JOURNAL OF BONE AND MINERAL RESEARCH Volume 6, Number 4, 1991 Mary Ann Liebert, Inc., Publishers
Smoking and Bone Loss Among Postmenopausal Women ELIZABETH A. KRALL and BESS DAWSON-HUGHES
ABSTRACT We examined the effect of smoking on bone mineral density (BMD), rates of bone loss, and fractional whole-body retention of 47Cain healthy postmenopausal women enrolled in a 2-year calcium supplementation trial. Bone density was measured by single- and dual-photon absorptiometry. BMD of the radius at the study baseline was inversely related to pack-years of exposure when controlled for body mass index and years since menopause (partial r = -0.18, p = 0.05, n = 125). The adjusted mean (&SD) annualized rate of bone change from the radius was greater among smokers than nonsmokers (-0.914 f 2.624%/year, n = 34, versus 0.004 f 2.568%/year, n = 278, respectively; p = 0.05). Similar trends were observed at the femoral neck, 0s calcis, and spine. Rates were adjusted for caffeine intake, alcohol use, supplement type, and, at the spine only, menopausal status. At entry into the trial higher serum levels of alkaline phosphatase and lower levels of total and ionized calcium were found in smokers compared to nonsmokers. These differences did not persist with supplementation. In 44 women studied fractional 47Ca retention was lower in the 8 smokers than the 36 nonsmokers (16.6 versus 19.1%, respectively; p = 0.03). These results demonstrate an increased rate of bone loss at the radius after menopause and suggest that smoking is associated with decreased calcium absorption.
INTRODUCTION
studies, however, have included small numbers of subj e c t ~ ' or ~ )women in the early years of when T IS IMPORTANT to assess the influence of life-style facrates of bone loss are strongly linked to estrogen withtors on the development of low bone mass because these drawal. factors are open to intervention. Cigarette smoking, for We examined the influence '3f smoking status on baseexample, has been implicated as a risk factor in several ret- line bone mineral density (BMD) and on rates of bone rospective'1-31 and cross-sectional and p r o s p e ~ t i v e ' ~ ' ~change ~ at four sites in a group of 320 healthy postmenostudies; however, others have found no evidence of an in- pausal women. Selected serum and urinary parameters dependent deleterious effect of smoking on bone were examined for evidence of ;i smoking effect on calcium mass. 19-1 21 metabolism. In addition, fractional whole-body retention The mechanisms by which smoking influences bone of "Ca, an estimate of calcium absorption, was measured mass are unknown. Because a smoking-related deficit in in a subset of volunteers. bone mass has been observed among pre- and perimenopausal women,(5,8,91it has been speculated that cigarette MATERIALS Ah D METHODS use reduces the peak bone mass attained in early adultSubjects hood.'51 Smoking may also increase the rate of bone loss in later adulthood, but none of the few prospective studies The subjects were 320 women with low to moderate examining smoking and bone change has been able to iden- usual calcium intakes (half under 400 mg/day and half tify accelerated rates of loss among ~ m o k e r s . ' ~These .~) 400-650 mg daily) who participated in a calcium supple-
I
USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. The contents of this publication do not necessarily reflect the views or policies of the U.S. Departmen] of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
331
332 mentation trial. Each woman was ambulatory, postmenopausal (6 months or longer since last menses), and between the ages of 40 and 70. None was taking medication known to influence calcium metabolism or had a history of postmenopausal estrogen use, nontraumatic fracture, or renal, hepatic, or gastrointestinal disorders associated with abnormal calcium or bone metabolism. Each had a normal physical examination and liver and kidney function and no evidence of a compression fracture on lateral thoracic or lumbar spine radiograph. Participation in the 2 year trial involved assessments, as described here, at baseline and at 6 month intervals. Written informed consent was obtained from each volunteer. Of the 361 women who began the trial, 337 completed at least 1 year of the study. Excluded from analyses were 15 women with abnormal serum thyroid stimulating hormone (TSH) and 2 with elevated serum parathyroid hormone levels. The subjects were taking one of three supplements: 500 mg/day of elemental calcium as citrate malate (CCM, n = 102), 500 mg calcium per day as carbonate (CaCO,, n = 106), or microcrystalline cellulose (placebo, n = 112). All calcium and placebo tablets were supplied by Procter and Gamble (Cincinnati, OH). Information on the use of dietary supplements and current and past cigarette and alcohol consumption was obtained by questionnaire. Pack-years was computed by multiplying the duration (years) by the average number of packs consumed per day (20 cigarettes per pack). At each examination height was measured with a stadiometer and weight with a beam balance. Body mass index (BMI) was computed (kg/m*). Trunk thickness was measured at the level of the umbilicus while the subject was prone. Age and type of menopause were obtained by selfreport at the baseline examination.
Bone measurements
KRALL AND DAWSON-HUGHES 242) was used. If 2 year changes were not available because of incomparability of scans (e.g., incorrect positioning of subject at one of the scans) or dropout from the study, the 1 year change in BMD between any two comparable scans was substituted. First year changes were substituted for 17 spine, 46 femur, and 33 radius measurements. Second year changes were used for 8 spine, 8 femur, and 16 radius measurements. 0 s calcis measurements were performed only at year 1 and year 2. As a result all changes in heel BMD are second year changes. All changes in BMD were expressed as a percentage of the initial BMD and standardized to a 1 year interval. The number of women with comparable scans at a minimum of two examinations was 312 for the radius, 308 for the femur, 267 for the spine, and 282 for the 0s calcis.
Nutrient intake Consumption of foods that are major sources of calcium and caffeine was assessed at baseline and semiannually by questionnaire. Nutrient values of the reported portions sizes were derived from Pennington and Church.(16)The estimates of usual dietary calcium and caffeine intakes were derived by computing the means of intakes at baseline and each of the four subsequent interviews. Individuals who were assigned to a calcium supplement group received an additional 500 mg elemental calcium daily. No other supplemental source of calcium was allowed during the trial. No one was taking supplements containing caffeine.
Activity measurements Physical activity level was estimated after 6 and 18 months in the trial by having each volunteer wear a Caltrac accelerometer (Hemokinetics Inc., Madison, WI), which recorded total kilocalories expended (a basal metabolic value based on age, height, and weight plus kilocalories used for physical movement). Volunteers recorded the monitor display three times daily for 7 days on each occasion. The mean kilocalories expended per day in physical activity was computed by subtracting the basal metabolic component from the total kilocalories.
Measurements of BMD were made at the baseline, first year, and second year examinations. Lumbar spine and femoral neck BMD were measured with a dual-photon absorptiometer (Model DP3, Lunar Radiation Corp., Madison, WI) utilizing a 1 Ci ls3Gd source. Spine BMD was computed in lumbar vertebrae 2-4 with software version 08B (Lunar Radiation Corp.). The coefficient of variation ) at the femoral neck, at the spine was ~ . O V O ( ' ~and Laboratory measurements 3.3%.(") Lumbar spine BMD was corrected for variation At baseline and on each annual visit, blood was obrelated to Is3Gd source and truncal thickne~s."~) Subjects with aortic calcification or osteophytes apparent on lateral tained by venipuncture after a 10 h fast and a 24 h urine radiograph of the lumbar spine ( n = 48) were excluded sample was collected from each volunteer. Serum total and ionized calcium were determined with a from analyses of the spine.(1s) Heel (0s calcis) density was measured with a single-pho- Nova-7 analyzer (Nova Biochemical, Waltham, MA). Ionton absorptiometer (Osteon Corp., Wahiawa, HI). The co- ized calcium values were normalized to pH 7.4. Urinary efficient of variation at the heel, obtained on six measure- creatinine and serum levels of phosphorus, alkaline phosments on each of two subjects, was 1.5%. BMD at the ra- phatase, and creatinine were assayed using a Cobas Fara dius (two-thirds distal site) was measured on the nondomi- centrifugal analyzer (Roche Instrument, Belleville, NJ). nant arm with a single-photon absorptiometer (Lunar Urinary calcium was measured by direct current plasma Model SP-2) with a coefficient of variation of 1%. emission spectroscopy with a Spectrascan-6 (Beckman InFor individuals with comparable scans at baseline and struments, Palo Alto, CA). Intact parathyroid hormone the end of the second year, the 2 year change in BMD at (PTH) was assayed in duplicate by the method of Nussthe radius ( n = 263), femur ( n = 254), and spine ( n = baum et al.'") using Allegro intact PTH kits obtained
333
SMOKING AND POSTMENOPAUSAL BONE LOSS from Nichols Institute (Los Angeles, CA). The coefficient of variation of this method was 5.6%. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] was measured by the competitive protein binding method of Reinhardt et al. ( I B ) The coefficient of variation (4.9%) at a serum concentration of 110 pmol/liter was determined from seven aliquots of control serum assayed in duplicate. Serum 25-hydroxyvitamin D (25-OHD) was measured in ethanol extracts of serum by a competitive protein binding assay.(19)The coefficient of variation of this method (5.0%) was determined from six aliquots of control serum assayed in duplicate. Thyroid stimulating hormone levels were assayed with TSH immunoradiometric assay (IRMA) kits obtained from Celltech Diagnostics, Ltd. (Berkshire, UK). Serum estrone and 17P-estradiol were measured by radioimmunoassay,(zo)with coefficients of variation of estrone and estradiol of 4.6 and 3.6%, respectively.
Calcium retention measurements All women in the trial were given the option to participate in the calcium retention study. A total of 66 enrolled women completed this measurement between the 18 and 24 month examinations. After a 10 h fast each volunteer consumed a test beverage consisting of 5 pCi of 47Ca(Amersham, UK), 500 mg elemental calcium as citrate malate (Procter & Gamble Co, Cincinnati, OH), 0.25 g Sweet & Low, and 0.2 ml imitation peppermint extract in 100 ml distilled water. The serving cup was rinsed three times with 10 ml distilled water each time, and all rinse water was consumed. The subject consumed a calcium-free beverage containing 5 pCi of T r (an unabsorbable stool marker), 2.36 g sodium caseinate, and 0.52 g whey (equivalent to the protein content of 90 ml milk) in distilled water to a total volume of 90 ml 2 h and 45 minutes after ingesting the "Ca beverage. Milk proteins were obtained from New Zealand Milk Products (Petaluma CA). This serving cup was rinsed with water as before. Subjects remained fasting, except for water, for 1 h after ingestion of the W r . The 47Ca and slCr counts were measured in a whole-body counter just before tracer ingestion (background), 45 minutes after ingestion of T r (or 3 % h after the calcium beverage), and 9-11 days (mean = 10 days) after the doses were The 47Cacounts were corrected for variation in count rate associated with trunk thickness. The retention of 47Cawas expressed as the percentage of the administered dose that remained at follow-up (10 days). Participants who retained more than 5% of the W r dose after 10 days (n = 6) were excluded from analyses. Individuals with values of dietary calcium intake (n = 1) and 47Caretention fraction (n = 1) greater than f 3 SD (standard deviation) from the respective means were also excluded. A total of 58 women had valid fractional 47Caretention measurements. As described previously, whole-body retention is measured with a reproducibility of 2.6% of the administered dose or approximately 8% of the retained dose of 47Ca.c2'JRadiation exposure from each measurement was 13 mrem.
Statistical analyses Because its distribution was skewed, caffeine intake was transformed with the square-root function before inclusion in analyses. This transformation normalized the distribution. Unpaired t-tests were used to assess differences between smokers and nonsmokers. Rates of change in BMD were adjusted by analysis of covariance for characteristics that differed between current .smokers and nonsmokers and are associated with bone loss. For the analysis of covariance of the spine a dichotomous variable for menopausal status ( 5 5 or > 5 years since menopause) was created because the rate of loss at the spine in the entire study population was accelerated within I he first 5 years since last menses. The seven women over age 60 with uncertain dates of menopause were placed in the > 5 category. Adjusted least-square means were evaluated with the unpaired t-test. Associations between pack-year s and baseline BMD and between current packs per day and rates of bone loss were evaluated with stepwise regfession models, with BMD or rates of loss as the dependent variables and cigarette exposure as an independent variable Other independent variables (years postmenopause, dietary calcium intake, caffeine intake, BMI, and supplement type) were included if the p value was less than 0.10. The significance of packyears or current packs per day was assessed by the p value of its regression coefficient (B). Regression and covariance analyses were performed with SAS."')
RESULTS Of the 320 women 55% had never smoked, 34% were former smokers who had stopped more than 1 month before entry into the trial, and l l To smoked for all or part of their tenure in the trial. The 35 current smokers smoked 15 10 (mean f SD) cigarettes per day, had started at a mean age of 23 years, and had a mean ( f SD) total exposure time of 28 + 18 pack-years. Other characteristics of the women are summarized it1 Table 1. Smokers were slightly younger and consumed less calcium and more alcohol and caffeine than nonsmokers, but only caffeine intake was significantly different between the groups (p = 0.001). Among smokers 43% were assigned to the placebo group, 37% to the CCM group, and 20% to the CaC03 group. Among nonsmokers the assignments to placebo, CCM, and CaCO, were 34, 33, and 33%, respectively. At enrollment, the BMD of the radius, hip, and heel among current smokers tended to be lower (1-3qo) than that of nonsmokers (Table 1). but none of the differences was significant. Among the 125 women who ever smoked (former and current), pack-years was a significant predictor of baseline BMD at the radius (B SEM = -0.0005 f 0.0002 g/cm2 per pack-year; p = 0.05), independently of BMI and years since menopause. The adjusted rates of bone change at the radius were significantly different between smokers and nonsmokers (p = 0.05; Fig. 1 and Table 2). The same trend was seen at each of the other three sites. Each adjusted rate is the least-squares mean estimated from an analysis of covariance model that
KRALL AND DAWSON-HUGHES
334
n
20
*,
3
W
8
pD
a
a a
0”-
0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -1.8 -2.0 -2.2
r Radius . 1 -
Femoral Neck
0s Calcis
-
-
A
1 *
I
1
’
=
Nonsmoker
Spine
T
Smoker
FIG. 1. Adjusted mean ( f S E ) change in BMD (%/year). *Significantly different from nonsmokers, p
TABLE1. CHARACTERISTICS OF THE STUDY COHORT
Current nonsmoker
Age, yearsa Years postmenopausea.b Age of spontaneous menopause Body mass index, kg/m2a Dietary intakes Calcium, mg/day Caffeine, mg/dayc Ethanol, g/weekc Physical activity, kcallday Bone mineral density, g/cm’a+e Radius Femoral neck 0 s calcisf Spine Estradiol, pg/mla Estrone, pg/mla
Current smoker
Mean
+ SD
n
Mean
59 11 49 26.2
6 7 5 4.2
285 274 223 285
58
f f f f
f
f
SD
5
10 f 6
48 26.2
f f
4 4.4
401 f 161 300 (137-482)d 5 (0-46) 360 + 139
285 285 285 263
372 f 156 453 (299-717) 11 (0-95) 339 f 151
0.614 0.793 0.468 1.080 20 33
265 267 267 238 205 285
0.611 0.787 0.457 1.084 21 35
f f f f f f
0.005 0.007
0.006 0.009 11 22
f f
f f f f
0.012 0.015 0.013 0.021 8 21
n 35 35 29 35 35 35 35 34 34 35 34 22 27 35
Walue at the time of enrollment in study. bProportions of women within first 5 years of menopause were 26% of nonsmokers and 26% of smokers. fValues presented as median and interquartile range due to skewed distributions. Wgnificantly different from smokers, p = 0.001. eMean f SEM. fMeasurement at end of first year of study.
=
0.05.
335
SMOKING AND POSTMENOPAUSAL BONE LOSS
TABLE2.
~ J U S T E D MEAN ~ f
Radius Femoral neck 0 s calcis Spine
SD RATESOF CHANGEIN BMD (%/YE,4R)
Current nonsmoker
n
0.004 f 2.568 -0.155 z t 2.842 -1.194 f 3.264 -0.971 f 2.160
278 273 25 1 245
Current smoker
n
-0.914 -0.576 -1.424 -1.305
34 35 31 22
f f f f
2.624b 2.900 3.318 2.186
aRates at the radius, femoral neck, and 0s calcis were adjusted for supplement type (placebo, CCM, or CaCO,), current alcohol status (user or nonuser), and caffeine intake. Rates at the spine were adjusted for these same variables plus menopausal status ( 5 5 or >,5 years since menopause). bRate in smokers is significantly different from that in nonsmokers, p = 0.05.
included caffeine intake, current alcohol status (user or nonuser), supplementation group (placebo, CCM, or calcium carbonate), and, at the spine only, menopausal status (I 5 or > 5 years). Caffeine and alcohol intakes were included in the models because each was significantly correlated with bone loss at one or more skeletal sites. The regression analysis of packs per day smoked during the 2 year trial and rate of change in radius BMD indicated that packs per day was not a significant predictor of rate of loss in these 34 women. Table 3 presents laboratory values at the study baseline and after supplementation with either calcium or placebo. The aftertreatment values are the means of laboratory measurements at the first and second annual examinations. At baseline smokers had a significantly higher mean serum level of alkaline phosphatase and lower levels of total and ionized calcium than nonsmokers. These same relationships tended to remain throughout the trial in the group receiving the placebo. Smokers and nonsmokers responded similarly to supplementation, with increases in serum total and ionized calcium and urinary calcium excretion and decreases in alkaline phosphatase. In the subset of 58 women with 47Caretention measurements all the smokers were taking a calcium supplement whereas 70% of the nonsmokers were taking extra calcium. To avoid the confounding of fractional *7Caretention values by total calcium intake, we limited the analysis to the 44 women taking calcium supplements. Mean total calcium intakes in smokers and nonsmokers were similar (856 + 178 and 854 f 119 mg/day). The mean f SD fractional whole-body retention of ingested 47Cawas lower in current smokers than in nonsmokers (16.6 f 2.3, n = 8, versus 19.1 f 4.3, n = 36, respectively; p = 0.03).
DISCUSSION The results of this study demonstrate an accelerated rate of postmenopausal bone loss from the radius attributable to cigarette use. Although the higher rates of bone loss at the hip, spine, and heel in smokers compared to nonsmokers were not significant, the consistency of the trends at all sites strengthens the plausability of this finding. Other pro-
spective studies examining the effect of smoking on bone loss are few. Lindsay(4)reported no differences in rates of loss over 8 years between 11 smokers and 11 nonsmokers matched for age, weight, and height. Slemenda et al. also found no differences in rates (of loss from the radius or spine in the early years of menopause among nonsmokers, light smokers, and heavy smokers. 15) Cross-sectional analyses of fhe effects of smoking on BMD have yielded conflicting findings. Several studies have reported an inverse relationship between smoking and BMD‘”’ others have found no An inverse correlation existed in this stud) between radius BMD and pack-years when former as well as current smokers were considered. This suggests that the harmful effect on bone is not completely reversed upon cessation of smoking. The detection of a significant relationship between current smoking status and rate of change in radius BMD but no difference by smoking status in baseline radius BMD may reflect the limitations of a small sample of current smokers and the large number of variables being compared or the influences of genetic and other stronger environmental factors throughout the life span before this measurement. The prevalence of current smoking in this group of women was lower than expected when compared to national data(z3’and other studies of smoking and rates of bone loss.“ ’1 However, the proportion of women in this study who ever smoked (45%) and the amount currently smoked (83% smoked fewer than 25 cigarettes per day) are very comparable to those seen in national data on older women.tz3) Lower body weight is frequentlyt4 m ) but not always(7”) observed among postmenopausal women who smoke. Low body weight, in turn, is associated with less bone mass, perhaps because of mechanical stress on the skeleton or decreased conversion of adrenal androgens to estrone in adipocytes.(262 7 ) Since the smokers and nonsmokers in this study were siniilar in body size and had similar levels of estrone, these could not account for the differences in rates of bone loss in the two groups. Smokers tend to have an earlier menopause.(z8)The resulting estrogen depletion at an earlier age may also contribute to lower bone mass in smokers. No significant difference in age at menopause was observed between the
336
KRALL AND DAWSON-HUGHES
TABLE3. LABORATORY VALUES (MEANf SD) AT STUDY BASELINE AND DURINGTRIAL BY SMOKING STATUS IN 318 WOMEN
During triala ~~
~
Baseline ~
~~
Alkaline phosphatase, ukat/liter Nonsmoker Smoker Total calcium, mmol/liter Nonsmoker Smoker Ionized calcium, mmol/liter Nonsmoker Smoker Phosphorus, mmol/liter Nonsmoker Smoker 1,25-(OH)*vitamin D, pmol/liter Nonsmoker Smoker 25-OH-vitamin D, nmol/liter Nonsmoker Smoker PTH, ng/liter Nonsmoker Smoker Urine calcium/creatinine ratio, mmoVmol per 24 h Nonsmoker Smoker
~
~~
1.23 1.34
f
2.32 2.28
Placebo ~
~
0.28b 0.30
1.26 1.32
f
0.09b 0.09
2.31 2.21
1.27 1.25
f
0.04b 0.04
1.28 1.27
f
f
1.09 1.13
f
0.14 0.14
1.12 1.20
f
f
f
f
86 81
f
80 76
f
33 32
378 407
f
f
f f
+ f
f f f f
f
f
20 21
86 88
29 27
73 66
f
13 11
33 32
f
182 193
f f
f
f
~
~
Calcium ~
~
0.28 0.28
1.16 f 0.27 1.18 f 0.20
0.06b 0.08
2.34 f 0.07 2.32 f 0.05
0.03 0.02
1.29 f 0.04 1.29 f 0.03
0.llb 0.19
1.13 1.17
f f
0.12 0.10
20 21
73 72
f
25 22
75 73
f
10 7
29 f 11 29 f 10
398 f 174 385 f 169
503 517
f
f
f f
18 13 25 24
210 213
=Mean of laboratory values at first year and second year examinations. The numbers of nonsmokers and smokers on placebo were 96 and 15, respectively; on calcium, 187 and 20, respectively. Two nonsmokers (one placebo and one calcium) had missing calcium measurements and are not included in the table. bNonsmokers differ significantly from smokers, p < 0.05.
smokers and nonsmokers. Furthermore, the influence of time since menopause on rate of bone loss is limited, with accelerated loss in the first few years after menopause and a fairly constant rate thereafter. (29-31) The proportions of smokers and nonsmokers within the first 5 years of menopause were identical in this study. Other life-style factors, such as alcohol intake,C9' caffeine and physical inactivity,(33)which may differ in smokers and nonsmokers, have also been associaed with low bone density. In this study these three factors could not explain the association between smoking and accelerated bone loss. Levels of physical activity were similar. The higher intake of caffeine in smokers and the tendency to consume more alcohol were controlled in the analyses.
Fractional "Ca retention and laboratory measurements were examined in an attempt to clarify the observed relationship between smoking and loss of BMD at the radius. This study is in agreement with a previous report that found an inverse relationship between smoking and calcium abs~rption.'~') In both studies the mean calcium intakes were between 700 and 850 mg daily. It is unknown if smoking has a similar influence on absorption at other levels of calcium intake. Because of the small number of smokers with retention measurements, these data can only suggest an impairment in absorption. The reduced serum calcium levels in smokers at baseline were also consistent with poor absorption. In conclusion, smoking in amounts of less than one pack per day increased the rate of bone loss from the radius in
SMOKING AND POSTMENOPAUSAL BONE LOSS postmenopausal women. The adverse effect of smoking on bone may be related to decreased intestinal absorption of calcium.
ACKNOWLEDGMENTS This study was supported by the USDA Human Nutrition Research Center on Aging at Tufts University (Contract No. 53-3K06-5-10)and the Procter and Gamble Company.
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KRALL AND DAWSON-HUGHES
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Address reprint requests to:
Elizabeth A . Krall, Ph.D. USDA Human Nutrition Research Center on Aging at Tufts University 71I Washington Street Boston, MA 02111 Received for publication March 19, 1990; in revised form November 6, 1990; accepted November 9, 1990.
Smoking and Bone Loss Among Postmenopausal Women ELIZABETH A. KRALL and BESS DAWSON-HUGHES
ABSTRACT We examined the effect of smoking on bone mineral density (BMD), rates of bone loss, and fractional whole-body retention of 47Cain healthy postmenopausal women enrolled in a 2-year calcium supplementation trial. Bone density was measured by single- and dual-photon absorptiometry. BMD of the radius at the study baseline was inversely related to pack-years of exposure when controlled for body mass index and years since menopause (partial r = -0.18, p = 0.05, n = 125). The adjusted mean (&SD) annualized rate of bone change from the radius was greater among smokers than nonsmokers (-0.914 f 2.624%/year, n = 34, versus 0.004 f 2.568%/year, n = 278, respectively; p = 0.05). Similar trends were observed at the femoral neck, 0s calcis, and spine. Rates were adjusted for caffeine intake, alcohol use, supplement type, and, at the spine only, menopausal status. At entry into the trial higher serum levels of alkaline phosphatase and lower levels of total and ionized calcium were found in smokers compared to nonsmokers. These differences did not persist with supplementation. In 44 women studied fractional 47Ca retention was lower in the 8 smokers than the 36 nonsmokers (16.6 versus 19.1%, respectively; p = 0.03). These results demonstrate an increased rate of bone loss at the radius after menopause and suggest that smoking is associated with decreased calcium absorption.
INTRODUCTION
studies, however, have included small numbers of subj e c t ~ ' or ~ )women in the early years of when T IS IMPORTANT to assess the influence of life-style facrates of bone loss are strongly linked to estrogen withtors on the development of low bone mass because these drawal. factors are open to intervention. Cigarette smoking, for We examined the influence '3f smoking status on baseexample, has been implicated as a risk factor in several ret- line bone mineral density (BMD) and on rates of bone rospective'1-31 and cross-sectional and p r o s p e ~ t i v e ' ~ ' ~change ~ at four sites in a group of 320 healthy postmenostudies; however, others have found no evidence of an in- pausal women. Selected serum and urinary parameters dependent deleterious effect of smoking on bone were examined for evidence of ;i smoking effect on calcium mass. 19-1 21 metabolism. In addition, fractional whole-body retention The mechanisms by which smoking influences bone of "Ca, an estimate of calcium absorption, was measured mass are unknown. Because a smoking-related deficit in in a subset of volunteers. bone mass has been observed among pre- and perimenopausal women,(5,8,91it has been speculated that cigarette MATERIALS Ah D METHODS use reduces the peak bone mass attained in early adultSubjects hood.'51 Smoking may also increase the rate of bone loss in later adulthood, but none of the few prospective studies The subjects were 320 women with low to moderate examining smoking and bone change has been able to iden- usual calcium intakes (half under 400 mg/day and half tify accelerated rates of loss among ~ m o k e r s . ' ~These .~) 400-650 mg daily) who participated in a calcium supple-
I
USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. The contents of this publication do not necessarily reflect the views or policies of the U.S. Departmen] of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
331
332 mentation trial. Each woman was ambulatory, postmenopausal (6 months or longer since last menses), and between the ages of 40 and 70. None was taking medication known to influence calcium metabolism or had a history of postmenopausal estrogen use, nontraumatic fracture, or renal, hepatic, or gastrointestinal disorders associated with abnormal calcium or bone metabolism. Each had a normal physical examination and liver and kidney function and no evidence of a compression fracture on lateral thoracic or lumbar spine radiograph. Participation in the 2 year trial involved assessments, as described here, at baseline and at 6 month intervals. Written informed consent was obtained from each volunteer. Of the 361 women who began the trial, 337 completed at least 1 year of the study. Excluded from analyses were 15 women with abnormal serum thyroid stimulating hormone (TSH) and 2 with elevated serum parathyroid hormone levels. The subjects were taking one of three supplements: 500 mg/day of elemental calcium as citrate malate (CCM, n = 102), 500 mg calcium per day as carbonate (CaCO,, n = 106), or microcrystalline cellulose (placebo, n = 112). All calcium and placebo tablets were supplied by Procter and Gamble (Cincinnati, OH). Information on the use of dietary supplements and current and past cigarette and alcohol consumption was obtained by questionnaire. Pack-years was computed by multiplying the duration (years) by the average number of packs consumed per day (20 cigarettes per pack). At each examination height was measured with a stadiometer and weight with a beam balance. Body mass index (BMI) was computed (kg/m*). Trunk thickness was measured at the level of the umbilicus while the subject was prone. Age and type of menopause were obtained by selfreport at the baseline examination.
Bone measurements
KRALL AND DAWSON-HUGHES 242) was used. If 2 year changes were not available because of incomparability of scans (e.g., incorrect positioning of subject at one of the scans) or dropout from the study, the 1 year change in BMD between any two comparable scans was substituted. First year changes were substituted for 17 spine, 46 femur, and 33 radius measurements. Second year changes were used for 8 spine, 8 femur, and 16 radius measurements. 0 s calcis measurements were performed only at year 1 and year 2. As a result all changes in heel BMD are second year changes. All changes in BMD were expressed as a percentage of the initial BMD and standardized to a 1 year interval. The number of women with comparable scans at a minimum of two examinations was 312 for the radius, 308 for the femur, 267 for the spine, and 282 for the 0s calcis.
Nutrient intake Consumption of foods that are major sources of calcium and caffeine was assessed at baseline and semiannually by questionnaire. Nutrient values of the reported portions sizes were derived from Pennington and Church.(16)The estimates of usual dietary calcium and caffeine intakes were derived by computing the means of intakes at baseline and each of the four subsequent interviews. Individuals who were assigned to a calcium supplement group received an additional 500 mg elemental calcium daily. No other supplemental source of calcium was allowed during the trial. No one was taking supplements containing caffeine.
Activity measurements Physical activity level was estimated after 6 and 18 months in the trial by having each volunteer wear a Caltrac accelerometer (Hemokinetics Inc., Madison, WI), which recorded total kilocalories expended (a basal metabolic value based on age, height, and weight plus kilocalories used for physical movement). Volunteers recorded the monitor display three times daily for 7 days on each occasion. The mean kilocalories expended per day in physical activity was computed by subtracting the basal metabolic component from the total kilocalories.
Measurements of BMD were made at the baseline, first year, and second year examinations. Lumbar spine and femoral neck BMD were measured with a dual-photon absorptiometer (Model DP3, Lunar Radiation Corp., Madison, WI) utilizing a 1 Ci ls3Gd source. Spine BMD was computed in lumbar vertebrae 2-4 with software version 08B (Lunar Radiation Corp.). The coefficient of variation ) at the femoral neck, at the spine was ~ . O V O ( ' ~and Laboratory measurements 3.3%.(") Lumbar spine BMD was corrected for variation At baseline and on each annual visit, blood was obrelated to Is3Gd source and truncal thickne~s."~) Subjects with aortic calcification or osteophytes apparent on lateral tained by venipuncture after a 10 h fast and a 24 h urine radiograph of the lumbar spine ( n = 48) were excluded sample was collected from each volunteer. Serum total and ionized calcium were determined with a from analyses of the spine.(1s) Heel (0s calcis) density was measured with a single-pho- Nova-7 analyzer (Nova Biochemical, Waltham, MA). Ionton absorptiometer (Osteon Corp., Wahiawa, HI). The co- ized calcium values were normalized to pH 7.4. Urinary efficient of variation at the heel, obtained on six measure- creatinine and serum levels of phosphorus, alkaline phosments on each of two subjects, was 1.5%. BMD at the ra- phatase, and creatinine were assayed using a Cobas Fara dius (two-thirds distal site) was measured on the nondomi- centrifugal analyzer (Roche Instrument, Belleville, NJ). nant arm with a single-photon absorptiometer (Lunar Urinary calcium was measured by direct current plasma Model SP-2) with a coefficient of variation of 1%. emission spectroscopy with a Spectrascan-6 (Beckman InFor individuals with comparable scans at baseline and struments, Palo Alto, CA). Intact parathyroid hormone the end of the second year, the 2 year change in BMD at (PTH) was assayed in duplicate by the method of Nussthe radius ( n = 263), femur ( n = 254), and spine ( n = baum et al.'") using Allegro intact PTH kits obtained
333
SMOKING AND POSTMENOPAUSAL BONE LOSS from Nichols Institute (Los Angeles, CA). The coefficient of variation of this method was 5.6%. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] was measured by the competitive protein binding method of Reinhardt et al. ( I B ) The coefficient of variation (4.9%) at a serum concentration of 110 pmol/liter was determined from seven aliquots of control serum assayed in duplicate. Serum 25-hydroxyvitamin D (25-OHD) was measured in ethanol extracts of serum by a competitive protein binding assay.(19)The coefficient of variation of this method (5.0%) was determined from six aliquots of control serum assayed in duplicate. Thyroid stimulating hormone levels were assayed with TSH immunoradiometric assay (IRMA) kits obtained from Celltech Diagnostics, Ltd. (Berkshire, UK). Serum estrone and 17P-estradiol were measured by radioimmunoassay,(zo)with coefficients of variation of estrone and estradiol of 4.6 and 3.6%, respectively.
Calcium retention measurements All women in the trial were given the option to participate in the calcium retention study. A total of 66 enrolled women completed this measurement between the 18 and 24 month examinations. After a 10 h fast each volunteer consumed a test beverage consisting of 5 pCi of 47Ca(Amersham, UK), 500 mg elemental calcium as citrate malate (Procter & Gamble Co, Cincinnati, OH), 0.25 g Sweet & Low, and 0.2 ml imitation peppermint extract in 100 ml distilled water. The serving cup was rinsed three times with 10 ml distilled water each time, and all rinse water was consumed. The subject consumed a calcium-free beverage containing 5 pCi of T r (an unabsorbable stool marker), 2.36 g sodium caseinate, and 0.52 g whey (equivalent to the protein content of 90 ml milk) in distilled water to a total volume of 90 ml 2 h and 45 minutes after ingesting the "Ca beverage. Milk proteins were obtained from New Zealand Milk Products (Petaluma CA). This serving cup was rinsed with water as before. Subjects remained fasting, except for water, for 1 h after ingestion of the W r . The 47Ca and slCr counts were measured in a whole-body counter just before tracer ingestion (background), 45 minutes after ingestion of T r (or 3 % h after the calcium beverage), and 9-11 days (mean = 10 days) after the doses were The 47Cacounts were corrected for variation in count rate associated with trunk thickness. The retention of 47Cawas expressed as the percentage of the administered dose that remained at follow-up (10 days). Participants who retained more than 5% of the W r dose after 10 days (n = 6) were excluded from analyses. Individuals with values of dietary calcium intake (n = 1) and 47Caretention fraction (n = 1) greater than f 3 SD (standard deviation) from the respective means were also excluded. A total of 58 women had valid fractional 47Caretention measurements. As described previously, whole-body retention is measured with a reproducibility of 2.6% of the administered dose or approximately 8% of the retained dose of 47Ca.c2'JRadiation exposure from each measurement was 13 mrem.
Statistical analyses Because its distribution was skewed, caffeine intake was transformed with the square-root function before inclusion in analyses. This transformation normalized the distribution. Unpaired t-tests were used to assess differences between smokers and nonsmokers. Rates of change in BMD were adjusted by analysis of covariance for characteristics that differed between current .smokers and nonsmokers and are associated with bone loss. For the analysis of covariance of the spine a dichotomous variable for menopausal status ( 5 5 or > 5 years since menopause) was created because the rate of loss at the spine in the entire study population was accelerated within I he first 5 years since last menses. The seven women over age 60 with uncertain dates of menopause were placed in the > 5 category. Adjusted least-square means were evaluated with the unpaired t-test. Associations between pack-year s and baseline BMD and between current packs per day and rates of bone loss were evaluated with stepwise regfession models, with BMD or rates of loss as the dependent variables and cigarette exposure as an independent variable Other independent variables (years postmenopause, dietary calcium intake, caffeine intake, BMI, and supplement type) were included if the p value was less than 0.10. The significance of packyears or current packs per day was assessed by the p value of its regression coefficient (B). Regression and covariance analyses were performed with SAS."')
RESULTS Of the 320 women 55% had never smoked, 34% were former smokers who had stopped more than 1 month before entry into the trial, and l l To smoked for all or part of their tenure in the trial. The 35 current smokers smoked 15 10 (mean f SD) cigarettes per day, had started at a mean age of 23 years, and had a mean ( f SD) total exposure time of 28 + 18 pack-years. Other characteristics of the women are summarized it1 Table 1. Smokers were slightly younger and consumed less calcium and more alcohol and caffeine than nonsmokers, but only caffeine intake was significantly different between the groups (p = 0.001). Among smokers 43% were assigned to the placebo group, 37% to the CCM group, and 20% to the CaC03 group. Among nonsmokers the assignments to placebo, CCM, and CaCO, were 34, 33, and 33%, respectively. At enrollment, the BMD of the radius, hip, and heel among current smokers tended to be lower (1-3qo) than that of nonsmokers (Table 1). but none of the differences was significant. Among the 125 women who ever smoked (former and current), pack-years was a significant predictor of baseline BMD at the radius (B SEM = -0.0005 f 0.0002 g/cm2 per pack-year; p = 0.05), independently of BMI and years since menopause. The adjusted rates of bone change at the radius were significantly different between smokers and nonsmokers (p = 0.05; Fig. 1 and Table 2). The same trend was seen at each of the other three sites. Each adjusted rate is the least-squares mean estimated from an analysis of covariance model that
KRALL AND DAWSON-HUGHES
334
n
20
*,
3
W
8
pD
a
a a
0”-
0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -1.8 -2.0 -2.2
r Radius . 1 -
Femoral Neck
0s Calcis
-
-
A
1 *
I
1
’
=
Nonsmoker
Spine
T
Smoker
FIG. 1. Adjusted mean ( f S E ) change in BMD (%/year). *Significantly different from nonsmokers, p
TABLE1. CHARACTERISTICS OF THE STUDY COHORT
Current nonsmoker
Age, yearsa Years postmenopausea.b Age of spontaneous menopause Body mass index, kg/m2a Dietary intakes Calcium, mg/day Caffeine, mg/dayc Ethanol, g/weekc Physical activity, kcallday Bone mineral density, g/cm’a+e Radius Femoral neck 0 s calcisf Spine Estradiol, pg/mla Estrone, pg/mla
Current smoker
Mean
+ SD
n
Mean
59 11 49 26.2
6 7 5 4.2
285 274 223 285
58
f f f f
f
f
SD
5
10 f 6
48 26.2
f f
4 4.4
401 f 161 300 (137-482)d 5 (0-46) 360 + 139
285 285 285 263
372 f 156 453 (299-717) 11 (0-95) 339 f 151
0.614 0.793 0.468 1.080 20 33
265 267 267 238 205 285
0.611 0.787 0.457 1.084 21 35
f f f f f f
0.005 0.007
0.006 0.009 11 22
f f
f f f f
0.012 0.015 0.013 0.021 8 21
n 35 35 29 35 35 35 35 34 34 35 34 22 27 35
Walue at the time of enrollment in study. bProportions of women within first 5 years of menopause were 26% of nonsmokers and 26% of smokers. fValues presented as median and interquartile range due to skewed distributions. Wgnificantly different from smokers, p = 0.001. eMean f SEM. fMeasurement at end of first year of study.
=
0.05.
335
SMOKING AND POSTMENOPAUSAL BONE LOSS
TABLE2.
~ J U S T E D MEAN ~ f
Radius Femoral neck 0 s calcis Spine
SD RATESOF CHANGEIN BMD (%/YE,4R)
Current nonsmoker
n
0.004 f 2.568 -0.155 z t 2.842 -1.194 f 3.264 -0.971 f 2.160
278 273 25 1 245
Current smoker
n
-0.914 -0.576 -1.424 -1.305
34 35 31 22
f f f f
2.624b 2.900 3.318 2.186
aRates at the radius, femoral neck, and 0s calcis were adjusted for supplement type (placebo, CCM, or CaCO,), current alcohol status (user or nonuser), and caffeine intake. Rates at the spine were adjusted for these same variables plus menopausal status ( 5 5 or >,5 years since menopause). bRate in smokers is significantly different from that in nonsmokers, p = 0.05.
included caffeine intake, current alcohol status (user or nonuser), supplementation group (placebo, CCM, or calcium carbonate), and, at the spine only, menopausal status (I 5 or > 5 years). Caffeine and alcohol intakes were included in the models because each was significantly correlated with bone loss at one or more skeletal sites. The regression analysis of packs per day smoked during the 2 year trial and rate of change in radius BMD indicated that packs per day was not a significant predictor of rate of loss in these 34 women. Table 3 presents laboratory values at the study baseline and after supplementation with either calcium or placebo. The aftertreatment values are the means of laboratory measurements at the first and second annual examinations. At baseline smokers had a significantly higher mean serum level of alkaline phosphatase and lower levels of total and ionized calcium than nonsmokers. These same relationships tended to remain throughout the trial in the group receiving the placebo. Smokers and nonsmokers responded similarly to supplementation, with increases in serum total and ionized calcium and urinary calcium excretion and decreases in alkaline phosphatase. In the subset of 58 women with 47Caretention measurements all the smokers were taking a calcium supplement whereas 70% of the nonsmokers were taking extra calcium. To avoid the confounding of fractional *7Caretention values by total calcium intake, we limited the analysis to the 44 women taking calcium supplements. Mean total calcium intakes in smokers and nonsmokers were similar (856 + 178 and 854 f 119 mg/day). The mean f SD fractional whole-body retention of ingested 47Cawas lower in current smokers than in nonsmokers (16.6 f 2.3, n = 8, versus 19.1 f 4.3, n = 36, respectively; p = 0.03).
DISCUSSION The results of this study demonstrate an accelerated rate of postmenopausal bone loss from the radius attributable to cigarette use. Although the higher rates of bone loss at the hip, spine, and heel in smokers compared to nonsmokers were not significant, the consistency of the trends at all sites strengthens the plausability of this finding. Other pro-
spective studies examining the effect of smoking on bone loss are few. Lindsay(4)reported no differences in rates of loss over 8 years between 11 smokers and 11 nonsmokers matched for age, weight, and height. Slemenda et al. also found no differences in rates (of loss from the radius or spine in the early years of menopause among nonsmokers, light smokers, and heavy smokers. 15) Cross-sectional analyses of fhe effects of smoking on BMD have yielded conflicting findings. Several studies have reported an inverse relationship between smoking and BMD‘”’ others have found no An inverse correlation existed in this stud) between radius BMD and pack-years when former as well as current smokers were considered. This suggests that the harmful effect on bone is not completely reversed upon cessation of smoking. The detection of a significant relationship between current smoking status and rate of change in radius BMD but no difference by smoking status in baseline radius BMD may reflect the limitations of a small sample of current smokers and the large number of variables being compared or the influences of genetic and other stronger environmental factors throughout the life span before this measurement. The prevalence of current smoking in this group of women was lower than expected when compared to national data(z3’and other studies of smoking and rates of bone loss.“ ’1 However, the proportion of women in this study who ever smoked (45%) and the amount currently smoked (83% smoked fewer than 25 cigarettes per day) are very comparable to those seen in national data on older women.tz3) Lower body weight is frequentlyt4 m ) but not always(7”) observed among postmenopausal women who smoke. Low body weight, in turn, is associated with less bone mass, perhaps because of mechanical stress on the skeleton or decreased conversion of adrenal androgens to estrone in adipocytes.(262 7 ) Since the smokers and nonsmokers in this study were siniilar in body size and had similar levels of estrone, these could not account for the differences in rates of bone loss in the two groups. Smokers tend to have an earlier menopause.(z8)The resulting estrogen depletion at an earlier age may also contribute to lower bone mass in smokers. No significant difference in age at menopause was observed between the
336
KRALL AND DAWSON-HUGHES
TABLE3. LABORATORY VALUES (MEANf SD) AT STUDY BASELINE AND DURINGTRIAL BY SMOKING STATUS IN 318 WOMEN
During triala ~~
~
Baseline ~
~~
Alkaline phosphatase, ukat/liter Nonsmoker Smoker Total calcium, mmol/liter Nonsmoker Smoker Ionized calcium, mmol/liter Nonsmoker Smoker Phosphorus, mmol/liter Nonsmoker Smoker 1,25-(OH)*vitamin D, pmol/liter Nonsmoker Smoker 25-OH-vitamin D, nmol/liter Nonsmoker Smoker PTH, ng/liter Nonsmoker Smoker Urine calcium/creatinine ratio, mmoVmol per 24 h Nonsmoker Smoker
~
~~
1.23 1.34
f
2.32 2.28
Placebo ~
~
0.28b 0.30
1.26 1.32
f
0.09b 0.09
2.31 2.21
1.27 1.25
f
0.04b 0.04
1.28 1.27
f
f
1.09 1.13
f
0.14 0.14
1.12 1.20
f
f
f
f
86 81
f
80 76
f
33 32
378 407
f
f
f f
+ f
f f f f
f
f
20 21
86 88
29 27
73 66
f
13 11
33 32
f
182 193
f f
f
f
~
~
Calcium ~
~
0.28 0.28
1.16 f 0.27 1.18 f 0.20
0.06b 0.08
2.34 f 0.07 2.32 f 0.05
0.03 0.02
1.29 f 0.04 1.29 f 0.03
0.llb 0.19
1.13 1.17
f f
0.12 0.10
20 21
73 72
f
25 22
75 73
f
10 7
29 f 11 29 f 10
398 f 174 385 f 169
503 517
f
f
f f
18 13 25 24
210 213
=Mean of laboratory values at first year and second year examinations. The numbers of nonsmokers and smokers on placebo were 96 and 15, respectively; on calcium, 187 and 20, respectively. Two nonsmokers (one placebo and one calcium) had missing calcium measurements and are not included in the table. bNonsmokers differ significantly from smokers, p < 0.05.
smokers and nonsmokers. Furthermore, the influence of time since menopause on rate of bone loss is limited, with accelerated loss in the first few years after menopause and a fairly constant rate thereafter. (29-31) The proportions of smokers and nonsmokers within the first 5 years of menopause were identical in this study. Other life-style factors, such as alcohol intake,C9' caffeine and physical inactivity,(33)which may differ in smokers and nonsmokers, have also been associaed with low bone density. In this study these three factors could not explain the association between smoking and accelerated bone loss. Levels of physical activity were similar. The higher intake of caffeine in smokers and the tendency to consume more alcohol were controlled in the analyses.
Fractional "Ca retention and laboratory measurements were examined in an attempt to clarify the observed relationship between smoking and loss of BMD at the radius. This study is in agreement with a previous report that found an inverse relationship between smoking and calcium abs~rption.'~') In both studies the mean calcium intakes were between 700 and 850 mg daily. It is unknown if smoking has a similar influence on absorption at other levels of calcium intake. Because of the small number of smokers with retention measurements, these data can only suggest an impairment in absorption. The reduced serum calcium levels in smokers at baseline were also consistent with poor absorption. In conclusion, smoking in amounts of less than one pack per day increased the rate of bone loss from the radius in
SMOKING AND POSTMENOPAUSAL BONE LOSS postmenopausal women. The adverse effect of smoking on bone may be related to decreased intestinal absorption of calcium.
ACKNOWLEDGMENTS This study was supported by the USDA Human Nutrition Research Center on Aging at Tufts University (Contract No. 53-3K06-5-10)and the Procter and Gamble Company.
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Elizabeth A . Krall, Ph.D. USDA Human Nutrition Research Center on Aging at Tufts University 71I Washington Street Boston, MA 02111 Received for publication March 19, 1990; in revised form November 6, 1990; accepted November 9, 1990.
