Popoff S N, McGuire J L, Zerwekh J E, Marks S C
Department of Cell Biology, University of Massachusetts Medical School, Worcester.
J Bone Miner Res. 1989 Feb;4(1):57-67. doi: 10.1002/jbmr.5650040109.
Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. Osteopetrosis has been described in several animal species (mouse, rat, and rabbit) and in children. Bone marrow transplantation, originally shown to reverse the skeletal sclerosis in some animal mutations, has been effective in curing osteopetrosis in some children. Unfortunately, not all children with osteopetrosis are candidates for or respond to bone marrow transplantation. Recent studies have shown that several animal mutations and some children inheriting osteopetrosis have significantly elevated serum levels of 1,25-(OH)2D. Based on the possibility that there may be a resistance to 1,25-(OH)2D, high-dose calcitriol therapy has been used to treat some children and stimulated some parameters of resorption. In this study, we have examined the effects of high-dose calcitriol therapy on various serum and skeletal parameters in the osteopetrotic rabbit. Mutant rabbits and normal littermates were given continuous infusions of calcitriol via subcutaneously implanted osmotic minipumps for 2 weeks at a dose of 0.5, 2.5, or 25 micrograms/kg/per day. Untreated mutant rabbits are hypocalcemic and hypophosphatemic in the presence of elevated serum 1,25-(OH)2 levels in comparison with their normal littermates. Calcitriol infusions resulted in dose-dependent increases in circulating 1,25-(OH)2D levels in both normal and mutant rabbits. However, evaluation of other serum parameters and the skeletal response demonstrated significant differences between osteopetrotic and normal rabbits. At the highest dose, normal animals rapidly became hypercalcemic and osteoporotic, accompanied by weight loss and a failure to thrive; mutants remained hypocalcemic and osteopetrotic but did not exhibit the deleterious physical effects seen in treated normal littermates. Although the number of osteoclasts increased in both mutants and normals, osteoclast phenotype in the former remained abnormal. These data indicate that although very high levels of circulating 1,25-(OH)2D were achieved in osteopetrotic mutants, activation of osteoclast-mediated bone resorption with subsequent improvement of skeletal sclerosis was not observed.
骨质石化症是一种先天性代谢性骨病，其特征是由于破骨细胞介导的骨吸收缺陷导致骨骼硬化。骨质石化症已在多种动物物种（小鼠、大鼠和兔子）以及儿童中被描述。骨髓移植最初被证明可逆转某些动物突变中的骨骼硬化，对一些儿童的骨质石化症治疗有效。不幸的是，并非所有患有骨质石化症的儿童都适合进行骨髓移植或对其有反应。最近的研究表明，一些动物突变和一些遗传性骨质石化症儿童的血清1,25-(OH)2D水平显著升高。基于可能存在对1,25-(OH)2D的抵抗，高剂量骨化三醇疗法已被用于治疗一些儿童，并刺激了一些吸收参数。在本研究中，我们研究了高剂量骨化三醇疗法对骨质石化症兔子各种血清和骨骼参数的影响。通过皮下植入渗透微型泵，以0.5、2.5或25微克/千克/天的剂量，对突变兔子和正常同窝仔兔连续输注骨化三醇2周。与正常同窝仔兔相比，未经治疗的突变兔子在血清1,25-(OH)2水平升高的情况下出现低钙血症和低磷血症。骨化三醇输注导致正常和突变兔子循环1,25-(OH)2D水平呈剂量依赖性增加。然而，对其他血清参数和骨骼反应的评估表明，骨质石化症兔子和正常兔子之间存在显著差异。在最高剂量时，正常动物迅速出现高钙血症和骨质疏松症，伴有体重减轻和生长不良；突变体仍为低钙血症和骨质石化症，但未表现出在治疗的正常同窝仔兔中所见的有害身体影响。尽管突变体和正常动物的破骨细胞数量均增加，但前者的破骨细胞表型仍异常。这些数据表明，尽管在骨质石化症突变体中实现了非常高的循环1,25-(OH)2D水平，但未观察到破骨细胞介导的骨吸收激活以及随后骨骼硬化的改善。
