Frolik C A, Bryant H U, Black E C, Magee D E, Chandrasekhar S
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Bone. 1996 Jun;18(6):621-7. doi: 10.1016/8756-3282(96)00085-3.
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.
与绝经后骨质疏松症相关的骨质流失可以通过使用抗吸收剂（如雌激素或双膦酸盐）进行治疗来减少。双膦酸盐主要影响骨质流失，而雌激素具有降低血清胆固醇水平的优势，尽管它们对子宫有不良影响。最近，盐酸雷洛昔芬，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，而不会产生负面的子宫效应。这些抗吸收剂可降低骨转换，这可以通过测量骨转换标志物来评估。为了比较雌激素、两种SERM（盐酸雷洛昔芬和他莫昔芬）以及阿仑膦酸钠（一种通过非雌激素依赖途径抑制骨质流失的双膦酸盐）对代谢性骨标志物和胆固醇水平的影响，在对大鼠进行每日口服盐酸雷洛昔芬（3mg/kg）、乙炔雌二醇（0.1mg/kg）、他莫昔芬（3mg/kg）或阿仑膦酸钠（3mg/kg）治疗3周前2周将其卵巢切除。治疗开始后4天内，盐酸雷洛昔芬、他莫昔芬和乙炔雌二醇将血清胆固醇降至低于对照值的水平，而阿仑膦酸钠则无此作用。治疗3周后，乙炔雌二醇治疗的动物血清胆固醇值虽仍低于对照值，但已上升了6.4倍；盐酸雷洛昔芬和他莫昔芬的值仅上升了1.4至1.5倍。因此，与雌激素相比，SERM可能对血清胆固醇有更长期的抑制作用。治疗4天时，卵巢切除的大鼠血清骨钙素水平与对照组相比增加了1.4倍。乙炔雌二醇在治疗1周内将该水平降低了18%，在3周时更显著地降低了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作用很小（降低6%至13%），尽管在3周时降低了18%至25%。与对照组相比，卵巢切除的大鼠术后2周尿吡啶啉水平升高了1.4倍，在用盐酸雷洛昔芬、乙炔雌二醇、他莫昔芬或阿仑膦酸钠治疗2周后降至对照值。这些数据支持了雌激素、盐酸雷洛昔芬、他莫昔芬和阿仑膦酸钠通过减少骨吸收来抑制卵巢切除动物骨质流失的概念。结果还表明，对于绝经后骨质疏松症的治疗，盐酸雷洛昔芬除了具有抑制骨吸收的能力外，在无子宫营养作用和降胆固醇作用方面可能比其他研究的抗吸收剂更具优势。
