Pathogenesis of Bone Diseases in Chronic Renal Failure

由于新近开发的治疗方法有效地抑制了甲状旁腺激素，这种背景异常已被发现，目前被认为是与骨转换有关的相对甲状旁腺功能减退症。本研究的目的是阐明尿毒症患者甲状旁腺素抵抗的病理生理学机制。第一，高估甲状旁腺素活性。正如我们最近发展的“整体甲状旁腺素试验”所证明的那样，传统的完整甲状旁腺激素试验不仅可以检测到1-84个甲状旁腺激素，还可以检测到7-84个甲状旁腺激素，这是由于抗体的识别部位。7-64PTH的积聚似乎是由于肾脏清除减少所致。第二个机制是尿毒症毒素对成骨细胞功能的可能抑制作用。在我们的ABD模型大鼠中，骨形成率的下降依赖于肾功能障碍的程度。间歇性甲状旁腺素治疗改善了成骨细胞功能(矿物质沉积率)和骨形成(骨形成率)的抑制，并呈剂量依赖关系。口服尿毒症毒素吸收剂在不影响肾功能的情况下部分逆转了这种异常。因此，一些累积的尿毒症毒素可能与这种抑制成骨功能有关。第三个机制是抑制了成骨细胞的激活。尿毒症患者血清护骨素(OPG)水平明显升高，OPG分子是一种诱饵受体，阻断甲状旁腺激素(PTH)在成骨细胞上表达的信号分子。骨组织形态计量学显示，骨吸收参数与血清OPG水平呈负相关。因此，累积的OPG可能在尿毒症破骨细胞功能减弱中起关键作用。因此，纠正骨骼对甲状旁腺素的抵抗对于肾功能衰竭时骨代谢和甲状旁腺功能的平衡控制是强制性的。

Due to the effective suppression of PTH by recently developed therapeutic modalities, this background abnormality has been uncovered and currently recognized as 'relative hypoparathyroidism' in terms of its relation to bone turnover. The purpose of this study was to elucidate the pathophysiological mechanisms underlying such a skeletal resistance to PTH in uremia.Fist mechanism is the overestimation of PTH activity. As we demonstrated by a recently developed 'whole PTH assay', conventional intact PTH assay detects not only 1-84PTH, but also 7-84 PTH due to the recognition site of the antibody. Accumulation of 7-64PTH seemed to be due to the reduced clearance from the kidney.Second mechanism is the possible suppressive effects of uremic toxins on osteoblastic function. In our model rats of ABD, decline of bone formation rate was dependent on the degree of renal dysfunction. Intermittent PTH treatment ameliorated the suppression of osteoblast function (mineral appositional rate), and bone formation (bone formation rate) in a dose dependent manner. Oral absorbent for uremic toxin partly reversed such abnormalities without affecting renal function. Thus, some of the accumulated uremic toxins may be responsible for such a suppression of osteobtastic function.Third mechanism is the suppressed activation of osteoctasts. In uremic patients, serum level of osteoprotegerin (OPG) markedly increased, which molecule is a decoy receptor blocking a signal molecule expressed on osteoblasts by PTH. By bone histomorphometry, parameters of bone resorption negatively correlated with serum OPG levels. Thus, accumulated OPG may play a critical role in the attenuated osteoclastic function in uremia.As a conclusion, correction of skeletal resistance to PTH is mandatory for the balanced control of bone metabolism and parathyroid function in renal failure.