Effects of Hypervitaminosis A on the Bone and Mineral Metabolism of the Rat*

Abstract

Vitamin A toxicity has been associated with alterations in mineral metabolism and may result in osteopenia, fractures, deformities, and growth arrest. The pathogenesis of the bone lesions that occur in vitamin A toxicity is, however, ill defined and was examined in the present study. The administration of pharmacological doses of vitamin A to growing male rats resulted in weakness and spontaneous fractures. Undecalcified bone histology of vitamin A toxic animals was characterized by increased bone resorption, osteoclastosis, a paucity of trabecular surfaces covered with osteoid, and lesions which appear to be pathognomonic of hypervitaminosis A. The serum calcium and magnesium levels of vitamin A-toxic animals were unremarkable, but serum phosphate levels were significantly higher than control values. Urinary hydroxyproline excretion reflected bone histology and was significantly increased in experimental rats. Circulating levels of the potent bone resorbers, PTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D, were, however, comparable in vitamin A-toxic and control animals, suggesting a possible direct effect of vitamin A on bone. Subsequently, the effects of vitamin A (retinol) on in vitro collagen synthesis (incorporation of [3H]proline into collagen) and bone resorption (45Ca release from bone) were examined using a fetal rat calvarial culture. Retinol added to the culture medium for 20-24 h in concentrations ranging from 0.5-10 micrograms/ml selectively inhibited collagen synthesis in a dose-dependent fashion. Higher concentrations of retinol were toxic and resulted in a general inhibition of protein synthesis. Bone resorption was stimulated by 0.5 and 2.5 micrograms/ml retinol. We conclude that vitamin A toxicity in rats causes bone lesions, the genesis of which can be explained, at least in part, by a direct effect of the vitamin on skeletal tissue.

Retinol, retinol-binding protein 4, abdominal fat mass, peak bone mineral density, and markers of bone metabolism in men: the Northern Osteoporosis and Obesity (NO2) Study

“…The protein is considered to be an indicator of osteoblast activity and is regarded as a marker of bone formation (20)(21)(22). Previous experimental studies have found that vitamin A hypervitaminosis decreases bone formation in rats (23), and that the retinol metabolite, retinoic acid, decreases production of alkaline phosphatase, osteocalcin, and interleukin-6 in human osteoblast cells, and simultaneously decreases differentiation of those cells (24). Thus, our results may indicate that retinol decreases bone formation in young men.…”

“…These results are of interest also with respect to the present study, since vitamin A has been suggested to antagonize vitamin D's positive influence on bone mineralization and calcium uptake (23,(36)(37)(38). We therefore also investigated whether levels of vitamin A and RBP-4 were associated with levels of vitamin D presented in a previous study (19).…”

Significance of Vitamin A (Retinol) in Ageing

“…Thus, there have been numerous animal studies demonstrating that a prolong excessive intake of vitamin A can cause ossification of cartilage, increased bone resorption, extraosseous calcification, hypercalcaemia, and suppressed parathyroid hormone levels [23][24][25]. More recently, there have been many cross-sectional studies (Table 3), which have compared the dietary intake of retinol and Bone Mineral Density (BMD).…”

Retinoids and Bone

“…These observations suggest that retinal may be an additional vitamin A derivative that plays an important role as a mediator of biological processes. Hypervitaminosis A in experimental animals has been linked to increased bone resorption, decreased bone mass, and increased fractures [Frankel et al 1986, Hough et al 1988, Johansson et al 2002. There are also case studies in humans showing that significantly increased intake of vitamin A increases bone resorption, causes hypercalcemia, and induces skeletal pain [Frame et al 1974].…”