Letters regarding Serum Retinol Levels and Fracture Risk

[Guest guest]

Hi All, The below are letters regarding the Serum Retinol Levels and

Fracture Risk. Moderation seems the way to go. Further of possible

interest, " ratios of serum retinol to 25-hydroxyvitamin D...., but also by

evaluating the skeletal effects with methods that measure both bone density

and bone size. "

Cheers, Al.

Alan Pater, Ph.D.; Faculty of Medicine; Memorial University; St. 's, NL

A1B 3V6 Canada; Tel. No.: (709) 777-6488; Fax No.: (709) 777-7010; email:

apater@...

New Engl J Med, 2003

Serum Retinol Levels and Fracture Risk

Barbara J. Bouche

To the Editor: Michaëlsson et al. (Jan. 23 issue)1 show that the risk of

fracture increases

in Swedish men with increased intake (and serum levels) of vitamin A.

Furthermore, Lips,

in an accompanying editorial,2 points out that bone mineral density decreases at

both the

lower and upper extremes of " normal " human vitamin A intake.3 However, vitamin D

deficiency also contributes to osteoporosis, and excessive vitamin A reduces the

efficacy of

vitamin D, preventing vitamin D intoxication and causing rickets in normally

replete

animals.4 This is because vitamin D acts through ligand-bound vitamin D

receptor–retinol X

receptor heterodimeric complexes, whereas excessive vitamin A increases the

formation of

retinol X receptor–retinoic acid receptor complexes, thereby reducing the

availability of

retinol X receptor.5 Since serum 25-hydroxyvitamin D (a reflection of vitamin D

status)

survives prolonged storage, the authors should consider measuring

25-hydroxyvitamin D to

clarify the relative contributions vitamins A and D make to bone mineral

density. Optimal

bone mineral density may depend on favorable ratios of vitamin A intake to

vitamin D

repletion or optimal ratios of serum retinol to 25-hydroxyvitamin D.

Alternatively,

excessive vitamin A may have toxic effects on bone mineral density that are

independent of

vitamin D status. Many oily and supplemented foods contain both vitamins. The

findings

could therefore have important implications for reducing the risk of

osteoporotic fracture

and for optimizing nonskeletal-tissue function.

References

1.Michaëlsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the

risk of fracture. N Engl J Med

2003;348:287-294.[Abstract/Full Text]

2.Lips P. Hypervitaminosis A and fractures. N Engl J Med

2003;348:347-349.[Full Text]

3.Promislow JHE, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake

and bone mineral density in the

elderly: the Rancho-Bernardo Study. J Bone Miner Res

2002;17:1349-1358.[iSI][Medline]

4.Metz AL, Walser MM, Olson WG. The interaction of dietary vitamin A and

vitamin D related to skeletal development in

the turkey poult. J Nutr 1985;115:929-935.[iSI][Medline]

5.Colston KW. New concepts in hormone receptor action. Lancet

1993;342:67-68.[iSI][Medline]

Ranjit K. Chandra

To the Editor: All nutrients have an upper threshold of safety. This is

particularly true for fat-soluble vitamins and trace

elements.1 In the study by Michaëlsson et al., the risk of fracture was highest

among men with the highest serum retinol levels.

Besides the well-known side effect of acute or chronic hypervitaminosis A,

described in the editorial by Lips, recent

observations indicate that vitamin A in doses used in malnourished populations

impairs immune responses. Such vitamin A

supplementation reduced the lymphocyte response for a short time, even in those

with obvious vitamin deficiency,2 and

decreased the antibody response to measles vaccination in infants.3 A single

dose of 100,000 IU of vitamin A was associated

with a lower proportion of infants who had protective antibody levels six months

after measles vaccination.4 On the basis of an

inverted, U-shaped relation between immune responses and the amount of vitamin A

intake, a modest amount of vitamin A in

supplements for older persons has been advocated.5 It is important to caution

against the use of large doses of vitamin A,

particularly for those older than 50 years.

References

1.Chandra RK. Graying of the immune system: can nutrient supplements improve

immunity in the elderly? JAMA

1997;277:1398-1399.[CrossRef][iSI][Medline]

2.Chandra RK. 1990 McCollum Award Lecture: nutrition and immunity: lessons

from the past and new insights into the

future. Am J Clin Nutr 1991;53:1087-1101.[iSI][Medline]

3.Semba RD, Munasir Z, Beeler J, et al. Reduced seroconversion to measles in

infants given vitamin A with measles

vaccination. Lancet 1995;345:1330-1332.[iSI][Medline]

4.Cherian T, Varkki S, Raghupathy P, et al. Effect of vitamin A

supplementation on the immune response to measles

vaccination. Vaccine (in press).

5.Chandra RK. Effect of vitamin and trace-element supplementation on immune

responses and infection in elderly subjects.

Lancet 1992;340:1124-1127.[iSI][Medline]

Håkan Melhus, Karl Michaëlsson

The authors reply: Dr. Boucher brings up the important issue of interactions

between vitamin A and vitamin D. These

interactions have been suggested ever since they were first described, 70 years

ago, by Bomskov and Seemann, who noted that

high doses of vitamin A inhibited the healing effect of vitamin D in rats with

rickets,1 but convincing evidence of (weak)

antagonism was not presented until more recently.2,3 At low levels of vitamin D

and with a normocalcemic diet, high levels of

vitamin A can reduce the serum calcium response to vitamin D in rats,2

suggesting that the antagonism may be exerted at the

level of intestinal absorption. In agreement with these data, we found in a

double-blind, crossover clinical trial that a single large

dose of retinyl palmitate (15 mg) decreased the serum calcium response to a

single dose of the activated form of vitamin D (2

µg of 1,25-dihydroxyvitamin D3) several hours after the administration of both

vitamins together.3

However, the ability of vitamin A to cause bone resorption seems to be

independent of vitamin D. and Wang were

unable to prevent the appearance of bone fractures in rats with hypervitaminosis

A by administering high doses of vitamin D,4

and a recent study showed that the effects of retinoids on diminishing bone mass

are not significantly greater in vitamin D –

deficient rats than in vitamin D – replete rats.5 Although hypervitaminosis A

can lead to reductions in bone mineral density in

laboratory animals,5 the major finding is a pronounced reduction in bone

diameter.4 Thus, measurement of bone mineral density

may not be the optimal method to detect the adverse effects of vitamin A on

bone, and future studies in humans may be

improved not only by including ratios of serum retinol to 25-hydroxyvitamin D,

as suggested by Dr. Boucher, but also by

evaluating the skeletal effects with methods that measure both bone density and

bone size.

We thank Dr. Chandra for emphasizing that there may be several reasons to

advocate modest amounts of vitamin A in

supplements, both in well-nourished and in malnourished populations.

References

1.Bomskov C, Seemann G. Über eine Wirkung des Vitamin A auf den

Mineralhaushalt. Z Gesamte Exp Med

1933;89:771-779.

2.Rohde CM, Manatt M, Clagett-Dame M, DeLuca HF. Vitamin A antagonizes the

action of vitamin D in rats. J Nutr

1999;129:2246-2250.[Abstract/Full Text]

3.Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D

in man. J Bone Miner Res

2001;16:1899-1905.[iSI][Medline]

4. T, Wang YL. Hypervitaminosis A. Biochem J 1945;39:222-228.[iSI]

5.Rohde CM, DeLuca H. Bone resorption activity of all-trans retinoic acid is

independent of vitamin D in rats. J Nutr

2003;133:777-783.[Abstract/Full Text]