Effects of Anti-RANKL Antibody and Zoledronate on Development of Young Mice

[Speaker] Akiko Karakawa:1
[Co-author] Motoki Isawa:1,2, Nobuhiro Sakai:1, Takako Negishi-Koga:1, Masahiro Chatani:1, Masamichi Takami:1
1:Department of Pharmacology, School of Dentistry, Showa University, Japan, 2:Department of Pediatric Dentistry, School of Dentistry, Showa University, Japan

Anti-bone-resorptive drugs such as denosumab (an anti-RANKL antibody drug) and bisphosphonates are used to treat bone diseases, including osteogenesis imperfecta, steroidal osteoporosis, and giant cell tumors, in both adults and young patients. However, the precise effects of those anti-bone-resorptive drugs on younger patients are unknown. In the present study, we analyzed the effects of anti-mouse RANKL antibody and zoledronate (a bisphosphonate) on body size, bone metabolism and tooth development of young mice.
An anti-mouse RANKL antibody (OYC1®, 2.5 mg/kg) or zoledronate (3.0 mg/kg) was subcutaneously administrated into 1-week-old mice by once-weekly injections for 7 weeks or a single-injection. At the age of 8 weeks, body length and weight were measured as a growth index. Femur bone mass and tooth development were analyzed using micro-computed tomography. Osteoclasts and osteoblasts in proximal tibiae or around tooth roots were histologically analyzed.
The survival rate of saline- (control), anti-RANKL antibody- or zoledronate-treated 8-week-old mice, with once-weekly injections for 7 weeks, were 100%, 100% and 83%, respectively. Body length and weight measurements in the anti-RANKL antibody-treated group were normal, while those in the zoledronate-treated group were significantly reduced even with a single-injection. Apparent increases in femur bone mass were observed in both the anti-RANKL antibody-treated and zoledronate-treated groups compared to control group. The number of tartrate-resistant acid phosphatase (TRAP) positive cells, which were identified as osteoclasts, were markedly decreased in tibiae in the anti-RANKL antibody-treated group but not zoledronate-treated group. Although no osteoclasts existed around the tooth roots, teeth in the anti-RANKL antibody-treated group showed normal development, while those in the group treated with zoledronate exhibited very short tooth roots with increased osteoclasts and decreased osteoblasts around them after once-weekly injections for 7 weeks.
Our results suggest that denosumab, an anti-RANKL antibody, has fewer undesirable effects in young patients as compared to zoledronate.
Non-member co-researchers: Masashi Sato, Yukie Shimada and Mitsuko Inoue (Department of Pediatric Dentistry, School of Dentistry, Showa University).

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