Kippo K, Hannuniemi R, Virtamo T, Laurén L, Ikävalko H, Kovanen V, Osterman T, Sellman R
Leiras Oy, Biomedical Research Center, Turku, Finland.
Bone. 1995 Dec;17(6):533-42. doi: 10.1016/8756-3282(95)00388-6.
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.
本研究旨在探讨氯膦酸盐抑制大鼠卵巢切除术后骨丢失及骨转换增加的能力。雌二醇作为参比化合物给药。70只90日龄的Sprague-Dawley大鼠接受卵巢切除术（OVX）或假手术（Sham），并分为7组。两组假手术组和两组卵巢切除组分别皮下注射氯膦酸盐的赋形剂或雌二醇的赋形剂。其他卵巢切除组皮下给予两种剂量水平（5mg/kg或12.5mg/kg，每周两次）的氯膦酸钠或17β-雌二醇（10μg/kg，每周五次），持续8周。测定股骨长度、体积、干重和灰重，并将胫骨近端用于骨组织形态计量学分析。从尿液和血清中检测骨代谢标志物。卵巢切除术后8周，胫骨近端干骺端小梁骨面积显著减少54%。氯膦酸盐和雌二醇抑制了（p<0.001）这种骨质减少。两种药物均防止了股骨灰重/体积的降低。氯膦酸盐和雌二醇对卵巢切除大鼠骨吸收的抑制作用还可通过尿羟脯氨酸和赖氨酰吡啶啉排泄减少来检测（p<0.001）。氯膦酸盐和雌二醇使卵巢切除引起的胫骨外侧皮质骨内膜矿物质沉积率（Ec.MAR）升高降低（p<0.001）至假手术组水平。相反，在卵巢切除/赋形剂组中，胫骨皮质骨内侧的骨膜MAR没有显著变化。雌二醇使骨膜MAR降至假手术组水平以下（p<0.01）。这些结果表明，成年大鼠卵巢切除术后两个月会导致胫骨和股骨骨质减少。氯膦酸盐以及雌二醇均可抑制卵巢切除大鼠的骨吸收和骨转换，抑制骨质减少的发展。两种氯膦酸盐剂量（5mg/kg和12.5mg/kg）对卵巢切除动物均有有益作用。
