Elevated levels of vitamin D-dependent calcium-binding protein (calbindin-D9k) in the osteosclerotic (oc) mouse.

The osteosclerotic (oc) mouse is an osteopetrotic mutation that has recently been identified as having rickets associated with its osteopetrosis. The presence of this rachitic lesion, unexplainable from a nutritional standpoint, prompted an investigation into the vitamin D endocrine system in these animals. The developmental appearance of vitamin D-dependent calcium-binding protein (calbindin-D9k) and alkaline phosphatase was studied in oc mutant and normal mice from birth to weaning, as were serum concentrations of 25-hydroxyvitamin D3 (25OHD3), 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], calcium, and phosphorus. Intestinal and renal calbindin-D9k levels were markedly and precociously elevated (4- to 9-fold) in young suckling, but not newborn, mutant mice compared to values in normal controls. Serum 25OHD3 levels were very low to undetectable in 2-week-old mutant mice compared to normal values, while 1,25-(OH)2D3 levels were 6 times higher in mutants. The exact cause of this premature induction in mutants is unknown, but may be due to elevated circulating levels of 1,25-(OH)2D. Alkaline phosphatase activity was similar between phenotypes at all ages. These studies indicate that the rachitic lesion present in oc mutants may be the result of some inherited disorder in vitamin D metabolism in these animals. Alternatively, these data are also consistent with a normal appropriate response to hypocalcemia and hypophosphatemia resulting from decreased osteoclastic bone resorption.

Rickets and osteopetrosis: the osteosclerotic (oc) mouse.

A new mouse osteopetrotic mutation, osteosclerosis, has been examined with respect to rickets. These osteopetrotic mice were hypocalcemic and hypophosphatemic, and had greatly thickened epiphyseal plates with abnormalities in matrix vesicles when compared with normal littermates. Such biochemic and morphologic manifestations of rickets in this osteopetrotic mutation may explain the failure of osteosclerotic mice to be cured by transplantation of bone marrow from normal littermates and indicate that vitamin D metabolism and matrix vesicle biochemistry warrant further study.

Qualitative bone defect in uremic osteosclerosis.

Osteosclerosis, an increased volume of trabecular bone, is a common but often misinterpreted feature of uremic osteodystrophy. Despite the apparent radiographic density of osteosclerotic bone, pain and fracture may be associated. If accumulated osteoid and woven bone exceed the volume of lamellar bone removed in chronic renal insufficiency, bone density may be reduced despite increased trabecular volume. Concomitant histomorphometric and photon absorption determinations of transileal bone biopsies were done to investigate the relationship between quantity and quality of bone in uremic and non-uremic osteopenic patients. In osteopenic patients with uremia, bone core density had no significant relationship to trabecular bone volume or mineralized bone volume whereas in non-uremic osteopenic patients, these parameters were directly related (r = 0.867 and r = 0.921, respectively, p less than 0.001). The bone core density in the uremic patients was negatively correlated with the total osteoid volume (r = -0.764, p less than 0.05) and positively related to the serum phosphorus concentration (r = 0.739, p less than 0.05). Serum levels of immunoreactive parathyroid hormone (iPTH) and alkaline phosphatase activity were higher in the patients with radiographic osteosclerosis than in the other uremic patients. The lack of correlation between bone volume and density indicates a qualitative defect in uremic bone. It appears that in uremia, elevated iPTH and serum phosphorus levels may augment bone formation, albeit poorly mineralized with woven architecture. While radiographic density paradoxically increases, the amount of normally mineralized bone may be reduced.