uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Subclinical hypervitaminosis A causes fragile bones in rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
Show others and affiliations
2002 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 31, no 6, 685-689 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2002. Vol. 31, no 6, 685-689 p.
Keyword [en]
Peripheral quantitative computed tomography (pQCT), Vitamin A, Rat, Hypervitaminosis A, Retinol, Osteoporosis
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92405DOI: 10.1016/S8756-3282(02)00910-9PubMedID: 12531562OAI: oai:DiVA.org:uu-92405DiVA: diva2:165464
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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Lind, MonicaÖrberg, JanMelhus, Håkan
By organisation
Department of Medical SciencesDepartment of Physiology and Developmental Biology
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 236 hits
ReferencesLink to record
Permanent link

Direct link