Can colon cancer incidence and death rates be reduced with calcium and vitamin D?13 Cedric

F Garland,

ABSTRAC1’ calcium

It was could

was based north

Frank

reduce

C Garland,

proposed the

on the decreasing

to south,

influence

in

risk

suggesting

ofcalcium.

1980

of colon

gradient

that

D Gorham

vitamin

D and

This

assertion

of mortality

rates

related

to a favorable

vitamin

A l9-y

Edward

cancer.

a mechanism

of ultraviolet-induced

tabolism

and

D metabolites

prospective

study

from

Chicago

men found that a dietary intake associated with a 50% reduction

of >3.75 g vitamin D/d was in the incidence of colorectal

cancer,

1200

whereas

an

intake

with a 75% reduction. support these findings. serum drawn from moderately elevated the range 65-100 (P < 0.05) in the

Nutr

199l;54:

of

mg

Ca/d

was

Clinical and laboratory A nested case-control

nmol/L, incidence

were associated of colorectal

with cancer.

neoplasms,

calcium,

large

cer,

that D, in

reductions Am J C/in

1935-2015.

as observed

Colonic

hydroxycholecalciferol, studies,

vitamin

1,25-dihydroxycholecalciferol,

case-control

hydroxyvitamin the

It was reduce

from

suggested the

risk

in of colon

the geographic

which

tend

sunlight

relative

and

calcium

death

rates

east, for example, were white males in sunnier in urban and epidemiologic with

centrations centrations

or to diets

was

derived

rates ofcolon latitude

and

males

in parts

low

suggestion ofdietary

that

of dietary

North-

of colon of calcium,

Am i C/in Nutr

D and

serum

cancer moderately

(2, 5), a result

supported

(7, 8). Several

reviews

199 l;54: l93S-2OlS.

colon

Printed

of can(2),

a

recent epidemiologic between serum

(3). Reviews

of colon has

cancer

and

light,

25-

reported

have also noted D (9,

cancer

a parallel has been

were 12).

its association

vitamin

D status,

in nutritional historically

rickets.

D (which

provides

(17).

Since

the

formulas has been

in the United States, sufficient to control

continue

to have

deficient

existing standards, Even now, children oil (17)

even

in sunny

may

paradoxically the

cholecalciferol

the vitamin rickets but

dietary

develop

indoors

rickets

too often

climates

which

and

2 zg infant

of children of adults

of vitamin

D by all

in further detail below. fortified milk or take cod-

if kept

the rate

provides

D intake the majority

intakes

or

industrialized

of milk

from

or by wearing

(15-19).

increase

Very

ultraviolet

excessive

low

intakes

ofexcretion

light

clothing), of calcium

ofsome

vitamin

may also play an as yet undetermined

pathogenesis nmol/L)

fortification

as will be described who do not drink

can

D metabolites, in

10 ig

( 15, 16), and elsewhere in the widespread use ofcod-liver oil (which

of

rickets

D in serum (1 5) are

far lower

(20).

The

needed than

those

role

concentrations

to

prevent

associated

rickets in a re-

was

and

ephigh

25-hydroxyvitamin and death associated

cancer

D, and

men

of vitamin

of ultraviolet

of 25-hydroxyvitamin

(3). Such conto ultraviolet

studies vitamin

study role

pattern

vitamin

after

(17-25

D (4).

with reduced incidence dietary calcium is also

laboratory

cancer

of Chicago

ofcolonic

cohort

deficiencies

(by remaining

decreasing

colonic

D (2) or low con-

D in the serum inadequate exposure

in vitamin

vitamin

with

liver

cancer,

ofthe

colon

vitamin

the geographic distribution ofcolon studies of individuals suggest that

are associated lonic cancer,

miology

assertion

D may

to be nearly three times those in ( 1 ). The effect was present both

the

low intakes

of25-hydroxyvitamin may result from

Although idemiologic

incidence

in white

found regions

supported

associated

(6) and

increasing

vitamin

presence

and

Rickets in infants and children associated with the same deficiencies (13, 14). Nutritional rickets all but disappeared from the United States after supplementation of

world

rural areas. Within a few years ofthis observation, studies ofthe dietary and serum vitamin D status

of individuals

amounts

and

( 1). The ofdeath

cancer with

calcium

incidence

in individuals

cohort

intensity.

Age-adjusted

sunlight

that

epidemiology

to increase

geographic

cholecalciferol/g)

1980

study

anticarcinogenic

with

for the

intake

in this issue. The most the inverse association

a large Maryland

The

support

calcium

in Utah (5), and clinical and laboratory results later in this report (4, 9-12) and presented

D and

potential

ergocalciferol/L)

Introduction

between

in a prospective

study briefly

D, 25-

studies

of increasing

more fully elsewhere results concerning

milk

KEY WORDS

a pattern association

case-control mentioned

from

associated

studies further study based on

a cohort of 25 620 individuals reported concentrations of25-hydroxyvitamin

show

an inverse

on me-

of 1954

which

cancer in USA.

rates with

D from coreduced

by clinical

of the epideare available, © 1991 American

Downloaded from https://academic.oup.com/ajcn/article-abstract/54/1/193S/4690960 by Washington University in St. Louis user on 24 March 2018

I From the Department of Community and Family Medicine, Univrsity ofCalifornia, San Diego, La Jolla, and the Naval Health Research Center, San Diego. 2 Supported by the Department ofCommunity and Family Medicine and the Cancer Center of the University of California, San Diego (the National Cancer Institute’s Specialized Cancer Center Core grant CA 23100-10, the University ofCalifornia San Diego Cancer Center Foundation, and the University of California San Diego Cancer Center Associates). 3Address reprint requests to CF Garland, Department of Community and Family Medicine, M-007, University of California, San Diego, La Jolla, CA 92093-0607.

Society

for Clinical

Nutrition

l93S

1 94S

GARLAND

cent

report

nmol/L)

with

reduced

incidence

of colon

cancer

(65-100

ET

AL

deficient

(3).

both

for prevention

of hypertension Supplementation calcium

The

magnitude

Colon after

of the

cancer

lung

is the second

cancer

(2 1. 22).

Colon

ofthat

cancer

vanishing

within

relatively

uncommon

cause

States,

New Zealand, and centers at latitudes or south

almost north

rate

equator

(22).

and

in men

ulation

between

(2 1). The

itdropped

from

The reason rates

death rates 1930-1986,

from

but

this the

to be due

trend

adopted

to data

capita

almost

from

rate

has

per

change

in the

be expected produced

exclusively

only gene

Dietary adults

since

830

in the

have produced deficiency

II (NHANES

age a median

The

a median

of733

(RDA)

of 800

the daily calcium intakes tutes of Health Consensus mg Ca/d for women ment estrogens and In elderly

to

National

Health

of 474

to 950 ages of with a that in-

during

female

be considered. widespread and and

men

1976-1980,

data are available (26, the current recommended

mg Ca/d

(28)

recommended Conference

current

calcium

and

are

in

Nutrition

that women

mg Ca/d

past the menopause 1200 mg Ca/d for

people,

be

II) reported

mg Ca/d

recent period for which such These amounts are below

(29).

continues

States.

same

allowance

this effect should

Survey

y consumed

dropped to later

aged of the

the most 27). dietary

also

well

by the National on Osteoporosis-

below Insti1500

and not taking replacethose taking estrogens intakes

are

seriously

Downloaded from https://academic.oup.com/ajcn/article-abstract/54/1/193S/4690960 by Washington University in St. Louis user on 24 March 2018

suggest sufficient

relative

3.1

D are both

concentrations of each

ofdietary (37,

vitamin

is the primary 38).

in Massachusetts and

2.8

countries

(43),

and

Northern

adults

ig

have

higher

of vitamin

Ireland

is only

with

con-

vitamin

shown

D/d

similarly

median

in these

intake,

D in Finland,

below

countries

4.6

Zealand

is the

nor

reason

for

(G Radford,

was reported

zg/d,

in

76 y) (45, 46), although even for the relatively high dietary

intakes

in the

the RDA

below the 20 g/d recommended Low intakes ofdietary vitamin

New

D, which

(mean age (28). Except

are markedly

Intake of vitamin g/d (K Sylvester,

Neither

vitamin

intake 1990).

(44).

1.5-2.5

1990).

milk

Finnish elderly people this is below the RDA

of 5 g/d

for D, such

US, Canada, and (28) and greatly

elderly people as those present

(47, 48). in most

of Europe and North America, are seasonal variations in serum vitamin

associated with prominent D (49), 25-hydroxyvitamin

D (49), and

D (50, 5 1). Seasonal

tions

1,25-dihydroxyvitamin

in 25-hydroxyvitamin

are also present of vitamin in

States.

One

serum

D and

in Finland,

D (46).

ations reported

despite

It remains

survey

a low of69 near

D are

of children pmol/L

the beginning

its relatively

uncertain

1,25-dihydroxyvitamin

and

whether

seasonal

present

in the

adults

(aged

96-103

pmol/L

end of summer as consistent

seasonal

was

effect

because

cant (52). Because sunlight D (53,

of vitamin Northern

D and latitudes

the

exposure

54), major

D

high oral

result is the

deficiencies

25-hydroxyvitamin (55) or because

not

predominant ofcirculating

intake variUnited

18 mo-35

of 1,25-dihydroxyvitamin ofwinter,

varia-

1,25-dihydroxyvitamin

and a high of 1 18 pmol/L by the findings were, however, interpreted

tamin

in

consume

to sunlight

Ca/d

to

rates

importance

States

that

in adults

of vitamin blood

on

a median

men

the amount

mg

data been

consume

women

408

in industrial

Zealand

A relatively

It

the and

postmenopausal

the unusually low dietary personal communication,

1909.

of

data

widespread

sources

United

because

or use of exogenous

United

45-54

in

in

for 1976-

cancer death be excluded.

circulating

exposure

fortifies

(USDA),

mg/d

role 77.2%

D intakes. Vitamin D intakes have been assessed in older adults in the United States (40, 41), Canada

Holland

Europe

have

middle-aged

Casual

communication,

intake

These

not

is also

D in the of only

studies

a small

collected

women

but

Australia

1930. One

ofAgriculture was

white

a median other

(33).

dietary

location

personal

ofthe effect in certain the decline is due to a

by women

and

(36).

Healthy

mitigation

Corresponding

may

(34);

of increasing

pattern

use ofcalcium supplements by women, in this review. The pattern cannot be cxdecrease in calcium disappearance. Ac-

of oophorectomy

calcium

Examination

pool

D/d

D metabolites

D in New

in certain The

early age at first birth is associated of colon cancer (25). The possibility

incidence

might

death

reported

Middle-aged

exposure means

of vitamin

sume

only

were

D deficiency

States.

D consumed

(33).

alone

by geographic

source

(39);

been

vitamin

low vitamin as deficient

in women

to affect both men and such a strong sex differ-

The limitation suggests that

disappearance

because incidence

hormones

pop-

varies

(42),

Canada.

climbed to a peak of 1080 mg/d in 1946 and mg/d in 1974 (24). The effect cannot be due

creased

100 000

and female

occurred and

the US Department

calcium

childbirth reduced

in 1991

steadily in There was a

to 24 in 1986;

States

to any

possibility, the increased is discussed elsewhere plained by any overall per

will be

daily

2.2 ig vitamin

effective

range

and

1971-1975,

the decrease in colon this possibility cannot

United

ofonly

cancer in women a 39% increase in

for male

pattern

United

ential during this interval. countries and in women

cording

death

not

Nutritional

tg/d(35). Sunlight

22 in 1930 to 17 in 1986 (21).

such a genetic change would women and could not have

practice

ofcolon and

18 in 1930

for the opposite

including

is unlikely

have climbed since 1930.

age-adjusted

rose

is unknown

countries,

have

played During

supplements

supplementation

in the

the sixties ofthe

but

(30)

no vitamin or mineral supplements and in any lO-y age group took a calcium

ofspecific

have produced women, although

along river courses until the mid- 1960s

it to the low end

from colon cancer steadily in women

in US men

historically

D intakes.

D supplement

of vitamin

22% decline in age-adjusted in the United States during rates

1980

is also

In the United States alone it is expected that there 1 57 500 new cases and 60 500 deaths from colon cancer (2 1). Death rates men and declined

has vitamin

ofuse

calcium

virtually

cancer

vitamin

frequency

it has a distinctive

doubled

bringing

or

hemisphere

Colon

in large cities was uncommon

(22),

King-

latitudes,

In China

approximately

and the midseventies for Western countries.

cancer

all Western countries of37#{176}in the northern

at low

in the Orient.

but the incidence

from

the United

in the southern

is uncommon

pattern ofhigher occurrence (23). In Japan colon cancer

ofdeath

Canada,

latitude

10#{176} of the

and

the US population took < 2% of the population

leading

in the United

dom, Ireland, with population hemisphere

problem

of hip fractures

(3 1, 32).

y)

D in the in the spring,

(52). These with

statistically

lack

of a

signifi-

source

of vi-

concentrations

D occur in the winter in of habits of staying indoors

more (36, 45). Age-adjusted mortality rates of colon cancer have been reported by the National Cancer Institute for all 506 state economic

CALCIUM, areas

in the United

States

and

The highest rates occurred northeast, and the lowest amount

of sunlight

United

States

12 Mi/rn2

,

highest

reaching

tries

a low northeast

daily states

death

at high latitudes.

format

solar

rates

from

The lowest

the equator

(1). (21),

colon

some

plain data

in the level Mi/rn2

those

cancer

rates tend

(although

(56).

radiation of 20

with tend

to occur

exceptions

mission

factors

density

such

19% in the

northeast,

Countries

with

the

in coun-

of ultraviolet

effect

B light

on transmission

through

may

the atmosphere

be important

in the

range

of 290-3

10 nm

skin

(37).

Gorham

et al (57)

in the notably

high

America

death

may

rates

be associated

which

haze-related and

scatter

proposed

cancer

with

in

This

mortality

levels

rates

it (57).

Similar

the

North

in Italy

(58)

and

in the

and

cancer

Soviet

acid-

fat has long

dietary

patterns

varies

tribution

been

fat intake in the

of colon

dietary

opposite

cancer

fat in colon

risk factor

a suspected

as measured direction

in the

consumption

to the

United

carcinogenesis

geographic

dis-

States

(1).

The

within

the

ordinary

role

of di-

etary range found in the United States is uncertain (60, 61). Although six case-control studies cited in a recent review reported a positive association between total and saturated fatty acids and odds ratios for colon cancer, five studies found no association The

studies

that

reported

no association

included

a 19-y

prospective study that found that intake of energy as total fat was 42% in colon cancer cases and 43% in control subjects (2). Mean dietary intake oftotal fats in this cohort was 145 g/d (2). Three studies, all case-controlled, found no association between total dietary Although

fat and risk of colon cancer many individuals may have

of saturated

fatty

risk ofheart

disease,

generally dietary

acids

in recent

estimates

years

in an effort

ofdisappearance

increased throughout this century. fat per person was 127 g/d in 1909;

in 1950, to 158 g/d in 1974, and (24,

(62-64). decreased

their

cancer. was

The

polished

and

staple rice

Furthermore,

fiber during

mortality

from

which

intestinal

Fruits

vegetables

the

fats have

Disappearance it rose to 145

colon cancer a beneficial

(66). effect

Although of cereal

some fiber

that

might

(75)

and

a traditional the incidence

are very high (2 1, 74, 77).

and vegetables

has been

surprisingly

(Table l)(7 1). Intake offruits and vegetables was slightly in the northeast than in other regions. This is not the that would be expected if the north-south gradient in cancer

offruits a beneficial

were

to surveys

uniform

USDA higher pattern

of colon

according

due

completed

to regional

and vegetables. effect of fruit

by

differences

the

in con-

However, this in no way argues and vegetable consumption in

individuals. In summary, consumption patterns of fats, fiber, and fruits and vegetables do not display patterns that would indicate they could readily account for the peculiar geographic pattern of coIon-cancer mortality in the United States. However, note that this

regional

within Such but

each

analysis

region

very-high because

the USDA

did

not

take

or low intakes the

into

who had very-high

large

may

regions

account

subpopulations

or very-low

influence

for which

fiber intakes.

risk ofcolon

data

are

cancer

available

from

cut

across a wide variety of these subpopulations, comparisons based on these data may not reflect the wider differences in intake that actually exist.

TABLE I Per capita intake of selected

foods,

by region

(United

of g/d

prevent

epidemiologic studies reported on risk of colon cancer (67),

many did not (68, 69). Currently available data from a probability sample of the US population indicate that regional differences in crude cereal fiber intake within the United States cannot cx-

Downloaded from https://academic.oup.com/ajcn/article-abstract/54/1/193S/4690960 by Washington University in St. Louis user on 24 March 2018

States) High fiber from cereal and

to -‘--170 g/d in the 1980s

as a factor

had

times

eating where

Red meat*

Fruits*

Vegetables*

kg/wk suggested

dur-

fiber

United

Fiber has been

asso-

in Japan

in the

Region

fiber

(74)

the bran

transit

cancer

States,

D

its period

rates

carbohydrate

rates

of fruits

where

of 25-hydroxyvitamin

and death and

latitudes

of 1,25-dihydroxy-

the same in people on an English diet,

of colon

in-

These

to be low to be poorer, es-

tend

deficiency

(74)

high

(68).

of 25-hydroxyvitamin

stool mass (76) are about Japanese diet as in people

25).

Cereal

may

south, with

tend

concentrations

incidence

colon

cancer high

are

1) (70, 71).

to have

D metabolites

Deficiency

of the compared (Table

at relatively

to

bread

intake

to reduce

oftotal

low

period

sumption against

for colorectal

by regional

and

tend

to colon

of calcium

people. although

removed.

rates

Although

located

D (5 1, 73)

Intake

(59).

factors

cancer,

(61).

ing that

incidence

Union

intake

of vitamin

serum

with

been

of transmis-

according

grains

are highest

related

in reduced

ciated

north-south

with colon

result

D

that

rates

in elderly

vitamin

Fats

total

are generally

of extremely

1989

death

they

cereal-fiber

serum concentrations (55, 72) and absorption

B

in northeastern

diminished

are associated

gradients

Dietary

countries

ultraviolet

to create

rates;

cereal

D itself might be the critical factor. Japan had low intakes of crude cereal

sion of ultraviolet B light due to precursors of acid rain known as acid haze. Acid haze is composed primarily of sulfur dioxide, which selectively absorbs ultraviolet light, and ammonium sulfate particles,

and

vitamin

trans-

(57).

because

is needed

of colon

affect

where low

cidences

pecially

of stratospheric

can selectively

mortality

II, high-fiber

consumed by only 12% of the white population where death rates from colon cancer are lowest,

in

to be

l95S

in colon-cancer

NHANES

of

are present,

as the concentration

of air pollution

CANCER

variations from

can

Atmospheric

and

COLON

industrial (1). The

markedly

to a high

D, AND

Japan).

ozone

light

mean

varies

and 18 MJ/m2 in the South among 50 reporting nations

nearer

notably

the ground

from

age-adjusted

located

in map

in the high latitudes ofthe in the South and Southwest

in the

the Southwest Worldwide

are presented

VITAMIN

Northeast North central South West *

Reference

t Reference

1.5 1.6 1.5 1.6 7 1. 70.

1.9 1 .7 1.4 1.8

breadt % reporting

2.5 2.5 2.4 2.4

19 18 12 20

1 96S

GARLAND

Clinical

ET

studies

AL

Given

this caveat,

model Using

autoradiography

Newmark

(6) reported

induced

on that

a quiescent

individuals

tumors

calcium

risk

in rodents

with

(79).

Pence

on a high-fat

diet

and

diet

(NS)

that

was

also

(79)

resulted

in

a

inhibits

intestinal that

tu-

rats

F344

oil) given

identical

g

17%

D (79)

‘-0.9

(P < 0.05) in the incidence with rats given ---0.5 jzg/d

reduction

of 0.9

(78). of intes-

vitamin

as corn

otherwise

A 38%

spe-

D and

reported

of feed

(P

1% Ca as compared

combination

and 0.05)




Because

(82,

of human

of control

of calcium and one case-control

reported

for serum

MD, men and cancer incidence

takes>

that

intake (2) and

colon-tumor antigen

prospects

now

culture

the growth

colon cancer xenografts including an established

Epidemiologic

in estab-

assumes of calcium

if the drop in incidence of colon the data from this study suggest

approach

at which incidence The Utah study

men

1,25-dihydroxyvitamin

reported

reasonably

in incidence

its results

the

studies

intake

mgCa/d(2).

trapolation

Receptors

calcium

approach

reduction

1500

the

Laboratory

between

Ca/d, with a Pearson product-moment correlation of-0.94 (Fig 1). If the association between calcium intake and risk of colon cancer is linear, which is only one of several possibilities, then extrapolation from these results suggests the possibility that in-

but

received

epidemiologic

which

cancer.

regarding

approximation

The

oil had

that

relationship

of colonic

linear

as

received

a theoretical

of calcium,

thresholds or plateaus beyond which further offers no marginal benefit or even an adverse

Results

incidence

et al (8 1), rats that

tumors

ofcolon

These investigators 7.5 zg vitamin D/4.2

Mi and Ca/4.2

by Newmark

here

efficacy

the risk of colon cancer is linear. Other theoretical be equally plausible, including models that assume

odological

intakes

a lower

dose-response

67%

1% Ca

tumor

the

we propose

possible

mg Ca/d (Fig 1). Even is not linear, however,

(79).

According

corn

Buddingh by weight

Ca as gluconate.

gluconate

to rats

of

also

of vitamin

oforal

had a 45% reduction tumors compared

for a diet containing The

calcium

intake

orally

epithelium

Oral

Administration

(20%

ig vitamin D/d rate of intestinal

diet.

dietary

and

mg Ca/d

colonic

cancer.

D (80)

morigenesis.

0.5%

of 1250

Lipkin

the size ofthe proliferative compartment reported reductions in the incidence

associated

a control

level,

in the

for colon

or l-a-hydroxyvitamin

on

a supplement

equilibrium

at high

cifically decreased Animal studies tinal

a microscopic

of the

remain

Downloaded from https://academic.oup.com/ajcn/article-abstract/54/1/193S/4690960 by Washington University in St. Louis user on 24 March 2018

communication,

This

study

to detect was

not

Zealand

the

full

assessed

benefit in this

of calcium study

but

is low (K Sylvester,

vi-

personal

1990).

did not directly

intriguing patterns tamin D may have

are evident, been playing

address

vitamin

D status.

however, that indicate some undetermined

Some

that virole. Fish

CALCIUM, TABLE

VITAMIN

D, AND

COLON

CANCER

l97S

2

Summary

of selected

observational

epidemiologic

studies

of the relationship

Reference

between

calcium

and colon

cancer

Summary

Garland

and Garland

Garland

et al (2)

Slattery

et al (5)

(1)

Geographical epidemiologic study ofcolon cancer in both sexes, all ages, in the United States, 1959-61. This study proposed that a favorable influence of vitamin D metabolites on metabolism of calcium may reduce the death rate from colon cancer. The study was based on a detailed geographic analysis of vital statistics data. Prospective study of colon cancer in white men aged 40-55 y at baseline. This 19-y study of a cohort of 1954 men enrolled in 1957-1959 was based on 284 dietary histories obtained when plastic food models were used. The histories were administered by dietitians on two occasions 1 y apart; the follow-up rate was 99.9%. By the 20th anniversary of the initial examination, there were 29 cases of colon cancer [International Classification of Diseases, 9th ed (ICD-9, I 53) and 20 cases of rectal cancer (ICD-9, I 54). Quartiles of calcium intake (in mg/d) were 3 16-749, 750-949, 950I 189, and 1 190-2808. Incidence of colon cancer decreased with increasing intake ofcalcium. Odds ratios for calcium intakes from the lowest to highest quartiles were 1.0, 0.6, 0.6, and 0.3 (P trend < 0.05). Quartiles of vitamin D intake were 6-94, 95-149, 150-229, and 230-652 IU/d. Odds ratios for vitamin D intakes from lowest to highest quartiles were 1.0, 1.3, 0.5, and 0.5 (P trend 0.05). Similar results were obtained from a combined calcium-vitamin D index calculated as 5.0 plus the sum of standard (Z) scores for calcium and vitamin D intakes. This index ranged from 1.8 to 13.0 U with a mean of 5.0 U. Odds ratios from the lowest to the highest quartile ofthe index were 1.0, 0.6, 0.6, and 0.4. This is the only study ofthe association between dietary vitamin D and colorectal cancer. It reported that the incidence of colorectal cancer was reduced by half in those who consumed 3.8 ig/d compared with those who consumed less. Case-control study ofboth sexes (whites aged 40-79 y). This population-based study of men and women used a 99category, food-frequency interview. Intake was requested for the period 2 y previous to the date of onset (cases) or interview (control subjects). There were 231 cases ofcolon cancer (lCD ofOncology 1-530 to 1-534, 1-536 to 1-539,

and part ofcode 1-540) and 391 control subjects. The control subjects were obtained results were reported for vitamin D. Men. Quartiles ofcalcium intake (in mg/d) were 0-641, 642-975, 976-1401, and inverse, dose-response relationship beginning with the second quartile, with increased amount intake,

associated with decreased risk of colon cancer. Crude odds ratios, were 1.0, 1. 1 , 0.8, and 0.5. Odds ratios were similar after adjustment

Mormon),

Kune et al (65)

Heilbrun

Ct al (86)

Stemmermann

Garland

et al (87)

et al (3)

crude fiber, and energy intake,

by random-digit

dialing.

1402. There

was a linear,

calcium

No

intake above that

from highest to lowest quartile of calcium for age, religion (Mormon vs non-

Ic, 1.0, 1.3, 0.8, and 0.4, respectively.

The effect ofcalcium

was reported

as

statistically significant for the highest quartile compared with the lowest (P < 0.05, one tailed). Women. Quartiles ofcalcium intake (in mg/d) were 0-592, 593-826, 827-1 141, and > 1 141. Crude odds ratios, from lowest to highest quartile, were 1.0, 0.6, 0.8, and 0.8. Odds ratios after adjustment for age, religion, crude fiber, and energy intake were 1.0, 0.5, 0.5, and 0.5, respectively. These odds ratios were reported as not being statistically significant. However, a statistically significant effect was present when calcium was examined as mg/l000 Id. Quartiles of this variable (in mg/bOO kJ) were 0-97, 98-125, 126-159, and >159. Crude odds ratios, from lowest to highest quartile, were 1.0, 0.9, 0.6, and 0.5. Odds ratios after adjustment for age, religion, crude fiber, and calories were 1.0, 0.9, 0.6, and 0.4. The effect ofcalcium was statistically significant in either ofthe two highest quartiles compared with the lowest (P < 0.05, one tailed). Case-control study ofcolon cancer in both sexes (ages 40-79 y). This study used a dietary interview concerning the previous 20 y and was conducted by a dietitian. It included ‘-300 foods. The authors reported results for calcium, milk, and dairy products but not for vitamin D. Community controls were obtained by random-digit dialing. Men. There were 388 cases of cancer in males (202 ofcolon and 186 of rectal; 398 control subjects). Overall median calcium intake was 851 mg/d. Quintiles ofcalcium intake were 0-597, 598-771, 772-928, 929-1 150, and 1151 mg/d. Odds ratios, from lowest to highest quintile ofcalcium intake were 1.00, 0.61, 0.51, 0.62, and 1.06. Women. There were 327 cases of cancer in females (190 ofcolon and 137 of rectal; 329 control subjects). Overall median calcium intake was 758 mg/d. Quintiles ofcalcium intake were 0-529, 530-686, 687-829, 830-1043, and 1044 mg/d. Odds ratios, from lowest to highest quintile ofcalcium intake were 1.00, 1.04, 0.73, 0.78, and 0.56. Nested case-control study in Japanese-American men aged 46-68 y. The results of this study have been superseded by a site-specific prospective study ofthis cohort by Stemmermann et al, based on 277 cases (below). Prospective study ofcolon cancer (ICD-8 codes 153.0-153.3 and 154.0-154.1) in Japanese-American men. This study of7472 men aged 45-70 y at baseline in 1957-1959 was based on a 24-h diet-recall interview administered by a dietitian using food models to estimate portion sizes. Ascertainment of cases was from a cancer registry and other linked records. By December 31, 1987, approximately the 22nd anniversary of accession to the study. there were 189 cases ofcolon cancer (ICD-8, 153.0-153.4), 39 rectosigmoid (ICD-8, 154.0-154.1), and 49 rectal. Mean calcium intake in this cohort was only about half that in other studies reported here, ie, 503 mg/d. The standard deviation of total calcium intake was 303 mg. In the sigmoid, where the majority ofcolon cancers were located (1 13 of 189, or 60% of colon cancers), incidence decreased significantly with increasing intake of calcium. Relative risks for calcium intakes from the lowest to highest tertiles were 1.0, 0.8, and 0.6 (P trend < 0.02). No statistically significant effect of calcium intake was observed for other sites in the colon or rectum. Serum was collected in Washington County, MD, from 25 620 volunteers aged 18 y in August-November, 1974, and frozen at -73 #{176}C.Serum was analyzed from 34 individuals (17 men, 17 women; median age 55-64 y) who developed colon cancer (ICD-8 codes 153.0-153.8) between 1975 and 1983, and from 67 control subjects matched by race, sex, age, and month blood was taken. Quintiles of serum 25-hydroxyvitamin D (in nmol/L) were 10-49, 50-64, 65-79, 80-100, and 101-226, respectively. Estimated relative risks, by quintile, from lowest to highest 25hydroxyvitamin D were 1.0, 0.5, 0.2, 0.2, and 0.7. The relationship was statistically significant (P < 0.05, one-tailed).

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consumption

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was

associated for

with

found

reduced

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