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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 2 666-674
Copyright © 2002 by The Endocrine Society

Other Original Articles

Increased Bone Resorption in Moderate Smokers with Low Body Weight: The Minos Study

P. Szulc, P. Garnero, B. Claustrat, F. Marchand, F. Duboeuf and P. D. Delmas

INSERM, Research Unit 403, 69437 Lyon; Synarc (P.G.), 69437 Lyon; Hôpital Neuro-Cardiologique (B.C.), 69003 Lyon; and Société de Secours Minière de Bourgogne (F.M.), 71300 Montceau les Mines, France

Address all correspondence and requests for reprints to: Prof. Pierre D. Delmas, INSERM, Research Unit 403, Hôpital Edouard Herriot, Place d’Arsonval, 69437 Lyon, France. E-mail: delmas{at}lyon151.inserm.fr

Abstract

Tobacco was found to be a risk factor for osteoporosis, mainly in postmenopausal women. We studied the effect of smoking on bone mineral density (BMD) and bone turnover in a cohort of 719 men, aged 51–85 yr, composed of 83 current smokers, 405 former smokers, and 231 men who never smoked. Most current and former smokers were moderate smokers (median, 10 cigarettes/d). Current smokers were younger, thinner, and drank more coffee and more alcoholic beverages. After adjustment for age, body weight, alcohol intake, and caffeine intake, current and former smokers had similar BMD, except at the forearm. Former smokers had lower BMD compared with never-smokers at most skeletal sites. Men who had smoked more than 7120 packs (third quartile) had lower BMD of total hip (P < 0.01) and distal forearm (P = 0.03) compared with men in the 2 lower tertiles. In the 3 groups, levels of bone formation markers did not differ. After adjustment for confounding variables, levels of urinary markers of bone resorption (ß-isomerized C-terminal telopeptide, free and total deoxypyridinoline) were higher in the current smokers than in former smokers and never-smokers. Concentrations of T, total 17ß-E2, and androstenedione were higher, whereas that of 25-hydroxyvitamin D was lower, in current smokers. When men were divided according to tertiles of body weight, increased bone resorption, decreased BMD and biochemical indexes of secondary hyperparathyroidism were observed in current smokers in the lowest tertile of body weight (<75 kg) compared with the never-smokers, but not in men in the two highest tertiles of body weight. Current smokers had a higher prevalence of vertebral deformities after adjustment for age and body weight (13% vs. 5%; P < 0.005).

In summary, in moderate smokers with low body weight (<75 kg), increased bone resorption, not matched by increased bone formation, results in decreased BMD and an increased prevalence of vertebral deformities. In this group, low serum 25-hydroxyvitamin D and secondary hyperparathyroidism may explain, at least partly, the effect of tobacco on bone turnover. In former smokers, bone resorption is not increased, but BMD remains lower compared with that in never-smokers.

TOBACCO IS ONE of the major dangers for human health. Several studies show that tobacco smoking is also a risk factor for osteoporosis. Smokers have a lower bone mineral density (BMD) as well as a higher risk of hip fracture and vertebral deformities (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). However, these phenomena are observed mainly in heavy smokers.

Few studies have addressed the potential mechanisms underlying the effect of cigarette smoking on bone metabolism. These studies concern women, and their results are discordant. The osteocalcin (OC) concentration, a marker of bone formation, was found to be decreased in perimenopausal and early postmenopausal women who smoked, but not in elderly female smokers (13, 14, 15). Bone resorption was increased in elderly women who were heavy smokers, but not in perimenopausal or early postmenopausal women (13, 14, 15). There are no data on the potential effect of smoking on bone turnover in men.

It is not clear whether changes in hormonal status induced by smoking are responsible for bone loss in smokers. In some (16, 17), but not all (18, 19), studies the concentration of total 17ß-E2, which has a protective effect on bone in men (20, 21), was increased in current male smokers. Data on the influence of smoking status on the concentration of bioavailable fraction of 17ß-E2 in men are scarce (18). Results concerning concentrations of total and free T as well as SHBG in male smokers differ between studies (16, 18, 22, 23). Serum concentrations of adrenal androgens such as androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate were consistently elevated in current smokers (16, 18, 22, 23). Concentrations of 25-hydroxyvitamin D (25OHD) were decreased in current smokers compared with nonsmokers (14, 15, 24). In contrast, data concerning the effect of smoking on the PTH concentration are scarce and discordant (15, 24, 25).

To clarify the role of tobacco smoking on bone metabolism and osteoporosis in men, we analyzed BMD, the prevalence of vertebral deformities, as well as levels of biochemical markers of bone turnover and hormonal status in men who were or had been moderate smokers from a cohort of men, 51–85 yr of age.

Subjects and Methods

Description of the cohort

The MINOS study is a prospective study of osteoporosis and of its determinants in men that was initiated in 1995. It is a collaboration between INSERM (National Institute of Health and Medical Research) and Société de Secours Minière de Bourgogne (SSMB) in Montceau les Mines. Montceau les Mines is a town of about 20,000 inhabitants situated 130 km northwest of Lyon in the Department (District) of Saône et Loire. SSMB is one of the largest health insurance companies in this district. A detailed description of the cohort was published recently (26). Invitations to our study with explanations of the aim of the study were sent to a random sample of men, aged 51–85 yr, insured by SSMB. All men responded to an epidemiological questionnaire covering demographic and behavioral information as well as detailed medical history (diseases, accidents, and medications) of conditions that could influence bone mass and metabolism. An informed written consent was obtained from each participant. This analysis was performed in 719 men, aged 51–85 yr, who had measurements of BMD, biochemical markers of bone turnover, hormones (except bioavailable E2, 596 men), as well as radiographs of the spine. Men with diseases or receiving treatment known to affect bone metabolism (Paget’s disease, rheumatoid arthritis, ankylosing spondyloarthritis, primary hyperparathyroidism, Cushing’s disease, hemochromatosis, liver cirrhosis, gastrectomy, Klinefelter’s syndrome, or treatment with fluoride, bisphosphonate, T4, or oral corticosteroids) were excluded from the analysis.

Bone mass measurement

BMD and bone mineral content (BMC) were measured at the lumbar spine, right hip, and whole body using pencil-beam, dual energy x-ray absorptiometry (QDR-1500, Hologic, Inc., Waltham, MA) and at the distal and ultradistal nondominant forearm using single energy x-ray absorptiometry (DTX 100, Osteometer, Copenhagen, Denmark). Antero-posterior spine BMD was measured at lumbar vertebrae 2–4. At the hip, five regions of interest were evaluated: femoral neck, trochanter, intertrochanteric region, Ward’s triangle, and total hip. At the forearm, two regions of interest were evaluated. The distal site includes 20 mm of ulna and radius situated proximally to site where the spacing between the two bones is 8 mm. The ultradistal region comprises only the most distal part of the radius. Details concerning the quality assurance have been recently described (26).

Bone mineral apparent density of L3 as well as those of total hip and trochanter were calculated by the method of Carter et al. (BMC/volume, where volume = scanned area3/2) (27). Estimated volumetric BMD of radius and ulna (vBMD) was calculated by the method of Bradney et al. (28). Estimated vBMD of the radius was derived as the BMC of distal radius divided by the estimated radius volume ({pi} x r2[times] measured length), where r = scanned area/(2 x measured length), assuming the radius to be cylindrical. The same procedure was used for distal ulna.

Biochemical measurements

Fasting serum as well as 24-h urine were collected and stored at -80 C until assayed.

Serum total OC was measured with a human-specific two-site immunoradiometric assay (ELSA-OSTEO, CIS-Bio International, Bagnols/Cèze, France), which recognizes a large N-terminal midfragment in addition to the intact molecule (29). Intra- and interassay coefficients of variation are less than 4% and 6%, respectively, and the sensitivity is 0.08 nM/liter. Serum bone-specific alkaline phosphatase (BAP) was measured with an immunoassay using a monoclonal antibody directed against BAP purified from human SAOS-2 osteosarcoma cells as a standard, followed by a conventional colorimetric detection using paranitrophenyl phosphate (Alkphase-B, Metra Biosystems, Mountain View, CA) (30). This assay has a low cross-reactivity with the circulating liver, placental, and intestinal isoenzymes (<15%). The sensitivity of the assay is 0.7 U/liter. Intra- and interassay coefficients of variation are less than 6% and 8%, respectively. Serum N-terminal extension propeptide of type I collagen (PINP) was measured by an RIA that recognizes the intact circulating form of PINP (Intact PINP, Farmos Diagnostica, Uppsala, Sweden) (31). Intra- and interassay coefficients of variation are below 5% and 8%, respectively, and the detection limit is 1 ng/ml.

Urinary ß-isomerized C-terminal telopeptide of collagen type I (ßCTX-I) was measured with an ELISA (CrossLaps ELISA, OSTEOMETER BioTech A/S, Rodovre, Denmark) as described previously (32, 33). The antigen Glu-Lys-Ala-His-ß-Asp-Gly-Gly-Arg is a fragment of C-telopeptide of the {alpha}1-chain of type I collagen. The sensitivity of the assay is 0.5 µg/liter. Intra- and interassay coefficients of variation are less than 10% and 15%, respectively. This assay does not react with free cross-links, and its cross-reactivity with {alpha}CTX is less than 1%. Urinary total deoxypyridinoline (DPD) was measured by ELISA (Pyrilinks-D, Metra Biosystems Inc., Mountain View, CA) after acid hydrolysis. This assay uses a monoclonal antibody with less than 1% cross-reactivity with free pyridinoline and 10% cross-reactivity with cross-linked polypeptides (34). The sensitivity of the assay is 3 nM. Intra- and interassay coefficients of variation are less than 10%.

Hormones

Serum total 17ß-E2 and total T were measured by tritiated RIA after diethylether extraction (35). For T, the limit of detection is 0.06 nM/liter, and the interassay coefficient of variation is 10% for a concentration of 1 nM/liter and 7.8% for 6 nM/liter. For total 17ßE2, the limit of detection is 11 pM/liter, and the interassay coefficient of variation is 9.4% for a concentration of 169 pM/liter and 6.2% for 510 pM/liter. SHBG was measured by immunoradiometric assay (125 I SBP Coatria, Bio-Mérieux, Marcy l’Etoile, France) with an interassay coefficient of variation of 4.1% for a concentration of 16 nmol/liter and 5.3% for 100 nmol/liter. The limit of detection is 0.5 nmol/liter. Serum free T was measured by RIA (Coat-A-Count, Behring, Westwood, MA). The interassay coefficient of variation is 5.5% for a concentration of 0.16 pM/liter and 3.4% for 14.7 pM/liter. The limit of detection is 0.05 pM/liter. As the concentration of free T may be influenced by the serum protein concentration, we calculated the bioavailable T level (bio-T) using the formula: bio-T = free T x (3.6 x 104 liter/mol x albumin concentration + 1) (36). Serum androstenedione was measured by tritiated RIA after diethylether extraction (35). The interassay coefficient of variation is 6% for a concentration of 1.96 nM/liter and 8.3% for 3.98 nM/liter. Serum bio-17ß-E2 was measured using the method described by Tremblay and Dube (37). This measurement was performed in 596 men due to the lack of sufficient volume of serum in 123 men (21). Briefly, SHBG and the hormones bound to it are precipitated using 50% ammonium sulfate. In the supernatant, bio-17ß-E2 is measured using the same RIA as that for total 17ß-E2. The interassay coefficient of variation is 13% for a concentration of 56 pM/liter.

Serum 25OHD was measured by an RIA (INCSTAR Corp., Stillwater, MN) that excludes any interference from lipids (38). Intra- and interassay coefficients of variation were 5% and 11%, respectively. The detection limit was 7.5 nmol/liter. The serum PTH concentration was measured by immunochemiluminometric assay (Magic Lite, Ciba Corning, Inc., Medfield, MA) (38). Intra- and interassay coefficients of variation were 5% and 7%, respectively. The detection limit was 0.2 pmol/liter.

Semiquantitative evaluation of vertebral deformities

We classified vertebral deformities using the semiquantitative method described by Genant et al. (39, 40), which was slightly modified at the level of thoracic kyphosis (T6 to T9). At that level, grade 1 wedge deformities were defined as a 25–30% decrease in anterior vertebral height, and grade 2 deformities were defined as a 30–40% decrease. The same cut-off of 40% was used for grade 3 for all vertebrae from T4 to L4.

Statistical methods

All calculations were performed using SAS software (SAS Institute, Inc., Cary, NC). BMDs of different sites of measurement and levels of bone biochemical markers were compared using analysis of covariance adjusted for age, body weight, self-reported coffee intake, and self-reported ethanol intake. Simple and partial Pearson correlation coefficients were calculated for continuous variables. The relation among the prevalence of vertebral deformities, smoking status, and continuous variables was evaluated using {chi}2 test and logistic regression adjusted for age, body weight, self-reported coffee intake, and self-reported ethanol intake.

To evaluate the effect size, the smallest difference significant for 50 cases and 50 controls was calculated given the variability observed in our study. For the t test, these differences were as follows: 5.5% for total hip BMD, 4.7% for distal forearm BMD, 15% for total DPD, 20% for ßCTX-I, 15% for total T, 10% for 17ß-E2, and 17% for 25OHD. To evaluate the power of our study design, the smallest number of subjects necessary for detecting a significant trend was calculated according to differences in variables between groups and their variability. For the t test, these numbers were as follows: 294 for total hip BMD, 144 for distal forearm BMD, 59 for total DPD, 67 for ßCTX-I, 98 for total T, 102 for 17ß-E2, and 115 for 25OHD.

Results

Description of the cohort

Current smokers were younger and thinner then nonsmokers (Table 1Go). They had lower lean body mass and lower fat mass. Current and former smokers were moderate smokers. In both groups, the median amount smoked was 10 cigarettes/d, and less than 10% of men in both groups smoked more than 20 cigarettes/d. The median smoking period was 40 yr in the current smokers and 25 yr in the former smokers. Current smokers drank more alcoholic beverages and more coffee than nonsmokers. Consumption of alcoholic beverages and coffee did not differ between former smokers and never-smokers. Tea consumption, calcium intake, and intensity of daily activity were similar in the 3 groups. The 3 groups did not differ in terms of medication (diuretics or inhaled corticosteroids) or hospitalization during the year preceding the study.


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  		Table 1. Description of the MINOS cohort according to the smoking status

 
BMD according to smoking status

After adjustment for confounding variables (age, body weight, and alcohol and coffee intake), current and former smokers had similar average BMD, except for distal forearm, where BMD and vBMD were lower in current smokers (Table 2Go). In contrast, BMD was lower in former smokers compared with never-smokers at the levels of hip, whole body, and distal forearm. BMD was correlated neither with the number of cigarettes smoked daily, the time of smoking, nor the period since cessation of smoking. The duration of smoking was not correlated with the number of cigarettes smoked daily (r = 0.07; P = 0.08). Thus, we evaluated the effect of the cumulative dose of tobacco on BMD. In 488 current and former smokers, the second tertile of the number of cigarette packs during all the life span was equal to 7120 packs, which is approximately equivalent to 20 pack-years. The smokers in the third tertile (>7120 packs) had a lower BMD at the levels of hip and forearm as well as a lower whole body BMC compared with the men in the 2 lowest tertiles (Fig. 1Go).


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  		Table 2. Comparison of bone mineral density in current smokers, former smokers, and men who never smoked (never-smokers) after adjustment for age, body weight, caffeine intake, and ethanol intake

 


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  		Figure 1. BMD in current and former smokers who smoked more than 7120 pack during their lifetime (third tertile, left bar) and those who smoked less than 7120 packs (two lower tertiles, right bar) at the level of total hip (P < 0.01), whole body (P < 0.05), distal forearm (P < 0.02), and ultradistal forearm (P < 0.01) after adjustment for confounding variables.

 
Biochemical markers of bone turnover according to smoking status

Average serum concentrations of markers of bone formation (OC, BAP, and PINP) were similar in the three groups (Table 3Go). As current smokers had a lower lean body mass, which is the main source of creatinine, all comparisons of urinary bone resorption markers (expressed as mass of marker per mM creatinine) were adjusted for lean body mass as well as other confounding variables. Current smokers had higher urinary excretion of bone resorption markers compared with former smokers and never-smokers. In contrast, urinary excretion of biochemical markers of bone resorption was similar in former smokers and never-smokers. Current smokers also had higher average urinary levels of bone resorption markers, expressed as mass of marker per glomerular filtrate volume (Fig. 2Go).


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  		Table 3. Comparison of biochemical markers of bone turnover in current smokers, former smokers, and men who never smoked (never-smokers) after adjustment for age, body weight, caffeine intake, and ethanol intake

 


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  		Figure 2. Urinary excretion of the bone resorption markers (expressed per glomerular filtrate volume) in current smokers (left bar) and nonsmokers (right bar) after adjustment for confounding variables (total DPD, P < 0.05; free DPD, P < 0.04; ßCTX-I, P < 0.03).

 
Partial correlation coefficients between BMD and biochemical markers of bone turnover adjusted for age, body weight, and alcohol intake and coffee intake were calculated in current smokers, former smokers, and never-smokers (Table 4Go). In the three groups, coefficient values were roughly similar.


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  		Table 4. Partial correlation coefficients between bone mineral density and biochemical markers of bone turnover after adjustment for age, body weight, and alcohol and coffee intake

 
Serum concentrations of hormones according to smoking status

PTH levels were similar in the three groups (Table 5Go). Current smokers had a lower 25OHD concentration than former smokers and never-smokers. The average concentration of 25OHD was similar in former smokers and never-smokers.


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  		Table 5. Comparison of serum concentrations of hormones in current smokers, former smokers, and men who never smoked (never-smokers)

 
In current smokers, total, free, and bioavailable T levels were higher than those in former smokers and never-smokers (Table 5Go). The T concentration was correlated negatively with age (free T: r = -0.24; P = 0.0001) and body weight (total T: r = -0.29; P = 0.0001). As current smokers were younger and thinner, adjustment for age and body weight rendered these differences nonsignificant. Current smokers had higher average adjusted levels of androstenedione, total 17ß-E2, and SHBG, but not of free T, bioavailable T, and bioavailable 17ß-E2. In contrast, former smokers and never-smokers had similar concentrations of sex steroid hormones, except for androstenedione.

BMD, biochemical markers of bone turnover, and hormone levels according to smoking status and body weight

Current smokers in the lowest tertile of body weight (<75 kg; n = 35) had higher age- and lean mass-adjusted urinary levels of all markers of bone resorption compared with never-smokers (Table 6Go). In current smokers in the highest tertiles of body weight, bone resorption markers levels did not differ from those in never-smokers (P > 0.3). Serum bone formation markers did not differ between current smokers and never-smokers regardless of body weight.


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  		Table 6. Comparison of levels of biochemical markers of bone turnover, of concentrations of hormones and of bone mineral density in current smokers and in never-smokers weighing less than 75 kg (adjusted for age, body weight, coffee intake, alcohol intake)

 
25OHD was lower, and PTH was higher in current smokers for men in the lowest tertile (Table 6Go), but not for those in the two highest tertiles. Androstenedione was higher in current smokers regardless of body weight (P = 0.0001). 17ß-E2 and SHBG were higher in current smokers [9% (P < 0.02) and 17% (P < 0.03), respectively] only in men in the two highest tertiles (>74 kg). No differences in total or free T were found.

Trends were similar for BMD evaluated according to body weight (<75 kg). In the lowest tertile of body weight, adjusted BMD was lower in current smokers at the level of total hip, whole body, distal forearm, and ultradistal radius. In men in the two highest tertiles (>74 kg), BMD did not differ between current smokers and never-smokers. Trends for bone markers and BMD were similar when men were divided according to lean or fat body mass.

Prevalence of vertebral deformities according to smoking status

The prevalence of vertebral deformities was higher in current smokers compared with former smokers and never-smokers jointly 13 vs. 5/100 men, after adjustment for confounding variables [odds ratio (O.R.) = 2.7; P < 0.04]. In former smokers, the prevalence of vertebral deformities was not increased (6% vs. 4%; P = 0.5). Age- and body weight-adjusted prevalence of vertebral deformities was higher in current smokers weighing less than 75 kg (O.R. = 3.4, P < 0.05) but not in those weighing more than 74 kg (O.R. = 1.7, P < 0.42). In former smokers, prevalence of vertebral deformities increased with increasing urinary levels of total DPD and of peptide-bound DPD (after adjustment for confounding variables, O.R. = 1.2, P < 0.03 and O.R. = 1.3, P < 0.02 per 1 nM/mM creatinine). No relation between vertebral deformities and bone markers was found in current smokers and in never-smokers.

Discussion

In former smokers, BMD was similar to that in current smokers (except at the forearm) and lower compared with that in never-smokers at most skeletal sites. Urinary excretion of bone resorption markers was increased, and hormonal levels were disturbed in current, but not in former, smokers. In moderate current smokers with low body weight (<75 kg), bone resorption was increased, BMD was decreased, and the prevalence of vertebral deformities was increased. In this group, 25OHD was decreased, and PTH was increased. Bioavailable fractions of 17ß-E2 and T were similar in the three groups regardless of body weight.

Several studies showed a decreased BMD in male smokers. Egger et al. (2) and Bendavid et al. (1) showed decreased BMD at the level of lumbar spine. Hollenbach et al. (5) showed lower BMD in smokers only at the level of the hip. Vogel et al. (12) and van Daele et al. (41) showed lower speed of sound and lower broad ultrasound attenuation at the level of calcaneum in smokers. In the Framingham study, in which smoking was evaluated every other year, BMD was lower in current and former male smokers at all sites of measurement (6).

Discrepancies result partly from methodological differences. Certain smokers deny smoking. Smoking status is often categorized into current smokers vs. nonsmokers. The number of cigarettes and the duration of smoking may be false due to a recall bias, and the number of cigarettes is rarely constant during the entire smoking period. Inhalation of smoke is difficult to evaluate. The period after cessation of smoking may also influence the results. It is difficult to compare studies if the number of cigarettes smoked per d is not given. Results are influenced by confounding factors that were not controlled for. Some of them (body weight and alcohol intake) differ between smokers and nonsmokers, and themselves may influence BMD. Results may be influenced by the selection of the control group. Thus, two studies seem to be particularly important (42, 43). In two groups of twins, women who smoked more cigarettes had lower BMD at the levels of lumbar spine and femoral neck compared with women who smoked less.

Certain (12, 44, 45), but not all (46, 47, 48), researchers found a faster bone loss at the levels of distal forearm, hip, and calcaneum in current smokers. Cigarette smoking was also described as a risk factor for vertebral deformities and hip fracture (3, 7, 10, 11, 49).

Bone turnover and mechanisms underlying the effect of tobacco received a limited attention. A lower concentration of OC in perimenopausal and early postmenopausal women smokers and an increased bone resorption in elderly women smokers were described recently (13, 14, 15). The increased bone resorption in current smokers, which is not followed by increased bone formation, may suggest indirectly that osteoblasts are also damaged in smokers. Tobacco and smoke constituents may induce the apoptosis of different cells (50, 51, 52, 53). However, data on the effect of tobacco on the proliferation and function of osteoblasts are discordant and inconclusive, mainly due to differences in experimental models (54, 55, 56, 57).

The circulating 17ß-E2 concentration has three determinants: its testicular synthesis, peripheral aromatization of T and androstenedione, as well as its catabolism. The peripheral aromatization of androgens depends on the amount of substrate; the fat body mass, which is the main localization of aromatase; and the aromatase activity. Smokers are thinner, and higher body weight is accompanied by lower T level. Tobacco stimulates the secretion of ACTH and adrenal steroids (cortisol, androstenedione, and dehydroepiandrosterone) (58). Thus, in male smokers, concentrations of estrone and of 17ß-E2 are increased because the amount of aromatase substrate is increased (16, 17, 18). However, the total activity of aromatase is lower because fat body mass is smaller, and tobacco components inhibit its activity (59). In smokers, the 2-hydroxylation pathway of 17ß-E2 inactivation is stimulated, and urinary levels of 2-hydroxyestrone and 2methoxyestrone deprived of estrogenic activity are increased (19, 60, 61, 62). Some components of smoke may displace 17ß-E2 from its receptor and prevent the action of 17ß-E2 (63). These mechanisms may explain why 17ß-E2 replacement therapy is less efficient in postmenopausal women who are current smokers (13).

Bioavailable fractions of sex steroid hormones not bound to SHBG are biologically active fractions. As current smokers have increased SHBG, which is a transporter of sex steroid hormones, concentrations of bioavailable T and 17ß-E2 are similar in smokers and nonsmokers despite higher levels of total hormones (18, 22).

Current smokers have lower 25OHD concentrations (24, 64, 65). However, the mechanisms underlying low 25OHD level in smokers are not clear. A lower vitamin D dietary intake was suggested (66). To our knowledge, the effect of tobacco smoking on cutaneous vitamin D synthesis or its intestinal absorption has not been studied. Smokers have less outdoor leisure activity and thus less exposure to sunlight (67, 68). However, in our cohort, physical activity was similar in smokers and nonsmokers. The PTH concentration in smokers was lower, similar, or higher compared with nonsmokers depending on the study (24, 25, 64). As tobacco components stimulate hydroxylation of 17ß-E2, a similar mechanism is possible for 25OHD, but has not been studied. Thus, mechanisms underlying disturbances of vitamin D and PTH levels in smokers remain unclear.

Increased bone resorption and decreased BMD were observed only in smokers in the lowest tertile of body weight, whereas in the highest tertiles, markers of bone turnover and BMD did not differ among the groups. Thus, low body weight may contribute to the deleterious effect of tobacco on bone. In men in the lowest tertile, the level of androstenedione, but not 17ß-E2, was higher in current smokers, suggesting that aromatization of androstenedione was lower due to a lower body fat mass. The nutrition of this subgroup of men may be suboptimal, as suggested by a lower level of 25OHD and secondary hyperparathyroidism.

The main limitation of studies concerning the effect of smoking on bone is that smokers differ in many ways from nonsmokers. They are younger, thinner, and present more lifestyle behavior or comorbidity that may be deleterious for bone. We evaluated several factors (age, body weight, alcohol consumption, caffeine intake, calcium intake, and physical activity) and adjusted calculations when necessary. However, it should be remembered that "in smokers" does not necessarily mean "tobacco-induced." Some differences between smokers and nonsmokers were not significant in contrast to other studies. However, average values could not be established with confidence due to the small number of subjects and the variability of some parameters, such as urinary markers of bone turnover.

In conclusion, in former smokers bone resorption was not increased, whereas BMD was lower compared with that in never-smokers. This suggests that former smokers do not lose or regain BMD after cessation of smoking. In moderate current smokers with low body weight (<75 kg), increased bone resorption can result at least partly from secondary hyperparathyroidism. Increased bone resorption, which is not matched by bone formation, can contribute to the lower BMD and the higher prevalence of vertebral deformities in smokers.

Footnotes

Presented in abstract form at the 22nd Annual Meeting of the American Society for Bone and Mineral Research, Toronto, Canada, September 2000.

Abbreviations: BAP, Bone-specific alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; ßCTX-I, ß-isomerized C-terminal telopeptide of collagen type I; DPD, deoxypyridinoline; OC, osteocalcin; 25OHD, 25-hydroxyvitamin D; O.R., odds ratio; PINP, N-terminal extension propeptide of type I collagen; SSMB, Société de Secours Minière de Bourgogne; vBMD, volumetric bone mineral density.

Received January 29, 2001.

Accepted October 29, 2001.

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