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Institute on Aging, University of Wisconsin-Madison, Madison, WI
2To whom correspondence should be addressed. E-mail: tnkawahara{at}facstaff.wisc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • vitamin A • retinol • osteoporosis • bone turnover • men
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and up to 25% of men (2
) will sustain osteoporotic fractures, which engender substantial expense, (3
) morbidity (4
) and mortality (5
). The pathogenesis of osteoporosis is multifactorial (6
); however, nutritional practices can contribute to bone loss (7
). Appropriately, nutrient inadequacies (notably calcium and vitamin D) have received emphasis in osteoporosis pathogenesis, but nutritional excesses may also contribute. For example, high dietary protein intake increases urinary calcium excretion, thereby potentially contributing to bone loss over time (8
,9
). Other currently unrecognized nutritional excesses may contribute to bone loss; it may be that vitamin A is one such nutrient (10
,11
).
Vitamin A stimulates bone resorption in vitro (12
–14
). Similarly, a few studies suggest that excess vitamin A stimulates bone resorption in vivo (15
,16
). Furthermore, it has been reported that vitamin A toxicity decreases bone formation in addition to increasing resorption (13
, 17
). This uncoupling of bone resorption and formation would be anticipated to produce bone loss (10
). Consistent with this, observational studies suggest that high vitamin A intake is associated with lower bone mineral density (18
) and increased risk for osteoporotic fracture (19
). However, no prospective studies have evaluated the effect of vitamin A supplementation on bone turnover, bone mass or fracture. To this end, the purpose of this study was to evaluate skeletal turnover prospectively in healthy normal men after supplementation with the highest dose of vitamin A available in the United States.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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This study was approved by the University of Wisconsin Health Sciences Institutional Review Board and informed consent obtained from all volunteers. All 80 participants were normal men recruited from southern Wisconsin. Eligible volunteers were required to have normal screening laboratory values including complete blood count, prothrombin time/international normalized ratio and serum chemistry panel. Volunteers with renal or hepatic disease, a history of malabsorption or regular use of compounds known to interfere with fat absorption (olestra, orlistat, mineral oil) were excluded. Those subjects who were taking multivitamins containing vitamin A were asked to not alter their supplementation; no multivitamin contained > 1515 µg (5000 IU) of vitamin A. Men who were 
50 y old were required to have normal bone density determined by dual energy X-ray absorptiometry within the preceding year. Eighty men age 18–58 y (31.4 ± 0.95, mean ± SEM) were enrolled.
Study design and procedures.
This study was a single-blind, placebo-controlled, 6-wk trial in which volunteers were randomly assigned to receive daily a tablet containing 7576 µg (25,000 IU) of retinol palmitate (Vitamer Labs, Lake Forest, CA) or a nonmatching placebo consisting primarily of microcrystalline cellulose. This supplement was chosen because it provided the highest dose available and was purchased from a local health food store, thus reflecting a "real-world" approach that supplement users might employ.
All study participants were instructed to consume the study preparation with their evening meal. Compliance was calculated by tablet count at each study visit. Serum was obtained at baseline and after 2, 4 and 6 wk of treatment for skeletal turnover marker measurement. These specimens were obtained by routine venipuncture between 0800 and 1030 h after at least an 8-h fast. Specimens were allowed to clot for 30–45 min at room temperature, centrifuged at 200 x g for 15 minutes and quick-frozen in liquid nitrogen. Samples were subsequently kept at -80°C until thawed for analysis.
Biochemical measurements.
A local reference laboratory (General Medical Laboratories, Madison, WI) performed screening chemistry panels. Commercially available kits were utilized for measurement of serum markers of skeletal turnover as follows: osteocalcin (Oc),3 ELSA-OSTEO (CIS-US, Bedford, MA); bone specific alkaline phosphatase (BSAP), Metra.BAP EIA (Quidel/Metra Bio Systems, San Diego, CA); N-telopeptide of type-1 collagen, Osteomark NTx-serum (Ostex, Seattle, WA). Skeletal turnover assays were run in batch mode by placing all aliquots from an individual subject on a single plate to avoid interassay variability. In our laboratory, the intra- and interassay %CV are 3.3 and 7.7%; 7.5 and 5.1%; and 4.5 and 7.9% for Oc, BSAP and NTx, respectively.
In addition, to further explore potential divergent effects on bone formation and resorption, an uncoupling index (UI) was calculated using the method of Eastell et al., (20
) as follows: UI = NTx T-score - BSAP T-score. T-scores were derived by subtracting the subjects value from the young normal mean and dividing by the standard deviation of a young normal male population. These normative data values were obtained by measurement of BSAP and NTx in 87 normal young men in our laboratory (21
).
Statistical analysis.
All analyses were conducted using StatView software (version 4.5, Abacus Concepts, Cary, NC). Baseline parameter comparisons between groups were examined for significant differences using a one-way (factorial) ANOVA with post-hoc analysis utilizing the Bonferroni method. Change over time in serum Oc, BSAP, NTx and UI was evaluated by repeated-measures ANOVA. Differences with P-values < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Demographic characteristics and compliance with study preparation did not differ between groups (Table 1)
. At baseline, albumin, creatinine, alanine transaminase (ALT) and alkaline phosphatase did not differ (data not shown). Compliance with the study preparation was excellent in both groups (Table 1)
and did not differ over the course of the study or between treatment groups at wk 2, 4 and 6 (data not shown). Two subjects discontinued the trial due to adverse events; both were in the placebo group. An additional four subjects in the vitamin A group did not return for the final visit. Biochemical marker data from those individuals not completing the study were excluded from analyses.
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Serum osteocalcin was lower (P < 0.01) in the vitamin A group at baseline but BSAP and NTx did not differ (Table 2)
. Over the course of the study there was no change in any measured marker of skeletal turnover in the placebo group. Additionally, vitamin A supplementation did not affect serum BSAP, NTx, or Oc (Fig. 1
A–C). Furthermore, vitamin A supplementation did not alter the uncoupling index (Fig. 2
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, 16
,22
) and animal (13
,17
,23
,24
) studies suggest that vitamin A toxicity increases bone resorption and decreases bone formation. Consistent with this, individuals with the highest vitamin A intake have increased fracture risk (11
,18
). Additionally, human hypervitaminosis A, whether acute, chronic or pharmacologically induced, clearly involves the skeleton, with toxicity manifest by hypercalcemia, bone pain and radiographic changes (25
–27
). Thus, it seems likely that high vitamin A intake contributes to the development of osteoporosis; however, it is unclear what intake is required to produce skeletal toxicity. The current study demonstrated that 7576 µg administered for 6 wk does not alter serum markers of bone turnover in healthy men. As such, short-term ingestion of this amount is unlikely to affect the skeleton adversely.
Skeletal turnover is a closely regulated process in which bone is removed by osteoclastic resorption, and through a complex coupling interaction, replaced by osteoblasts (28
). Serum measures of this process accurately reflect histomorphometric observations (29
). Although serum Oc and BSAP are classically viewed as indicators of osteoblastic activity, i.e., "formation" markers and NTx as a "resorption" marker, in most circumstances, these markers change in concert (30
). For example, treatment with bisphosphonates, agents that reduce osteoclastic bone resorption, also promptly lowers serum markers of bone formation (31
, 32
). Elevated bone turnover is associated with both rapid bone loss and higher fracture risk (33
,34
). Conversely, reduction in bone turnover with pharmacologic agents (35
,36
) or calcium/vitamin D supplementation (37
–39
) is associated with an increase in bone mineral density and/or reduction in fracture risk. In these studies, relatively modest changes in markers of bone turnover (as little as 12%) are associated with a reduction in vertebral fracture incidence (35
). Furthermore, the magnitude of changes in turnover markers is greater than that observed in bone mineral density. Finally, these changes are demonstrable much earlier than are changes in bone mass. Thus, measurement of serum markers of skeletal turnover is a reasonable surrogate for skeletal effect of agents, in this case vitamin A.
The current Recommended Dietary Allowance for vitamin A is 700 µg for women and 900 µg for men (
2300–3000 IU), and the Tolerable Upper Intake Level is 3000 µg (10,000 IU) (40
). As such, it may seem that the dose selected for this study is excessive; however, because this amount is easily attainable and had been utilized in a large randomized clinical trial (41
), it seemed appropriate for this study. Additionally, because the 99th percentile of total daily vitamin A intake (diet plus supplements) may be as high as 21,000–23,000 IU, the level of intake chosen for this study is clinically relevant for a minority of the population (40
).
That this study was of short duration and limited to men does limit generalizability. However, an initial short duration study in men was felt necessary to ensure subject skeletal safety because the inhibition of bone formation and stimulation of bone resorption reported for vitamin A is reminiscent of a corticosteroid effect on bone. Corticosteroids are established causes of osteoporosis. Women were not included due to the potential teratogenic effect of vitamin A. An additional limitation is small sample size. We calculated that a study of this size, based upon variability observed among healthy men in our laboratory, allows 90% power to detect BSAP changes of 2.5 U/L (21
). However, smaller changes in bone turnover could potentially contribute to bone loss over a longer time. It remains unknown whether longer exposure at this level of intake would produce deleterious skeletal consequences.
In conclusion, daily supplementation with 7576 µg of retinol palmitate for 6 wk did not alter serum markers of skeletal turnover in healthy men. Whether this amount of supplementation over a longer duration would affect the skeleton is not known. Prospective longitudinal studies of longer duration focusing on skeletal turnover and bone mass appear indicated to establish the safe vitamin A upper intake level.
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FOOTNOTES |
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3 Abbreviations used: ALT, alanine transaminase; BSAP, bone specific alkaline phosphatase; NTx, N-telopeptide of type-1 collagen; Oc, osteocalcin; UI, uncoupling index.
Manuscript received 24 January 2002. Initial review completed 30 January 2002. Revision accepted 7 March 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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