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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 590-596
Copyright © 2000 by The Endocrine Society

Original Studies

The Influence of Thinness and Smoking on Bone Loss and Response to Hormone Replacement Therapy in Early Postmenopausal Women

Nina Hannover Bjarnason and Claus Christiansen

Center for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark

Address all correspondence and requests for reprints to: Dr. Nina Hannover Bjarnason, Center for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark. E-mail: nb{at}ccbr.dk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We studied the influence of thinness and smoking in 153 early postmenopausal women from a 3-yr period, comparing treatments of 1 or 2 mg estradiol with placebo. The baseline body mass index (BMI) was significantly associated with bone resorption (r = -0.26, P < 0.01 for urinary CrossLaps with 21% difference between extreme tertiles) with a consequent association between BMI and bone mineral density (BMD; r = 0.38, P < 0.001 for BMD of hip with 10% difference between extreme tertiles). A low BMI led to an increased rate of loss (r = 0.45, P < 0.01 for BMD of spine), whereas response to treatment with either 1 or 2 mg estradiol was independent of BMI.

Smoking was associated with a 4% lower BMD at baseline compared with that in nonsmokers. This effect was additive with that of BMI. For smokers the increase in serum estradiol during hormone replacement therapy was only half of that in nonsmokers. For women treated with placebo or 2 mg estradiol, serum FSH levels were similar in smokers and nonsmokers, but during treatment with 1 mg estradiol, serum FSH was significantly less suppressed in smokers. This was mirrored in the BMD response, where smokers responded similarly to 2 mg estradiol and placebo as did nonsmokers, whereas smokers receiving 1 mg estradiol experienced only half the increase compared to nonsmokers.

In conclusion, thinness and smoking are important risk factors for osteoporosis development, but are counteracted by hormone replacement therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS is a serious and frequent disease that occurs worldwide. The most important risk factor for osteoporosis is estrogen deficiency, and the increasing life expectancy of women indicates that the problems of osteoporosis will be overwhelming in the years to come (1). Because the treatments available today can only arrest the progression of the disease, an intervention before the occurrence of fractures is recommended. An estimate of simple clinically evaluable risk factors at this time would thus be an important tool for the future management of the disease.

Thinness is a major risk factor for both low bone mineral density (BMD) (2, 3, 4, 5, 6, 7, 8) and the rate of bone loss in untreated women (2, 4, 9). Thus, thin, otherwise healthy women have a lower BMD and will lose bone faster than heavier women. The potential impact of thinness on risk of osteoporosis development is of particular interest in developing countries, because of the high incidence of starvation, and in industrialized countries where slimness is promoted as ideal and dieting has been shown to be the most important risk factor for the development of anorexia (10), which leads to malnutrition.

Another frequently occurring risk factor is smoking. Data suggest that the risk of hip fracture is increased in smokers (11). Several mechanisms are involved, among others increased estrogen degradation (12). Because female smoking is an increasing problem, this risk factor may also be estimated to cause considerable problems in the future.

We wanted to study in a target population of postmenopausal women for early application of life style advice the influence of thinness and smoking in untreated women compared to that in women during hormone replacement therapy (HRT). For this purpose we used post-hoc analyses from a trial designed to investigate the effects of traditional and low dose HRT in early postmenopausal women (13).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Two hundred and seventy-eight healthy women within 1–6 yr after menopause were recruited by blinded, direct mail invitation using social security numbers. They each had an intact uterus, were not treated with medication known to affect bone metabolism, and had no clinical or laboratory evidence of confounding diseases. Further details of inclusion and exclusion criteria were described previously (13). After consenting, the women were enrolled in a double blind, 2-yr, monocenter study and subsequently randomized to daily oral treatment with 2 mg 17ß-estradiol sequentially combined with 25 µg Gestodene (n = 55), 2 mg 17ß-estradiol sequentially combined with 50 µg Gestodene (n = 56), 1 mg 17ß-estradiol sequentially combined with 25 µg Gestodene (n = 56), 1 mg 17ß-estradiol continuously combined with 25 µg Gestodene (n = 55), or placebo (n = 56). The medication was given in 28-day cycles, during which Gestodene was administrated from days 17–28 in the sequential groups. The study was prolonged for a third year in a continued blinded fashion, with a total of 39 cycles. Thus, cycle 7 corresponded to 0.5 yr, 13 cycles corresponded to 1 yr, and 26 and 39 cycles corresponded to 2 and 3 yr, respectively. In the present analyses 153 women, who completed all 3 yr of the study, were included. As previously described, these women were comparable with those women dropping out (13). Furthermore, the responses of bone mineral density (BMD) and bone markers were comparable in the two groups treated with 2 mg estradiol. Similarly so in the two groups treated with 1 mg estradiol (13). Thus, using various Gestodene treatment regimens for equal amounts of estradiol influenced neither bone mass nor markers of bone turnover. Therefore, the 1-mg groups were pooled as were the 2-mg groups for the present analyses.

Methods

At baseline, height was determined using a Harpenden Stadiometer, and weight was measured on an electronic scale. Both assessments were performed wearing in-door clothes and no shoes. Body mass index (BMI) was calculated as the weight in kilograms divided by the squared height in meters. Information about smoking status was elicited by interview.

Bone mass

Densitometry was performed at baseline and semiannually throughout the study measuring BMD in the lumbar spine (L2–L4) and left femur (QDR-2000, software version 7.10B, Hologic, Inc., Waltham, MA).

Biochemistry

Serum and urine samples (second void) were collected in the morning after an overnight fast and tobacco abstinence at baseline, mid (day 15 or 16), and end (day 27 or 28) of cycle 1 and at the end of cycles 7, 13, 26, and 39 (for all within days 24–28 of the cycle). The samples were obtained fasting in the morning just before tablet intake.

Indicators of bone resorption

Urinary and serum CrossLaps (Osteometer Biotech, Herlev, Denmark), the C-terminal telopeptide fragments of type I collagen in urine and serum compartments, were measured by enzyme-linked immunosorbent assay (14, 15). Urinary CrossLaps was corrected for creatinine excretion. The intrapatient variabilities calculated from five assessments within 2 weeks were 9.6% and 7.9% for urinary and serum CrossLaps/creatinine, respectively.

Indicators of bone formation

The N-terminal midsegment of serum osteocalcin was determined by enzyme-linked immunosorbent assay (Osteometer Biotech, Herlev, Denmark) (16). Serum bone specific alkaline phosphatase (Tandem-R OSTASE) was assessed by immunoradiometric assay (Hybritech, Liege, Belgium). The intrapatient variability calculated from five assessments within 2 weeks was 10.5% for osteocalcin.

Hormones

Serum FSH was determined before treatment and in the end of cycles 7, 13, 26, and 39 by immunoradiometric assay (Coat-A-Count). Serum estradiol was determined at the same time points using RIA. In a subset of women comprising 88 of the completing women (those treated with 2 mg estradiol sequentially combined with 50 µg Gestodene, 1 mg 17ß-estradiol sequentially combined with 25 µg Gestodene, and 1 mg 17ß-estradiol continuously combined with 25 µg Gestodene), measurements of estrone and sex hormone-binding globulin (SHBG) were available at baseline. The assessments were performed using by gas chromatographic mass spectrometry (AAI Deutschland GmbH & Co. KG, Neu-Ulm, Germany) and by immunoradiometric assay (Diagnostic Products, Los Angeles, CA), respectively.

Statistics

Values of bone mass (and biochemical bone markers) were expressed as percentages of baseline. The response in bone mass was calculated as the percent annual change in BMD from baseline calculated by linear regression from all seven measurements. Spearman’s correlation was used to assess associations between continuous variables. One-way ANOVA was used to test for significant differences among the three groups with regard to continuous baseline characteristics. A {chi}2 test was used to compare baseline categorical variables, such as treatment allocation frequencies. ANOVA was furthermore used to compare follow-up variables. If the tests revealed significant differences, Student’s t test was used for the group by group comparison. A multiple linear regression model (general linear model procedure) was used to examine the independent effects of baseline BMI and smoking on baseline BMD and the independent effects of smoking and treatment time on serum hormones. Significance was accepted at the 5% level. The statistical analyses were performed using SAS (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thinness

At baseline, BMD and resorption markers were significantly correlated to BMI (Table 1Go). On the average, women in the lowest tertile of BMI had 10% lower BMD compared with those in the highest tertile. In general, there was, on the average, a 20% difference between women in the extreme tertiles of the biochemical indexes of resorption and hormones, whereas there was no association between formation markers and thinness status (Table 1Go).


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  		Table 1. Baseline associations among bone parameters, hormones, demographics (mean ± SD), smokers and treatment groups [no. (%)], and BMI shown as correlation coefficients (r) and BMI tertiles (cut-offs, 23.48 and 26.75 kg/m2)

 
In the placebo group the association between baseline BMI and serum CrossLaps during follow-up was significant and unchanged (for example, r = -0.35; P < 0.05 at baseline and r = -0.35; P < 0.05 at 24 months), whereas in the treated groups, the association disappeared at all time points after initiation of treatment, that is already after 2 weeks (as an example, the 2 mg estradiol group had r = -0.32; P < 0.05 at baseline and r = -0.091; P = NS at 24 months). Consequently, the response of spinal bone mass was significantly correlated to baseline BMI in the placebo group in contrast to the estradiol-treated groups, in which the response was independent of BMI (Fig. 1Go). Interestingly, the loss was almost eliminated in the upper BMI tertile of the placebo group. The responses in hip bone mass were comparable (data not shown).



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  		Figure 1. The figure depicts the response of the BMD of spine in tertiles of BMI in the placebo group (cut-offs, 23.70 and 27.15 kg/m2), in the group treated with 1 mg estradiol (cut-offs, 23.90 and 27.00 kg/m2), and in the group treated with 2 mg estradiol (cut-offs, 22.50 and 24.55 kg/m2).

 
The association between baseline BMI and the consecutive follow-up BMD measurements in the placebo group showed a weak tendency of becoming stronger with time, suggesting that the explanatory value of thinness on osteoporosis risk increases with age. For example, the r values at baseline and 3 yr were 0.28 (not significant) and 0.33 (BMD of spine), r = 0.44 and 0.57 (BMD of hip), and r = 0.41 and 0.47 (BMD of neck), respectively. The increments were, however, small.

Smoking

At baseline, smoking and nonsmoking women were comparable with regard to the number of years past menopause; however, women who smoked were, on the average, 1 yr younger than nonsmokers (Table 2Go). Thus, the smoking women had passed through menopause 1 yr earlier than the nonsmoking women. Whereas there was no difference with regard to resorption markers or hormone status, formation markers were about 10% decreased in smokers. Correspondingly, BMD at baseline was, on the average, 4% lower in smokers than in nonsmokers (Table 2Go). Analysis of covariance relating baseline BMD as the dependent variable with BMI and smoking status as covariates showed that both BMI and smoking status independently predicted baseline BMD. Absolute values of BMD in tertiles of BMI separated by smoking status are given in Table 3Go. There was, on the average, a 14% difference in BMD between the extreme sixtiles.


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  		Table 2. Baseline values in smokers and nonsmokers, respectively (mean ± SD)

 

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  		Table 3. Baseline BMD (grams per cm2) in tertiles of baseline BMI separated by smoking status (mean ± SD)

 
Serum estradiol was constant in the postmenopausal range in the placebo group throughout the study, and there was no difference between smokers and nonsmokers. In the estradiol-treated groups there was a dose-related increase in serum estradiol. With both estradiol doses, smokers had only half the serum estradiol levels as nonsmokers (Fig. 2Go, left panel). In the group treated with 2 mg estradiol, FSH was equally suppressed in both smokers and nonsmokers, whereas in the group receiving 1 mg estradiol, the smokers had a significantly higher FSH level than the nonsmokers (Fig. 2Go, right panel). This was mirrored in the bone mass change, as smokers and nonsmokers responded similarly to placebo and 2 mg estradiol, but nonsmokers treated with 1 mg estradiol had a significantly larger response than smokers (Fig. 3Go).



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  		Figure 2. The left panel shows serum estradiol in the placebo group (A), in the group treated with 1 mg estradiol (B), and in the group treated with 2 mg estradiol (C). The right panel depicts serum FSH in the placebo group (A), in the group treated with 1 mg estradiol (B), and in the group treated with 2 mg estradiol (C). Filled circles represent current smokers, and open circles represent nonsmokers.

 


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  		Figure 3. The left panel shows the response of the BMD of spine in the placebo group (A), in the group treated with 1 mg estradiol (B), and in the group treated with 2 mg estradiol (C). The right panel shows the response of the BMD of the femoral neck in the placebo group (A), in the group treated with 1 mg estradiol (B), and in the group treated with 2 mg estradiol (C). Filled circles represent current smokers, and open circles represent nonsmokers.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This post-hoc analysis was based on data from a randomized, placebo-controlled, double-blind study of four combinations of estradiol and Gestodene; two groups were treated with 2 mg estradiol, and two groups were treated with 1 mg estradiol. Although the Gestodene dose regimens were not similar within each estradiol dose level, we pooled the treatment groups to form three groups, 2 mg estradiol, 1 mg estradiol, and placebo. This was possible because we previously showed that the Gestodene dose regimens chosen do not influence bone (13). Moreover, the androgenic effect of Gestodene seems to be negligible, as Gestodene has been estimated to have two thirds of the androgenic activity of levonorgestrel, for equipotent doses, in the endometrium (personal communication, Schering AG, Berlin, Germany). All determinations were performed blinded, thus supporting the validity of the results.

The principal results of 3 yr of follow-up were that thinness is an important risk factor for both low bone mass and increased bone loss in early postmenopausal women. However, during treatment with an effective HRT dose regimen, the influence of thinness is counteracted. Smoking is a risk factor for low bone mass, which is additive to that of thinness. Smoking reduces the bmd response to therapy with 1 mg estradiol, but not to treatment with 2 mg estradiol or placebo.

An initial low bone mass and a subsequent fast bone loss are additive factors to increase the risk of osteoporosis. We found that a thin, smoking woman has a 14% lower BMD than a heavy nonsmoker and that thin women experience a loss of 1.6%/yr in the spine compared to 0.2%/yr in heavier women. When predicting the future bone mass based on our 3 yr of follow-up, the average thin smoking woman would be diagnosed with osteoporosis before the age of 62 yr. Therefore, it is very important to advice thin, smoking women on life style and diet as well as consider including a diagnostic procedure and a preventive treatment. Thin women respond equally well as heavier women to both 1- and 2-mg estradiol dose regimens. Smoking women respond less well than nonsmoking women to 1 mg estradiol, but the number of nonresponders in terms of bone loss prevention is insignificant. For example, if a nonresponder was defined as one who had a bone mass response less than -1%/yr (i.e. a loss of bone after accounting for an estimate of the precision error of BMD measurements), there was one nonresponder among nonsmokers and also one among the smokers. Thus, in general, smoking women with a normal bone mass at the time of the menopause will be sufficiently treated with 1 mg estradiol. However, a thin, smoking woman with a low bone mass, who cannot be persuaded to stop smoking might benefit from a dose higher than the equivalent of 1 mg estradiol, assuming that risk factors for other health conditions would not be magnified by the choice of a higher dose.

Our data show that thinness is associated with a higher level of SHBG and lower levels of serum estrone and estradiol than those in heavier women. This relative estrogen deficiency may lead to the observed increased bone resorption, thereby causing loss of bone mass. The protective effect of obesity on osteoporosis risk has been investigated previously both cross-sectionally (2, 3, 4, 5, 6, 7, 8) and longitudinally (2, 4, 9); both showed a positive effect of obesity, but with variable degrees of effect. A substantial loss of body weight after the age of 25 yr increases the risk of hip fracture in elderly women, whereas the rate of hip fracture is comparable between women with a constant weight and those with a weight increase (17). A case-control study following overweight postmenopausal women on a high fiber diet showed that bone loss in the diet group increased compared to that in nondiet controls over 6 months. During a 6-month follow-up period the women gained the weight they lost, but not the bone (18). Thus, it is not clear whether a weight increase in thin women would be a treatment equivalent, and a randomized, controlled study would be needed to investigate this. That HRT efficacy is independent of BMI is supportive of recent data from a comparable cohort of early postmenopausal women, in whom treatment with 5 mg alendronate ameliorated the deleterious effect of thinness on bone loss (2). Thus, any effective treatment would probably have this influence.

The present results indicate that smoking causes an increased degradation of estradiol, thereby diminishing the response to low dose estradiol therapy, whereas treatment with 2 mg estradiol is so potent that smoking is eliminated as a risk factor. Interestingly, smoking women were 1 yr younger than nonsmokers, but the number of years since menopause were similar. This confirms previous data, based on a large questionnaire investigation (19). That smoking women experience menopause earlier than nonsmoking women may be explained by a promoting effect of smoking on menopause, and a likely mechanism would be increased estradiol turnover. The difference in baseline BMD may thus theoretically be caused by an increased loss during the perimenopausal time period. An increased estradiol metabolism in smokers was found more than 10 yr ago (12), but the present data show that decreased bone formation may be another factor to influence low bone mass in smokers. This is a new finding, which clearly warrants further investigation, but we do not consider this finding to be surprising considering the slowing effects smoking is known to have on reparation processes in other tissues. A reason why we did not find increased bone loss among smokers in the placebo group may be that our power to detect such a loss was not ideal. Our data are, however, supported by a previous report from Slemenda showing an additive deleterious effect of thinness and smoking on bone mass, whereas only thinness influenced bone loss (20). Furthermore, neither estradiol nor estrone and SHBG concentrations distinguished smokers from nonsmokers, whereas this was the case when investigating tertiles of BMI. One recent study of elderly men and women showed an increased loss of bone in smokers, but the group of smokers was relatively small (21). In this study a decreased calcium absorption was seen in the smokers, indicating another mechanism by which smokers may be at risk of osteoporosis. Whether smoking will cause less response in bone mass to other therapies than HRT remains to be investigated, but the mechanism of increased estrogen metabolism is likely to be exclusive for HRT, whereas a possible decreased level of bone formation compared to resorption would be expected to be universal.

In conclusion, thinness and smoking significantly increase osteoporosis development, but this is counteracted by HRT. Future screening strategies may benefit from including these easily evaluable clinical risk factors.


   Acknowledgments
 
The authors thank Schering AG (Berlin, Germany) for supplying study drug and for collaborating on the study protocol (92024), and Lise Smith for assistance with data collection.

Received August 10, 1999.

Revised October 21, 1999.

Accepted November 2, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Consensus Development Statement. 1997 Who are candidates for prevention and treatment for osteoporosis? Osteop Int. 7:1–6.
  2. Ravn P, Cizza G, Bjarnason NH, et al. 1999 Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. J Bone Miner Res. 14:1622–1627.[CrossRef][Medline]
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  4. Tremollieres FA, Pouilles JM, Ribot C. 1993 Vertebral postmenopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women. J Clin Endocrinol Metab.77:683–686.
  5. Lindsay R, Cosman F, Herrington BS, Himmelstein S. 1992 Bone mass and body composition in normal women. J Bone Miner Res.7:55–63.
  6. Stevenson JC, Lees B, Davenport M, Cust MP, Ganger KF. 1989 Determinants of bone density in normal women: risk factors for futures osteoporosis? Br Med J. 298:924–928.
  7. Hassager C, Christiancen C. 1989 Influence of soft tissue body composition on bone mass and metabolism. Bone. 10:415–419.[Medline]
  8. Ribot C, Tremollieres F, Pouilles JM, Bonneu M, Germain F, Louvet JP. 1987 Obesity and postmenopausal bone loss: the influence of obesity on vertebral density and bone turnover in postmenopausal women. Bone. 8:327–331.[Medline]
  9. Christiansen C, Riis BJ, Rødbro P. 1987 Prediction of rapid bone loss in postmenopausal women. Lancet. 1:1105–1108.[Medline]
  10. Patton GC, Slezer R, Coffey C, Carlin JB, Wolfe R. 1999 Onset of adolescent eating disorders: population based cohort study over 3 years. Br Med J. 318:765–768.[Abstract/Free Full Text]
  11. Cornuz J, Feskanich D, Willett WC, Colditz GA. 1999 Smoking, smoking cessation and risk of hip fracture in women. Am J Med. 106:311–314.[CrossRef][Medline]
  12. Jensen J, Christiansen C, Rødbro P. 1985 Cigarette smoking, serum estrogens and bone loss during hormone replacement therapy early after menopause. N Engl J Med. 313:973–975.[Abstract]
  13. Bjarnason NH, Byrjalsen I, Hassager C, Haarbo J, Christiansen C. Low dose estradiol in combination with gestodeue is fully preventive on early postmenopausal bone loss. Am J Obstet Gynecol. In press.
  14. Bonde M, Qvist P, Fledelius C, Riis BJ, Christiansen C. 1995 Applications of an enzyme immuno assay for a new markers of bone resorption (CrossLaps): follow-up on hormone replacement therapy and osteoporosis risk assessment. J Clin Endocrinol Metab. 80:864–868.[Abstract]
  15. Rosenquist C, Fledelius C, Christgau S, Pedersen BJ, Bonde M, Qvist P, Christiansen C. 1998 Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen. Clin Chem. 44:2281–2289.[Abstract/Free Full Text]
  16. Rosenquist C, Qvist P, Bjarnason NH, Christiansen C. 1995 Measurement of a more stable region of osteocalcin in serum by ELISA with two monoclonal antibodies. Clin Chem. 41/10:1439–1445.
  17. Cummings SR, Nevitt MC, Browner WS, et al. 1995 Risk factors for hip fracture in white women. N Engl J Med. 332:767–773.[Abstract/Free Full Text]
  18. Avenell A, Richmond PR, Lean ME, Reid DM. 1994 Bone loss associated with a high fibre diet reduction diet in postmenopausal women. Eur J Clin Nutr. 48:561–566.[Medline]
  19. Andersen FS, Transbol I, Christiansen C. 1982 Is cigarette smoking a promotor of the menopause? Acta Med Scand. 212:137–139.[Medline]
  20. Slemenda CW, Hui SL, Longcope C, Johnston Jr CC. 1989 Cigarette smoking, obesity, and bone mass. J Bone Miner Res. 4:737–741.[Medline]
  21. Krall EA, Dawson-Hughes B. 1999 Smoking increases bone loss and decreases intestinal calcium absorption. J Bone Miner Res.14: 215–220.



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