Increase in femoral bone mass by ipriflavone alone and in combination with 1 alpha-hydroxyvitamin D3 in growing rats with skeletal unloading.
We assessed the possibility that ipriflavone treatment might result in bone restoration in immobilized rats. We also investigated the effect of combined treatment with ipriflavone and vitamin D3 on the bone. Male Sprague-Dawley rats, 6 weeks of age, were subjected to unilateral sciatic neurectomy. Three weeks after the operation, ipriflavone (100 mg/kg), 1 alpha-hydroxyvitamin D3 [1 alpha (OH)D3, 25 ng/kg], or both ipriflavone and 1 alpha (OH)D3 were orally administered every day for 12 or 24 weeks. After 12 weeks of treatment, only the group receiving combined treatment with ipriflavone and 1 alpha (OH)D3 showed increases in total femur calcium content (+16.4%, compared with the control). After 24 weeks, both animals treated with ipriflavone alone and those that had received the combination of ipriflavone and 1 alpha (OH)D3 showed significant increases in femur calcium content (+18.0% and +23.8%, respectively). In these treatment groups, X-ray analysis revealed an increase in bone mineral density over the entire length of the femur, and an increase in cortical diameter at the midshaft without affecting medullary width. Administration of 1 alpha (OH)D3 (25 ng/kg) alone had no effect. Body weight, femur length, and serum markers of calcium and bone metabolism were not affected in any group. We evaluated the relationship between ipriflavone and vitamin D3 in bone cells in a culture system using rat bone marrow stromal cells in which the cells subsequently form mineralized bone-like tissue. Continuous treatment with ipriflavone (10(-5) M) for 21 days resulted in an increase in osteocalcin secretion, and enhanced its response to 1 alpha, 25-dihydroxyvitamin D3 (10(-11) M-10(-8 M)). These findings indicate that ipriflavone treatment increases the femoral bone mass in immobilized rats. In addition, a low dose of 1 alpha (OH)D3, which did not induce hypercalcemia, in combination with ipriflavone, augmented the stimulatory effect of ipriflavone alone on the bone mass, possibly due to a direct effect of each agent on osteoblastic cells.
Notoya
K
K
Department III, Pharmaceutical Research Laboratories II, Takeda Chemical Industries Ltd., Osaka, Japan.
Yoshida
K
K
Tsukuda
R
R
Taketomi
S
S
Tsuda
M
M
D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D016723:Bone Remodeling / Q000187:drug effects*; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D004338:Drug Combinations; D005269:Femur / Q000737:chemistry / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects*; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D014807:Vitamin D / Q000494:pharmacology*; D016474:Weight-Bearing
D004338:Drug Combinations; D007529:Isoflavones; D010281:Parathyroid Hormone; D015675:Osteocalcin; D014807:Vitamin D; C018986:ipriflavone; D002118:Calcium