Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone

• Published in: Journal of bone and mineral research 2012-02, Vol.27 (2), p.461-473
• Main Authors: Harada, Suguru, Mizoguchi, Toshihide, Kobayashi, Yasuhiro, Nakamichi, Yuko, Takeda, Satoshi, Sakai, Sadaoki, Takahashi, Fumiaki, Saito, Hitoshi, Yasuda, Hisataka, Udagawa, Nobuyuki, Suda, Tatsuo, Takahashi, Naoyuki
• Format: Article
• Language: English
• Subjects: ACTIVE VITAMIN D; Animals; Biological and medical sciences; Body Weight - drug effects; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone Density - drug effects; BONE METABOLISM; Bone Resorption - blood; Bone Resorption - pathology; Bone Resorption - physiopathology; Calcitriol - administration & dosage; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Calcium - blood; Drug Administration Schedule; ELDECALCITOL; Femur - drug effects; Femur - pathology; Fundamental and applied biological sciences. Psychology; Male; Mice; Mice, Inbred C57BL; OSTEOCLAST; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; Ovariectomy; RANK Ligand - metabolism; RANKL; Skeleton and joints; Vertebrates: osteoarticular system, musculoskeletal system; Vitamin D - analogs & derivatives
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.555

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. © 2012 American Society for Bone and Mineral Research