Effects of KCA-098 on bone metabolism: comparison with those of ipriflavone.
We previously found that 3,9-bis(N,N-dimethylcarbamoyloxy)-5H- benzofuro[3,2-c]quinoline-6-one (KCA-098) inhibited bone resorption in organ culture. In this study, to determine if KCA-098 is therapeutically applicable for the treatment of osteoporosis, we compared the effect of KCA-098 on bone tissues with that of ipriflavone, a drug that is clinically used for the treatment of osteoporosis. Both KCA-098 and ipriflavone inhibited parathyroid hormone-, prostaglandin E2-, 1 alpha,25-dihydroxyvitamin D3- and interleukin 1 beta-induced bone resorption of fetal rat bones, but the inhibitory activity of KCA-098 was more potent than that of ipriflavone. In fact, the effective concentrations of KCA-098 were 10 to 100 times lower than those of ipriflavone. Oral administration of KCA-098 (1 and 3 mg/kg) or ipriflavone (100 mg/kg) to ovariectomized rats on a low-calcium diet increased the breaking force and bone density of the femora, indicating that KCA-098 is an effective on the whole animal as ipriflavone. Furthermore, KCA-098 increased the length and calcium content of 9-day chick embryonic femora cultured in vitro, whereas ipriflavone did not, suggesting that KCA-098 had a direct stimulatory effect on bone mineralization. Therefore, KCA-098 seems to be more potent than ipriflavone in stimulating bone tissue formation and may thus be expected to become a useful agent for the treatment of osteoporosis.
Tsutsumi
N
N
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Kawashima
K
K
Nagata
H
H
Tsuyuki
J
J
Itoh
F
F
Arai
N
N
Kojima
M
M
Ujiie
A
A
Endo
H
H
D015650:24,25-Dihydroxyvitamin D 3 / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002136:Calcium, Dietary / Q000008:administration & dosage; D002642:Chick Embryo; D003375:Coumestrol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D010024:Osteoporosis / Q000378:metabolism; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D002136:Calcium, Dietary; D007375:Interleukin-1; D007529:Isoflavones; D010281:Parathyroid Hormone; C088191:KCA 098; D015650:24,25-Dihydroxyvitamin D 3; C018986:ipriflavone; D015232:Dinoprostone; D002118:Calcium; D003375:Coumestrol