Mondelo N, Peluffo V A, Parma M D, Cointry G R, Capozza R F, Ferretti J L, Piccinni E, Montuori E
Departamento de Farmacologia Experimental, Gador SA, Buenos Aires, Argentina.
Medicina (B Aires). 1997;57 Suppl 1:93-100.
Bisphosphonates regulate bone turnover by inhibiting osteoclastic bone resorption. Due to their pharmacodynamic and pharmacokinetic characteristics, bisphosphonates have a special pharmacotoxicological profile related to their high degree of specificity: low or non-existent distribution in soft tissues and strong affinity for calcified tissues. Some general conclusions may be drawn from the pre-clinical toxicological studies, whose main aim is to identify the toxicity target organ/s and estimate the safety margins of a "prospective therapeutic agent" in laboratory animals. They are based on our own results and on data from the available literature as regards various bisphosphonates: Alendronate, Clodronate, Etidronate, Olpadronate and Pamidronate. Generally, very high doses of bisphosphonates are required to produce in different levels and incidence various extra-skeletical toxic side effects: local reaction, hypocalcemia (and its consequences on the cardiovascular system and the possibility of tetany), affection of the dental structures and renal dysfunction. Most of side effects may be related to the low solubility in biological fluids, the formation of calcium complexes, the potent inhibitory effect of endogenous or induced bone resorption as well as to its main excretion pathway. Some other side effects (on the eye, lungs and liver), may be related to repeated excessive high doses. A safety margin of 200 to 300 : 1 between the "toxic" and "pharmacological" doses may be estimated if the total quantity of Olpadronate given to various animal species in toxicological studies and in pharmacodynamic experimental models (osteopenias due to estrogen deprivation or immobilization and retinoid-induced hypercalcemia) is considered. If the toxic doses in animals are related to the highest doses suggested for human beings, then the ratio increases from 300 to 1000 : 1 depending on the pathology and the route of administration. As regards their effect on the bone, experimental data with the new bisphosphonates suggest a significant dissociation between pharmacologically active doses and those ones producing defective mineralization. The excessive inhibition of bone remodelling, due to the use of high doses in normal animals, is the natural consequence of the pharmacological effect of this family of compounds. A bisphosphonate's toxic potential effect on bone should not be evaluated in normal animals but in particular situations with a high bone turnover. Furthermore, the doses should be adjusted in order to regulate the magnitude of bone remodelling inhibition so as to take it to a normal level without totally suppressing it. Potency, safety margins, doses and proper administration schemes, should be considered as key elements for the optimum use of the therapeutic potentiality of these compounds.
双膦酸盐通过抑制破骨细胞的骨吸收来调节骨转换。由于其药效学和药代动力学特性，双膦酸盐具有与高度特异性相关的特殊药物毒理学特征：在软组织中的分布低或不存在，对钙化组织具有强亲和力。可以从临床前毒理学研究中得出一些一般性结论，其主要目的是确定毒性靶器官并估计实验动物中“潜在治疗剂”的安全范围。这些结论基于我们自己的结果以及有关各种双膦酸盐（阿仑膦酸盐、氯膦酸盐、依替膦酸盐、奥帕膦酸盐和帕米膦酸盐）的现有文献数据。一般来说，需要非常高剂量的双膦酸盐才能在不同程度和发生率上产生各种骨骼外毒性副作用：局部反应、低钙血症（及其对心血管系统的影响和手足搐搦的可能性）、牙齿结构的影响和肾功能障碍。大多数副作用可能与在生物流体中的低溶解度、钙复合物的形成、内源性或诱导性骨吸收的强效抑制作用以及其主要排泄途径有关。其他一些副作用（对眼睛、肺和肝脏）可能与反复过量的高剂量有关。如果考虑在毒理学研究和药效学实验模型（因雌激素缺乏或固定导致的骨质减少以及类维生素A诱导的高钙血症）中给予各种动物物种的奥帕膦酸盐总量，则可以估计“毒性”和“药理”剂量之间的安全范围为200至300：1。如果动物中的毒性剂量与建议用于人类的最高剂量相关，则该比例根据病理情况和给药途径从300增加到1000：1。关于它们对骨骼的影响，新型双膦酸盐的实验数据表明药理活性剂量与产生矿化缺陷的剂量之间存在明显的差异。在正常动物中使用高剂量导致的骨重塑过度抑制是这类化合物药理作用的自然结果。双膦酸盐对骨骼的潜在毒性作用不应在正常动物中评估，而应在骨转换率高的特定情况下评估。此外，应调整剂量以调节骨重塑抑制的程度，使其达到正常水平而不完全抑制它。效力、安全范围、剂量和适当的给药方案应被视为最佳利用这些化合物治疗潜力的关键要素。
