Sass D A, Bowman A R, Yuan Z, Ma Y, Jee W S, Epstein S
Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
Bone. 1997 Jul;21(1):65-70. doi: 10.1016/s8756-3282(97)00071-9.
Post-transplantation bone disease is an increasingly recognized clinical entity whose etiology is multifactorial. The immunosuppressant agent cyclosporine-A (CsA) has repeatedly been shown experimentally to induce a high-turnover osteopenic state. Alendronate (Alen.) is a new generation bisphosphonate having far greater antiresorptive potency than previous bisphosphonates. It inhibits osteoclast resorption in vitro and in vivo without adversely affecting bone mineralization. This study was designed to investigate whether alendronate could prevent CsA-induced osteopenia in the rat. Forty-eight 8-month-old male Sprague Dawley rats were randomized into four groups to receive the following for 28 days: (1) CsA vehicle (veh.) p.o. daily and alendronate vehicle subcutaneously (s.c.) twice/week, (2) CsA 15 mg/kg p.o. daily and Alen. veh. s.c. twice/week, (3) Alen. 70 micrograms/kg s.c. twice/ week and CsA veh. p.o. daily, and (4) CsA 15 mg/kg p.o. daily and Alen. 70 micrograms/kg s.c. twice/week. Rats were weighed and bled and serum was assayed serially for calcium, PTH, 1,25(OH)2vit.D, and osteocalcin. Tibiae were removed following sacrifice on day 28, after double demeclocycline and calcein labeling, for histomorphometric analysis. Treated groups were compared to the vehicle-treated control. We confirmed previous findings that CsA produces elevated 1,25(OH)2 vitamin D and serum osteocalcin levels. Alendronate treatment by itself decreased osteocalcin by day 28 and resulted in a marginal decrease in serum total calcium on day 14. The histomorphometry findings reconfirmed that the administration of CsA induces a state of high-turnover osteopenia. Alendronate prevented CsA's adverse effects, particularly in maintaining trabecular bone volume, presumably by decreasing bone remodeling. Alendronate would seem to hold therapeutic promise in post-transplantation bone disease.
移植后骨病是一种日益被认识到的临床实体，其病因是多因素的。免疫抑制剂环孢素A（CsA）已多次在实验中被证明可诱导高转换型骨质减少状态。阿仑膦酸盐（Alen.）是新一代双膦酸盐，其抗吸收效力远高于先前的双膦酸盐。它在体外和体内均能抑制破骨细胞吸收，且不会对骨矿化产生不利影响。本研究旨在调查阿仑膦酸盐是否能预防大鼠CsA诱导的骨质减少。48只8月龄雄性Sprague Dawley大鼠被随机分为四组，接受以下处理28天：（1）每日口服CsA赋形剂（veh.），每周两次皮下注射（s.c.）阿仑膦酸盐赋形剂；（2）每日口服15 mg/kg CsA，每周两次皮下注射阿仑膦酸盐赋形剂；（3）每周两次皮下注射70微克/千克阿仑膦酸盐，每日口服CsA赋形剂；（4）每日口服15 mg/kg CsA，每周两次皮下注射70微克/千克阿仑膦酸盐。对大鼠进行称重、采血，并连续检测血清中的钙、甲状旁腺激素（PTH）、1,25(OH)2维生素D和骨钙素。在第28天处死大鼠后，取出胫骨，进行双去甲金霉素和钙黄绿素标记，然后进行组织形态计量分析。将治疗组与赋形剂治疗对照组进行比较。我们证实了先前的发现，即CsA会使1,25(OH)2维生素D和血清骨钙素水平升高。到第28天时，单独使用阿仑膦酸盐治疗可降低骨钙素水平，在第14天时血清总钙略有下降。组织形态计量学结果再次证实，给予CsA会诱导高转换型骨质减少状态。阿仑膦酸盐可预防CsA的不良反应，特别是在维持小梁骨体积方面，可能是通过减少骨重塑实现的。阿仑膦酸盐似乎在移植后骨病中具有治疗前景。
