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Subclinical Hypervitaminosis A in Rat: Measurements of bone mineral density (BMD) do not reveal adverse skeletal changes
Institute of Environmental Medicine, Karolinska Institutet.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Clinical Pharmacogenetics and Osteoporosis)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Clinical Pharmacogenetics and Osteoporosis)
2006 (English)In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, no 1, 73-80 p.Article in journal (Refereed) Published
Abstract [en]

We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

Place, publisher, year, edition, pages
2006. Vol. 159, no 1, 73-80 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92406DOI: 10.1016/j.cbi.2005.10.104PubMedID: 16289060OAI: oai:DiVA.org:uu-92406DiVA: diva2:165465
Available from: 2004-11-17 Created: 2004-11-17 Last updated: 2012-03-02Bibliographically approved
In thesis
1. Vitamin A and Osteoporosis: Experimental and Clinical Studies
Open this publication in new window or tab >>Vitamin A and Osteoporosis: Experimental and Clinical Studies
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vitamin A in high doses is severely toxic to the rat skeleton, and the active metabolite retinoic acid (RA) can induce bone resorption in vitro. An excessive dietary intake of vitamin A has been associated with reduced bone mineral density and an increased risk of hip fracture. In this thesis, mechanisms of vitamin A toxicity have been investigated.

In the human osteosarcoma cell line MG-63 and in human primary osteoblast-like cultures, stimulation with RA decreased expression of osteoprotegerin (OPG), a potent inhibitor of osteoclast formation and activity. Expression of receptor activator of NF-κΒ ligand (RANKL), which stimulates osteoclastogenesis, was induced. This increase of the RANKL/OPG ratio is a likely mechanism of RA-induced bone resorption.

An interaction between vitamin A and D was demonstrated in humans for the first time. Fifteen mg retinyl palmitate antagonized the serum calcium-increasing effect of 2 μg 1,25-(OH)2-D3. This antagonism did not appear to be mediated via PTH.

Rats with subclinical hypervitaminosis A after 3 months’ exposure to approximately 9,000 IU retinyl palmitate per day had decreased bone strength, as measured by three-point-bending analysis of femur. Bone diameter and volume, but not bone mineral density, were reduced, suggesting the use of measurements other than BMD for evaluation of early hypervitaminosis A. Indirect mechanisms of toxicity may develop over time, since serum levels of other fat-soluble vitamins were decreased.

In summary, vitamin A can increase bone fragility in the rat at doses considerably lower than previously shown. The regulation of RANKL/OPG is a likely pathway for direct effects of vitamin A in bone. An antagonistic effect between vitamin A and vitamin D has been demonstrated in humans, suggesting indirect mechanisms for vitamin A toxicity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 65 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1392
Internal medicine, vitamin A, bone, osteoporosis, Invärtesmedicin
National Category
Clinical Medicine
urn:nbn:se:uu:diva-4677 (URN)91-554-6100-X (ISBN)
Public defence
2004-12-10, Enghoffsalen, UAS, Uppsala, 13:15
Available from: 2004-11-17 Created: 2004-11-17Bibliographically approved

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