Evaluation of pharmaceuticals with a novel 50-hour animal model of bone loss.
Osteoporosis remains a major public health problem through its associated fragility fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require surgical skills and several weeks to establish. Osteoclast differentiation and activation is mediated by RANKL. Here we report the establishment of a novel and rapid bone loss model by the administration of soluble RANKL (sRANKL) to mice. Mice were injected intraperitoneally with sRANKL and used to evaluate existing anti-osteoporosis drugs. sRANKL decreased BMD within 50 h in a dose-dependent manner. The marked decrease in femoral trabecular BMD shown by pQCT and the 3D images obtained by microCT were indistinguishable from those observed in the OVX model. Histomorphometry showed that osteoclastic activity was significantly increased in the sRANKL-injected mice. In addition, serum biochemical markers of bone turnover such as Ca, C-telopeptide of type 1 collagen (CTX), and TRACP5b were also significantly increased in the sRANKL-injected mice in a dose-dependent manner. Bisphosphonates (BPs), selective estrogen receptor modulators (SERMs), and PTH are commonly used for the treatment of osteoporosis. We successfully evaluated the effects of anti-bone-resorbing agents such as BPs, a SERM, and anti-RANKL-neutralizing antibody on bone resorption in a couple of weeks. We also evaluated the effects of PTH on bone formation in 2 wk. A combination of sRANKL injections and OVX made it possible to evaluate a SERM. The sRANKL model is the simplest, fastest, and easiest of all osteoporosis models and could be useful in the evaluation of drug candidates for osteoporosis.
Tomimori
Yoshiya
Y
Nagahama Institute for Biochemical Science, Oriental Yeast Co., Nagahama, Shiga, Japan.
Mori
Kaoru
K
Koide
Masanori
M
Nakamichi
Yuko
Y
Ninomiya
Tadashi
T
Udagawa
Nobuyuki
N
Yasuda
Hisataka
H
D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents; D002454:Cell Differentiation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D051379:Mice; D010010:Osteoclasts; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010281:Parathyroid Hormone / Q000494:pharmacology; D053245:RANK Ligand / Q000633:toxicity; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013997:Time Factors
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D010281:Parathyroid Hormone; D053245:RANK Ligand; D020845:Selective Estrogen Receptor Modulators; C505689:Tnfsf11 protein, mouse