Tobacco smoking and risk of hip fracture in men and women

Susanne Høidrupa, Eva Prescotta, Thorkild IA Sørensena, Adam Gottschaua, Jes Bruun Lauritzenb, Marianne Schrollc and Morten Grønbæka

a Copenhagen Centre for Prospective Population Studies, Danish Epidemiology Science Centre at the Institute of Preventive Medicine, Copenhagen University Hospital, Denmark.
b Department of Orthopaedic Surgery, Hvidovre Hospital, Copenhagen, Denmark.
c Department of Geriatrics, Bispebjerg Hospital, Copenhagen, Denmark.

Reprint requests to: Dr Susanne Høidrup, Institute of Preventive Medicine, Kommunehospitalet, DK-1399 Copenhagen, Denmark. E-mail: shoeidrup{at}ipm.hosp.dk


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background Previous findings suggest that tobacco smoking increases the risk of hip fracture in women. A similar adverse effect of smoking is suspected to be present in men, but bone mineral density studies have raised the concern that men may be more sensitive to the deleterious effect of smoking on bone than women. In this study we prospectively determined the influence of current, previous, and cumulative smoking history on risk of hip fracture in men and women and addressed the issue of possible gender difference in the susceptibility to tobacco smoking.

Methods Pooled data from three population studies conducted in Copenhagen with detailed information on smoking habit. A total of 13 393 women and 17 379 men, initially examined between 1964 and 1992, were followed until 1997 for first admission due to hip fracture. The relative risks (RR) of hip fracture associated with smoking were estimated by means of multiplicative Poisson regression models.

Results During follow-up, 722 hip fractures were identified in women, and 447 in men. After adjustment for potential confounders, including body mass index, female current smokers had an RR of hip fracture of 1.36 (95% CI : 1.12–1.65) and male smokers 1.59 (95% CI : 1.04–2.43) relative to never smokers. In both sexes, the RR of hip fracture gradually increased by current and accumulated tobacco consumption. The RR were consistently higher in men than in women, but the test for interaction between sex and tobacco smoking was insignificant. After 5 years, male ex-smokers had an adjusted RR of 0.73 (95% CI : 0.55–0.98) relative to current smokers, while no significant decrease in risk was observed in female ex-smokers (RR = 0.91; 95% CI : 0.72–1.17)). Approximately 19% of all hip fractures in the present study population were attributable to tobacco smoking.

Conclusion Tobacco smoking is an independent risk factor for hip fracture in men and women, and there appears to be no gender differences in smoking related risk. Smoking cessation reduces the risk of hip fracture in men after 5 years, while the deleterious effect of smoking seems to be more long-lasting in female ex-smokers.

Keywords Hip fracture, osteoporosis, smoking, smoking cessation, gender difference, cohort study

Accepted 15 October 1999


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Since the first suggestion of an association between tobacco smoking and osteoporosis was published in 1976,1 several studies have examined the effect of tobacco smoking on bone mineral density and risk of hip fracture in women. A meta-analysis based on these studies recently concluded that postmenopausal bone loss is greater in smokers than in non-smokers and that tobacco smoking increases lifetime risk of hip fracture in women by about 50%.2 A similar adverse effect of smoking is suspected to be present in men, but recent bone mineral density studies have raised the concern that men may

be more sensitive to the deleterious effect of smoking on bone than women.3,4 Prospective fracture studies on men are limited and only two studies, so far, have included a sufficient number of male hip fractures to compare the effect of smoking on hip fracture risk in men and women.5,6 In the Leisure World Study, male smokers had a somewhat greater relative risk of hip fracture than female smokers,5 while no gender difference in risk estimates was observed in a Norwegian cohort study.6

Based on pooled data from three large population studies, we determined the influence of current, previous, and cumulative smoking history on risk of hip fracture in men and women, while taking putative confounders into account. Furthermore, we addressed the issue of possible gender difference in the effects of smoking on hip fracture risk.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study population
This study is based on data from three longitudinal population studies: The Copenhagen County Centre of Preventive Medicine (CCCPM—formerly The Glostrup Population Study) with 11 119 subjects from Copenhagen suburbs, the Copenhagen City Heart Study (CCHS) with 15 786 subjects from central Copenhagen, and the Copenhagen Male Study (CMS), which sampled 5246 subjects from 14 major work sites in the Copenhagen area. Overall response rate at first examination was 77% (range 69–88%). Approximately 60% of the subjects were examined more than once during follow-up. The studies have been described in detail previously.7–10 The present study population comprises a pooling of all study cohorts with sufficient information on tobacco exposure. Characteristics of the study population are summarized in Table 1Go.


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Table 1 Characteristics of the substudies included in the Copenhagen Centre for Prospective Population Studies, Copenhagen, Denmark, (1964–1992)
 
Examination procedure
The examination included a self-administered questionnaire with detailed questions regarding lifestyle habits and other health related items as well as a clinical examination. In some items, the questionnaires differed slightly between the three sub-studies, but the items used for the present analyses could be harmonized without noteworthy loss of information.

Subjects were classified as never smokers, ex-smokers, and current smokers. Inhaling habits were recorded for current smokers, as were years of smoking for both current and former smokers. In former smokers, years since smoking cessation were recorded as <5 years or >=5 years. In current smokers tobacco consumption was calculated by equating a cigarette to 1 g tobacco, a cheroot to 3 g tobacco, and a cigar to 5 g tobacco. For the analysis, five groups were defined: never-smokers; ex-smokers; current non-inhaling smokers; and current inhaling smokers of 1–14 and >=15 g per day. Pack-years in current smokers were calculated as years of smoking multiplied by packs (of 20 cigarettes) currently consumed and were categorized as: 1–14; 15–29; and >=30 pack-years. Duration of smoking in ex-smokers was categorized as: 1–14; 15–29; and >=30 years.

Daily alcohol intake was divided into five categories: abstainers, 1–2; 3–5 ; 6–10; and >=11 drinks per day (one drink contained on average 12 g alcohol). Physical activity in leisure time was classified into three categories: sedentary; moderate activity 2–4 h per week; and moderate activity >=4 h per week or energetic activity >=2 h per week. Educational level was divided into three categories: <8 years of schooling (completed primary school); 8–11 years; and >=12 years. Weight in light clothes and height without shoes were measured at the clinical examination. Body mass index was calculated as weight (kg) divided by height squared (m2) and was classified into four groups: <20; 20–24; 25–29; and >=30 kg/m2. In women, age at menopause was divided into three groups: <45 years; 45–51 years; and >=52 years. Different phrasing of questions concerning hormone replacement therapy (HRT) in the CCHS and the CCCPM (current use of HRT yes/no and ever use of HRT yes/no, respectively) disabled harmonization of this variable, excluding information on hormone use from the pooled data.

Follow-up
Subjects were followed from their date of entry into the study to the date of their first hip fracture, death, disappearance, or emigration or until the end of follow-up (31 December 1997), whichever occurred first. Information on incident hip fractures was obtained through individual-based linkage to the National Register of Hospital Discharges by means of each person's unique identification number.

The Danish National Register of Hospital Discharges includes all patient and hospital unit specified discharge diagnoses according to the World Health Organization's International Classification of Diseases (Eighth Revision until 1994, Tenth Revision hereafter[ICD-8/10]).11,12 Follow-up in the present study concerned the first occurrence of a cervical or trochanteric hip fracture (ICD-8 diagnosis code 820 or ICD-10 diagnosis codes S72.0–S72.2). Subjects with hip fracture before enrolment were excluded (n = 88). A sample of 110 first-time registered hip fracture diagnosis codes identified in the present study population was validated by reviewing hospital records. The validation showed that almost 93% of all first time registered hip fracture diagnosis codes in the National Register of Hospital Discharges are likely to represent low energy, first-ever fractures. A more detailed description of our follow-up and validation procedure has been published elsewhere.13

Statistical analysis
The purpose of our analysis was to estimate the relative risk (RR) of hip fracture by current, previous and accumulated tobacco exposure in men and women, while taking potential confounding into account. Both hip fracture incidence rate and distribution of risk factors differed in the three sub-studies, but risk estimates did not differ. We therefore report results from the pooled data adjusted for study of origin.

Each subject's person-years of observation from study entry until first hip fracture or censoring were split into several observations by expanding data by 5-year age bands using a Lexis-programme.14 Subjects were examined repeatedly and contributed person-years to the smoking category in which they had most recently described themselves. Thus, a given subject who changed his or her habits during follow-up contributed person-years to several smoking categories. If values were missing at any re-examination, values were extrapolated forward from the last examination the subject had attended. For current smokers, duration of smoking, like age, was updated every 5 years. We estimated the RR associated with smoking by means of multiplicative Poisson regression models using Stata Statistical Software 5.0 (Stata Corporation, College Station, Texas). The models were estimated by the maximum likelihood method and the effects of covariates were tested by likelihood ratio tests.

To examine whether gender modified the association between tobacco smoking and hip fracture, a full model containing the interaction term between smoking (yes/no) and sex was tested against a reduced model without this interaction term by means of likelihood ratio test. To eliminate interference from potential gender differences in smoking behaviour, the test for interaction was performed in a model that excluded non-inhaling smokers and ex-smokers.

The fraction of all hip fractures attributable to tobacco smoking (the population attributable fraction) was calculated by using the formula:

where RR is the multivariate and sex-adjusted RR of hip fracture in ever smokers (current smokers + ex-smokers) relative to never smokers. The 95% limits for the population attributable fraction were calculated according to the formulae proposed by Rothman and Greenland.15


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Analyses were based on 13 393 women and 17 379 men (Table 1Go). During follow-up, 722 first hip fractures were identified in women, and 447 in men.

Male current smokers had an RR of 1.89 (95% CI : 1.30–2.76) and female smokers 1.48 (95% CI : 1.25–1.76) as compared to never smokers after adjustment for age and study of origin. Adjustment for other risk factors, however, attenuated the association between smoking and hip fracture in both sexes (RR = 1.59; 95% CI : 1.04–2.43 and 1.36; 95% CI : 1.12–1.65 in men and women, respectively) and also reduced the gender difference in RR. Tests for interaction between smoking and sex were insignificant both before and after adjustment for confounders (P-value of interaction term between smoking [never smokers/inhaling current smokers] and sex was 0.32 and 0.48, respectively).

In both sexes, the risk of hip fracture gradually increased with tobacco exposure (Table 2Go). Adjustment for confounders, especially adjustment for body mass index in women and alcohol intake in men, weakened the association, but the linear trend remained significant in both sexes (Table 2Go). Current tobacco exposure categorized by pack-years showed similar association with hip fracture (Table 3Go). Again adjustment for other risk factors weakened the association, but the linear trend remained significant in both sexes.


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Table 2 The relative risk (RR) of hip fracture by current tobacco exposure in men and women. Copenhagen Centre for Prospective Population Studies (1964–1997)
 

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Table 3 The relative risk (RR) of hip fracture by accumulated tobacco exposure in men and women. Copenhagen Centre for Prospective Population Studies (1964–1997)
 
In both female and male ex-smokers, the risk of hip fracture gradually increased by duration of previous smoking, but the relation was not significant in male ex-smokers (Table 3Go). Male ex-smokers experienced significantly lower rates of hip fracture than continuing smokers and the risk decreased by time since quitting (Table 4Go). Men who had quit for >5 years appeared to have hip fracture rates close to that of never smokers. After adjustment for age and study of origin, female ex-smokers had a significantly lower risk of hip fracture than continuing smokers, but further adjustment for confounders attenuated the association and no decline in risk was observed in the course of 5 years (Table 4Go).


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Table 4 The relative risk (RR) of hip fracture in male and female ex-smokers by time since smoking cessation. Copenhagen Centre for Prospective Population Studies (1964–1997)
 
In the present study population, the fraction of all hip fractures attributable to tobacco smoking was 0.19 (95% CI : 0.08–0.29).


    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In this prospective study, we confirmed that tobacco smoking is an independent risk factor for hip fracture in women and observed a similar negative effect of smoking to be present in men. In both sexes, a dose-response effect between both current and accumulated tobacco exposure and hip fracture was observed, strongly supporting a causal relation between smoking and hip fracture. We also found that smoking cessation leads to a decline in hip fracture risk in men after 5 years, while there was no apparent benefit from quitting smoking in women. Approximately 19% of all hip fractures in the present study population were attributable to tobacco smoking, implying that a similar fraction of hip fractures may have been prevented if the population never had smoked.

Our results are in agreement with some of the previous cohort5,6 and case-control studies.16–23 These studies found statistically significant associations between tobacco smoking and hip fracture rates and demonstrated persistent elevated risk after adjustment for body mass index and other confounders. On the other hand, several other previous cohort24–30 and case-control studies31–34 found no significant associations between smoking and hip fracture. The majority of these discrepant cohort studies, however, were characterized by low study power due to small population samples, inclusion of too young subjects, or short duration of follow up, resulting in few hip fracture cases. The present study overcomes these difficulties by including a large population sample with an appropriate age distribution and with a follow-up long enough to produce a sufficient number of hip fractures. Finally, the prospective design of the present study excludes selection and recall bias which is of major concern in most case-control studies.

We found that the RR of hip fracture associated with smoking in men almost always exceeded that of female smokers. The gender difference in RR, however, was reduced after adjustment for confounders, and the interaction term between sex and tobacco smoking was insignificant. Potential gender differences in rates of stopping smoking are not likely to have influenced the results as the percentage of smokers who gave up smoking between two examinations was almost the same in men and women (9 and 11 %, respectively). Thus, in the present study, susceptibility to smoking appeared to be similar in men and women. Our finding of similar risk estimates in men and women supplements observations from a large Norwegian cohort study6 and presumably also the findings from the Leisure World Study, since the gender-specific estimates in this study hardly differed significantly.5 On the other hand, two studies of the relation between smoking and bone mineral density in elderly men and women found a greater difference in bone mineral density between smokers and non-smokers among men than among women.3,4 The weaker association in women in these studies, however, may be explained by the fact that the women included had been postmenopausal for several years, and therefore may have already lost a relatively great part of the bone reserve, leaving only minor potential for environmental factors such as smoking to further influence bone density. Alternatively, gender differences in the response to smoking on bone density may not necessarily translate into gender differences in hip fracture risk since several mechanisms unrelated to osteoporosis, for example propensity to fall and energy absorbing properties of soft tissue, also are important determinants of hip fracture.35

We found that the risk of hip fracture in male ex-smokers almost reversed 5 years after smoking cessation. Since the benefits of smoking cessation may be exaggerated if former smokers have less cumulative exposure to tobacco than do continuing smokers, we also included duration of smoking in the multivariate models. This adjustment, however, did not alter the risk estimates substantially. The multivariate analyses performed with and without adjustment for body mass index, showed that only a minor part of the beneficial effect of smoking cessation in men appears to be mediated through weight gain associated with quitting smoking. Our findings in men, contrast the findings from a Norwegian cohort study where no reversibility in risk was observed in male ex-smokers 5 years after smoking cessation.36 Our finding of a persistent elevated risk of hip fracture in female ex-smokers 5 years after smoking cessation, suggests that the adverse effect of smoking in women is permanent or at least more long-lasting than in men. This finding is in accordance with observations from the Norwegian cohort study, where an elevated risk of hip fracture in women persisted 5 years after smoking cessation.36 The Nurses Health Study, however, recently found that the risk in female ex-smokers declined 10 years after smoking cessation.37 In the present study, we were not able to analyse the effect of long-term smoking cessation in women since the information on duration of smoking cessation was recorded as: <5 years or >=5 years. Previous studies on men and women that addressed the overall effect of smoking cessation on hip fracture risk almost always found an elevated risk of hip fracture in ex-smokers that was intermediate between that in never smokers and current smokers,5,16,18,19,21,29,36 suggesting that smoking cessation may have a beneficial effect on hip fracture risk, but also that some of the adverse effects of smoking on fracture risk are irreversible.

Several biological effects of smoking may influence the risk of fracture in smokers. Smoking may exert adverse effects on bone strength through direct toxicity of nicotine and non-nicotine components of cigarette smoke on bone cells, as demonstrated in vitro.38,39 Further, smoking may indirectly affect bone strength through decreased intestinal calcium absorption,40 increased metabolism or decreased production of oestrogen,41–43 and through hypercortisolism.44 In addition, smoking may influence the fracture risk through other mechanisms unrelated to osteoporosis, such as poorer balance and physical performance due to neurovascular and peripheral vascular deleterious effects of smoking.45 The observation of a gender difference in the reversibility of the effect of smoking on hip fracture risk in our study suggests that smoking may affect hip fracture risk through different biological mechanisms in men and women.

Some methodological problems may influence the interpretation of our results. The accuracy of self-reported tobacco exposure may be questioned and concerns about underreporting may be raised. In general, the validity of self-reported tobacco exposure has been shown to be rather high in observational studies.46 Moreover, tobacco smoking was completely socially acceptable in Denmark during the present study period, and the prevalence of smoking in the study population resembled the prevalence observed in other Danish population samples.47 Underreporting of smoking habits in the present study therefore seems unlikely. In addition, differential underreporting is unlikely since the information on smoking history was collected before a possible hip fracture.

The completeness of hip fracture identification during the course of follow-up, and the reliability of hip fracture diagnosis codes from the National Register of Hospital Discharges may also be questioned. The National Register of Hospital Discharges has covered approximately 98% of all discharges in Denmark since 1977, ensuring an almost complete case ascertainment in the present study beginning with this year.12 The study period 1964–1977, representing 10% of the total person-years of follow-up, was not covered by the register. During this period, hip fracture cases from the Copenhagen County Centre of Preventive Medicine were identified from validated, self-reported diagnoses collected during successive examinations of the cohorts and by screening admissions at the regional hospitals for cohort members. During 1970–1977, no fracture diagnoses were available from the Copenhagen Male Study. Since this period represents only 5% of the total person-years of follow-up, it is unlikely that any serious bias was introduced this way.

We conclude that tobacco smoking is an independent risk factor for hip fracture in men and women and that approximately 19% of all hip fractures could be prevented if tobacco smoking was eliminated in the present study population. The fact that today's smokers are characterized by being heavy smokers and by having started to smoke early in life 47,48 means that the accumulated amount of tobacco exposure in future generations of elderly people will increase. Along with the ageing of the population, this will enhance the major public health problem of hip fracture in future. Our findings stress the importance of continuation and reinforcing the anti-smoking policy directed at the entire population.


    Acknowledgments
 
The study was supported financially by the Copenhagen Hospital Corporation, the Research Academy, the Health Insurance Fund, the Danish Medical Research Foundation, the Danish Medical Research Council, the Danish National Board of Health, and the Danish Insurance Association. The authors thank the Copenhagen Center for Prospective Population Studies for collecting the original data and secretary B Bredesen for her linguistic assistance.


    Notes
 
Copenhagen Centre for Prospective Population Studies consists of the Copenhagen County Centre of Preventive Medicine, the Copenhagen City Heart Study and the Copenhagen Male Study.


    References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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