Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: Effects of raloxifene HCl, tamoxifen, estrogen, and alendronate
Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: Effects of raloxifene HCl, tamoxifen, estrogen, and alendronate
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DOI：
10.1016/8756-3282(96)00085-3
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发表时间：
1996-06-01
期刊：
影响因子：
4.1
通讯作者：
Chandrasekhar, S
中科院分区：
文献类型：
--
作者：
Frolik, CA;Bryant, HU;Chandrasekhar, S
与绝经后骨质疏松症相关的骨质流失可以通过雌激素或双膦酸盐等抗吸收剂治疗来减少。双磷酸盐主要影响骨质流失，而雌激素还具有降低血清胆固醇水平的优势，尽管它们对子宫有不利影响。最近，雷洛昔芬盐酸盐是一种选择性雌激素受体调节剂 (SERM)，已被证明可以减少骨质流失和胆固醇水平，且不会对子宫产生负面影响。这些抗吸收剂会减少骨转换，这可以通过测量骨转换标记物来评估。为了比较雌激素、两种 SERM（雷洛昔芬盐酸盐和他莫昔芬）和阿仑膦酸盐（一种通过雌激素独立途径抑制骨质流失的双膦酸盐）对代谢骨标志物和胆固醇水平的影响，在每天口服雷洛昔芬盐酸盐（3 mg/kg）、乙炔雌二醇（0.1 mg/kg）、他莫昔芬 (3 mg/kg) 或阿仑膦酸钠 (3 mg/kg)。盐酸雷洛昔芬、他莫昔芬和乙炔雌二醇在治疗开始后 4 天内将血清胆固醇降低至低于对照值的水平，而阿仑膦酸钠没有效果。治疗3周后，乙炔雌二醇治疗动物的血清胆固醇值虽然仍低于对照值，但已上升6.4倍；盐酸雷洛昔芬和他莫昔芬的值仅上升了 1.4-1.5 倍。因此，与雌激素相比，SERMs可能对血清胆固醇具有更长期的抑制作用。治疗第 4 天时，与对照组相比，切除卵巢的大鼠血清骨钙素水平增加了 1.4 倍。乙炔雌二醇在治疗 1 周内将该水平降低了 18%，在 3 周时降低幅度更显着，达到 34%。相比之下，盐酸雷洛昔芬、他莫昔芬或阿仑膦酸钠在第一周后效果非常小（减少 6% 至 13%），尽管 3 周后减少了 18% 至 25%。手术后 2 周，卵巢切除大鼠的尿吡啶啉水平比对照组升高 1.4 倍，用盐酸雷洛昔芬、乙炔雌二醇、他莫昔芬或阿仑膦酸钠治疗 2 周后，尿吡啶啉水平降至对照值。这些数据支持这样的概念：雌激素、雷洛昔芬盐酸盐、他莫昔芬和阿仑膦酸钠通过减少骨吸收来抑制去势动物的骨丢失。结果还表明，对于治疗绝经后骨质疏松症，雷洛昔芬盐酸盐除了具有抑制骨吸收的能力外，还可能比其他研究的抗骨吸收药物具有非子宫营养和低胆固醇作用的优势。
Bone loss associated with postmenopausal osteoporosis can be reduced by treatment with antiresorptive agents such as estrogen or bisphosphonates. Whereas bisphosphonates primarily affect bone loss, estrogens have an advantage of also lowering serum cholesterol levels, although they have a detrimental effect in the uterus. Recently, raloxifene HCl, a selective estrogen receptor modulator (SERM), has been shown to decrease both bone loss and cholesterol levels without the negative uterine effects. These antiresorptive agents reduce bone turnover, which can be evaluated by measuring bone turnover markers. To compare the effects of estrogen, two SERMs (raloxifene HCl and tamoxifen), and alendronate, a bisphosphonate that inhibits bone loss by an estrogen-independent pathway, on metabolic bone markers and cholesterol levels, rats were ovariectomized 2 weeks prior to 3 weeks of daily oral treatment with raloxifene HCl (3 mg/kg), ethynyl estradiol (0.1 mg/kg), tamoxifen (3 mg/kg), or alendronate (3 mg/kg). Raloxifene HCl, tamoxifen, and ethynyl estradiol reduced serum cholesterol to levels below control values within 4 days after initiation of treatment, whereas alendronate had no effect. After 3 weeks of treatment, serum cholesterol values in ethynyl estradiol treated animals, although still below the control value, had risen 6.4-fold; raloxifene HCl and tamoxifen values rose by only 1.4-1.5-fold. Therefore, compared with estrogen, SERMs may have a longer-term suppressive effect on serum cholesterol. At 4 days of treatment, ovariectomized rats had a 1.4-fold increase in serum osteocalcin level compared with controls. Ethynyl estradiol lowered this level within 1 week of treatment by 18%, with a more pronounced reduction of 34% at 3 weeks. In contrast, raloxifene HCl, tamoxifen, or alendronate had very little effect after the first week (6% to 13% reduction), although there was an 18% to 25% reduction by 3 weeks. Urinary pyridinoline levels, elevated 1.4-fold in the ovariectomized rat compared with controls 2 weeks after surgery, were reduced to control values after 2 weeks of treatment with raloxifene HCl, ethynyl estradiol, tamoxifen, or alendronate. These data support the concept that estrogen, raloxifene HCl, tamoxifen, and alendronate inhibit bone loss in the ovariectomized animal by reducing bone resorption. The results also indicate that for treatment of postmenopausal osteoporosis, raloxifene HCl may have an advantage over the other antiresorptives studied in having both non-uterotrophic and hypocholesterolemic effects in addition to its ability to inhibit bone resorption.