Pathogenesis of Bone Diseases in Chronic Renal Failure

由于最近发展的治疗方式对甲状旁腺激素的有效抑制，这种背景异常已经被发现，目前被认为是“相对甲状旁腺功能低下”，就其与骨转换的关系而言。本研究的目的是阐明在尿毒症中骨骼对甲状旁腺激素抵抗的病理生理机制。第一个机制是对甲状旁腺激素活性的高估。正如我们最近开发的“全PTH检测”所证明的那样，由于抗体的识别位点，传统的完整PTH检测不仅可以检测1-84PTH，还可以检测7-84 PTH。7-64PTH的积累似乎是由于肾脏清除率降低所致。第二个机制可能是尿毒症毒素对成骨细胞功能的抑制作用。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。间歇性甲状旁腺激素治疗以剂量依赖的方式改善了成骨细胞功能（矿物质附着率）和骨形成（骨形成率）的抑制。口服尿毒症毒素吸收剂可部分逆转这种异常，且不影响肾功能。因此，一些积累的尿毒症毒素可能是造成成骨细胞功能抑制的原因。第三种机制是抑制破骨细胞的激活。尿毒症患者血清中骨保护素（osteoprotegerin， OPG）水平显著升高，该分子是一种诱骗受体，阻断PTH在成骨细胞上表达的信号分子。骨组织形态学测定结果显示，骨吸收指标与血清OPG水平呈负相关。因此，积累的OPG可能在尿毒症的破骨功能减弱中起关键作用。因此，纠正骨骼对甲状旁腺激素的抵抗对于平衡控制肾功能衰竭患者的骨代谢和甲状旁腺功能是必要的。

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.