King L E, Grynpas M D, Tomlinson G, Vieth R
Mount Sinai Hospital, Toronto, Ontario, Canada.
Bone. 1997 May;20(5):405-11. doi: 10.1016/s8756-3282(97)00017-3.
Therapeutic efficacy of bisphosphonates depends on how much drug is present in bone. Therefore, it is important to measure the amount of bone bisphosphonate in toxicological and pharmacological studies. We analyzed pamidronate content of bone samples from two previously published long-term dose studies. In the first study, mature beagle dogs were given oral pamidronate at doses of 0, 2.5, 12.5 and 25 mg/kg per day for 1 year. The dogs in the second study received the same dosages for 1 year followed by 1 year without drug. In both studies, the amount of pamidronate measured was dependent upon dose in bone samples of ilium, sternum, and vertebral body. After 1 year of treatment, vertebral bone had more pamidronate than sternum or iliac bone on a permilligram basis. After 2 years, there was significantly less pamidronate in the vertebral body, sternum, and ilium than there had been at 1 year. The fall in pamidronate content was largest in vertebral body and least in the ilium. The higher uptake of pamidronate by the vertebral body during the 1 year study, and its greater loss of pamidronate after a year without drug treatment, would reflect the higher turnover of trabecular bone in the vertebral body vs. cortical bone in the ilium. The percent difference in bone pamidronate content between the 1 and 2 year dogs varied with dose. The largest percent loss occurred in the intermediate-dose group. These data suggest that, after 1 year without the drug, bone turnover rates in dogs treated with the highest dose of pamidronate were lower than at the intermediate dose. Thus, the time required for bone turnover rates to return to pretreatment levels is probably dose-dependent.
双膦酸盐的治疗效果取决于骨骼中存在的药物量。因此，在毒理学和药理学研究中测量骨骼双膦酸盐的含量很重要。我们分析了之前发表的两项长期剂量研究中骨样本的帕米膦酸盐含量。在第一项研究中，成年比格犬每天口服0、2.5、12.5和25 mg/kg的帕米膦酸盐，持续1年。第二项研究中的犬只接受相同剂量的药物治疗1年，随后1年不使用药物。在两项研究中，所测量的帕米膦酸盐量均取决于髂骨、胸骨和椎体骨样本中的剂量。治疗1年后，以每毫克为基础，椎体骨中的帕米膦酸盐比胸骨或髂骨更多。2年后，椎体、胸骨和髂骨中的帕米膦酸盐明显少于1年时。椎体中帕米膦酸盐含量的下降最大，髂骨中最小。在为期1年的研究中，椎体对帕米膦酸盐的摄取较高，在1年无药物治疗后其帕米膦酸盐的损失更大，这反映了椎体小梁骨与髂骨皮质骨相比具有更高的更新率。1年和2年犬只之间骨帕米膦酸盐含量的百分比差异随剂量而变化。最大的百分比损失发生在中等剂量组。这些数据表明，在停药1年后，接受最高剂量帕米膦酸盐治疗的犬只的骨转换率低于中等剂量组。因此，骨转换率恢复到治疗前水平所需的时间可能取决于剂量。
