Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of chronic hypervitaminosis A and long-term isotretinoin treatment on bone include cortical hyperostosis, ligament calcification and premature epiphyseal closure. Similar effects have now been reported in patients under maintenance treatment with etretinate in high doses. Etretinate, an oral, aromatic, synthetic vitamin A derivative, is widely used in Europe for disorders of keratinization. We report the cases of two patients--one with lamellar ichthyosis, the other with pachyonychia congenita--who developed such bone diseases during treatment with etretinate over 2 and 6 years respectively. The doses ranged from 0.5 to 1 mg/kg/day. Two years after starting treatment (total dose 25 g), the patient with lamellar ichthyosis complained of mechanical pain in the lumbar region and hips. Radiography showed calcification of the extraspinal tendons and ligaments and hyperostosis of the calcaneus bone at the insertion of the plantar ligament. After six years of etretinate treatment (total dose 50 g), the patient with pachyonychia congenita presented with scoliosis and limb length discrepancy. The musculoskeletal abnormalities resembled chronic hypervitaminosis A, with such osseous changes as demineralization, thinning and increased curvature of long bones with osteopenia, and premature closure of the epiphyses. Acroosteolysis was also present. Etretinate has been implicated in the formation of spinal hyperostoses and calcification of extraspinal ligaments in patients who had taken the drug for many years. The occurrence of premature epiphyseal closure in children certainly is a consequence of therapy with relatively high doses of etretinate for six years. But premature epiphyseal closure may also result from trauma to a fragile bone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Rheumatologic effects of etretinate]. 266 Jul 11

Arotinoids, which are analogs of retinoic acid (RA) and retinol (RO) with the carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on SMR-2(analog of RO) and SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/day of SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for SMR-2 and SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57. Hypervitaminosis A (weight loss, alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups; weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on weight loss, than RA. In the SMR dose groups with hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node hyperplasia was observed in SMR-2 and RA low-dose groups. Enlarged thymus, lymph node hyperplasia, leukopoiesis in spleen and bone marrow, elevated alkaline phosphatase with bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for retinoid toxicity.
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PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

Excessive intake of vitamin A has been associated with an increased risk of hip fracture in humans. This finding has raised the question of whether long-term intake of relatively moderate doses ("subclinical" hypervitaminosis A) contributes to fracture risk. Although it has been known for more than half a century that toxic doses of vitamin A lead to spontaneous fractures in rats, the lowest intake that induces adverse effects is not known, and the result of exposure to excessive doses that do not cause general toxicity has been rarely investigated. In this study, mature female rats were fed a standard diet with 12 IU vitamin A/g pellet (control, C), or standard diet supplemented with either 120 IU ("10 x C") or 600 IU ("50 x C") vitamin A/g pellet for 12 weeks. Fifteen animals were included in each group. The supplemented diets correspond to a vitamin A intake of approximately 1800 IU/day and 9000 IU/day, respectively. The latter dose is about one third of that previously reported to cause skeletal lesions. At the end of the study, serum retinyl esters were elevated 4- (p < 0.01) and 20-fold (p < 0.001) and the total amount of liver retinoid had increased 3- (p < 0.001) and 7-fold (p < 0.001) in the 10 x C and 50 x C group, respectively. The animals showed no clinical signs of general toxicity, and there were no significant bone changes in the 10 x C group. However, in the 50 x C group, a characteristic thinning of the cortex (cortical area -6.5% [p < 0.001]) and reduction of the diameter of the long bones were evident (bone cross-sectional area -7.2% [p < 0.01] at the midshaft and -11.0% [p < 0.01] at the metaphysis), as measured by peripheral quantitative computed tomography. In agreement with these data and a decreased polar strength strain index (-14.0%, p < 0.01), the three-point bending breaking force of the femur was reduced by 10.3% (p < 0.01) in the 50 x C group. These data indicate that the negative skeletal effects appear at a subchronic vitamin A intake of somewhere between 10 and 50 times the standard diet. This level is considerably lower than previously reported. Our results suggest that long-term ingestion of modest excesses of vitamin A may contribute to fracture risk.
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PMID:Subclinical hypervitaminosis A causes fragile bones in rats. 1253 62

Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces.
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PMID:Excessive dietary intake of vitamin A reduces skull bone thickness in mice. 2842 56