Vitamin and Mineral Supplement Use Is Associated with Reduced
Risk of Prostate Cancer1
Alan R. Kristal,2Janet L. Stanford, Jennifer H. Cohen,
Kristine Wicklund, and Ruth E. Patterson
Cancer Prevention Research Program, Fred Hutchinson Cancer Research
Center, Seattle, Washington 98109 [A. R. K., J. H. C., R. E. P.]; Department of
Epidemiology, University of Washington, Seattle, Washington 98195 [A. R. K.,
J. L. S., J. H. C., R. E. P.]; and Epidemiology Program, Fred Hutchinson
Cancer Research Center, Seattle, Washington 98109 [J. L. S., K. W.]
This population-based, case-control study in King
County, Washington examined supplement use in 697
incident prostate cancer cases (ages 40–64) identified
from the Puget Sound Surveillance, Epidemiology and
End Results program registry and 666 controls recruited
from the same overall population using random-digit
dialing sampling. Participants reported their frequency of
use of three types of multivitamins and single
supplements of vitamins A, C, and E, calcium, iron, and
zinc over the 2 years before diagnosis. Logistic regression
analyses controlled for age, race, education, family
history of prostate cancer, body mass index, number of
prostate-specific antigen tests in the previous 5 years, and
dietary fat intake. Adjusted odds ratios (95% confidence
limits) for the contrast of >7/week versus no use were as
follows: multivitamins, 0.96 (0.73, 1.26); vitamin A, 0.59
(0.32, 1.06); vitamin C, 0.77 (0.57, 1.04); vitamin E, 0.76
(0.54, 1.08); calcium, 1.04 (0.61, 1.78); iron, 0.50 (0.13,
1.76); and zinc, 0.55 (0.30, 1.00). Odds ratios differed
little when cases were stratified by stage of disease at
diagnosis or by histopathological grade. There were
significant dose-response effects for zinc and ordered
dose-response trends for vitamins C and E. Overall, these
results suggest that multivitamin use is not associated
with prostate cancer risk, but use of individual
supplements of zinc, vitamin C, and vitamin E may be
protective. Further study is needed to investigate the
direct role of these dietary supplements, as well as the
role of lifestyle variables associated with supplement use,
on prostate cancer risk.
In the United States, prostate cancer is the most common cancer
among men and second only to lung cancer as the leading cause
of cancer-related mortality (1). Control of prostate cancer is
based primarily on early detection and treatment, because
known risk factors for prostate cancer are either not modifiable
(increasing age and a family history of prostate cancer) or not
well understood (black race). However, there is increasing
evidence that dietary patterns and use of dietary supplements
are associated with prostate cancer risk (2, 3). Further research
on dietary supplements is of considerable importance, because
supplementation could be an inexpensive and easily imple-
mented means for primary prevention.
Few epidemiological studies have reported on associations
between supplement use and prostate cancer risk (4). The
strongest evidence for a protective effect of dietary supplements
comes from two large, randomized controlled trials. In the
ATBC3trial, which tested 50 mg of ?-tocopherol and 20 mg of
?-carotene for the prevention of lung cancer among smokers,
there was an unexpected 30% reduction in prostate cancer
incidence among participants randomized to receive ?-tocoph-
erol compared to placebo (5). In the Dietary Prevention of
Cancer Trial, which tested 100 ?g of organic selenium for the
prevention of skin cancer, there was an unexpected 60% re-
duction among prostate cancer incidence in participants ran-
domized to receive the active agent (6). The only other signif-
icant finding of supplement use with prostate cancer risk was
from the Health Professionals Follow-Up Study, which found
an approximate 3-fold increase for advanced disease associated
with calcium supplementation of greater than 900 mg (7). No
associations of supplementation were found in three random-
ized trials of ?-carotene (8–10) or in a cohort study of the
elderly examining vitamins A, C, and E (11).
This report gives results from a large population-based
case-control study of middle-aged men and examines associa-
tions of dietary supplement use with prostate cancer risk.
Participants and Methods
Data are from a subset of participants in a study of risk factors
for prostate cancer. Eligible participants were white and black
male residents of King County (Seattle) Washington, ages
40–64 years, who were newly diagnosed with histologically
confirmed prostate cancer between January 1, 1993, and De-
cember 31, 1996. Cases were identified from the Seattle-Puget
Sound SEER cancer registry. Only cases with a residential
telephone were eligible, because controls were selected using
Furthermore, because the emphasis was on recruiting
younger men, only a random 75% sample of cases ages 60–64
were recruited. Of 917 cases selected for participation, 753
(82.1%) were interviewed. Reasons for nonresponse were phy-
sician refusal to allow contact (2.6%), case refusal (12.5%),
Received 3/22/99; revised 6/23/99; accepted 7/21/99.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1Supported by NIH Grants R01-CA56678, P30-CA15704, T32-CA09661, and
2To whom requests for reprints should be addressed, at Fred Hutchinson Cancer
Research Center, MP-702, 1100 Fairview Avenue North, Seattle, WA 98109-
3The abbreviations used are: ATBC, ?-Tocopherol, ?-Carotene; PSA, prostate-
specific antigen; SEER, Surveillance, Epidemiology and End Results program.
887Vol. 8, 887–892, October 1999
Cancer Epidemiology, Biomarkers & Prevention
inability to locate (1.5%), illness (0.4%), and death (0.2%).
Controls were identified using random-digit dialing, frequency
matched to cases by age (same 5-year group), and recruited
evenly throughout the ascertainment period for cases. Of the
21,116 residential numbers contacted, 94% provided household
census data. Of the 1025 eligible men identified, 941 (91.8%)
agreed to receive mailed information about the study, and 703
(74.7%) were interviewed. Reasons for nonresponse were re-
fusal (24.2%), loss to follow-up (?1%), and illness (?1%).
Participants completed in-person interviews conducted by
trained male interviewers. Information was collected on a broad
range of topics, including demographic characteristics, height
and weight, family history of prostate cancer, and 5-year history
of screening using PSA and digital rectal examination. For
cases, all time-sensitive questions used diagnosis date as the
reference date. For controls, the reference date was randomly
assigned from dates that approximated the distribution of cases’
diagnosis date. A calendar of life events was used to enhance
recall. Following the interview, participants were given a self-
administered food frequency questionnaire and a questionnaire
on use of vitamin and mineral supplements and were asked to
complete these at home and return them by mail. Vitamin and
mineral supplement questionnaires were completed by 697
cases (92.6%) and 666 controls (94.7%). Clinical information
was abstracted from the SEER registry. Stage of disease at
diagnosis was coded according to the Whitmore-Jewett system
(12), and histopathological grade was classified using the Glea-
son system (13).
The vitamin and mineral supplement questionnaire asked
about the frequency and duration of using four types of multi-
vitamins (with minerals, without minerals, stress type, and “not
sure what kind”) and six individual supplements [vitamins A
(retinol, not including ?-carotene), C, and E; calcium; iron; and
zinc]. The questionnaire did not allow respondents to write in
other supplements they may have used. For each type of mul-
tivitamin and single supplement, participants reported the fre-
quency of use (never, 1 or less per week, 2–5 per week, 1 per
day, 2 or more per day) and duration of use (less than 6 months,
1⁄2 year to 11⁄2 years, 11⁄2 years or more) during the 2 years prior
to the reference date. Supplement use was calculated as the
average exposure over the 2-year period: weekly use was cal-
culated as 0, 1, 3.5, 7, and 14 times per week corresponding to
frequency of use categories, and these were weighted for du-
ration of use using 0.125, 0.5, and 1.0 corresponding to the
duration categories. The food frequency questionnaire included
99 food items and 19 questions on food purchasing and prep-
aration used to adjust nutrient calculations (14, 15), and the
nutrient database is from the University of Minnesota Nutrient
Data System (16).
Unconditional logistic regression was used to calculate
odds ratios for risk of prostate cancer associated with each
supplement. Associations were adjusted for age (in 5-year
groups), race (white versus black), family history of prostate
cancer (none, second degree only, and first degree), education
(?12, 13–15, 16, and ?17 years), body mass index the year
before diagnosis (?24, 24-?27, 28-?29, ?30 kg/m2), number
of screening PSA tests in the 5 years before reference date (0,
1–2, 3–4, and ?5), and dietary intakes of energy and fat (log
transformed). Effect modification was examined in two ways.
For analyses comparing effects of supplements by stage of
disease, polytomous logistic regression was used to model odds
ratios for controls versus stages A and B and controls versus
stages C and D simultaneously (17). For analyses examining
whether effects differed by fat intake, total fat was dichoto-
mized at the midpoint, and regression models examined the
interaction this dichotomous variable with supplement use.
Table 1 gives distributions of demographic characteristics, fam-
ily history, PSA use, and stage of disease at diagnosis. As
determined by the study design, more than 60% of study par-
ticipants were under age 60. Fewer than 5% were black and
approximately 50% had completed college, consistent with the
overall population of the Seattle/King County area. Cases were
more likely than controls to have a family history of prostate
cancer (P ? 0.001), be black (P ? 0.003), and have received
PSA screening tests (P ? 0.001). The majority of cases were
stage B, and only 25% were diagnosed with advanced stage C
and D disease.
Table 2 gives distributions of supplement use among cases
and controls. The most commonly used supplements were mul-
tivitamins, used at least daily by 30% of cases and 27% of
controls. The most commonly used were multivitamins with
minerals (22%), whereas use of multivitamins without minerals
(3%), stress types (3%), and type unknown (2%) were rare.
Other frequently used supplements were vitamin C, used daily
by approximately 21% of participants, and vitamin E, used
daily by approximately 14% of participants. Only 5% of par-
ticipants used zinc, calcium, or vitamin A daily, and only 1%
Table 3 gives associations of supplement use with prostate
Demographic and health-related characteristics of cases and controls
(n ? 697) (%)
(n ? 666) (%)
Family history of prostate cancer
No family history
Body mass index (kg/m2)
PSA tests within previous 5 yr
Stage at diagnosis
aNA, not applicable.
Vitamin and Mineral Supplements and Prostate Cancer
cancer risk. Odds ratios are given unadjusted and adjusted for
confounding variables. There were no statistically significant
associations of multivitamin supplement use with risk, nor were
there suggestions of trends across levels of use. Results were
similar for each type of multivitamin, and for those with min-
erals (minerals plus unknown types) and without minerals
(without minerals plus stress types; data not shown). There was
some evidence of a protective effect of vitamin C. The adjusted
odds ratio for those using vitamin C at least daily was 0.77, with
an upper 95% confidence limit of 1.04. Similarly, there was
some evidence of a protective effect for vitamin E, with an
adjusted odds ratio of 0.76 and upper 95% confidence limit of
1.08 for those using vitamin E daily. Although zinc use was
rare, there was a borderline statistically significant 45% reduc-
tion in risk among those using zinc daily, with a significant test
for trend. Analyses of calcium, vitamin A, and iron showed no
consistent trends across use categories, although there were
nonsignificant decreases in risk associated with daily use of
iron and vitamin A.
Table 3 also shows associations of supplement use with
prostate cancer risk among the subset of participants who
reported using at least one type of single supplement. This
analysis is an attempt to control for unmeasured confounding
factors that may be associated with both prostate cancer risk
and supplement use, because it includes only persons who use
supplements. The power to detect significant trends is low
because the sample size is reduced to only 620, and none of
these trends was statistically significant at P ? 0.05. However,
consistency of results between analyses based on all partici-
pants, and this subset of participants provides some assurance
that unmeasured confound factors are not affecting results.
Results based on supplement users only did not differ markedly
for zinc. For vitamin C, estimates of the protective effects were
somewhat larger at all levels of use, although these did not
reach statistical significance. For vitamin E, the strength of
association was reduced at all levels of use, such that daily use
was associated with only a modest 14% reduced risk.
The analyses shown in Table 3 were repeated, stratified by
stage of disease at diagnosis. There was no suggestion of
different effects among participants with early (stages A and B)
and advanced (stages C and D) disease. The adjusted odds
ratios (95% confidence limits) for none versus ?7/week were
as follows: zinc, 0.65 (0.33, 1.25) and 0.46 (0.15, 1.17); vitamin
E, 0.72 (0.48, 1.06) and 0.71 (0.40, 1.22); and vitamin C, 0.77
(0.55, 1.08) and 0.71 (0.44, 1.12) for stages A and B versus
stages C and D, respectively. Analyses stratified by grade
(Gleason scores 2–7 versus 8–10) found somewhat stronger
protective effects for zinc in higher-grade disease, although
trends were similar in both groups. Analyses also examined
whether there were differences in effects of supplementation
between participants with low and high fat intakes. In particu-
lar, we considered whether effects of the fat-soluble antioxidant
vitamin E were more pronounced among persons with high fat
intake. There was no evidence of effect modification by fat
intake for any supplement (data not shown).
In this large population-based case-control study, designed to
investigate risk factors for prostate cancer in middle-aged men,
we found modest evidence of association between some vita-
min and mineral supplements and prostate cancer risk. There
were statistically significant protective effects for zinc, border-
line although not statistically significant protective effects for
vitamin C, and suggestive trends for vitamin E. There was no
evidence for associations of multivitamins, calcium, vitamin A,
These results are only partially consistent with the few
previous studies on supplement use and prostate cancer. The
estimated 24% reduction in risk associated with vitamin E
supplementation is somewhat less than the 32% decrease found
in the ATBC trial (5), although the dose of vitamin E found in
single supplements is generally 8 times higher than the 50 mg
tested in the ATBC trial. There was no evidence that calcium
supplementation was associated with elevated risk, either for
the total sample or, as reported by Giovannucci et al. (7) in
those with advanced disease. Furthermore, although Shibata et
al. (11) reported a relative risk of 1.0 (95% confidence interval,
0.8–1.3) comparing vitamin C users to nonusers, we found a
borderline statistically significant finding of a 23% reduction in
risk from daily vitamin C use.
The finding of a protective effect for zinc supplementation
is consistent with many clinical studies that find much lower
tissue zinc concentrations in prostates with cancer compared to
those without, as reviewed in Ref. 18. Some studies also find
lower plasma zinc concentrations in persons with prostate can-
cer compared to controls (19, 20), although there are no pro-
spective studies that have examined serum zinc levels and
prostate cancer risk. Zinc, which is concentrated in the prostate,
is a component of many physiologically active proteins that
play a role in regulating apoptosis, transcription, and cellular
Distribution of vitamin and mineral supplement use in cases and
(n ? 697) (%)
(n ? 666) (%)
Cancer Epidemiology, Biomarkers & Prevention
differentiation (21). Research is needed to investigate whether
zinc intake affects prostate tissue zinc concentrations and
whether tissue zinc concentrations affect mechanisms poten-
tially related to prostate cancer development.
It is unclear to what extent previous studies on vitamins C
and E and prostate cancer are informative about the potential
effects of supplementation. Studies of dietary intake are prob-
ably not relevant, because the amounts of nutrients obtained
from supplements are generally between 2 and 30 times greater
than the amounts obtained from foods. Prospective studies
based on serum micronutrient concentrations may be informa-
tive, but only if significant proportions of the cohorts under
study use dietary supplements. There are few prospective stud-
ies of serum ascorbate (vitamin C) and ?-tocopherol (vitamin
E) and prostate cancer risk. In the single prospective study of
vitamin C, based on 30 prostate cancer deaths, there was no
association of plasma ascorbate concentration with prostate
cancer risk (22). Studies of serum ?-tocopherol prostate cancer
risk are inconsistent, but taken together, they are not strongly
supportive of an association (22–27). Protective effects of high
serum ?-tocopherol levels have been found in subgroup anal-
yses, for example among men over 70 (26), among smokers
(22), or in interactions with other nutrients (28). Both vitamin
C and E are potent antioxidants, which can protect DNA from
damage from reactive oxidants, such as superoxide and hy-
droxyl radicals (29), and it is possible that high doses obtained
from supplements could affect carcinogenesis.
There are two important differences between this study
and most earlier studies on supplements and prostate cancer
risk. First, this study examined risk factors in a relatively
low-risk age group. Prostate cancer incidence in ages eligible
for this study range between 5 and 500 per 100,000, far lower
than rates over 1,000 per 100,000 for men age 65 and over (1).
Studies of risk factors in low-incidence groups [for example, in
China (30)] may allow more clear identification of environ-
mental exposures related to risk, but it is also possible that
cancer in low-incidence age groups is due primarily to inherited
susceptibility genes. However, such genes are thought to ex-
plain less than 30% of cancers diagnosed in men less that 65
years of age (31). Second, this study controlled for important
confounding factors, including prostate cancer screening. Men
who receive PSA screening are more likely to have prostate
cancer detected (32), and they are also more likely to be better
educated, have higher incomes, practice healthful dietary be-
havior, and use dietary supplements (33, 34). Consistent with
these associations, control for covariates increased the magni-
tude of associations of most supplements with cancer risk.
The most significant limitation of this study was that we
Odds ratios of prostate cancer associated with use of vitamin and mineral supplements
Unadjusted odds ratio
(95% confidence limits)
Adjusted odds ratioa
(95% confidence limits)
Adjusted odds ratioa
(95% confidence limits),
1.12 (0.69, 1.82)
0.78 (0.54, 1.10)
1.16 (0.91, 1.49)
1.15 (0.67, 1.98)
0.69 (0.46, 1.02)
0.96 (0.73, 1.26)
0.76 (0.49, 1.16)
0.86 (0.60, 1.21)
0.90 (0.69, 1.18)
0.73 (0.45, 1.17)
0.83 (0.56, 1.22)
0.77 (0.57, 1.04)
0.62 (0.32, 1.19)
0.70 (0.39, 1.26)
0.64 (0.37, 1.11)
0.86 (0.47, 1.57)
1.10 (0.68, 1.68)
0.90 (0.66, 1.23)
1.12 (.057, 2.20)
0.85 (0.51, 1.41)
0.76 (0.54, 1.08)
1.17 (0.59, 2.34)
0.93 (0.55, 1.59)
0.86 (0.57, 1.28)
1.00 (0.47, 2.19)
0.88 (0.44, 1.77)
0.65 (0.38, 1.11)
0.73 (0.31, 1.71)
0.79 (0.36, 1.72)
0.55 (0.30, 1.00)
0.82 (0.35, 1.92)
0.81 (0.37, 1.76)
0.59 (0.32, 1.09)
0.85 (0.30, 2.37)
1.10 (0.54, 2.24)
1.28 (0.80, 2.08)
0.67 (0.22, 2.04)
1.13 (0.52, 2.45)
1.04 (0.61, 1.78)
0.83 (0.27, 2.49)
1.23 (0.56, 2.70)
1.25 (0.73, 2.17)
0.95 (0.35, 2.59)
1.50 (0.73, 3.20)
0.66 (0.38, 1.13)
1.05 (0.34, 3.18)
1.46 (0.66, 3.30)
0.59 (0.32, 1.06)
1.16 (0.39, 3.46)
1.56 (0.71, 3.55)
0.67 (0.37, 1.22)
0.78 (0.31, 1.91)
2.64 (0.90, 9.55)
0.69 (0.20, 2.16)
0.52 (0.20, 1.33)
2.74 (0.82, 10.8)
0.50 (0.13, 1.76)
0.60 (0.23, 1.55)
2.80 (0.85, 10.93)
0.55 (0.15, 1.91)
aControlled for fat, energy, race, age, family history of prostate cancer, body mass index, PSA tests in previous 5 years, and education.
bUsers of at least one type of single supplement: n ? 312 cases, n ? 308 controls.
Vitamin and Mineral Supplements and Prostate Cancer
did not collect a comprehensive and detailed history of dietary
supplement use. We had no strong a priori hypotheses about
supplement use when designing this study, and we collected
modest amounts of information on supplements to augment
nutrient intake estimates based on the food frequency question-
naire. In particular, we did not collect information on all sup-
plements (e.g., selenium), on dose, on use over a longer period
prior to cancer diagnosis, or on reasons study participants used
each supplement. Thus, our inferences about dose are based on
frequency of use rather than actual intake of supplement nutri-
ents. Furthermore, because we do not know the reasons partic-
ipants chose to use certain supplements, it is possible that health
conditions or lifestyle factors association with specific supple-
ments, and not use of supplements per se, are associated with
reduced prostate cancer risk. Our measure of supplement use
was similar to that used in standard dietary assessment ques-
tionnaires (35), collecting both frequency and duration of use
over a specified time period. In a validation study, Patterson et
al. (36) found good agreement between supplemental nutrient
intake assessed using a similar self-administered questionnaire
and intake assessed from an in-person, interviewer-adminis-
tered supplement inventory. However, it is likely that studies on
supplement use and cancer risk could be improved by using
supplement inventories, as recommended for prescription drugs
(37). In addition, because the induction and latent periods for
most cancers are quite long, information should be collected on
long-term (e.g., 10-year) supplement use (38). These sources of
error in measurement were most likely random, and their effect
should be to bias relative risk estimates toward 1.0. It is thus
possible that true associations between supplement use and
cancer risk are underestimated in our results.
An additional limitation of this study is that control par-
ticipants may have been a biased sample of men who were more
interested in health and more likely to use dietary supplements
than the overall population. We completed short telephone
interviews of 66 potential controls who chose not to participate
in the full study. These men were slightly younger, less well
educated, and had lower body mass indexes then controls,
suggesting that there was biased nonresponse among eligible
controls. One argument against a selection bias strongly affect-
ing results of this study was that there were no associations
between supplements and cancer risk for most supplements,
including multivitamins. Furthermore, results were consistent
when analyses were restricted to cases and controls who used at
least one type of single supplement. Still, we cannot rule out
selection bias and believe this should be considered when
interpreting results. Lastly, because of their lower use of PSA
screening, some controls may have had undiagnosed prostate
cancer. Although we cannot exclude the possibility of this bias,
there are two reasons that it may not strongly affect results.
First, the incidence of prostate cancer in the age groups in-
cluded in this study is very low, so it is unlikely that many
control men had undetected disease. Second, when analyses
were restricted to cases with stage C and D cancers, which
would likely be detected clinically, there were no differences in
Additional research on dietary supplement use and pros-
tate cancer risk is needed. There is heightened interest in
chemoprevention using dietary supplements, because of the
unanticipated prostate cancer outcomes of two randomized
controlled trials (5, 6), and a randomized trial of selenium and
?-tocopherol supplements to prevent prostate cancer is under
development. However, there is still need for carefully designed
observational studies. Cohort studies may be the best approach
to answering questions about supplements and cancer risk,
because they will allow us to examine exposures to different
combinations of supplements at a variety of doses, they avoid
the persistent concern of selection bias in case-control studies,
and they can collect serum to use as objective measures of
supplement use. We believe that it is important to remember the
generally negative or entirely unanticipated results of the large,
randomized chemoprevention trials using dietary supplements
(5, 6, 8–10, 39) and thus to refrain from making public health
recommendations for supplement use for prevention of prostate
cancer until there is a much broader and more compelling
consensus of evidence.
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