The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats
The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats
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DOI：
10.1210/en.138.11.4607
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发表时间：
1997-11-01
期刊：
影响因子：
4.8
通讯作者：
Turner, RT
中科院分区：
文献类型：
--
作者：
Dobnig, H;Turner, RT
甲状旁腺素治疗可导致正常和骨质减少大鼠松质骨体积的显著增加。然而，这种潜在的有益反应仅在脉冲治疗后观察到;持续输注PTH导致高钙血症和骨异常。这些研究的目的是确定PTH脉冲的最佳持续时间。初步研究表明，人PTH-（1-34）（hPTH）在皮下注射合成代谢剂量的激素（80 μ g/kg）后6小时内从循环中清除。为了确定逐渐延长暴露于hPTH的持续时间而不增加每日剂量的效果，我们对植入的Alzet渗透泵进行编程，以在1、2和6小时/天的脉冲期间递送80 μ g/kg/天剂量的激素，或连续递送40 μ g/kg.day。通过交替间隔hPTH溶液和芝麻油的外部管路实现不连续输注。治疗6天后，我们评估了血清化学和骨组织形态计量学。作为阴性和阳性对照，大鼠组接受泵，其通过每日皮下注射分别递送仅载体和80 μ g/kg.day hPTH。动态和静态骨组织形态计量学显示，每日皮下注射和1小时/天输注显著增加胫骨近端干骺端的成骨细胞数量和骨形成，而更长时间的输注导致全身副作用，包括体重减轻高达10%，高钙血症和胫骨近端的组织学变化，类似于慢性原发性甲状旁腺功能亢进患者中观察到的异常，包括小梁周围骨髓纤维化和局灶性骨吸收。输注时间短至2小时/天导致轻微体重减轻和骨组织学变化，介于皮下给药和连续给药之间。结果表明，hPTH暴露的治疗间隔很短，但植入激素的程序化给药是每日注射作为激素给药途径的可行替代方案。
PTH treatment can result in dramatic increases in cancellous bone volume in normal and osteopenic rats. However, this potentially beneficial response is only observed after pulsatile treatment; continuous infusion of PTH leads to hypercalcemia and bone abnormalities. The purpose of these studies was to determine the optimal duration of the PTH pulses. A preliminary study revealed that human PTH-(1-34) (hPTH) is cleared from circulation within 6 h after sc administration of an anabolic dose of the hormone (80 mu g/kg). To establish the effects of gradually extending the duration of exposure to hPTH without increasing the daily dope, we programmed implanted Alzet osmotic pumps to deliver the 80 mu g/kg day dose of the hormone during pulses of 1, 2, and 6 h/day, or 40 mu g/kg.day continuously. Discontinuous infusion was accomplished by alternate spacing of external tubing with hPTH solution and sesame oil. After 6 days of treatment, we evaluated serum chemistry and bone histomorphometry. As negative and positive controls, groups of rats received pumps that delivered vehicle only and 80 mu g/kg.day hPTH by daily sc injection, respectively. Dynamic and static bone histomorphometry revealed that the daily sc injection and 1 h/day infusion dramatically increased osteoblast number and bone formation in the proximal tibial metaphysis, whereas longer infusion resulted in systemic side-effects, including up to a 10% loss in body weight, hypercalcemia, and histological changes in the proximal tibia resembling abnormalities observed in patients with chronic primary hyperparathyroidism, including peritrabecular marrow fibrosis and focal bone resorption. Infusion for as little as 2 h/day resulted in minor weight loss and changes in bone histology that were intermediate between sc and continuous administration. The results demonstrate that the therapeutic interval for hPTH exposure is brief, but that programmed administration of implanted hormone is a feasible alternative to daily injection as a route for administration of the hormone.