Miller M A, Chin J, Miller S C, Fox J
NPS Pharmaceuticals, Inc., Salt Lake City, UT 84108, USA.
Bone. 1998 Sep;23(3):257-66. doi: 10.1016/s8756-3282(98)00098-2.
The subtotally nephrectomized rat has often been used to investigate the etiology and treatment of secondary hyperparathyroidism (secondaryHPT), but it has been used less frequently to study the effects of secondaryHPT on bone. The recent development of a reliable and specific rat parathyroid hormone (PTH) immunoradiometric assay has provided an opportunity for a thorough investigation of the relationship between circulating, biologically active PTH, and the skeletal abnormalities that occur in chronic renal insufficiency (CRI). Rats were 5/6 nephrectomized (Nx) or sham operated and fed diets with varying levels of Ca and P for 12-14 weeks to induce differing magnitudes of secondaryHPT. Parathyroid gland volume increased by 80%-90% in 5/6 Nx rats in the mild and moderate secondaryHPT groups (2.3- and 7.7-fold higher PTH levels, respectively) and by 3.3-fold in the severe secondaryHPT group (12-fold increase in PTH). The increases in gland volume were caused primarily by cell hyperplasia. Mild secondaryHPT resulted in a 12% decrease in bone mineral density (BMD) across the entire femur, increased osteoclast numbers (N.Oc), unchanged osteoblast numbers (N.Ob), and decreased cancellous bone volume (Cn.BV) in the tibial metaphysis but, apart from increased marrow area, no major changes in cortical bone at the tibio-fibular junction. Moderate secondaryHPT was associated with no changes in femoral BMD, or in tibial Cn.BV, but N.Ob and bone formation rate (BFR) were markedly elevated. Increased periosteal, intracortical, and endocortical BFR and turnover were evident, and contributed to increased cortical porosity (Ct.Po). The changes were exaggerated in the severe secondaryHPT group; BMD was lower in the proximal, but higher in the distal femur, and Cn.BV, N.Ob, N.Oc, and BFR were increased by six-, seven-, three-, and 30-fold, respectively. Endocortical BFR was elevated 31-fold and the extensive Ct.Po (10%) decreased bone strength. However, Ct.Po was not apparent until PTH levels exceeded 500 pg/mL. Thus, in rats with CRI of similar magnitude, progressive secondaryHPT is associated with dramatically different effects on bone. Mild secondaryHPT caused loss of cancellous and endocortical bone, and moderate secondaryHPT tended to maintain both types of osseous tissue, whereas PTH levels >500 pg/mL resulted in substantial cortical bone loss, but cancellous bone gain.
次全肾切除大鼠常被用于研究继发性甲状旁腺功能亢进（继发性甲旁亢）的病因及治疗，但较少用于研究继发性甲旁亢对骨骼的影响。近期可靠且特异的大鼠甲状旁腺激素（PTH）免疫放射分析的发展，为深入研究循环中具有生物活性的PTH与慢性肾功能不全（CRI）时出现的骨骼异常之间的关系提供了契机。将大鼠进行5/6肾切除（Nx）或假手术，并给予不同钙磷水平的饮食12 - 14周，以诱导不同程度的继发性甲旁亢。在轻度和中度继发性甲旁亢组（PTH水平分别升高2.3倍和7.7倍），5/6 Nx大鼠的甲状旁腺体积增加80% - 90%，在重度继发性甲旁亢组增加3.3倍（PTH升高12倍）。腺体体积增加主要由细胞增生引起。轻度继发性甲旁亢导致整个股骨骨密度（BMD）降低12%，破骨细胞数量（N.Oc）增加，胫骨近端干骺端成骨细胞数量（N.Ob）不变，松质骨体积（Cn.BV）减少，但除骨髓面积增加外，胫腓关节处皮质骨无明显变化。中度继发性甲旁亢时，股骨BMD及胫骨Cn.BV无变化，但N.Ob和骨形成率（BFR）显著升高。骨膜、皮质内及皮质下BFR和骨转换增加明显，导致皮质骨孔隙率（Ct.Po）增加。重度继发性甲旁亢组这些变化更为明显；股骨近端BMD降低，远端升高，Cn.BV、N.Ob、N.Oc和BFR分别增加6倍、7倍、3倍和30倍。皮质内BFR升高31倍，广泛的Ct.Po（10%）降低了骨强度。然而，直到PTH水平超过500 pg/mL时Ct.Po才明显。因此，在程度相似的CRI大鼠中，进行性继发性甲旁亢对骨骼的影响差异显著。轻度继发性甲旁亢导致松质骨和皮质内骨丢失，中度继发性甲旁亢倾向于维持两种骨组织，而PTH水平>500 pg/mL则导致大量皮质骨丢失，但松质骨增加。
