The effects of clodronate on increased bone turnover and bone loss due to ovariectomy in rats.
The present study was carried out to investigate the ability of clodronate to inhibit ovariectomy-induced bone loss and increased bone turnover in rats. Estradiol was administered as a reference compound. Seventy Sprague-Dawley rats were ovariectomized (OVX) or sham-operated (Sham) at the age of 90 days and divided into seven groups. Two Sham and two OVX groups received subcutaneously either the vehicle of clodronate or the vehicle of estradiol. Other OVX groups were given s.c. either disodium clodronate at two dose levels (5 mg/kg or 12.5 mg/kg twice a week) or 17 beta-estradiol (10 micrograms/kg five times a week) for 8 weeks. Femur length, volume, dry weight, and ash weight were determined, and proximal ends of tibiae were used for bone histomorphometry. Markers of bone metabolism were measured from urine and serum. A significant loss of 54% of trabecular bone area of proximal tibial metaphysis was found at 8 weeks after ovariectomy. Clodronate and estradiol inhibited (p < 0.001) this osteopenia. Both drugs prevented the decrease in ash weight/volume of the femur. The inhibitory effect of clodronate and estradiol on bone resorption in OVX rats could be detected also in decreased urinary excretion of hydroxyproline and lysylpyridinoline (p < 0.001). Clodronate and estradiol decreased (p < 0.001) the ovariectomy-induced enhanced tibial endocortical mineral apposition rate (Ec.MAR) on the lateral cortex to the level of the Sham group. In contrast, periosteal MAR analyzed on the medial side of tibial cortical bone did not change significantly in the OVX/Veh group. Estradiol decreased periosteal MAR to below the level in the Sham group (p < 0.01). These results suggest that ovariectomy of growing rats resulted in tibial and femoral osteopenia two months later. Clodronate as well as estradiol can suppress bone resorption and turnover in ovariectomized rats, inhibiting the development of osteopenia. Both clodronate doses (5 and 12.5 mg/kg) had beneficial effects in ovariectomized animals.
Kippo
K
K
Leiras Oy, Biomedical Research Center, Turku, Finland.
Hannuniemi
R
R
Virtamo
T
T
Laurén
L
L
Ikävalko
H
H
Kovanen
V
V
Osterman
T
T
Sellman
R
R
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D018488:Bone Demineralization, Pathologic / Q000209:etiology / Q000503:physiopathology*; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000737:chemistry / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology*; D018483:Diaphyses / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005260:Female; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry; D014599:Uterus / Q000473:pathology
D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D004002:Clodronic Acid