smoing.pdf

ORIGINAL ARTICLE

Impact of smoking on bone mineral density and bonemetabolism in elderly men: the Fujiwara-kyo OsteoporosisRisk in Men (FORMEN) study

J. Tamaki & M. Iki & Y. Fujita & K. Kouda & A. Yura &

E. Kadowaki & Y. Sato & J. S. Moon & K. Tomioka &

N. Okamoto & N. Kurumatani

Received: 26 November 2009 /Accepted: 1 March 2010 /Published online: 10 April 2010# International Osteoporosis Foundation and National Osteoporosis Foundation 2010

AbstractSummary Our cross-sectional analysis of 1,576 men aged≥65 years examined smoking effects on bone status.Number of smoking years was associated with decreasedbone mineral density (BMD), after adjusting for age,height, weight, and number of cigarettes smoked daily.Smoking did not affect biochemical marker serum valuesfor bone turnover.Introduction The impact of smoking on bone status in menhas not been conclusively established. We examined howsmoking and its cessation influence bone status andmetabolism in men.Methods We analyzed 1,576 men among a baseline survey ofJapanese men aged ≥65 years, the Fujiwara-kyo OsteoporosisRisk in Men study, conducted during 2007–2008.Results Lumbar spine (LS) BMD values among never,former, and current smokers were 1.045±0.194, 1.030±

0.189, and 1.001±0.182 g/cm2 (P=0.005), respectively,while total hip (TH) BMD values were 0.888±0.120,0.885±0.127, and 0.870±0.124 (P=0.078), respectively.The significant trend for LS BMD remained after adjustingfor the covariates; age, height, weight, physical activity, milkconsumption, and drinking habit (P=0.036). Among neverand ever (current and former) smokers, LS and TH BMDdecreased with the number of pack years or the number ofsmoking years, respectively, adjusted for those covariates.Among ever smokers, LS and TH BMD decreased with thenumber of smoking years after adjusting for age, height,weight, and number of cigarettes smoked daily. Smoking didnot reveal significant effect for serum osteocalcin or tartrateresistant acid phosphatase isoenzyme 5b.Conclusion The impact of smoking on bone status ismainly associated with the number of smoking years inelderly men.

Keywords Bone metabolism . Bone mineral density . Men .

Smoking

Introduction

Hip fractures is expected to increase throughout Asia andLatin America by 2050, while the proportion of all hipfractures among the elderly in Europe and North Americawill fall from about one half to around one quarter by 2050[1]. In Japan, 22% of all hip fractures occurred in men in2002 [2]. Osteoporosis is now becoming a major publichealth issue, even among men.

Smoking is associated with an increased risk forosteoporosis [3, 4] and osteoporotic fractures [5]. Currently,the smoking rate has decreased in developed countries, but

J. Tamaki :M. Iki (*) :Y. Fujita :K. Kouda :A. Yura :E. KadowakiDepartment of Public Health,Kinki University School of Medicine,377-2, Oono-higasi, Osaka-sayama,Osaka 589-8511, Japane-mail: [email protected]

Y. SatoDepartment of Human Life, Jin-ai University,Echizen, Japan

J. S. MoonFaculty of Human Sciences, Taisei Gakuin University,Sakai, Japan

K. Tomioka :N. Okamoto :N. KurumataniDepartment of Community Health and Epidemiology,Nara Medical University School of Medicine,Kashihara, Japan

Osteoporos Int (2011) 22:133–141DOI 10.1007/s00198-010-1238-x

has increased in developing countries including Asia [6].This has contributed to the global tobacco epidemic asreported by the World Health Organization in 2008 [6]. InJapan, the smoking rate among men has continued todecrease to approximately 40% [7], but this rate is stillhigher than that of other developed countries [6].

Meta-analyses of the effects of smoking on bone statushave demonstrated decreased bone mass in current smokerscompared to non-smokers, although data for men is limited[3, 4]. Ward et al. [4] reported that the decrease in bonemass for smokers is greater in men than in women.Additionally, smoking has more adverse effects on bonemass for individuals aged 60 years or more [4]. A reviewby Wong et al. [8] indicated that effects of smoking on bonemass appears to be dose-dependent based on a meta-analysis [4]. However, this meta-analysis was conductedwithout making distinctions between different smokingcharacteristics such as the number of smoking years,number of cigarettes smoked per day, and number of packyears. Hence, more work is required to confirm whichsmoking characteristic is adverse.

Regarding the effects of smoking on biochemical markersof bone turnover, Compston [9] indicated that higher levelsof bone resorption in studies with older smokers and lowerlevels of bone formation in studies with early postmeno-pausal women have been reported in smokers, though themechanisms have not been clearly established.

No large-scale study to date has focused on the effects ofsmoking in Asian men, except for the Mr. OS study whichdemonstrated that age- and weight-adjusted bone mineraldensity (BMD) at the lumbar spine (LS) decreased withincreases in the number of pack years [10]. In Japan, therelatively large osteoporosis or osteoporotic fracture studiesthat included male participants are the Hiroshima cohortstudy with atomic bomb survivors (male subjects, n=781),and the Miyama cohort study (male subjects, n=166) [11];neither has reported findings focused on the effects ofsmoking on BMD. Thus, it would be valuable to ascertainthe impact of smoking or smoking cessation on bone statusand bone metabolism in elderly Japanese men. This is thefirst large-scale Asian study to clarify relationships betweensmoking and BMD in men. We analyzed a samplepopulation from a large-scale community-based single-center study for elderly Japanese men, the Fujiwara-kyoOsteoporosis Risk in Men (FORMEN) study.

Methods

Study setting

The baseline survey for the FORMEN study was conductedduring 2007–2008 as part of a larger prospective cohort

study, Fujiwara-kyo study (the Primary Investigator: NorioKurumatani, MD, PhD, Professor and Chairman, Depart-ment of Community Health and Epidemiology, Nara MedicalUniversity School of Medicine), which was conducted as acollaborative study with Nara Medical University and fourcities: Nara, Kashihara, Yamato-Koriyama, and Kashiba inNara Prefecture. Participants were recruited by the Adminis-trative Center of the Fujiwara-kyo study, with the cooperationof local resident associations and elderly people’s clubsorganized in each of the four cities. The present study brieflyexplains the Fujiwara-kyo study. Details of the Fujiwara-kyostudy and the FORMEN study have been described elsewhere[12]. The FORMEN study examined bone health of the maleparticipants of the Fujiwara-kyo study. Briefly, 2,012 menaged 65 years or older who were participants in theFujiwara-kyo study completed the baseline survey during2007–2008.

Study population

Of these 2,012 men, 347 were excluded due to a history ofillness and/or medication usage known to affect bonemetabolism (type 1 diabetes mellitus, uncontrolled hyper-thyroid disease, parathyroid disease, connective tissuedisease, operated stomach cancer or ulcer, prostate cancerwith anti-androgen therapy, and oral glucocorticoid therapywith 5 mg/day or more for a period of more than 3 months).Among the remaining 1,665 men, 1,576 with completeinformation on lifestyle factors, including smoking habits,were included in the cross-sectional analysis.

The study protocol was approved by the Ethics Com-mittee of the Kinki University School of Medicine and theMedical Ethics Committee of the Nara Medical University.Study procedures were explained to all participants andwritten informed consent was obtained prior to participationin the survey.

Baseline bone density characteristics

BMD was measured by dual X-ray absorptiometry at thelumbar spine (L2-4) and total hip (QDR4500A, Hologic,Bedford, MA, USA) [12, 13]. Short-term precision (coeffi-cient of variance, CV) of BMD measurements in vivo was1.2% for the LS and total hip (TH) [13]. We excluded fromthe analysis densitometric data of the spine from participantswith vertebral fractures or grade four osteophytes accordingto Nathan's classification [14], or those with hip deformitiesin the regions of interest, as described elsewhere [12].

Explanatory variables

Non-skeletal measures were obtained in the Fujiwara-kyostudy. Detailed information of the measurements is de-

134 Osteoporos Int (2011) 22:133–141

scribed elsewhere [12]. We state briefly some measuresused in the present study.

Height and weight were measured using an automatic scale(Tanita TBF-215, Tanita Inc., Japan). Body mass index (BMI)was calculated as body weight (kilogram) divided by bodyheight squared (square meter). Variables assessed in thesurveys included smoking and drinking habits, milk con-sumption, past medical history, and medication history. Eachparticipant was interviewed by trained public health nurses,nurses, or medical doctors. Regarding smoking history, bothcurrent and former smokers were asked at what age theybegan smoking, at what age they quit smoking (formersmokers), and the average number of cigarettes smoked daily.Energy expenditure by daily physical activities was estimatedusing an International Physical Activity Questionnaire [15]validated in the Japanese elderly [16].

Biochemical marker of bone turnover

Fasting venous blood samples were drawn into serumseparator tubes from all subjects on their visits. The serumwas taken after a centrifugation under room temperatureand stored at −80°C until it was assayed. We measured thelevels of biochemical markers of bone turnover; serumosteocalcin (OC) and tartrate resistant acid phosphataseisoenzyme 5b using commercially available kits accordingto their manufacturer’s protocols.

OC (nanograms/milliliter) was measured by a two-siteimmunoradiometric assay (BGP IRMA kit Mitsubishi,Mitsubishi Kagaku Iatron Inc., Tokyo, Japan) with asensitivity of 1 ng/ml [17]. Intraassay, interassay, andoverall precision was represented by the CV determinedwere 4.9%, 3.7%, and 6.1%, respectively.

TRACP-5b was measured by a fragment-absorbedimmunocapture enzyme assay (Osteolinks-TRAP-5b, NittoBoseki, Kooriyama, Japan) with a sensitivity of 19.2 mU/dl[18]. The intraassay CV, interassay CV, and overall CV ofthis measurement in our laboratory were 4.9%, 7.3%, and8.8%, respectively.

Statistical analysis

We evaluated the effect of smoking status (never, former, andcurrent smokers) and smoking characteristics (number ofsmoking years, number of pack years, number of cigarettessmoked per day, and number of years since smoking cessationfor former smokers) on BMD values. Pack years werecalculated by multiplying the number of years smoked bythe number of cigarettes smoked per day and then dividing thevalue by 20. Effects of confounding variables were adjustedfor using analysis of covariance when appropriate incomparisons of the mean values of BMD between smokingstatus, or between smoking characteristics. The analyses

included adjustment for age, height, weight, energy consump-tion by daily physical activities, milk consumption, anddrinking habit. To accommodate multiple testing betweensmoking status and characteristics, we used a Bonferroni-adjusted test of significance. We rank-transformed the s-OCdata for the analysis because these data were not of a normaldistribution and values were presented as median values. Toreduce non-normality of distributions, s-TRACP-5b was logtransformed for the analysis and we presented the values asgeometric means with either a standard deviation or standarderror. The statistical significance was set at P<0.05.

Statistical analyses were performed with SPSS (version14.0J; SPSS, Tokyo, Japan) or SAS system software forpersonal computers (release 6.12; SAS Institute, Cary, NC,USA).

Results

Basic participant characteristics

Table 1 summarizes baseline data from the 1,576 studyparticipants according to smoking status. Proportions offormer smokers and current smokers were 59.2% and17.6%, respectively. Age and BMI were found to besignificant variables among never, former, and currentsmokers, and current smokers were significantly youngerand had significantly lower BMI values (Table 1). Weobserved a significant decrease in LS BMD values fromnever to former to current smokers (P value for trend test,0.005), while we observed a marginal significant decreasein TH BMD (P value for trend test, 0.078).

Smoking status and BMD

We observed a significant decrease in LS BMD values fromnever to former to current smokers after adjusting for age,height, weight, energy consumption by daily physicalactivities, milk consumption, and alcohol drinking habits (Pvalue for trend test; 0.036; Table 2). LS BMD values weresignificantly lower in current smokers compared to formersmokers after adjusting for the variables described abovethrough multiple comparisons. When current and formersmokers were combined as ever smokers, adjusted LS BMDvalues were significantly lower in ever smokers than in neversmokers. TH BMD, s-OC, and s-TRACP-5b values did notvary significantly by smoking status (Table 2).

Smoking exposure and BMD stratified by smokingcharacteristics

Adjusted LS and TH BMD values were significantly andnegatively associated with number of smoking years or

Osteoporos Int (2011) 22:133–141 135

Tab

le1

Baselinecharacteristicsof

participantsstratifiedby

smok

ingstatus

intheFORMEN

baselin

estud

y(200

7–20

08)

Total

(n=1,576)

Never

smokers(n=366)

Former

smokers(n=933)

Current

smokers(n=277)

Pvalued

Eversm

okerse

(n=1,210)

Pvaluef

Physicalcharacteristics

Age

(years)

73.1

(5.2)

73.1

(5.1)#

73.6

(5.4)*

71.5

(4.6)*,#

0.001

73.1

(5.3)

0.891

Height(cm)

162.8(5.7)

162.4(5.3)

163.1(5.8)

162.5(5.5)

0.698

162.9(5.7)

0.110

Weight(kg)

61.2

(8.5)

61.0

(8.2)

61.8

(8.6)

59.7

(8.6)

0.107

61.3

(8.6)

0.536

BMI(kg/m

2)

23.1

(2.7)

23.1

(2.7)

23.2

(2.7)*

22.6

(3.0)*

0.040

23.1

(2.8)

0.859

Lum

barspineBMD

a(g/cm

2)

1.029(0.190)

1.045(0.194)*

1.030(0.189)

1.001(0.182)*

0.005

1.023(0.188)

0.062

Total

hipBMD

(g/cm

2)

0.883(0.125)

0.888(0.120)

0.885(0.127)

0.870(0.124)

0.078

0.881(0.126)

0.371

Biochem

ical

markerof

bone

turnover

b

Serum

osteocalcin(ng/ml)

4.9(3.2,6.4)

5.1(3.3,6.7)

4.9(3.1,6.4)

4.7(3.4,6.4)

0.198

4.8(3.1,6.4)

0.075

Serum

TRACP-5b(m

U/dl)

209.7(1.7)

205.4(1.7)

210.0(1.7)

214.2(1.8)

0.325

211.0(1.7)

0.405

Lifestyle

characteristics

Physicalactiv

ityc(kcal/d

ay)

182(79,

381)

170(81,

378)

189(84,

375)

180(60,

410)

0.612

188(79,

38.3)

0.596

Milk

consum

ption(%

)

Twoor

moreglassesdaily

7.7%

9.3%

7.6%

5.8%

<0.001

7.2%

0.276

One

glassdaily

43.5%

45.9%

45.4%

33.6%

42.7%

One

glassper2-3

days

15.1%

13.9%

15.9%

14.1%

15.5%

One

glassor

less

weekly

33.2%

30.9%

31.1%

46.6%

34.6%

Alcohol

drinking

habit(%

)

Lessthan

once/week

36.5%

44.3%

34.6%

32.9%

<0.001

34.3%

<0.001

1-2tim

es/week

5.4%

8.2%

4.9%

3.2%

4.5%

3-5tim

es/week

9.2%

13.1%

8.8%

5.4%

8.0%

6or

moretim

es/week

48.9%

34.4%

51.7%

58.5%

53.2%

Smokingcharacteristics

Age

startedsm

oking(years)

--

20.9

(3.6)

21.0

(3.9)

0.628

20.9

(3.7)

-

No.

cigarettessm

oked

perday

--

24.0

(14.4)

17.1

(8.3)

<0.001

22.5

(13.6)

-

No.

smokingyears

--

32.1

(13.8)

49.2

(6.7)

<0.001

36.0

(14.4)

-

No.

pack

years

--

39.6

(29.3)

41.7

(20.2)

0.171

40.0

(27.5)

Valueswith

out%

unitrepresentgeom

etricmeans

(stand

arddeviation)

forTRACP-5b,

median(interqu

artilerang

e)forosteocalcinandph

ysical

activ

ityor

mean(stand

arddeviation)

forother

characteristics

BMIbo

dymassindex,

BMD

bone

mineral

density

;TRACP-5btartrate

resistantacid

phosph

ataseisoenzym

e5b

EachPvalueforosteocalcinwas

obtained

afterrank

transformation,

andeach

PvalueforTRACP-5bwas

obtained

byusinglog-transformed

values

aDataforBMD

atthelumbarspinewereob

tained

from

1,498participants

with

neith

erdeform

ities

norgrade4osteop

hytesaccordingto

Nathan’sclassificatio

n[14]

atthesecond,third,

orfourth

lumbar

vertebrae

bNum

bers

ofavailableparticipantswere1,535(never

smokers,36

1;form

ersm

okers,91

0;currentsm

okers,26

4)forosteocalcin,

1,564(never

smokers,36

4;form

ersm

okers,92

5;currentsm

okers,27

5)for

TRACP-5b,

respectiv

ely

cEnergyexpend

iture

bylevelof

daily

physical

activ

itywas

estim

ated

usingaph

ysical

activ

ityqu

estio

nnaire

valid

ated

inJapanese

elderlysubjects[15]

dA

trendtest,theCochran–A

rmitage

trendtestor

theKruskal-W

allis

testwas

performed

betweennever,form

er,andcurrentsm

okers

eEversm

okerswereform

eror

currentsm

okers

fA

ttest,chi-squaredtest,or

Mann-Whitney

Utestwas

performed

betweenneverandever

smokers

*,#P<0.05

with

Bonferronicorrectio

nmethodby

multip

lecomparisons

betweennever,form

er,\andcurrentsm

okersforeach

linein

thetable

136 Osteoporos Int (2011) 22:133–141

Table 2 Bone mineral density and biochemical markers of bone turnover by smoking status in the FORMEN baseline study (2007–2008)

Never smokers (n=366) Former smokers (n=933) Current smokers (n=277) P valueb Ever smokersc (n=1,210) P valueb

Lumbar spine BMD (g/cm2)

Age, height, and weight adjusted 1.047 (0.010) 1.024 (0.006) 1.020 (0.011) 0.085 1.023 (0.010) 0.028

Multivariate adjusteda 1.050 (0.010) 1.023 (0.006)* 1.019 (0.011)* 0.036 1.022 (0.005) 0.010

Total hip BMD (g/cm2)


Multivariate adjusteda 0.892 (0.006) 0.881 (0.004) 0.878 (0.007) 0.209 0.880 (0.003) 0.084

Serum osteocalcin (ng/ml)

Age, height, and weight adjusted 5.0 (4.8, 5.1) 4.8 (4.6, 5.0) 4.8 (4.7, 5.0) 0.406 4.6 (4.8, 5.0) 0.056

Multivariate adjusteda 5.0 (4.7, 5.3) 4.8 (4.5, 5.1) 4.8 (4.6, 5.1) 0.969 4.8 (4.5, 5.1) 0.305

Serum TRACP-5b (mU/dl)


Multivariate adjusteda 205.38 (0.06) 210.05 (0.04) 214.21 (0.07) 0.288 210.99 (0.03) 0.215

For use in the analysis of covariance, osteocalcin data were rank transformed and the TRACP-5b data were log transformed. Values in the tablerepresent mean (standard error) for BMD, median (interquartile range) for osteocalcin, or geometric mean (standard error) for TRACP-5b

BMD bone mineral density, TRACP-5b tartrate resistant acid phosphatase isoenzyme 5ba Values were adjusted for age, height, weight, dummy variables for each of the upper three quartiles of energy expenditure by daily physical activities with thebottom quartile as a reference, for each level of milk consumption (two or more glasses daily, one glass daily, one glass per 2-3 days) with one glass or less weeklyas a reference, and for each level of alcohol drinking (1-2 times/week, 3-5 times/week, 6 or more times/week) with less than once/week as a referenceb A trend test was performed between never, former, and current smokers, or between never and ever smokersc Ever smokers were former or current smokers* P<0.05 with Bonferroni correction by multiple comparisons between never, former, and current smokers for lumbar spine BMD

Table 3 BMD at the different skeletal sites by cigarette smoking characteristics among ever smokers compared with never smokers

Lumbar spine (N=1,498) Total hip (N=1,576)

Distribution ofsmokingcharacteristics

Age-, height-,and weight-adjusted BMD

Multivariate-adjustedb BMD


Age-, height-, andweight-adjusted BMD

Multivariate-adjustedb

BMD

n Min Max Mean (SE) Mean (SE) n Min Max Mean (SE) Mean (SE)

Yeas of smoking

Never smokers 350 1.047 (0.010)* 1.050 (0.010)*, # 366 0.889 (0.006) 0.892 (0.006)

1st tertile of years of smoking 400 1.0 30.0 1.041 (0.009) 1.039 (0.009) 424 1.0 30.0 0.899 (0.005)*, # 0.896 (0.005)*, #

2nd tertile of years of smoking 347 30.1 45.0 1.010 (0.010)* 1.010 (0.010)* 360 30.1 45.0 0.873 (0.006)* 0.872 (0.006)*

3rd tertile of years of smoking 401 45.0 66.7 1.016 (0.009) 1.015 (0.009)# 426 45.0 68.0 0.870 (0.005)# 0.871 (0.005)#

P valuea for trend 0.003 0.001 <0.001 0.001

Cigarettes smoked per day

Never smokers 350 1.047 (0.010) 1.050 (0.010)* 366 0.889 (0.006) 0.892 (0.006)

1st tertile of cigarettes smoked per day 388 1 15 1.022 (0.009) 1.019 (0.009) 409 1 15 0.883 (0.006) 0.879 (0.006)

2nd tertile of cigarettes smoked per day 418 16 20 1.031 (0.009) 1.031 (0.009) 440 16 20 0.879 (0.005) 0.881 (0.005)

3rd tertile of cigarettes smoked per day 342 22 100 1.014 (0.010) 1.013 (0.010)* 361 22 100 0.881 (0.006) 0.881 (0.006)

P valuea for trend 0.037 0.023 0.325 0.233

Pack years

Never smokers 350 1.047 (0.010) 1.050 (0.010)* 366 0.889 (0.006) 0.892 (0.006)

1st tertile of pack years 389 0.5 25.0 1.036 (0.009) 1.034 (0.009) 397 0.5 24.6 0.894 (0.006) 0.891 (0.006)

2nd tertile of pack years 376 25.2 45.9 1.019 (0.009) 1.017 (0.009) 410 25.0 46.0 0.874 (0.006) 0.872 (0.005)

3rd tertile of pack years 383 46.0 192.0 1.014 (0.009) 1.015 (0.009)* 403 46.1 192.0 0.875 (0.006) 0.877 (0.006)

P value a for trend 0.047 0.027 0.028 0.026

BMD bone mineral densitya A trend test was performed between never and ever smokersb BMD was adjusted for age, height, weight, dummy variables for each of the upper three quartiles of energy expenditure by daily physical activities with thebottom quartile as a reference, for each level of milk consumption (two or more glasses daily, one glass daily, one glass per 2-3 days) with one glass or less weeklyas a reference, and for each level of alcohol drinking (1-2 times/week, 3-5 times/week, 6 or more times/week) with less than once/week as a reference*, # P<0.05 with Bonferroni correction method by multiple comparisons between never and ever smokers for each column in the table

Osteoporos Int (2011) 22:133–141 137

number of pack years, respectively, in both never and eversmokers (Table 3). Adjusted LS BMD values in subjects inthe third tertile of cigarettes smoked per day (≥22/day) weresignificantly lower than those in never smokers (1.050 [SE;0.010] vs. 1.013 [SE; 0.010], P<0.05 with Bonferronicorrection method), as shown in Table 3. A similar analysisas was done for Table 3 revealed that for every smokers, weobserved a significant and negative association betweennumber of smoking years and LS and TH BMD (P value fortrend test; 0.007 and 0.008, respectively), after adjusting forage, height, weight, and number of cigarettes smoked perday. Number of smoking years was categorized by tertilevalues in the same manner as was done in Table 3. Thesignificant association between number of smoking yearsand TH BMD remained after we adjusted for the variablesused in the model in Table 3 (P value for trend test, 0.045).

Among current smokers, neither number of smokingyears, number of cigarettes smoked per day, nor number of

pack years was significantly associated with BMD values(data not shown).

Among never and former smokers, LS and TH BMDvalues were significantly associated with number ofsmoking years, but not with number of cigarettes smokedper day (Table 4). The number of pack years wasassociated with decreased LS and TH BMD values withmarginal significance (Table 4). A similar analysis as wasdone for Table 4 revealed that for former smokers, numberof smoking years was significantly and negatively associ-ated with LS and TH BMD values (P value for trend test;0.004 and <0.001, respectively). No statistically signifi-cant associations were observed between the number ofpack years and LS and TH BMD value among formersmokers (data not shown). The correlation coefficientbetween the number of smoking years and number ofyears since smoking cessation was −0.892 (P<0.001) informer smokers.

Table 4 BMD at the different skeletal sites by cigarette smoking characteristics among former smokers compared with never smokers

Lumbar spine (N=1,234) Total hip (N=1,299)


Age, height, weight-adjusted BMD



Age, height, weight-adjusted BMD


n Min Max Mean (SE) Mean (SE) n Min Max Mean (SE) Mean (SE)

Yeas of smoking

Never smokers 350 1.051 (0.010)* 1.054 (0.010)* 366 0.890 (0.006) 0.893 (0.006)

1st tertile of years ofsmoking

309 1.0 25.0 1.056 (0.010)# 1.054 (0.010)# 325 1.0 25.0 0.907 (0.006)*, # 0.905 (0.006)*, #

2nd tertile of years ofsmoking

300 26.0 40.0 1.007 (0.010)*, # 1.006 (0.010)*, # 316 26.0 40.0 0.874 (0.006)* 0.872 (0.006)*

3rd tertile of years ofsmoking

275 41.0 62.0 1.018 (0.011) 1.019 (0.011) 292 41.0 68.0 0.868 (0.007)# 0.870 (0.007)#

P value a for trend 0.001 0.001 <0.001 <0.001

Cigarettes smoked per day

Never smokers 350 1.051 (0.010) 1.054 (0.010) 366 0.890 (0.006) 0.893 (0.006)

1st tertile of cigarettessmoked per day

262 1 18 1.021 (0.011) 1.017 (0.011) 278 1 18 0.885 (0.007) 0.881 (0.007)

2nd tertile of cigarettessmoked per day

327 20 22 1.042 (0.010) 1.043 (0.010) 344 20 24 0.881 (0.006) 0.883 (0.006)

3rd tertile of cigarettessmoked per day

295 23 100 1.018 (0.011) 1.018 (0.011) 311 25 100 0.886 (0.006) 0.885 (0.006)

P value a for trend 0.092 0.074 0.541 0.448

Pack years

Never smokers 350 1.051 (0.010) 1.054 (0.010) 366 0.890 (0.006) 0.893 (0.006)

1st tertile of pack years 294 0.5 22.5 1.044 (0.011) 1.041 (0.011) 314 0.5 22.5 0.899 (0.006) 0.895 (0.006)

2nd tertile of pack years 303 23.0 45.0 1.022 (0.010) 1.021 (0.010) 314 23.0 45.0 0.878 (0.006) 0.876 (0.006)

3rd tertile of pack years 287 45.1 192.0 1.018 (0.011) 1.019 (0.011) 305 45.1 192.0 0.875 (0.006) 0.877 (0.006)

P valuea for trend 0.056 0.049 0.028 0.047

BMD bone mineral densitya A trend test was performed between never and former smokersb BMD was adjusted for age, height, weight, dummy variables for each of the upper three quartiles of energy expenditure by daily physical activities with thebottom quartile as a reference, for each level of milk consumption (two or more glasses daily, one glass daily, one glass per 2-3 days) with one glass or less weeklyas a reference, and for each level of alcohol drinking (1-2 times/week, 3-5 times/week, 6 or more times/week) with less than once/week as a reference*, # P<0.05 with Bonferroni correction method by multiple comparisons between never and ever smokers for each column in the table

138 Osteoporos Int (2011) 22:133–141

Smoking status, smoking characteristics, and biochemicalmarkers of bone turnover

SerumOC or TRACP-5b values did not differ significantly bysmoking characteristics (Table 5). When stratified by smok-ing characteristics, these same values did not vary betweennever smokers, current smokers, current smokers with 20 orfewer cigarettes smoked per day, and current smokers withmore than 20 cigarettes smoke per day (data not shown),though we indicated in Table 3 that ever smokers with morethan 20 cigarettes smoked per day had significantly higherLS BMD values compared to never smokers.

Discussion

This study provides evidence that smoking status isassociated with decreased BMD in men aged 65 years orolder in large-scale community-based single-center studyelderly Japanese men, the FORMEN baseline study.Regarding smoking characteristics, the number of packyears, and more significantly, the number of smoking yearswere associated with decreased BMD. The number of

cigarettes smoked per day was only associated with areduction in LS BMD among ever smokers and neversmokers. A strength of this study was that it is a population-based study with a relatively large sample size of Asianmen following the Mr. OS study [10].

Findings of this study are consistent with those from twometa-analyses [3, 4], which revealed that the bone mass ofcurrent smokers was lower than that of never and formersmokers. We revealed significant trends for LS BMD, butnot for TH BMD, among three (never, former, current)smoking status groups, which findings are consistent withfindings by Ward et al. [4].

Previous studies classifying men by smoking character-istics have shown a decrease in bone mass with the numberof smoking years [19–24] and pack years [10, 20, 25–30],which was consistent with our findings. Regarding thenumber of cigarettes smoked per day, results with men haveshown inconsistent positive [22, 23, 25, 31] and negativefindings [24, 32]. Smokers with 20 or more cigarettes perday generally revealed significant lower BMD comparedwith that in never smokers [22, 23, 25], which wasconsistent with our findings. Negative findings could bedue to a relatively small numbers of subjects (total of 222

Table 5 Biochemical markers of bone turnover by cigarette smoking characteristics among never and current smokers

Serum osteocalcin (ng/ml) Serum TRACP-5b (mU/dl)

Age, height, weight-adjusted Multivariate-adjustede Age, height, weight-adjusted Multivariate-adjustede

Years of smokinga

Never smoker 5.0 (4.8, 5.1) 5.0 (4.7, 5.3) 205.38 (0.06) 205.38 (0.06)

Years of smoking<median 4.6 (4.5, 4.7) 4.6 (4.2, 4.9) 202.31 (0.10) 202.31 (0.10)

Years of smoking≥median 5.0 (4.9, 5.2) 5.0 (4.7, 5.4) 227.30 (0.10) 227.30 (0.10)

P valueb for trend 0.935 0.473 0.226 0.222

Cigarettes smoked per dayc

Never smoker 5.0 (4.8, 5.1) 5.0 (4.7, 5.3) 205.4 (0.1) 205.4 (0.1)

Cigarettes smoked per day<median 4.9 (4.7, 5.1) 4.9 (4.6, 5.3) 223.1 (0.1) 223.1 (0.1)

Cigarettes smoked per day≥median 4.7 (4.6, 4.8) 4.7 (4.3, 5.1) 206.1 (0.1) 206.1 (0.1)


Pack yearsd

Never smoker 5.0 (4.8, 5.1) 5.0 (4.7, 5.3) 205.4 (0.1) 205.4 (0.1)

Pack years<median 4.9 (4.7, 5.0) 4.9 (4.6, 5.2) 221.8 (0.1) 221.8 (0.1)

Pack years≥median 4.7 (4.6, 4.9) 4.8 (4.4, 5.1) 206.9 (0.1) 206.9 (0.1)


For use in the analysis of covariance, osteocalcin data were rank transformed, and the TRACP-5b data were log transformed. Values in the tablerepresent median (interquartile range) for osteocalcin, and geometric mean (standard error) for TRACP-5b. Numbers of available participants werenever smokers, 361; current smokers, 264 for osteocalcin, never smokers, 364; current smokers, 275 for TRACP-5b, respectively.a The median value: 49.2b A trend test was performed between never and current smokers.c The median value: 17d The median value: 40.2e Values were adjusted for age, height, weight, dummy variables for each of the upper three quartiles of energy expenditure by daily physical activities withthe bottom quartile as a reference, for each level of milk consumption (two or more glasses daily, one glass daily, one glass per 2-3 days) with one glass orless weekly as a reference, and for each level of alcohol drinking (1-2 times/week, 3-5 times/week, 6 or more times/week) with less than once/week as areference

Osteoporos Int (2011) 22:133–141 139

male) [32], or low numbers of cigarettes per day (meanvalues; 12 cigarettes per day among smokers) [24].

Regarding the effects of smoking cessation, Wong et al. [8]indicated that there was insufficient data to determine thenumber of years since smoking cessation necessary for ameaningful biological effect in the meta-analysis [3, 4].However, we could not analyze the effects of the number ofyears since smoking cessation, as the numbers of smokingyear and years since smoking cessationwere highly correlated.

Concerning a novel bone resorption marker; TRACP-5b,we had no comparable data, while Supervia et al [33] reportedno effect of smoking on serum TRACP which was not aspecific marker for an osteoclast activity. With regard to theeffect of smoking on other bone resorption markers, the datawere also scare and discordant. In male smoker with lowbody weight, bone resorption marker (C-terminal telopep-tide, free and total deoxypyridinoline) was increased [34].No difference of urinary hydroxyproline among men [25] orurinary N-telopeptiode (NTX) among men [33] werereported, while an increase of u-NTX was seen in femalesmokers [9]. Our findings about TRACP-5b, which has alow diurnal variability and is not affected by feeding [35]and did not vary significantly with age among Japanese men[36], would indicate that the current smoking does not affectosteoclast activities. A review about biochemical markers ofbone turnover in men by Szulc et al [37] indicated anapparent stability of the levels of bone markers in betterhealth status. As long as we know, there was no availabledata of smoking effect on s-OC in elderly men, while therewere no different values of serum osteocalcin betweensmokers and non-smokers in studies with young men [25,33]. Further studies about the effects of smoking on boneformation and resorption should be conducted.

Our finding revealed a significant effect of smokingcharacteristic on LS and TH BMD. Although LS BMD inthe elderly is well known to present measurement difficul-ties due to deformities or aortic calcifications and isaffected by these artifacts, a significant difference wasobserved. This finding is consistent with previous studies[4, 10, 23]. The underlying mechanism of the adversesmoking effect remains unclear, but one speculation on whyLS BMD values were affected by smoking is that the peakbone mass at LS is achieved later than that of TH [38],while the majority of peak bone mass at TH would beachieved during adolescence [38, 39]. This suggests thatTH bone mass could be achieved before smoking initiation.Thus, the smoking effect on LS BMD might be seen evenwhen values for the signal-to-noise ratio of LS BMD arelower than those of TH BMD.

There are several limitations to the present study. First,the study participants are volunteers, not a random sampleof the general population. It has been reported thatvolunteers involved in research studies tend to be better

educated and slightly less likely to smoke than the generalpopulation [40]. The participants in our study also revealeda lower current smoking rate, but a higher former rate thanJapanese men in the general population [7]. However, wehave focused on the effect of smoking on bone statusamong healthy elderly male subjects who live independent-ly in community as few studies have been conducted withthose subjects. Second, the cross-sectional design of thestudy fails to establish causality between smoking andreduced bone density. Future follow-up studies will clarifysmoking effects on changes in BMD and osteoporoticfractures. Finally, data regarding smoking exposure wasentirely self-reported. However, trained public health nursesor medical doctors conducted all interviews. There might bean information bias regarding smoking exposure, somemight answer less number or years of cigarettes smoked, asit causes underestimation of the smoking effect.

Our findings obtained by the FORMEN study confirmthe deleterious effects of smoking on bone status. Thenumber of smoking years, rather than the number ofcigarettes smoked per day, is mainly associated withdecreased BMD in elderly male subjects living indepen-dently in a community. Bone metabolism among currentsmokers, as measured by biochemical markers, was notsignificantly different from that among never smokers. Ourfindings should be utilized to identify a strategy to promotebone health in elderly men.

Acknowledgments Financial support for the baseline survey wasprovided by St. Luke’s Life Science Institute Grant-in-Aid forEpidemiological Research, Foundation for Total Health Promotion, aGrand-in-Aid for study on Milk Nutrition (2008) from the Japan DairyAssociation, a Grant (2008) from Physical Fitness Research Institute,MEIJI YASUDA Life Foundation of Health and Welfare, Grants-in-aid for Scientific Research (#20659103: 2008-2009, B #21390210:2009-2011, C #20590661: 2008–2010), and Grant-in-Aid for YoungScientists ( B #20790451: 2008-2010) from the Japanese Ministry ofEducation, Culture, Sports, Science and Technology.

Conflicts of interest None.

References

1. Cooper C, Campion G, Melton LJ 3rd (1992) Hip fractures in theelderly: a worldwide projection. Osteoporos Int 2:285–289

2. Orimo H, Sakata K (2004) Report of the 4th nationwide survey forhip fracture. Nihon Iji Shinpo (Jpn Med J) 4180:25–30 (in Japanese)

3. Law MR, Hackshaw AK (1997) A meta-analysis of cigarettesmoking, bone mineral density and risk of hip fracture, recogni-tion of a major effect. BMJ 315:841–846

4. Ward KD, Klesges RC (2001) A meta-analysis of the effects ofcigarette smoking on bone mineral density. Calcif Tissue Int68:259–270

5. Kanis JA, Johnell O, Oden A, Johansson H, De Laet C, EismanJA, Fujiwara S, Kroger H, McCloskey EV, Mellstrom D, MeltonLJ, Pols H, Reeve J, Silman A, Tenenhouse A (2005) Smokingand fracture risk: a meta-analysis. Osteoporos Int 16:155–162

140 Osteoporos Int (2011) 22:133–141

6. World Health Organization (2008) WHO Report on the globaltobacco epidemic, 2008: the MPOWER package. In. WorldHealth Organization

7. Ministry of Health Labour and Welfare of Japan (ed) (2008)National Health and Nutrition Survey in Japan, 2005, Dai-Ichishyuppan, Tokyo (in Japanese)

8. Wong PK, Christie JJ, Wark JD (2007) The effects of smoking onbone health. Clin Sci (Lond) 113:233–241

9. Compston J (2007) Editorial: Smoking and the skeleton. J ClinEndocrinol Metab 92:428–429

10. Lau EM, Leung PC, Kwok T, Woo J, Lynn H, Orwoll E, CummingsS, Cauley J (2006) The determinants of bone mineral density inChinese men—results from Mr. Os (Hong Kong), the first cohortstudy on osteoporosis in Asian men. Osteoporos Int 17:297–303

11. Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J,Burckhardt P, Cooper C, Christiansen C, Cummings S, EismanJA, Fujiwara S, Gluer C, Goltzman D, Hans D, Krieg MA, LaCroix A, McCloskey E, Mellstrom D, Melton LJ 3rd, Pols H,Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van StaaT, Watts NB, Yoshimura N (2007) The use of clinical risk factorsenhances the performance of BMD in the prediction of hip andosteoporotic fractures in men and women. Osteoporos Int18:1033–1046

12. Iki M, Fujita Y, Tamaki J, Kouda K, Yura A, Kadowaki E, Sato Y,Moon JS, Okamoto N, Kurumatani N (2009) Design and baselinecharacterisitcs of a prespective cohort study for determinants ofosteoporotic fracture in community-dwelling elderly Japanesemen: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN)study. BMC Musculoskeletal Disorders 10:165

13. Iki M, Kagamimori S, Kagawa Y, Matsuzaki T, Yoneshima H,Marumo F (2001) Bone mineral density of the spine, hip anddistal forearm in representative samples of the Japanese femalepopulation: Japanese Population-based Osteoporosis (JPOS)Study. Osteoporos Int 12:529–537

14. Nathan H (1962) Osteophytes of the vertebral column. J BoneJoint Surg 44-A:243–269

15. Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML,Ainsworth BE, Pratt M, Ekelund U, Yngve A, Sallis JF, Oja P(2003) International physical activity questionnaire: 12-countryreliability and validity. Med Sci Sports Exerc 35:1381–1395

16. TomiokaK,Hazaki K, Iwamoto J (2009) The cross-sectional study ofdaily step count, physical function and health-related Quality of Lifefor community-dwelling older adults. The 24th Research-Aid Reportin medical and health science of Meiji Yasuda Life Foundation ofhealth and welfare 24:1-11 (in Japanese)

17. Kawaguchi H, Matsumoto T, Kurokawa T, Orimo H, MizunashiK, Takuwa Y, Niimi H, Shiraki M, Ohara T, Shishiba Y, TsuchiyaY, Takahshi H, Takatsuki K, Seino Y, Morii H, Fujita T, OkamotoS, Ogata E (1990) Serum levels of BGP determined by two-siteimmunoradiometric assay (IRMA) using monoclonal antibodies.Clin Endocrinol 38:1291–1296 (in Japanese)

18. Ishizawa Y, Unaba M, Ishii K, Yamashita H, Miki T, Goto H,Yamada S, Chaki O, Kurasawa K, Mochizuki Y (2005)Evaluation of newly developed kit for measurement of bone-specific tartrate-resistant acid phospatase in blood. Igaku toYakygaku 54:709–717 (in Japansese)

19. Johansson C, Mellstrom D, Lerner U, Osterberg T (1992) Coffeedrinking: a minor risk factor for bone loss and fractures. Age Ageing21:20–26

20. Nelson DA, Jacobsen G, Barondess DA, Parfitt AM (1995) Ethnicdifferences in regional bone density, hip axis length, and lifestylevariables among healthy black and white men. J Bone Miner Res10:782–787

21. Egger P, Duggleby S, Hobbs R, Fall C, Cooper C (1996) Cigarettesmoking and bone mineral density in the elderly. J EpidemiolCommunity Health 50:47–50

22. Vogel JM, Davis JW, Nomura A, Wasnich RD, Ross PD (1997) Theeffects of smoking on bone mass and the rates of bone loss amongelderly Japanese-American men. J Bone Miner Res 12:1495–1501

23. Kuo CW, Change TH, Chi WL, Chu TC (2008) Effect of cigarettesmoking on bone mineral density in healthy Taiwanese middle-aged men. J Clin Densitom 11:518–524

24. Sneve M, Emaus N, Joakimsen RM, Jorde R (2008) Theassociation between serum parathyroid hormone and bone mineraldensity and the impact of smoking: the Tromso Study. Eur JEndocrinol 158:401–409

25. Ortego-Centeno N, Munoz-Torres M, Jodar E, Hernandez-QueroJ, Jurado-Duce A, de la Higuera Torres-Puchol J (1997) Effect oftobacco consumption on bone mineral density in healthy youngmales. Calcif Tissue Int 60:496–500

26. Nguyen TV, Kelly PJ, Sambrook PN, Gilbert C, Pocock NA, EismanJA (1994) Lifestyle factors and bone density in the elderly:implications for osteoporosis prevention. J Bone Miner Res9:1339–1346

27. Hagiwara S, Tanabe Y, Nitta K (1997) Smoking influences malebone mineral density of the heel (abstract). J Bone Miner Res 12(suppl 1):S249

28. Hagiwara S, Izumotani-Sasao K, Kawakami H, Miki T, Morii H(1996) Smoking is one of the risk factors for middleaged maleosteoporosis (abstract). J Bone Miner Res 11(suppl 1):S224

29. Glynn NW, Meilahn EN, Charron M, Anderson SJ, Kuller LH,Cauley JA (1995) Determinants of bone mineral density in oldermen. J Bone Miner Res 10:1769–1777

30. Cheng S, Suominen H, Heikkinen E (1993) Bone mineral densityin relation to anthropometric properties, physical activity andsmoking in 75-year-old men and women. Aging (Milano) 5:55–62

31. Kiel DP, Zhang Y, Hannan MT, Anderson JJ, Baron JA, FelsonDT (1996) The effect of smoking at different life stages onbone mineral density in elderly men and women. OsteoporosInt 6:240–248

32. Kroger H, Laitinen K (1992) Bone mineral density measured bydual-energy X-ray absorptiometry in normal men. Eur J ClinInvest 22:454–460

33. Supervia A, Nogues X, Enjuanes A, Vila J, Mellibovsky L, SerranoS, Aubia J, Diez-Perez A (2006) Effect of smoking and smokingcessation on bone mass, bone remodeling, vitamin D, PTH and sexhormones. J Musculoskelet Neuronal Interact 6:234–241

34. Szulc P, Garnero P, Claustrat B, Marchand F, Duboeuf F, Delmas PD(2002) Increased bone resorption inmoderate smokers with low bodyweight: the Minos study. J Clin Endocrinol Metab 87:666–674

35. Halleen JM, Tiitinen SL, Ylipahkala H, Fagerlund KM, VaananenHK (2006) Tartrate-resistant acid phosphatase 5b (TRACP 5b) asa marker of bone resorption. Clin Lab 52:499–509

36. Nishizawa Y, Inaba M, Ishii M, Yamashita H, Miki T, Goto H,Yamada S, Chaki O, Kurasawa K, Mochizuki Y (2008) Referenceintervals of serum tartrate-resistant acid phosphatase type 5bactivity measured with a novel assay in Japanese subjects. J BoneMiner Metab 26:265–270

37. Szulc P, Delmas PD (2001) Biochemical markers of bone turnoverin men. Calcif Tissue Int 69:229–234

38. Henry YM, Fatayerji D, Eastell R (2004) Attainment of peak bonemass at the lumbar spine, femoral neck and radius in men andwomen, relative contributions of bone size and volumetric bonemineral density. Osteoporos Int 15:263–273

39. Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H, SizonenkoPC, Bonjour JP (1993) Longitudinal monitoring of bone massaccumulation in healthy adolescents, evidence for a marked reductionafter 16 years of age at the levels of lumbar spine and femoral neck infemale subjects. J Clin Endocrinol Meta 75:1060–1065

40. Miller AB, Baines CJ, To T, Wall C (1992) Canadian NationalBreast Screening study: 2. Breast cancer detection and death ratesamong women aged 50 to 59 years. CMAJ 147:1477–1488

Osteoporos Int (2011) 22:133–141 141

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