Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Effect of Cigarette Smoking on Risk of Hip Fracture in Men: A Meta-Analysis of 14 Prospective Cohort Studies

  • Zhen-Jie Wu ,

    Contributed equally to this work with: Zhen-Jie Wu, Peng Zhao

    Affiliation Department of Bone and Soft Tissue Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China

  • Peng Zhao ,

    Contributed equally to this work with: Zhen-Jie Wu, Peng Zhao

    Affiliation Department of Head and Neck Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China

  • Bin Liu,

    Affiliation Department of Bone and Soft Tissue Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China

  • Zhen-Chao Yuan

    yuanzhenchao126@126.com

    Affiliation Department of Bone and Soft Tissue Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China

Effect of Cigarette Smoking on Risk of Hip Fracture in Men: A Meta-Analysis of 14 Prospective Cohort Studies

  • Zhen-Jie Wu, 
  • Peng Zhao, 
  • Bin Liu, 
  • Zhen-Chao Yuan
PLOS
x

Abstract

Background

Several observational studies have suggested an association between cigarette smoking and risk of hip fracture. However, no formal systematic review or meta-analysis was performed to summarize this risk in men.

Materials and Methods

A search was applied to MEDLINE, EMBASE, and web of science (up to November 1 2016). All prospective cohort studies assessing risk of hip fracture with the factor of cigarette smoking in men without language restriction were reviewed, and qualities of all included studies were assessed using the Newcastle-Ottawa Scale. Two authors independently assessed literatures and extracted information eligibility, and any disagreement was resolved by consensus. Newcastle-Ottawa quality assessment scale was used to evaluate studies’ quality in meta-analyses. We calculated the RR with 95% CIs in a random-effects model as well as the fixed-effects model using the metan command in the STATA version 12.0 (StataCorp, USA).

Results

Fourteen prospective cohort studies were eligible for the present analysis. A meta-analysis of 12 prospective studies showed that the relative risk (RR) for current male smoking was 1.47 [95% confidence interval (CI) (1.28–1.66), p = 0.54; I2 = 0%]. Subgroup analyses show study characteristics (including geography region, length of follow-up, size of cohorts and study quality) did not substantially influence these positive associations. Eight studies reported the RRs for former smokers compared with never smokers and the pooled RR was 1.15 [95% CI, (0.97–1.34), (I2 = 0%, p = 0.975)].

Conclusions

The present meta-analysis of 14 prospective studies suggests that, compared with never smokers, cigarette smoking increases risk of hip fracture in man, specifically in current smokers. However, further larger prospective cohorts with more power or meta-analysis of individual patient data are needed to confirm this association.

Introduction

Hip fracture is a worldwide health issue, which is associated with a pronounced morbidity and excess mortality not only in North America but also in Asia and Europe [1]. It is suggested that the number of hip fracture in the world will increase from 1.66 million in 1990 to 6.26 million by 2050 [2].There is a demonstrated research show that approximately 19% of all hip fractures were attributed to cigarette smoking, and the relative risk (RR) for current smokers comparing with never smokers was consistently higher in male than in female [3].

Recently, a meta-analysis has suggested that there was a positive association between cigarette smoking and hip fracture in woman [4]. However there is, to our knowledge, no published meta-analysis had evaluated this association in man. Some researches demonstrated a significant positive association between cigarette smoking and risk of hip fracture in men [3, 57], and others did not research a significant association [812], and there were still some articles did not support this relationship [13].

In 2003, a meta-analysis, including cohort, case-control, and cross-sectional studies, had estimated that smoking was associated with an increased risk of hip fracture [14]. As we know, case-control studies and retrospective studies may generate bias. Therefore, we performed a meta-analysis using the data from published prospective cohort studies to evaluate the relationship between smoking and risk of hip fracture in male.

Materials and Methods

We conducted this meta-analysis according to the PRISMA guidelines (S1 Table). We systematically searched MEDLINE, EMBASE, and web of science for prospective cohort studies which evaluating the associations between cigarette smoking and risk of hip fracture in man from their inception to November 1, 2016 without any restrictions. In brief, search terms included: ‘fracture’ OR ‘osteoporosis’ AND (smoking OR cigarette OR tobacco). In addition, a manual search of the reference lists of potential relevant and practice guidelines were performed to identify any additional studies. In case of any differences in opinions, a third reviewer was consulted.

Study selection

The fully published studies were included only if they comprised the following criteria: (1) studies that were prospective cohorts studies designs; (2) studies reported RR or Odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) of hip fracture by different smoking categories or provided raw data to calculate these; (3) studies contained man both exposed and not exposed to smoking; and (4) data not duplicated in another article.

Data extraction and quality assessment

Two authors (ZW and PZ) independently assessed literatures and extracted information eligibility, and any disagreement was resolved by consensus. The following data were summarized from each study: first author, study years, location, duration of follow up, size of cohort, age, number of hip fracture patients, smoking status, RR (95% CI), study quality, and adjustment for covariates. The most adjusted relative risks were selected if studies reported more than one set of adjustments. Newcastle-Ottawa quality assessment scale was used to evaluate studies’ quality in meta-analyses based on three items: patient selection, comparability of controls, and ascertainment of outcome. This quality assessment scale ranges between zero up to nine stars [15].

Statistical analysis

We calculated the RR with 95% CIs in a random-effects model as well as the fixed-effects model using the metan command in the STATA version 12.0 (StataCorp, USA). And the Statistical heterogeneity across studies was assessed by the Q statistic test and I2 statistics test. However, we just reported the random-effect model, as it was considered to be more natural. A sensitivity analysis was also performed to eliminate each study at a time from the meta-analysis. And the Begg’s test and Egger’s test was used to assess the bias of publication while it was considered significant when p<0.05.

Result

Literature search

The process used to select the studies and participants included in present meta-analysis is summarized in Fig 1. We initially searched 5426 potentially eligible studies, but most of them were excluded by title and abstract screen. After that, a total of 101 potential papers were excluded in more details. Finally, fourteen prospective cohort studies were included in present mate-analysis.

Study characteristics

Characteristics of the 14 included cohort studies [3, 512, 1620] were shown in Table 1. They were published from 1991 [5] to 2016 [18], and the sample sizes varied from 1412 [19] to 50000 [9]. The mean durations of follow-up ranged from 3 [8, 16] to 30 years [7]. Eight studies were conducted in Europe, five in U.S.A., and one in Singapore. Obviously, only one [6] RR from the study was not adjusted for anything while two others [5,11] just based on age, and the rest of these publications adjusted for multivariable potential factors relating to hip fracture, such as health, body mass index (BMI), smoking status, alcohol consumption, physical activity, chronic disease, calcium intake, calories, protein consumption, and so on. According to the nine-star Newcastle-Ottawa Scale, the quality scores of included studies ranged from 6 to 9. Most of them (12/14) is greater than or equal 7 stars. (Table 1)

thumbnail
Table 1. Summary of the characteristics of the included prospective cohort studies.

https://doi.org/10.1371/journal.pone.0168990.t001

Current smokers compared with never smokers

Twelve of the included publications [3, 512, 1820] reported the RRs for current smokers compared with never smokers. Five of them [3, 57, 20] on the association of cigarette smoking and risk of hip fracture showed a statistically significant positive association, and the remaining seven studies [812, 18, 19] yielded positive but not significant association. The pooled RRs for these twelve studies was 1.47 (95% CI, 1.28–1.66), and no evidence of heterogeneity was found across these publications (p = 0.538; I2 = 0%) (Fig 2). The result was consistent when perform the analyses omitting one study at a time as a sensitivity analysis. Publication bias was not found when detected by Begg’s test (p = 0.83) or Egger’s test (p = 0.92). In order to detect the potential factors that may have influenced the combined RRs for current smokers compared with never smokers, subgroup analyses were conducted according to study region (Europe, USA, and Asia), duration of follow-up (<10, ≥10 years), sample size (<20000, ≥20000 participants), and study quality (<8, ≥8 stars). All these subgroup analyses suggested no significant difference in results (Table 2).

thumbnail
Fig 2. Meta-analysis of risk of hip fracture for current smokers compared with never smokers.

RR, relative risk; CIs, confidence intervals.

https://doi.org/10.1371/journal.pone.0168990.g002

thumbnail
Table 2. Subgroup meta-analyses for current smokers versus never smokers.

https://doi.org/10.1371/journal.pone.0168990.t002

Former smokers compared with never smokers

Eight studies [3, 5, 711, 20] reported the RRs for former smokers compared with never smokers. Almost all these studies showed non-significant positive relationship between cigarette smoking and risk of hip fracture except for Olofsson.et.al [20]. The pooled adjusted RR was 1.15 (95% CI, 0.97–1.34), with no heterogeneity (I2 = 0%, p = 0.975) (Fig 3). No publication bias was found with Begg’s test (p = 0.78) or Egger’s test (p = 0.85).

thumbnail
Fig 3. Meta-analysis of risk of hip fracture for former smokers compared with never smokers.

RR, relative risk; CIs, confidence intervals.

https://doi.org/10.1371/journal.pone.0168990.g003

Current smokers compared with nonsmokers

Three studies [5, 16, 17] provided the RRs for current smokers versus nonsmokers, including former smokers and never smokers. The pooled RRs indicate that, compared with nonsmoker, current smokers suffer two-fold risk of hip fracture (RR = 2.00, 95% CI, 1.46–2.55) (Fig 4).

thumbnail
Fig 4. Meta-analysis of risk of hip fracture for current smokers compared with nonsmokers.

RR, relative risk; CIs, confidence intervals.

https://doi.org/10.1371/journal.pone.0168990.g004

Discussion

The present meta-analysis of 14 prospective cohort studies involving 216301 participants who do not receive any anti osteoporotic medication and 1922 hip fracture patients diagnosed by radiographic examinations in hospitals, confirming a positive association between cigarette smoking and risk of hip fracture in male. Current smokers had a 1.47-fold risk of suffering hip fracture compared with never smoker. However, the relationship between former smoker and risk of hip fracture does not exist a significant positive correlation. We also found that current smokers had a 2-fold risk of developing hip fracture compared with nonsmoker, however, only three studies were included in this subgroup meta-analysis, which could have biased the results. Our results are similar with a recent meta-analysis, which reported that, compared with never smokers, the pooled RR of hip fracture for current female smokers was 1.30 (95%CI, 1.16–1.45), and for former female smokers was 1.02 (95%CI, 0.93–1.11) [4].

Nowadays, the mechanism of the positive association between smoking and risk of hip fracture is unclear, however, several biological factors may underlie the association found in the present meta-analysis. Calcium is one of the key point maintaining bone health [21]. Smoking may reduce bone mass through reducing the level of 25-hydroxyvitamin D, which impaired the absorption of calcium and the metabolism of vitamin D. One possible reason for that was smoking may improve hepatic metabolism of vitamin D metabolites, following induction of liver enzymes [22]. Parathyroid hormone, changing the proliferation of bone cells as well, specifically, osteoblast and osteoclast, which may influence the absorption of calcium in our body and the metabolism of bone [23].

Low bone mineral density (BMD) has been recognized as one of the major causes of the increasing risk of osteoporosis and hip fracture, while the BMI of people are associated with the BMD [24]. Smoking often makes people thinner and with a lower BMI. One possible mechanism which cigarette smoking cause bone loss through its effect on changing body weight by suppressing the appetite of smokers [25], the article from Klesges et al study [26] found that the weight of smokers less than nonsmokers for approximately 7–8 pounds in middle age, which strengthen the evidence that cigarette smoking increases the risk of bone loss. Furthermore this is reported to be higher in male smokers than in female smokers in Hannan’s research [27], perhaps man experience a higher exposure to smoking than woman. In general, we observed a higher risk ratios of fracture for male than female, specifically for osteoporotic fracture [28].

Smoking has been proved to affect level of adrenal cortical hormones which are precursors of estrogen and testosterone [29]. Nicotine has been determined to have anti-estrogenic effects and decrease the production of estrogen [30, 31], therefore, comparing with nonsmoker, menopause would occur approximately 2 years earlier in female smokers [32] and the age of menopause was recognized as a significant indicator of osteoporosis [33]. However, although some articles support that the level of testosterone in male smokers is higher than nonsmokers, the testosterone tend to influence metabolism of bone in man has not been well defined than the relative effect of estrogen in woman [29,34].

Cigarette smoking is associated with increased level of free radicals, which may contribute to bone resorption. A prospective cohort study from Sweden [35] found that current smokers with a low intake of vitamin E or C may increase the risk of hip fracture, which the OR was 3.0 (95% CI1.6–5.4) and 3.0 (1.6–5.6) respectively. In contrast, the OR of hip fracture risk would drop to 1.1 (95% CI 0.5–2.4) with vitamin E and 1.4 (95% CI 0.7–3.0) with vitamin C when current smokers with a high intake of vitamin E or C, in addition, comparing with the nonsmokers, hip fracture risk was almost fivefold increased (OR 4.9 [2.2–11.0]) in smokers with low intakes of vitamins E and vitamins C, furthermore, a direct toxic effect on the bone cells and tissues by nicotine and non-nicotine components, which may reduce blood supply to the bone [29,36]. An increasing number of researches are needed to determine whether these mechanisms underlie smoking's effect on bone metabolism.

Similar to other meta-analysis, several limitations in present meta-analysis should be of concern. First, we were unable to examine the dose-response relationship between smoking and risk of hip fractures, as well as the risk of hip fracture since cessation of smoking, because smoking history and classification method of smoking cessation from the including studies were significantly different. Second, the adjustment for confounders of all the included articles are not the same, which may exaggerate or underestimate the results. However, 13 of the 14 included prospective cohorts adjusted for age, and over half adjusted for major potential confounders, including BMI, alcohol use, and so on. Third, the present meta-analysis is based on published researches, and publication bias may affect the results. However, no evidence of publication bias was found when evaluated by Begg’s test and Egger’s test. Finally, the study has a significant geographical differences. Our pooled result based on 13 western reports and one Singapore report, thus the generalization of the conclusion should be cautious.

The present meta-analysis also has some strengths. First, to our knowledge, this is the first meta-analysis about the association between cigarette smoking and risk of hip fracture in male. Second, all the included articles were prospective cohort studies in design, which strengthened the power and minimized recall and selection bias compared with case-control and retrospective cohort studies. Third, the sample sizes were large (1922 patients with hip fracture and 216301participants) and the sensitivity analysis was consist with our result, indicating our findings were reliable and robust. Finally, no evidence of heterogeneity was found across the included publications.

In short, the present meta-analysis of 14 prospective studies suggests that, compared with never smokers, cigarette smoking increase risk of hip fracture in man, specifically in current smokers. However, further larger prospective cohorts with more power or meta-analysis of individual patient data are needed to confirm this association.

Supporting Information

Author Contributions

  1. Conceptualization: ZW ZY.
  2. Data curation: ZW PZ.
  3. Formal analysis: ZW BL.
  4. Funding acquisition: ZY.
  5. Investigation: ZW ZY.
  6. Methodology: PZ BL.
  7. Project administration: ZW ZY.
  8. Resources: BL.
  9. Software: PZ.
  10. Supervision: ZW.
  11. Validation: BL.
  12. Visualization: ZW.
  13. Writing – original draft: ZW PZ.
  14. Writing – review & editing: ZW ZY.

References

  1. 1. Delmas PD. Treatment of postmenopausal osteoporosis. The Lancet. 2002;359(9322):2018–26.
  2. 2. Lv QB, Fu X, Jin HM, Xu HC, Huang ZY, Xu HZ, et al. The relationship between weight change and risk of hip fracture: meta-analysis of prospective studies. Sci Rep. 2015;5:16030. pmid:26522962
  3. 3. Hoidrup S, Prescott E, Sorensen TI, Gottschau A, Lauritzen JB, Schroll M, et al. Tobacco smoking and risk of hip fracture in men and women. Int J Epidemiol. 2000;29(2):253–9. pmid:10817121
  4. 4. Shen GS, Li Y, Zhao G, Zhou HB, Xie ZG, Xu W, et al. Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort studies. Injury. 2015;46(7):1333–40. pmid:25956674
  5. 5. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Exercise and other factors in the prevention of hip fracture: the Leisure World study. Epidemiology. 1991;2(1):16–25. pmid:2021661
  6. 6. Stolee P, Poss J, Cook RJ, Byrne K, Hirdes JP. Risk factors for hip fracture in older home care clients. J Gerontol A Biol Sci Med Sci. 2009;64(3):403–10. pmid:19196903
  7. 7. Trimpou P, Landin-Wilhelmsen K, Oden A, Rosengren A, Wilhelmsen L. Male risk factors for hip fracture-a 30-year follow-up study in 7,495 men. Osteoporos Int. 2010;21(3):409–16. pmid:19475474
  8. 8. Forsen L, Bjartveit K, Bjorndal A, Edna TH, Meyer HE, Schei B. Ex-smokers and risk of hip fracture. Am J Public Health. 1998;88(10):1481–3. pmid:9772848
  9. 9. Hemenway D, Azrael DR, Rimm EB, Feskanich D, Willett WC. Risk factors for hip fracture in US men aged 40 through 75 years. Am J Public Health. 1994;84(11):1843–5. pmid:7977932
  10. 10. Koh WP, Wu AH, Wang R, Ang LW, Heng D, Yuan JM, et al. Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am J Epidemiol. 2009;170(7):901–9. pmid:19720865
  11. 11. Meyer HE, Tverdal A, Falch JA. Risk factors for hip fracture in middle-aged Norwegian women and men. Am J Epidemiol. 1993;137(11):1203–11. pmid:8322761
  12. 12. Mussolino ME, Looker AC, Madans JH, Langlois JA, Orwoll ES. Risk factors for hip fracture in white men: the NHANES I Epidemiologic Follow-up Study. J Bone Miner Res. 1998;13(6):918–24. pmid:9626622
  13. 13. Reyes C, Estrada P, Nogues X, Orozco P, Cooper C, Diez-Perez A, et al. The impact of common co-morbidities (as measured using the Charlson index) on hip fracture risk in elderly men: a population-based cohort study. Osteoporos Int. 2014;25(6):1751–8. pmid:24676845
  14. 14. Vestergaard P, Mosekilde L. Fracture risk associated with smoking: a meta-analysis. J Intern Med. 2003;254(6):572–83. pmid:14641798
  15. 15. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5. pmid:20652370
  16. 16. Forsen L, Bjorndal A, Bjartveit K, Edna TH, Holmen J, Jessen V, et al. Interaction between current smoking, leanness, and physical inactivity in the prediction of hip fracture. J Bone Miner Res. 1994;9(11):1671–8. pmid:7863817
  17. 17. Holmberg AH, Johnell O, Nilsson PM, Nilsson JA, Berglund G, Akesson K. Risk factors for hip fractures in a middle-aged population: a study of 33,000 men and women. Osteoporos Int. 2005;16(12):2185–94. pmid:16177836
  18. 18. Cauley JA, Cawthon PM, Peters KE, Cummings SR, Ensrud KE, Bauer DC, et al. Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS). J Bone Miner Res. 2016; 31(10):1810–9. pmid:26988112
  19. 19. Jutberger H, Lorentzon M, Barrett-Connor E, Johansson H, Kanis JA, Ljunggren O, et al. Smoking Predicts Incident Fractures in Elderly Men: Mr OS Sweden. J Bone Miner Res. 2010;25(5):1010–6. pmid:19929437
  20. 20. Olofsson H, Byberg L, Mohsen R, Melhus H, Lithell H, Michaelsson K. Smoking and the risk of fracture in older men. J Bone Miner Res. 2005;20(7):1208–15. pmid:15940374
  21. 21. Wang D, Chen XH, Fu G, Gu LQ, Zhu QT, Liu XL, et al. Calcium intake and hip fracture risk: a meta-analysis of prospective cohort studies. Int J Clin Exp Med. 2015;8(8):14424–31. pmid:26550430
  22. 22. Jones G, Scott FS. A cross-sectional study of smoking and bone mineral density in premenopausal parous women: effect of body mass index, breastfeeding, and sports participation. J Bone Miner Res. 1999;14(9):1628–33. pmid:10469293
  23. 23. Lutfy K, Aimiuwu O, Mangubat M, Shin CS, Nerio N, Gomez R, et al. Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors. J Neurochem. 2012;120(6):1108–16. pmid:22191943
  24. 24. Tang X, Liu G, Kang J, Hou Y, Jiang F, Yuan W, et al. Obesity and risk of hip fracture in adults: a meta-analysis of prospective cohort studies. PLoS One. 2013;8(4):e55077. pmid:23593112
  25. 25. Rasmussen DD. Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation. Psychoneuroendocrinology. 1998;23(3):245–59. pmid:9695129
  26. 26. Klesges RC, Meyers AW, Klesges LM, La Vasque ME. Smoking, body weight, and their effects on smoking behavior: a comprehensive review of the literature. Psychol Bull. 1989;106(2):204–30. pmid:2678202
  27. 27. Hannan MT1, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson PW, Kiel DP. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 2000;15(4):710–20. pmid:10780863
  28. 28. Kanis JA, Johnell O, Oden A, Johansson H, De Laet C, Eisman JA, et al. Smoking and fracture risk: a meta-analysis. Osteoporos Int. 2005;16(2):155–62. pmid:15175845
  29. 29. Cusano NE. Skeletal Effects of Smoking. Current Osteoporosis Reports. 2015;13(5):302–9. pmid:26205852
  30. 30. Kanungo J, Cuevas E, Guo X, Lopez AG, Ramirez-Lee MA, Trickler W, et al. Nicotine alters the expression of molecular markers of 7. Neurosci Lett. 2012;526(2):133–7. pmid:22922325
  31. 31. Hermann AP, Brot C, Gram J, Kolthoff N, Mosekilde L. Premenopausal smoking and bone density in 2015 perimenopausal women. J Bone Miner Res. 2000;15(4):780–7. pmid:10780870
  32. 32. Bjarnason NH, Christiansen C. The influence of thinness and smoking on bone loss and response to hormone replacement therapy in early postmenopausal women. J Clin Endocrinol Metab. 2000;85(2):590–6. pmid:10690860
  33. 33. Kenneth D. Ward RCK. A Meta-Analysis of the Effects of Cigarette Smoking on Mineral Density. Calcif Tissue Int. 2001;68(5):259–70. pmid:11683532
  34. 34. Murphy S, Khaw KT, Cassidy A, Compston JE. Sex hormones and bone mineral density in elderly men. Bone Miner. 1993;20(2):133–40. pmid:8453329
  35. 35. Melhus H, Michaëlsson K, Holmberg L, Wolk A, Ljunghall S. Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res. 1999;14(1):129–35. pmid:9893075
  36. 36. Wong PKK, Christie JJ, Wark JD. The effects of smoking on bone health. Clinical Science. 2007;113(5–6):233–41.