Osteopetro-rickets : a new cogenital bone disorder

Milhaud, G; Ml, Labat; Litwin, I.; Y, Moricard; Moutier, R; C, Rimbaut; Buffe, D; Juster, M

doi:10.1016/0221-8747(81)90026-6

Cited by 19 publications

(10 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are similar to those found in humans when rickets is associated with osteopetrosis (19,20). Circulating levels of immunoreactive calcitonin were significantly increased (P < 0.05) ( Table 1), whereas they are decreased in the op mutant rat (21) and normal in the tl mutant (17).…”

Section: Resultssupporting

confidence: 74%

See 1 more Smart Citation

(Dichloromethylene)diphosphonate-induced impairment of T-lymphocyte function.

Milhaud¹,

Ml²,

Y³

1983

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The daily subcutaneous administration of (dichloromethylene)diphosphonate (clodronate) to 3-day-old normal inbred Wistar-Furth rats for 30 days produces osteopetrotic bone lesions resembling those of the osteopetrotic mutants. Furthermore, tooth eruption is prevented, growth slows down, and signs of runt disease appear. The weight of the thymus is decreased, and T cells from the thymus and spleen respond weakly to mitogens. These thymic disorders associated with defective bone resorption are very similar to those previously reported in the osteopetrotic mutant op rat and support the hypothesis of a link between the thymus and normal bone modeling and remodeling.Diphosphonates are a class of compounds structurally related to pyrophosphate, an endogenous inhibitor of hydroxyapatite crystal formation. But, unlike pyrophosphate, which is rapidly hydrolyzed. these substances resist metabolic degradation and have effects in vivo (1). Therefore, the possibility that diphosphonates might prevent recurrent calcium stone formation, myositis ossificans, and ectopic calcification in scleroderma has been investigated (2, 3). The results of such clinical trials have been disappointing and the major clinical utility of diphosphonates has been based on another physical property: that due to their ability to bind strongly to the surface of crystals of hydroxyapatite, in vitro (4), and to slow down the rate of dissolution of the apatite crystal (5). Thus, in tissue culture and in vivo, diphosphonates are potent inhibitors of bone resorption (5).These observations have prompted use of diphosphonates in patients with pathological increases in bone resorption, such as Paget disease of bone (6), osteolytic metastases (7), and hyperparathyroidism (6). (1-Hydroxyethylidene)diphosphonate (etidronate) and (dichloromethylene)diphosphonate (clodronate) have been widely studied, but the basis of the inhibiting effect of P-C-P on bone resorption remains unknown. It is now recognized that clodronate affects osteoclast-like cells (8); however, the precise biochemical nature of the interaction remains elusive. When given to mice from birth, clodronate inhibits bone resorption to such an extent as to produce an osteopetrotic bone very similar to that of the osteopetrotic greylethal mice (9). In 1977, we reported (10) immunological defects in the osteopetrotic op mutant rat, as evidenced bv the impaired responses of thymocytes and splenic T lymphocytes to concanavalin A (Con A) and phytohemagglutinin (PHA P). These results suggested a link between the thymus and the bone resorbing system, because inherited osteopetrosis is attributable to defective bone resorption due to abnormal osteoclasts. Therefore, it was of interest to search for a common immunological defect in inherited and diphosphonate-induced osteopetrosis in the rat.MATERIAL AND METHODS Animals. Three-day-old Wistar-Furth inbred rats (Iffa Credo, Domaine des Oncins, I'Arbresle, France) were randomly distributed in two groups. They received daily, either clodronate (10 mg of P...

show abstract

Section: Resultssupporting

confidence: 74%

“…Osteoclasts were present but morphologically abnormal, in that few cytoplasmic vacuoles were observed. The Age, days 3D) were similar to the osteopetro-rickets of the tl (toothless) mutant rat (17) and the skeletal changes in murine runt disease (18).…”

Section: Resultsmentioning

confidence: 70%

(Dichloromethylene)diphosphonate-induced impairment of T-lymphocyte function.

Milhaud¹,

Ml²,

Y³

1983

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition, the oc/oc mouse exhibits serum 1,25(OH) 2 D 3 levels that are six times higher than their normal littermates 43 . In the tl/tl rat, rickets is demonstrated by broadened long bones, thickened epiphyseal plates, and the presence of osteoid 44 . Since affected animals and people often have high circulating levels of 1,25(OH) 2 D 3 and treatment with 1,25(OH) 2 D 3 does not ameliorate the symptoms of rickets in every case, it has been suggested that the rickets may be due to resistance to the vitamin D hormone.…”

Section: Introductionmentioning

confidence: 99%

Hypophosphatemia and the Development of Rickets in Osteopetrotic (op/op) Mice

McCary

Smith

DeLuca

1997

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Our previous work has shown that op/op mice hyperabsorb dietary calcium in the vitamin D-deficient state and shunt that calcium into bone. Under these conditions, the op/op mice are hypocalcemic. The purpose of this study was to examine calcium metabolism and bone mineralization in vitamin D-deficient op/op mice. First, the op/op mice and their normal littermates were placed on a vitamin D-deficient, low phosphorus diet to limit bone mineralization. Under these circumstances, op/op mice survived, even when calcium was also removed from the diet. If the diet contained phosphate, op/op mice died from hypocalcemic tetany when calcium was also removed from the diet. Furthermore, serum calcium levels became similar to wild type in the op/op mice administered the vitamin D-deficient, low phosphorus diet, and op/op mice were able to increase serum calcium in response to 1,25-dihydroxyvitamin D 3 . The op/op mice developed rickets when their serum phosphorus level was too low to support bone mineralization. The op/op mice became hypophosphatemic on regimens in which normal mice were able to maintain normal serum phosphorus levels. It appears that the op/op mouse simply requires a higher dietary calcium and phosphorus level to prevent rickets and hypocalcemic tetany since the bone is not available as a source of these minerals. However, the ability of the op/op mouse to mineralize bone at low serum calcium and phosphorus levels remains

show abstract

“…Infantile malignant osteopetrosis is characterised by abnormally dense bone secondary to decreased osteoclast-mediated bone resorption. In some patients with osteopetrosis a paradoxical rickets has been reported [1,2,4,5,7,8,10]. The word``osteopetrorickets'' is used to indicate this unusual association.…”

Section: Discussionmentioning

confidence: 99%