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.