshi
authors: S
authors: Takeda
authors: Sadaoki
authors: S
authors: Sakai
authors: Fumiaki
authors: F
authors: Takahashi
authors: Hitoshi
authors: H
authors: Saito
authors: Hisataka
authors: H
authors: Yasuda
authors: Nobuyuki
authors: N
authors: Udagawa
authors: Tatsuo
authors: T
authors: Suda
authors: Naoyuki
authors: N
authors: Takahashi
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D001862:Bone Resorption / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D004334:Drug Administration Schedule; D005269:Femur / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives*
chemical_list: D053245:RANK Ligand; D014807:Vitamin D; D002117:Calcitriol; C547512:eldecalcitol; D002118:Calcium