BONE FORMATION/RESORPTION COUPLING AND OSTEOPOROSIS

每日皮下注射甲状旁腺激素(PTH)或其 生物活性氨基末端片段，促进骨形成 戏剧性地“治愈”雌激素缺乏的骨小梁和皮质 大鼠骨质疏松。甲状旁腺素对骨形成的影响也是巨大的。 但它对人体骨量的影响要小得多 在大鼠中：皮质骨没有增加，而 骨小梁不够大，不足以逆转慢性骨质疏松症的影响 雌激素完全缺乏。甲状旁腺激素的合成代谢作用 大鼠骨小梁和皮质骨呈线性剂量依赖关系。第PTH 在人类身上使用的剂量比在老鼠身上使用的剂量低得多，因为PTH 对人类有更大的高钙化作用。我们相信这一结果 从骨骼钙动员和骨骼的物种差异- 甲状旁腺素的再吸收作用。通过使用抗吸收药物来治疗 甲状旁腺素治疗骨质疏松症人类，我们相信将有可能 增强甲状旁腺素对骨骼的合成代谢作用。处于实验阶段 动物，这种策略有不同的成功，不同的物种或 抗再吸收疗法。测试一种抗吸收药物是否 增强甲状旁腺素在骨质疏松症患者增加骨量的能力 绝经后的妇女，我们会给她们外源性甲状旁腺激素 长期连续测量他们脊柱、臀部、手臂的骨量， 和全身用双能x射线吸收法作为甲状旁腺激素 要么继续给药，辅以阿伦磷酸钠， 改用阿伦磷酸钠，或停用。这样的实验提供了一种 研究骨吸收-形成耦合的难得机会 人类。新合成的生长因子的相对重要性，与。 通过骨吸收局部释放预先形成的生长因子至甲状旁腺激素 人类骨骼合成代谢的影响尚不清楚。如果解放的话 骨骼合成代谢不需要预先形成的生长因子 甲状旁腺激素对人类的影响，正如我们假设的那样，然后伴随治疗 使用阻止骨吸收的药物不会降低甲状旁腺激素的能力 来刺激骨骼的形成。我们计划在以下方面测试这一假设 用甲状旁腺素治疗绝经后骨质疏松症妇女 骨吸收增加，然后加入阿伦磷酸钠，然后 I型胶原分泌型血、尿液指标的动态变化 和降解，以及示踪剂放射性的骨骼保留，如 他们升高的骨吸收被抑制到控制水平 添加阿伦磷酸钠。我们将在年进行平行观测 适当控制患者。

Daily subcutaneous injections of parathyroid hormone (PTH), or its biologically-active amino-terminal fragments, increase bone formation dramatically, and "cure" estrogen-deficiency trabecular and cortical osteoporosis in rats. PTH's effects on bone formation are also dramatic in humans but its effects on bone mass are much smaller in humans than in rats: there is no increase in cortical bone and the increase in trabecular bone is not large enough to reverse the effects of chronic estrogen deficiency completely. The anabolic effects of PTH on trabecular and cortical bone are linearly dose-dependent in rats. PTH doses used in humans are much lower than those used in rats, because PTH has a greater hypercalcemic effect in humans. We believe this results from a species difference in the skeletal calcium-mobilizing and bone- resorbing effects of PTH. By administering an anti-resorptive drug to PTH-treated osteoporotic humans, we believe it will be possible to augment PTH's anabolic effects on their skeleton. In experimental animals, this strategy had variable success, varying with the species or the anti-resorptive regimen. To test whether an anti-resorptive agent enhances PTH's ability to increase bone mass in osteopenic postmenopausal women, we will give them exogenous parathyroid hormone chronically and serially measure their bone mass in the spine, hip, arm, and total body with dual-energy x-ray absorptiometry as PTH administration is either continued, supplemented with alendronate, switched to alendronate, or withdrawn. Such an experiment provides an unusual opportunity to investigate bone resorption-formation coupling in humans. The relative importance of newly-synthesized growth factors, vs. pre-formed growth factors released locally by bone resorption, to PTH's skeletal anabolic effects in humans is unclear. If the liberation of pre-formed growth factors is unnecessary for the skeletal anabolic effect of PTH in humans, as we hypothesize, then concomitant treatment with an agent that blocks bone resorption will not reduce PTH's ability to stimulate bone formation. We plan to test this hypothesis in postmenopausaI osteoporotic women by treating them with PTH until their bone resorption is increased and then adding alendronate and following serial changes in serum and urine indices of type I collagen secretion and degradation, and skeletal retention of tracer radioactivity, as their elevated bone resorption is suppressed to control levels by the addition of alendronate. We will make parallel observations in appropriate control patients.