Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety
Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety
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DOI：
10.1080/01926230252929882
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发表时间：
2002-05-01
影响因子：
1.5
通讯作者：
Nold, JB
中科院分区：
文献类型：
--
作者：
Vahle, JL;Sato, M;Nold, JB
Fischer 344只大鼠(60只/性别/组)每天皮下注射重组人甲状旁腺激素(PTH)(1-34)，剂量分别为0、5、30或75µg/kg，连续2年。治疗导致骨量显著增加，与每日一次给药的已知药理作用一致。定量计算机断层扫描(QCT)和组织形态计量学结果显示，骨量明显增加。大量的新骨形成导致骨髓空间的大幅减少，并伴随着骨结构的改变。PTH(1-34)各剂量组均可见骨组织增生性病变。在5、30和75-MUG/kg治疗组中，分别有3、21和31只雄性大鼠和4、12和23只雌性大鼠发生骨肉瘤。局灶性成骨细胞增生、骨瘤和成骨细胞瘤的发生率要低得多。虽然大鼠骨肿瘤的具体细胞或分子机制尚未完全阐明，但数据表明，这些损伤是由于长期的治疗和大鼠骨骼对甲状旁腺素(1-34)日常治疗的夸大药理反应所致。在成年人类中的大鼠研究和临床应用之间的重要差异表明，治疗2年的大鼠骨肿瘤发生率的增加可能不能预测在治疗骨质疏松的有限时间内使用PTH(1-34)治疗骨骼成熟的成年人患骨癌的风险增加。
Fischer 344 rats (60/sex/group) were given daily subcutaneous injections of recombinant human parathyroid hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 mug/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologic effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometry, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanied by altered bone architecture. Bone proliferative lesions were observed in all PTH(1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-mug/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the specific cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologic response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.