Bowman A R, Sass D A, Marshall I, Ma Y F, Liang H, Jee W S, Epstein S
Department Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.
J Bone Miner Res. 1996 Aug;11(8):1191-8. doi: 10.1002/jbmr.5650110819.
Cyclosporin A (CsA) administered to the oophorectomized (Ox) rat exacerbates the high turnover osteopenia associated with estrogen deficiency. 17 beta-estradiol replacement therapy prevent this bone loss. The aim of this study was to see whether an estrogen-like compound, Raloxifene analog (LY117018 HCL, Ral) could likewise ameliorate CsA-induced osteopenia in the Ox rat. Sixty 6-month-old Sprague-Dawley rats, divided into five groups, underwent oophorectomy. One group acted as a basal group and the others received either vehicle (group B), CsA 15 mg/kg/day (group C), Ral 3 mg/kg/day (group D), or CsA 15 mg/kg/day and Ral 3 mg/kg/day (group E) for 28 days by gavage. A sixth sham operated group of 12 rats received vehicle only (group A). Rats were weighed and bled on days 0, 14, and 28 for measurement of ionized calcium, glucose, osteocalcin (BGP), 17 beta-estradiol, and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). Tibiae were removed on day 28 for bone histomorphometry after double tetracycline and calcein labeling. Oophorectomy caused a significant gain in weight in groups B and C which was prevented by Ral in groups D and E. Randomized blood glucose levels and 1,25(OH)2D3 levels were elevated in both CsA-treated groups. Blood ionized calcium levels were lower in vehicle (group B) compared with sham (group A) on day 28. Ox (group B) had significantly higher serum BGP levels compared with sham-operated rats. Serum BGP levels were further elevated in group C compared with vehicle and were lowered in both Ral-treated groups to vehicle levels by day 28. Bone histomorphometry revealed a high turnover osteopenia with increased parameters of bone formation and resorption and loss of cancellous bone volume postoophorectomy (group B). CsA (group C) exacerbated the effects of oophorectomy. Ral (group D) completely prevented the high turnover osteopenia caused by oophorectomy and was able to attenuate substantially the effects of CsA in the Ox rat (group E). Ral therapy ameliorated CsA-induced osteopenia in the Ox rat and might prove a useful agent in preventing bone loss in postmenopausal women receiving CsA.
给去卵巢（Ox）大鼠注射环孢素A（CsA）会加剧与雌激素缺乏相关的高转换型骨质减少。17β-雌二醇替代疗法可预防这种骨质流失。本研究的目的是观察一种雌激素样化合物，雷洛昔芬类似物（盐酸LY117018，Ral）是否同样能改善去卵巢大鼠中CsA诱导的骨质减少。将60只6月龄的Sprague-Dawley大鼠分为五组，进行去卵巢手术。一组作为基础组，其他组分别通过灌胃给予溶剂（B组）、15 mg/kg/天的CsA（C组）、3 mg/kg/天的Ral（D组）或15 mg/kg/天的CsA和3 mg/kg/天的Ral（E组），持续28天。第六组假手术的12只大鼠仅给予溶剂（A组）。在第0、14和28天对大鼠称重并取血，以测量离子钙、葡萄糖、骨钙素（BGP）、17β-雌二醇和1,25-二羟基维生素D3（1,25[OH]2D3）。在第28天，经双四环素和钙黄绿素标记后取出胫骨进行骨组织形态计量学分析。去卵巢导致B组和C组体重显著增加，而Ral在D组和E组中可预防这种情况。两个CsA治疗组的随机血糖水平和1,25(OH)2D3水平均升高。在第28天，溶剂组（B组）的血离子钙水平低于假手术组（A组）。与假手术大鼠相比，去卵巢组（B组）的血清BGP水平显著更高。与溶剂组相比，C组的血清BGP水平进一步升高，而在两个Ral治疗组中，到第28天时血清BGP水平降至溶剂组水平。骨组织形态计量学显示，去卵巢后（B组）出现高转换型骨质减少，骨形成和吸收参数增加，松质骨体积减少。CsA（C组）加剧了去卵巢的影响。Ral（D组）完全预防了去卵巢引起的高转换型骨质减少，并能够在很大程度上减轻CsA对去卵巢大鼠的影响（E组）。Ral治疗改善了去卵巢大鼠中CsA诱导的骨质减少，可能证明是预防接受CsA治疗的绝经后妇女骨质流失的有用药物。
