The pathogenesis of infantile malignant osteopetrosis: Bone mineral metabolism and complications in five infants

Bone mineral metabolism was studied in five infants aged 8 to 22 months with severe osteopetrosis. There were findings consistent with biochemical osteomalacia. These included hypocalcemia, hypophosphatemia, high serum acid phosphatase and alkaline phosphatase activity, high levels of serum parathyroid hormone, and high urinary cyclic AMP. Serum 1,25(OH)₂ vitamin D₃ level was high in the one patient tested. Radiographs in all infants revealed rachitic changes in the metaphyses. However, dense bones on radiographs, calcium balance studies, and radiocalcium absorption studies demonstrated markedly positive calcium balance. Iliac crest bone biopsies showed increased quantity of woven bone with abundant numbers of osteoclasts, excessive amounts of osteoid, myelofibrosis, and a decreased number of Howship's lacunae. The wide bands of unmineralized osteoid did not take up tetracycline. In vitro bone resorbing activity due to osteoclast activating factor from cultured stimulated leukocytes was normal. Bone turnover however, was low as evidenced by low urinary hydroxyproline levels. We interpret these findings as indicating there is decreased bone remodeling and resorption in spite of increased humoral stimuli and osteoclasts. Since calcitonin levels were normal for age, the most likely cause of the impaired bone remodeling sequence was defective osteoclast function. We postulate that there may be a common genetic defect in phagocyte cells, including monocytes, neutrophils, and osteoclasts, which accounts for the abnormalities of mineral metabolism and previously reported hematologic, neurologic, and infectious complications.