caffeine and bone 1

Am J C/in Nutr l99l;54:l57-63. Printed in USA. 1991 American Society for Clinical Nutrition 157

Caffeine, moderate alcohol intake, and risk of fractures ofthe hip and forearm in middle-aged women14Mauricio Hernandez-Avila, Graham A Colditz, Meir J Stampfer, Bernard Rosner,Frank E Speizer, and Walter C Willeit

ABSTRACT In 1 980, 84 484 US women aged 34-59 ycompleted an independently validated dietary questionnaire.During the ensuing 6 y, 593 forearm and 65 hip fractures oc-curred in association with mild to moderate trauma. We observeda positive relation between caffeine intake and risk of hip butnot forearm fracture. After potential risk factors were controlledfor the relative risk (RR) of hip fracture for women in the topquintile ofcaffeine consumption was 2.95 (95% CI = 1.18-7.38,P, trend = 0.003). Alcohol intake was independently associatedwith increased risk of both hip and forearm fractures and witha dose-response relation. Compared with nondrinkers, womenconsuming 25 g alcohol/d had an RR of2.33 (95% CI = 1.18-4.57) for hip fractures and an RR of 1.38 (95% CI = 1.09-1.74)for forearm fractures. These prospective data suggest that caffeineand alcohol consumption both increase the risk of osteoporoticfractures in middle-aged women. Am J Clin Nutr 199 1;54:157-63.

KEY WORDS Women, diet, caffeine, alcohol, fractures,incidence

Introduction

Dietary caffeine induces a negative calcium balance throughincreased urinary loss (1, 2) but information about the influenceof caffeine and coffee intake on bone mass is limited. No asso-ciation was noted in some studies (3-5) whereas an adverse effectof caffeine was observed in others (6; M Hernandez-Avila, per-sonal communication, 1990). Recently, Holbrook et al (8) re-ported an increase in hip fracture (18 cases) in women with highcaffeine intake and an inverse relation in men ( I 5 cases); how-ever, neither association was statistically significant. Kid et al(9) reported data from the Framingham Study showing thatwomen consuming > 2 units caffeine/d (one cup of coffee 1unit, one cup of tea 0.5 unit) had a relative risk of 1.69 (95%CI 1.49-1.92).

Alcohol abuse is strongly related to the risk of fractures (10)but the effects of moderate amounts of alcohol on bone metab-olism, osteoporosis, or fracture risk have not been extensivelystudied. In some reports, medium to high alcohol intake wasassociated with an increased risk of osteoporotic fractures ( 1 1-14). We previously reported an increased risk ofhip and forearmfractures combined in women consuming > 1 5 g alcohol/d (13),but we were not able to examine these fracture sites separately.

Osteoporotic fractures are an important cause of morbidityand mortality in the United States. Lifetime risk of death dueto hip fracture for a 50-y-old woman (2.8%) is equal to the life-time risk ofdeath due to breast cancer (1 5). Alcohol and caffeineare consumed regularly by the majority ofadults (16, 17). Thusany effect ofeither on the risk ofosteoporosis or fractures wouldrepresent a major public health concern. In this report we assessthe relation between caffeine and alcohol intake and risk of fore-arm fractures (largely reflecting cortical bone) and hip fractures(largely reflecting trabecular bone) by using prospectively col-lected data from the Nurses Health Study. This cohort has beenfollowed since 1976 to study the relation between exogenousfemale hormones and cancer and was expanded in 1980 to studythe relations between diet and major illnesses.

Methods

The Nurses Health Study cohort was established in 1976,when 12 1 700 female registered nurses 30-55 y ofage, from 1 1states, responded to a questionnaire requesting information ontheir medical history and lifestyle variables. This study is de-scribed in detail elsewhere (18, 19). The questionnaires includeditems on height, weight, menopausal status, postmenopausalhormone therapy, and cigarette smoking. Every 2 y, follow-upquestionnaires have been sent to update information on potentialrisk factors and to obtain data on newly diagnosed major medicalevents. In 1980 the follow-up questionnaire was expanded toinclude a 6 1-item semiquantitative food-frequency question-naire; this was returned by 98 462 participants.

I From the Channing Laboratory, the Department of Medicine,Brigham and Womens Hospital and Harvard Medical School, and theDepartments of Epidemiology, Biostatistics, and Nutrition, HarvardSchool of Public Health, Boston.

2 The contents ofthis publication do not necessarily reflect the viewsor policies of the US Department of Agriculture, nor does mention oftrade names, commercial products, or organizations imply endorsementby the US Government.

3 Supported by research grant CA 90356 from the National InstitutesofHealth and in part by the US Department ofAgriculture, AgriculturalResearch Service, under contract 53 3K06-5-10.

4 Address reprint requests to GA Colditz, 180 Longwood Avenue,Boston, MA 021 15-5899.

Received July 24, 1990.Accepted for publication November 28, 1990.

at UNAM Instituto de Investigaciones Biom

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158 HERNANDEZ-AVILA ET AL

The semiquantitativefood-frequency questionnaireA detailed description ofthe questionnaire and documentation

ofits reproducibility and validity were published elsewhere (19-23). Briefly, we identified a list of 6 1 foods and beverages [in-cluding coffee (not decaffeinated), carbonated cola beverages,beer, wine, and liquor] that gave maximal discrimination forintake of 18 nutrients. For each food a commonly used unit orportion size was specified, and participants were asked abouttheir average frequency of use over the preceding year. Ninepossible responses were provided, ranging from never to sixor more times a day. Nutrient intakes were computed by mul-tiplying the frequency of consumption of each unit of food bythe nutrient content of the specified food. Alcohol intake wasrecorded as the average frequency of intake of each beverageover the preceding year: beer (bottles or cans), wine (glasses),and liquor-whiskey, gin, etc (drinks). The alcohol content wasestimated as 13.2 g per bottle or can of beer (360 mL), 10.8 gfor a glass ofwine (120 mL), and 15.1 g for a drink of hardliquor (45 mL). Caffeine intake was estimated from average useover the past year for coffee, not decaffeinated (cups; 136 mg/cup), tea (cups; 64 mg/cup), and cola drinks (glasses; 46 mg/bottle or can). Following this general approach, we also calculatedcalcium intake from responses to the food-frequency question-naire.

The validity and reproducibility of the food-frequency ques-tionnaire to assess caffeine, alcohol, and calcium intake wasevaluated in a random sample of 194 members of the cohortliving in the greater Boston area. Participants in the validationstudy were instructed in weighing and measuring all food andbeverages that they consumed during a 7-d period. Four l-wkdiet records were completed at 3-mo intervals during the yearafter the completion ofthe food-frequency questionnaire. At theend ofeither the third or the fourth week ofrecording, a seconddietary questionnaire, identical to the first, was completed. Theassessment ofcaffeine, alcohol, and calcium intake were highlyreproducible over the l-y interval (Spearman r = 0.90 for alcohol,0.80 for caffeine, and 0.56 for calcium). Individual beverageswere also highly correlated with measurements made during the4-wk of diet recording (Spearman r = 0.78 for coffee, 0.93 fortea, 0.84 for cola drink, 0.94 for beer, 0.90 for wine, and 0.84for liquor) (24). The Pearson correlations for the nutrients ofinterest in this study were small; for intake of energy-adjustednutrients in 1980, r = 0.06 for caffeine and alcohol, 0.03 forcaffeine and calcium, and -0. 13 for alcohol and calcium. Hence,there was likely to be little or no influence of the effect of oneof these nutrients on the others.

Nondietary exposure variables

Weight and height were reported on the 1976 questionnaireand weight was updated every 2 y. We calculated body massindex (weight divided by height squared) as a measure of adi-posity. Menopausal status and current use of postmenopausalestrogens were updated every 2 y.

Population for analysisFour percent of the 98 462 women who returned the 1980

food-frequency questionnaire were excluded because 10 fooditems were left blank, and 2.7% were excluded because of im-plausibly high or low total food scores. Women reporting a di-

agnosis of cancer (other than nonmelanoma skin cancer), cor-onary heart disease, or osteoporosis at any time in the past or afracture in the 4 y before 1980 were also excluded, leaving atotal of 84 484 women who were included in the analyses.

Identification offracturesThe 1982, 1984, and 1986 follow-up questionnaires inquired

about the occurrence of hip or forearm fractures. Women wereasked for the date of occurrence and a description of the cu-cumstance in which the injury occurred. Women who reporteda forearm or hip fracture but did not provide the additionalinformation on circumstances were mailed a supplementaryquestionnaire inquiring about these details.

The validity of self-reported fractures was documented else-where (25). Briefly, we sought permission to review medical re-cords among a random sample of 50 women who reported frac-tures on the 1982 questionnaire. Forty-three women respondedand confirmed their previous self-report and 33 gave permissionto review medical records, which confirmed the self-reporteddiagnosis in all cases.

For this analysis we defined osteoporotic fractures as fracturesof the proximal femur (hip fractures) or fractures of the distalradius (Colles fractures) that occurred in association with low-impact trauma, predominantly about the house, during recre-ational activities, or after falls while on the level. Such traumawould not usually be expected to result in a fracture. Fracturesassociated with higher-impact trauma were excluded from theanalyses (mainly those associated with motor vehicle accidentsor recreational activities such as skiing, roller skating, and bi-cycling). These criteria were developed and applied before anyanalysis of the data. For the fractured wrists the most commoncauses were slip, trip, or stumble on a flat surface, 29.4%; slipon ice, 22.0%; slip or trip on a slippery or wet surface, 10.6%;and fall from standing on a chair, 9.3%. The most frequentcauses oflow-trauma hip fractures included in the analysis wereslip, trip, or stumble on a flat surface, 22 (32.4%); slip ortrip on a slippery or wet surface, 14 (20.6%); slip on ice, 9( 1 3.2%); fall from a standing position, 7 ( 10.3%); stress frac-ture, 5 (7.4%); and fall down two steps or more, 5 (7.4%).

Analysis

The primary analysis was based on incidence rates with person-months of follow-up used as the denominator. For each partic-ipant, person-months were allocated according to the 1980 cx-posure variables and for nondietary variables they were updatedaccording to information on subsequent follow-up question-naires. For women reporting a fracture or who died, follow-upterminated with the fracture or death. Women who reported adiagnosis ofcancer (other than nonmelanoma skin cancer), cor-onary heart disease, or osteoporosis on the 1982 or 1984 ques-tionnaire were excluded from subsequent follow-up. Thus thepopulation was free from major illness that would likely modifyrisk of fracture or diet. If no questionnaire was returned for afollow-up cycle, the most recently recorded covariate data wereused for the subsequent follow-up interval.

Person-time for each covariate was accumulated and newfractures were allocated to the status of each variable at the be-ginning of each follow-up interval. Age-specific incidence rates(using 5-y age intervals) were calculated by dividing the numberof fractures by the person-time of follow-up. We used relative



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Incidence/iC pers

- 35-39 40-44 45-49 50-54 55-59 60-64

CAFFEINE, ALCOHOL, AND RISK OF FRACTURES 159

risk as a measure of association, defined as the incidence offractures in women who consumed caffeine divided by the in-cidence in women who consumed < I 92 mg caffeine/d (thislevel defines the lowest quintile ofintake). For analyses of alcoholintake, the reference group was women who reported drinkingalcoholic beverages never or almost never. Additional stratifiedanalyses were carried out to control for potential risk factorsand to explore the possibility that the effect ofcaffeine and alcoholmight be modified by these factors. We used the Mantel test forlinear trend to examine the dose-response relations between caf-feine and risk offractures and alcohol and risk offractures (26).We used proportional hazards models to adjust for multiple riskfactors simultaneously and to examine the effects of specificbeverages while other sources of caffeine and alcohol were con-trolled for (27).

Results

Six hundred fifty-eight fractures (593 Colles and 65 femur)caused by mild to moderate trauma were documented during482 347 person-years of follow-up. The incidence of fracturesrose sharply with age, increasing from 1 .5 per 1000 person-yearsin women aged 35-39 y to 19.4 per 1000 person-years in womenaged 60-64 y for Colles fractures and from 0. 1 to 2.5 per 1000person-years for hip fractures (Fig 1).

Caffeine intakeOf the participants 75% were coffee drinkers and 68% were

tea drinkers; 44.8% ofwomen reported drinking carbonated colabeverages at least once per month. The median reported dailyintake for coffee drinkers was 2-3 cups/d and among tea drinkerswas 5-6 cups/wk. Caffeine consumption in this populationranged from a minimum intake ofO mg/d to a maximum intakeof 1439 mg/d; median intake was 404 mg/d.

We observed a strong positive association between caffeineconsumption and the risk of hip fractures. Compared withwomen in the lowest quintile who consumed < 192 mg caffeine!d, those with an intake of 192-359.9 mgJd had an age-adjustedrelative risk ofhip fractures that was 2.38 (95% CI 0.94-6.03)and those who consumed 8 1 7 mg/d had an age-adjusted rel-ative risk of2.96 (95% CI = 1.21-7.24). The test for linear trendrelating caffeine intake with the risk of hip fracture was of bor-derline statistical significant (x = 1 .84, P = 0.07).

Ofthe dietary sources ofcaffeine (coffee, tea, and cola drinks)the only significant predictor ofthe risk ofhip fracture was coffee(Table 1). When compared with women who almost never con-sumed coffee, women with a high consumption (> 4 cups/d)had a threefold increase in the risk ofhip fractures (age-adjustedrelative risk 3.62; 95% CI = 1.60-8.18). We observed a significanttrend of increasing risk of hip fractures with increasing coffeeconsumption x 2.90, P = 0.004). Tea was not significantlyassociated with the risk of hip fractures (x = - 1.18, P = 0.24).The consumption ofcola drinks was not associated with risk ofhip fractures except for nonsignificant elevation among womenconsuming 4 glasses/d (relative risk for 4 glasses/d = 1.57;95% CI = 0.49-4.98).

Adjustment for body mass index, menopausal status, post-menopausal hormone use, calcium intake, and cigarette smokingin stratified analyses did not materially alter the relation betweencaffeine consumption and hip fractures. When we controlled for

FIG 1. Age-specific incidence rates ofhip (U) and forearm (0) fracturesin 84 484 US women.

all these potential risk factors as well as alcohol intake, age, andfollow-up cycle simultaneously in a proportional-hazards model,the relative risks remained largely unchanged. All categories ofcaffeine consumption were associated with an increased risk ofhip fractures compared with women who consumed < 1 92 mgcaffeine/d (Table 1). The multivariate-adjusted relative risk forwomen who consumed 817 mg/d was 2.95 (95% CI 1.18-7.38). The test for linear trend was significant (X = 2.97, P= 0.003).

In a second model we included coffee, tea, and cola drinkssimultaneously and observed similar results: coffee was signifi-cantly associated with risk ofhip fractures, tea had no association,and the highest levels of intake of cola drinks were related to anonsignificant elevation in risk (Table I).

We observed no association between caffeine intake and therisk offorearm fracture (Table 1). Similar null associations wereobserved when we examined separately coffee, tea, or cola drinks.For all categories, the age-adjusted and multivariate-adjustedrelative risks were close to the null value of 1.0.

Akohol intake

We observed an increase in the risk of both hip and forearmfractures in women who reported moderate alcohol intake (5-24 g/d; Table 2). As compared with women who did not consumealcohol, the age-adjusted relative risk ofhip fracture for womenwho consumed 25.0 g/d was 2.35 (95% CI 1 .02-5.4 1). Aftermultivariate adjustment for potential confounding variables in-cluding caffeine intake, this relative risk decreased slightly to2.33 (95% CI = 1 . 18-4.57). The test for trend remained signif-icant (X = 2.07, P = 0.04). We also observed positive but smallerassociations for forearm fractures; the multivariate-adjusted rel-ative risk was 1.38 (95% CI = 1.09-1.74) for women who con-sumed > 25 g/d. The test for a trend relating alcohol intake torisk offorearm fracture was slightly reduced (x = 1 .73, P = 0.08).

We next examined the separate effects of alcohol from beer,wine, and liquor. We observed a significant trend relating beer



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* Adjusted for age (seven categories), Quetelet Index (five categories), menopause status (before, after, or uncertain), estrogen-replacement therapy,calcium intake, and caffeine intake (five categories).


TABLE 1Relative risk of hip and forearm fractures according to intake of caffeine, coffee, cola drinks, tea, and alcohol in a cohort of 88 484 US women

VariablePerson-

years

Hip fractures Forearm fractures

Observedcases

Relative risk (95% CI)Observed

cases

Relative risk (95% CI)

Age adjusted Multivariatet Age adjusted Multivariatet

Caffeine (mg/d)0- 19 1.9 94 778 6 Reference Reference I 20 Reference Reference192-359.9 97 415 14 2.38 (0.94-6.03) 2.30 (0.89-5.95) 1 13 0.94 (0.73-1.22) 0.93 (0.72-1.21)360-499.9 94 002 15 2.42 (0.97-6.03) 2.22 (1.15-5.67) 98 0.79 (0.60-1.03) 0.77 (0.58-1.00)500-816.9 99 037 13 2.00 (0.77-5.19) 0.80 (0.68-4.72) 139 1.08 (0.85-1.38) 1.05 (0.82-1.35)8l7 97 1 15 17 2.96 (1.21-7.24) 2.95 (1.18-7.38) 123 1.03 (0.80-1.32) 1.05 (0.82-1.35)Testfortrend x= l.84,P=0.07 x=2.97,P=0.003 x=0.70,P=0.48 x= l.26,P=0.21

Coffee(cups)Almost never I 1 1 385 7 Reference Reference 124 Reference Reference1-3/mo to 2-4/wk 29 154 1 0.57 (0.08-4.25) 0.58 (0.07-4.76) 84 1.08 (0.74-1.57) 1.01 (0.69-1.49)5-6/wk to 1/d 64 573 12 2.65 (1.08-6.53) 2.66 (0.99-7.17) 84 1.09 (0.82-1.43) 0.97 (0.73-1.30)2-3/d 157 355 20 1.87 (0.80-4.36) 1.77 (0.71-4.45) 197 1.05 (0.83-1.31) 0.98 (0.78-1.24)4/d 80 135 19 3.62(1.60-8.18) 3.35(1.32-8.49) 104 1.13(0.87-1.46) 1.10(0.85-1.44)Testfortrend x=2.90,P=0.004 x=2.26,P=0.02 x=0.70,P=0.48 x0.44,P=0.66

Tea (cups)Almost never 143 158 18 Reference Reference 184 Reference Reference1-3/mo to 2-4/wk 136 902 26 1.58 (0.88-2.87) 1.38 (0.75-2.56) 160 0.94 (0.76-1.16) 0.97 (0.77-1.21)5-6/wk to l/d 98 700 12 0.97 (0.47-2.02) 0.83 (0.39-1.77) 140 1.1 1 (0.89-1.38) 1.13 (0.89-1.43)2/d 98 716 7 0.60 (0.25-1.44) 0.71 (0.29-1.73) 104 0.88 (0.69-1.12) 1.01 (0.78-1.29)Testfortrend x=-1.18,P=0.24 x=-l.23,P=0.22 x-0.43,P0.66 x-0.51,P=0.61

Cola drinks (glasses)Almost never 269 357 46 Reference Reference 350 Reference Reference1-3/mo to 2-4/wk 68 317 5 0.54 (0.22-1.32) 0.60 (0.23-1.52) 82 1.06 (0.84-1.72) 1.03 (0.80-1.34)5-6/wk to 1/d 85 980 6 0.57 (0.24-1.35) 0.66 (0.28-1.58) 95 1.09 (0.87-1.37) 1.09 (0.86-1.38)2-3/d 48 600 5 0.94 (0.35-2.53) 1.53 (0.64-3.67) 54 1.18 (0.88-1.59) 1.13 (0.83-1.54)4/d 10 091 3 1.57 (0.49-4.98) 1.88 (0.58-6.1 1) 12 0.85 (0.48-1.51) 0.93 (0.52-1.66)Testfortrend x=-0.44,P=0.66 x0.04,P0.97 x0.79,P0.43 x0.44,P0.66

0 Number of cases do not always add up to 65 because of missing information for specific beverages.t Adjusted for age (seven categories), Quetelet Index (five categories), menopause status (before, after, or uncertain), estrogen-replacement therapy, calcium intake, and

alcohol intake (five categories). Multivariate results for specific beverages also had other caffeinated beverages controlled for.

(x = 2.51, P = 0.01) and liquor (x = 2.39, P = 0.02) but not significant data (X = 2.24, P = 0.03), an association that waswine (X = -0.53 P = 0.60) to the risk of hip fracture (Table 3). attenuated after multivariate adjustment (see Table 3).Few women in the cohort were heavy consumers ofwine, which .limited the possibility of examining the relation between wine Discussionand risk of fracture. We observed similar results for forearm In this study we observed that risk of hip fracture was signif-fractures; however, liquor was the only beverage with statistically icantly higher in women who consumed greater amounts of caf-

TABLE 2Relative risk of hip and forearm fracture according to alcohol intake in a cohort of 84 484 US women

Variable:alcohol

Person-years


Observedcases

Relative risk (95% CI)Observed

ca

Relative risk (95% CI)

Age adjusted Multivariate Age adjusted Multivariate*

None 153 721 14 Reference Reference 171 Reference Reference0.1-4.9 g/d 162 943 21 1.57 (0.80-3.06) 0.94 (0.35-2.68) 190 1.12 (0.91-1.38) 1.18 (0.91-1.52)5.0-14.9 g/d 97 143 12 1.41 (0.65-3.04) 1.99 (0.97-4.07) 123 1.16 (0.92-1.47) 1.21 (0.94-1.54)15.0-24.9 g/d 33 740 10 3.04 (1.40-6.60) 1.15 (0.51-2.61) 60 1.50 (1.12-2.01) 1.22 (0.95-1.57)25.0 gJd 34 800 8 2.35 (1.02-5.41) 2.33 (1.18-4.57) 49 1.18 (0.86-1.62) 1.38 (1.09-1.74)Testfortrend x=2.49,P=0.Ol x2.07,P0.04 x2.l1,P0.03 X 1.73,P0.08



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teoporosis (3-5). A recent 14-y follow-up study that included

TABLE 3Relative risk of hip and forearm fractures according to beer, wine, and liquor intake in a cohort of 84 484 US women

Variable


Observedcases

Relative risk (95% CI)*Observed

cases

Relative risk (95% CI)*

Age adjusted Multivariate Age adjusted Multivariate

Beer (drinks)Almost never 43 Reference Reference 452 Reference Reference1-3/mo to 2-4/wk 6 1.26 (0.54-2.94) 1.45 (0.60-3.51) 48 0.93 (0.69-1.25) 0.83 (0.60-1.14)5-6/wk to l/d 7 1.66 (0.76-3.62) 1.68 (0.69-4.08) 52 1.10 (0.83-1.47) 0.99 (0.72-1.30)2-3/d 9 4.13 (2.12-8.03) 4.20 (1.87-9.43) 27 1.16 (0.79-1.71) 1.06 (0.70-1.59)4/d - - - 14 1.40 (0.82-2.38) 1.30 (0.72-2.36)Testfortrend x=2.51,P=0.01 x=2.42,P=0.02 x = l.31,P=0.l9 X 0.80,P=0.42

Wine (drinks)Almost never 26 Reference Reference 238 Reference Reference1-3/mo to 2-4/wk 21 1.65 (0.94-2.90) 1.83 (0.86-3.89) 147 1.23 (1.00-1.51) 1.27 (0.98-1.04)5-6/wk to l/d 14 1.18 (0.62-2.25) 1.15 (0.50-2.64) 122 1.1 1 (0.89-1.38) 1.09 (0.83-1.45)2-3/d 4 0.62 (0.22-1.76) 0.52 (0.16-1.70) 80 1.34 (1.04-1.72) 1.30 (0.95-1.76)4/d - - - 6 0.99 (0.44-2.21) 0.74 (0.30- 1.82)Testfortrend x=-0.53,P=0.60 x-0.04,P=0.97 X 1.91,P0.06 X 1.76,P0.08

Liquor (drinks)Almost never 27 Reference Reference 302 Reference Reference1-3/mo to 2-4/wk 12 1.43 (0.73-2.80) 1.72 (0.71-4.17) 98 1.02 (0.81-1.28) 0.94 (0.69-1.29)5-6/wk to l/d 13 1.65 (0.85-3.17) 2.16 (0.91-5.1 1) 1 1 1 1.26 (1.01-1.56) 1.21 (0.89-1.64)2-3/d 1 1 1.94 (0.97-3.90) 2.32 (0.97-5.55) 72 1.19 (0.92-1.53) 1.06 (0.76-1.47)4/d 2 3.27 (0.84-12.7) 6.99 (1.55-31.60) 10 1.51 (0.81-2.82) 1.28 (0.60-2.71)Test fortrend x = 2.39, P = 0.02 x = 2.41, P = 0.02 x = 2.24, P= 0.03 x = 1.56, P = 0.12

S Adjusted for age (seven categories), Quetelet Index (five categories), menopause status (before, after, or uncertain), estrogen-replacement therapy,calcium intake, and caffeine intake (five categories), and other alcohol-containing beverages. Reference category for multivariate analyses is womenconsuming no alcohol.

feine compared with those women who drank little or none.This association was most evident for coffee consumption, themajor source of caffeine intake in this population. Moderatealcohol intake was associated with increased risk of both hipand forearm fractures. The strong association observed for coffeeconsumption but not for tea is possibly explained by the lessfrequent consumption of tea, its lower caffeine content, and itshigher fluoride content.

The prospective design of this study greatly reduces the pos-sibility of bias due to reporting dietary or other risk factors forfractures. In a validation study of a sample of Boston-area par-ticipants, caffeine, alcohol, and the individual beverages werereported with a high degree of validity. The positive associationbetween alcohol intake and breast cancer in this cohort (28) andthe protective association with coronary heart disease (29), whichagree with findings in other studies, also lend support to theaccuracy of self-report, because inaccurate self-reporting wouldtend to obscure associations with all end points.

A spurious association between alcohol or caffeine intake andfracture risk could arise ifwomen who consumed these beveragesand sustained fractures were more likely to respond to follow-up questionnaires or more likely to report fractures if they hadoccurred. However, this is unlikely because the response rateswere almost identical across levels ofalcohol and caffeine intake.Forexample, 90.3% ofnondrinkers responded in 1986 and 89.8%of women drinking 25 g alcohol/d responded. For caffeineintake the response was 90.2% for women in the lowest quintile

ofintake and 90.3% for women in the highest quintile. A positiveassociation could also arise ifwomen who drank coffee or alcoholwere at a higher risk ofsustaining accidents, that is, ifthey weremore active or engaged in more high-risk activities during thefollow-up period. However, such an association for caffeine seemsunlikely.

Considerable evidence supports a biological mechanism forthe effect of caffeine on bone density. Caffeine has a calciureticeffect in some studies (30-32), and high urinary excretion ofcalcium could promote a negative calcium balance. A random-ized trial of 16 women showed a 4% decrease in net calciumbalance that failed to attain statistical significance (33). However,even such a modest shift in calcium balance, if sustained overa prolonged period, could produce a biologically significant cal-cium depletion. Heaney and Reeker (1) observed a significantinverse association between calcium balance and caffeine intakein healthy premenopausal women. The relation between caffeineintake and bone density has been evaluated in several epide-miologic studies. Daniell (34) reported a high caffeine intake inosteoporotic women as compared with age-matched controlsubjects. Yano et al (6) reported an inverse correlation betweencaffeine intake and bone density. Kid et al (9) reported that menand women consuming > 2 units caffeine/d were at increasedrisk of hip fractures compared with those consuming < 2 units/d. However, other investigators have failed to find a significantinverse association between caffeine (or coffee) intake and os-



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33 hip fractures reported only a borderline increase in the riskassociated with caffeine consumption for females and no asso-ciation for males (8). These data relating caffeine to bone mass,together with our own, support a causal relation between caffeineand risk of fractures among women.

In several studies bone mass was reduced in alcoholics (35-40). The relation between alcohol and risk of fractures has beenevaluated in case-control and cohort studies. Hutchinson et al(1 1) reported that alcoholism (undefined) was associated withan increased risk of fractures in postmenopausal women. Pa-ganini-Hill et al ( 12) observed a positive trend in the risk offractures with increasing number of shots of liquor per weekafter menopause. Women drinking 8 shots/wk had a relativerisk of 1 .85 compared with women who never drink liquor. Inan analysis of data relating alcohol intake and hip fractures inparticipants in the Framingham Study, Felson et al (14) reportedincreasing risk with alcohol consumption (test for trend, P= 0.05). Women aged 31-95 y drinking 210 mL alcohol/wkhad a relative risk of 1.54, although this did not attain statisticalsignificance. However, when analyses were restricted to ages 31-65 y, a strong association was observed between alcohol intakeand the risk of hip fractures.

The association between alcohol intake and fractures may beexplained by a combination of acute and chronic effects of al-cohol. The increased prevalence offractures in alcoholics is due,in part, to intoxication, which is associated with an increasedrisk of trauma. A marked reduction in bone remodeling mdc-pendent of hormonal factors suggests that the consumption ofalcohol may also directly relate to the development of osteo-porosis (40).

Alcohol intake is inversely correlated with body mass indexin this population of women (41) and obesity is positively as-sociated with bone density and with a reduced risk ofhip fractures(42). Therefore, obesity may cause a spurious positive associationbetween alcohol and fracture risk. Indeed, after we adjusted forbody mass index, the relation between alcohol and fracture riskdecreased, but only slightly. Adjustment for other potential riskfactors, including menopause, estrogen-replacement therapy, andcalcium intake did not appreciably alter the relation betweenalcohol and risk of fracture.

From these prospective data we conclude that caffeine andalcohol may both contribute to the etiology of osteoporoticfractures of the hip in middle-aged women. Moderate alcoholintake was also associated with increased risk of forearm frac-tures, although this association was not evident for caffeine in-take. a

We thank the registered nurses who made this study possible. We arealso grateful to Gary Chase, Susan Wu, Steven Stuart, Karen Corsano,Cynthia Morrow, Lori Egan, Marion McPhee, and Chris Pappas, whoassisted in the research.

References

1. Heaney RP, Recker RR. Effects of nitrogen, phosphorous and cal-feine on calcium balance in women. J Lab Clin Med l982;99:46-55.

2. Massey LK, Hollingberry PW. Acute effects ofdietary caffeine andaspirin on urinary mineral excretion in pre- and postmenopausaiwomen. Nutr Res l988;8:845-5l.

3. Slemenda C, Hui SL, Longcope C, Johnston CC. Sex steroids andbone mass. A study about the time of menopause. J Clin Investl987;80: 1261-9.

4. Eliel LP, Smith LC, Iveyt JL, Baylink DJ. Longitudinal changes inradial bone mass. Dietary caffeine, milk, and activity. Calcif TissueInt 1983;35:669(abstr).

5. Picard D, Ste-Marie LO, Coutu D, et al. Premenopausal bone mineralcontents relates to height, weight and calcium intake during earlyadulthood. Bone Miner 1988;4:299-309.

6. Yano K, Heilbrun LK, Wasnich RD. Hankin JH, Vogel JM. Therelationship between diet and bone mineral content of multipleskeletal sites in elderly Japanese-American men and women livingin Hawaii. Am J Clin Nutr 1985;42:877-88.

8. Holbrook TL, Barrett-Connor E, Wingard DL. Dietary calcium andrisk of hip fracture: 14-year prospective population study. Lancet1988;2: 1046-9.

9. Kid DP, Felson DT, Hannan MT. Anderson JJ, Wilson PWF. Caf-feine and the risk of hip fracture: the Framingham Study. Am JEpidemiol l990;132:675-84.

10. Israel V, Orrego H, Holt S. MacDonald DW, Meema HE. Identi-fication of alcohol abuse: thoracic fractures on routine chest X-raysas indicators ofalcoholism. Alcoholism 1980;4:420-2.

1 1. Hutchinson TA, Polansky SM, Feinstein AR. Post-menopausal oes-trogens protect against fractures of hip and distal radius. Lancetl979;2:705-9.

12. Paganini-Hill A, Ross RK, Gerkins JR. Menopausal estrogen therapyand hip fractures. Ann Intern Med 1981;95:28-31.

13. Hemenway D, Colditz GA, Willett WC, et al. Fractures and life-style: effect ofcigarette smoking, alcohol intake and relative weighton the risk ofhip and forearm fractures in middle-aged women. AmJ Public Health 1988;78:l554-8.

14. Felson DT, Kid DP, Anderson JJ, Kannel WB. Alcohol consumptionand hip fractures: the Framingham Study. Am J Epidemiol 1988;128:I102-10.

15. Cummings SR. Black DM, Rubin SM. Lifetime risks ofhip, collesor vertebral fracture and coronary heart disease among white post-menopausal women. Arch Intern Med 1989;149:2445-8.

16. Barone JJ, Roberts H. Human consumption of caffeine. In: DwesPB, ed. Caffeine. Berlin: Springer-Verlag, 1984.

17. Graham DM. Caffeine-its identity, dietary sources, intake, andbiological effects. Nutr Rev 1978;36:97-102.

18. Willett WC, Stampfer MJ, Colditz GA, et al. Dietary fat and therisk ofbreast cancer. N Engl J Med l987;316:22-8.

19. Colditz GA. The Nurses Health Study: findings during 10 years offollow-up of a cohort of US women. Curr Probl Obstet GynecolFertil 1990;13:13l-74.

20. Willett WC, Sampson L, Browne ML, et al. Reproducibility andvalidity of a semiquantitative food frequency questionnaire. Am JEpidemiol 1985; 122:51-65.

21. Willett WC, Reynolds RO, Cottrell-Hoehner 5, Sampson L, BrowneML. Comparison ofa semiquantitative food frequency questionnairewith a one-year record. J Am Diet Assoc 1987;87:43-7.

22. Willett WC, Sampson L, Browne ML, et al. Comparison ofa semi-quantitative food frequency questionnaire to assess diet four yearsin the past. Am J Epidemiol l988;127:188-99.

23. Willett W. Nutritional epidemiology. New Yorlc Oxford Univ Press1990.

24. Salvini 5, Hunter DJ, Sampson L, et al. Food-based validation of adietary questionnaire: the effects ofweek-to-week variation in foodconsumption. Int J Epidemiol 1989;18:858-67.

25. Colditz GA, Martin P. Stampfer Mi, et al. Validation of question-naire information on risk factors and disease outcomes in a pro-spective cohort study of women. Am J Epidemiol l986;l23:894-900.



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nloaded from


26. Kleinbaum DO, Kupper LL, Morgenstern H. Epidemiologic re-search. Principles and quantitative methods. Belmont, CA: LifetimeLearning 1982.

27. Cox DR. Regression models and life-tables. J R Stat Soc (B) 1972;34:187-220.

28. Willett WC, Stampfer Mi, Colditz GA, et al. Moderate alcohol con-sumption and the risk of breast cancer. N Engl J Med l987;316:1174-80.

29. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective studyof moderate alcohol consumption and the risk of coronary diseaseand stroke in women. N Engl J Med 1988;319:267-73.

30. Massey LK, Wise KT. The effect ofdietary caffeine on urinary cx-cretion of calcium, magnesium, sodium and potassium in healthyyoung females. Nutr Res 1984;4:43-50.

31. Massey LK, Wise KT. The effects of dietary caffeine on urinaryexcretion ofcalcium, magnesium, sodium and potassium in healthyyoung males. Nutr Res 1985;5:1281-4.

32. Massey LK, Hollingberry PW. Acute effects ofdietary caffeine andsucrose on urinary mineral excretion on healthy adolescents. NutrRes 1988;8:l005-12.

33. Barger-Lux MJ, Heaney RP, Stegman MR. Effects ofmoderate cal-feine intake on the calcium economy of premenopausal women.Am J Clin Nutr 1990;52:722-5.

34. Daniell HW. Osteoporosis of the slender smoker. Vertebralcompression fractures and loss of metacarpal cortex in relation topostmenopausal cigarette smoking and lack ofobesity. Arch InternMed 1976;l 36:298-304.

35. Saville PD. Changes in bone mass with age and alcoholism. J BoneJoint Surg l965;47A:492-9.

36. Nilsson BE, Westlin NE. Changes in bone mass in alcoholics. CanOrthop 1973;90:229-32.

37. Dalen N, Feldreich AL. Osteopenia in alcoholism. Clin Orthop1974;99:201-2.

38. Seeman E, Melton LI III, OFallon WM, Riggs BL. Risk factors forspinal osteoporosis in men. Am J Med 1983;75:977-83.

39. Schnitzler CM, Menashe L, Sutton CG, Sweet MBE. Serum bio-chemical and hematological markers of alcohol abuse in patientswith femoral neck and intertrochanteric fractures. Alcohol Alcohol1988;23: 127-32.

40. Daniel DB, Geanant HK, Cann C, et al. Bone disease in alcoholabuse. Ann Intern Med 1985;103:42-8.

41. Colditz GA, WilleU WC, Stampfer MJ, et al. Patterns of weightchange and their relation to diet in a cohort ofhealthy women. AmJ Clin Nutr 1990;51:I 100-5.

42. Kreiger N, Kelsey JL, Holford TR, OConnor T. An epidemiologicstudy of hip fracture in postmenopausal women. Am J Epidemiol1982;l 16:141-8.



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