Dobnig H, Turner R T
Department of Internal Medicine, Karl Franzens University, Graz, Austria.
Endocrinology. 1997 Nov;138(11):4607-12. doi: 10.1210/endo.138.11.5505.
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 microg/kg). To establish the effects of gradually extending the duration of exposure to hPTH without increasing the daily dose, we programmed implanted Alzet osmotic pumps to deliver the 80 microg/kg x day dose of the hormone during pulses of 1, 2, and 6 h/day, or 40 microg/kg x 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 microg/kg x 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.
甲状旁腺激素（PTH）治疗可使正常和骨质减少的大鼠松质骨体积显著增加。然而，这种潜在的有益反应仅在脉冲式治疗后才会出现；持续输注PTH会导致高钙血症和骨骼异常。这些研究的目的是确定PTH脉冲的最佳持续时间。一项初步研究表明，皮下注射合成代谢剂量的人甲状旁腺激素-（1-34）（hPTH）（80微克/千克）后，该激素在6小时内从循环中清除。为了确定在不增加每日剂量的情况下逐渐延长hPTH暴露时间的影响，我们对植入的Alzet渗透泵进行编程，使其在每天1、2和6小时的脉冲期间或连续以40微克/千克/天的剂量输送该激素。通过将装有hPTH溶液的外部 tubing 与芝麻油交替间隔来实现间断输注。治疗6天后，我们评估了血清化学指标和骨组织形态计量学。作为阴性和阳性对照，大鼠组分别接受仅输送载体的泵以及通过每日皮下注射给予80微克/千克/天hPTH的泵。动态和静态骨组织形态计量学显示，每日皮下注射和每天1小时输注显著增加了胫骨近端干骺端的成骨细胞数量和骨形成，而较长时间的输注会导致全身副作用，包括体重减轻高达10%、高钙血症以及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所观察到的异常，包括小梁周围骨髓纤维化和局灶性骨吸收。每天输注仅2小时就会导致轻微体重减轻和骨组织学变化，介于皮下注射和持续给药之间。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作为该激素的给药途径是每日注射的一种可行替代方法。
