Calcified Tissue International

, Volume 103, Issue 5, pp 546–553 | Cite as

Is There Causal Relationship of Smoking and Alcohol Consumption with Bone Mineral Density? A Mendelian Randomization Study

  • Ran Guo
  • Lang Wu
  • Qin FuEmail author
Original Research


Observational studies examining associations of smoking and alcohol consumption with bone mineral density (BMD) have generated inconsistent results and suffer from several methodological limitations. We aim to evaluate whether there are causal associations between smoking, alcohol consumption, and BMD using a Mendelian randomization (MR) design. Genetic variants associated with smoking status (n = 142), no. of cigarettes smoked per day (CPD) (n = 3), smoking initiation (n = 1), and alcohol consumption (n = 6) identified in published genome-wide association studies (GWAS) were used as instruments. Summary statistics data of 32735, 28498, 8143, and 445921 European subjects included in The GEnetic Factors for Osteoporosis Consortium or UK Biobank were used to generate associations of genetically predicted smoking or alcohol consumption with femoral neck (FN-BMD), lumbar spine (LS-BMD), forearm (FA-BMD), and heel BMD, respectively, by using the inverse-variance weighted method. The BMD was measured using either ultrasound (for heel) or Dual-energy X-ray Absorptiometry (for others). In our analyses, smoking status tended to be negatively associated with several types of BMD (heel BMD: β = − 0.053, p = 0.003; FN-BMD: β = − 0.139, p = 0.053; FA-BMD: β = − 0.264, p = 0.077), although the association with LS-BMD was null. Smoking initiation was significantly inversely associated with heel BMD (β = − 0.201, p = 3.60 × 10−8). CPD was associated with a lower FN-BMD (β = − 0.014, p = 0.047) only. There was no clear association of genetically predicted alcohol consumption with BMD. Our study provided some evidence of a potential association between genetically predicted smoking and lower BMD, especially for heel BMD, but not for alcohol consumption. Considering the inconsistent findings with the different types of BMD and limitations of the current work, further studies are needed to better characterize the exact relationship between smoking, alcohol consumption, and BMD.


Bone mineral density Smoking Alcohol consumption Association Mendelian randomization Genetic instruments 


Author Contributions

RG, LW, and QF designed this study. RG and QF performed the catalog and literature search and data extraction with suggestions and help from LW. RG, LW, and QF performed the statistical analyses. All authors contributed to the data interpretation and manuscript writing. QF is responsible for the overall content as the guarantor of the paper.


This study was supported by the General project for scientific research of Liaoning Provincial Education Department (No. L2015572 for Ran Guo). The sponsors are not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Compliance with Ethical Standards

Conflict of interest

Ran Guo, Lang Wu, and Qin Fu declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

223_2018_452_MOESM1_ESM.docx (79 kb)
Supplementary material 1 (DOCX 78 KB)


  1. 1.
    Ward KD, Klesges RC (2001) A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif Tissue Int 68:259–270CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Berg KM, Kunins HV, Jackson JL, Nahvi S, Chaudhry A, Harris KA Jr, Malik R, Arnsten JH (2008) Association between alcohol consumption and both osteoporotic fracture and bone density. Am J Med 121:406–418CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R, National Osteoporosis F (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25:2359–2381CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Haycock PC, Burgess S, Wade KH, Bowden J, Relton C, Davey Smith G (2016) Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies. Am J Clin Nutr 103:965–978CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Davey Smith G, Hemani G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23:R89–R98CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Warodomwichit D, Sritara C, Thakkinstian A, Chailurkit LO, Yamwong S, Ratanachaiwong W, Ongphiphadhanakul B, Sritara P (2013) Causal inference of the effect of adiposity on bone mineral density in adults. Clin Endocrinol 78:694–699CrossRefGoogle Scholar
  7. 7.
    Ahmad OS, Leong A, Miller JA, Morris JA, Forgetta V, Mujammami M, Richards JB (2017) A Mendelian randomization study of the effect of type-2 diabetes and glycemic traits on bone mineral density. J Bone Miner Res 32:1072–1081CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Katikireddi SV, Green MJ, Taylor AE, Davey Smith G, Munafo MR (2017) Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization. Addiction 113:764–774CrossRefPubMedCentralGoogle Scholar
  9. 9.
    The Tobacco and Genetics Consortium (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42:441–447CrossRefGoogle Scholar
  10. 10.
    Kutalik Z, Benyamin B, Bergmann S, Mooser V, Waeber G, Montgomery GW, Martin NG, Madden PA, Heath AC, Beckmann JS, Vollenweider P, Marques-Vidal P, Whitfield JB (2011) Genome-wide association study identifies two loci strongly affecting transferrin glycosylation. Hum Mol Genet 20:3710–3717CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, Hinrichs AL, Budde J, Agrawal A, Bucholz K, Dick D, Harari O, Hesselbrock V, Kramer J, Nurnberger JI Jr, Rice J, Saccone N, Schuckit M, Tischfield J, Porjesz B, Edenberg HJ, Bierut L, Foroud T, Goate A (2013) A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks. Hum Genet 132:1141–1151CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivieres S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proenca C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernandez-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Nunez A, Nyholt DR, Onland-Moret CN, Oostra BA, O’Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tonjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A et al (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 108:7119–7124CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Loh P-R, Kichaev G, Gazal S, Schoech AP, Price AL. Mixed model association for biobank-scale data sets. BioRXiv. (2018)
  14. 14.
    Lawlor DA (2016) Commentary: two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol 45:908–915CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I (2015) Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol 30:543–552CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gomez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellstrom D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren O, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussiere J, Arp PP et al (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112–117CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Loh PR, Tucker G, Bulik-Sullivan BK, Vilhjalmsson BJ, Finucane HK, Salem RM, Chasman DI, Ridker PM, Neale BM, Berger B, Patterson N, Price AL (2015) Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet 47:284–290CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Burgess S, Butterworth A, Thompson SG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37:658–665CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44:512–525CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Clarke TK, Adams MJ, Davies G, Howard DM, Hall LS, Padmanabhan S, Murray AD, Smith BH, Campbell A, Hayward C, Porteous DJ, Deary IJ, McIntosh AM (2017) Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N = 112 117). Mol Psychiatry 22:1376–1384CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Law MR, Hackshaw AK (1997) A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ 315:841–846CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Stevenson JC, Lees B, Devenport M, Cust MP, Ganger KF (1989) Determinants of bone density in normal women: risk factors for future osteoporosis? BMJ 298:924–928CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Johnell O, Nilsson BE (1984) Life-style and bone mineral mass in perimenopausal women. Calcif Tissue Int 36:354–356CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Willett W, Stampfer MJ, Bain C, Lipnick R, Speizer FE, Rosner B, Cramer D, Hennekens CH (1983) Cigarette smoking, relative weight, and menopause. Am J Epidemiol 117:651–658CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Jick H, Porter J (1977) Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet 1:1354–1355CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Svartberg J, Jorde R (2007) Endogenous testosterone levels and smoking in men. The fifth Tromso study. Int J Androl 30:137–143CrossRefPubMedCentralGoogle Scholar
  27. 27.
    English KM, Pugh PJ, Parry H, Scutt NE, Channer KS, Jones TH (2001) Effect of cigarette smoking on levels of bioavailable testosterone in healthy men. Clin Sci 100:661–665CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Murphy S, Khaw KT, Cassidy A, Compston JE (1993) Sex hormones and bone mineral density in elderly men. Bone Miner 20:133–140CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Foresta C, Ruzza G, Mioni R, Guarneri G, Gribaldo R, Meneghello A, Mastrogiacomo I (1984) Osteoporosis and decline of gonadal function in the elderly male. Horm Res 19:18–22CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Riebel GD, Boden SD, Whitesides TE, Hutton WC (1995) The effect of nicotine on incorporation of cancellous bone graft in an animal model. Spine 20:2198–2202CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Broulik PD, Jarab J (1993) The effect of chronic nicotine administration on bone mineral content in mice. Horm Metab Res 25:219–221CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Krall EA, Dawson-Hughes B (1991) Smoking and bone loss among postmenopausal women. J Bone Miner Res 6:331–338CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Gordon T (1993) Factors associated with serum alkaline phosphatase level. Arch Pathol Lab Med 117:187–190PubMedPubMedCentralGoogle Scholar
  34. 34.
    Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg PA, Wilske J, Bengtsson BA (1995) Serum intact parathyroid hormone in a random population sample of men and women: relationship to anthropometry, life-style factors, blood pressure, and vitamin D. Calcif Tissue Int 56:104–108CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Forrest CR, Pang CY, Lindsay WK (1987) Dose and time effects of nicotine treatment on the capillary blood flow and viability of random pattern skin flaps in the rat. Br J Plast Surg 40:295–299CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Matsuo K, Hirohata T, Sugioka Y, Ikeda M, Fukuda A (1988) Influence of alcohol intake, cigarette smoking, and occupational status on idiopathic osteonecrosis of the femoral head. Clin Orthop Relat Res 234:115–123Google Scholar
  37. 37.
    Hirota Y, Hirohata T, Fukuda K, Mori M, Yanagawa H, Ohno Y, Sugioka Y (1993) Association of alcohol intake, cigarette smoking, and occupational status with the risk of idiopathic osteonecrosis of the femoral head. Am J Epidemiol 137:530–538CrossRefPubMedCentralGoogle Scholar
  38. 38.
    NIH Consensus Development Panel on Osteoporosis Prevention D, Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795CrossRefGoogle Scholar
  39. 39.
    Feskanich D, Korrick SA, Greenspan SL, Rosen HN, Colditz GA (1999) Moderate alcohol consumption and bone density among postmenopausal women. J Women’s Health 8:65–73CrossRefGoogle Scholar
  40. 40.
    Cauley JA, Fullman RL, Stone KL, Zmuda JM, Bauer DC, Barrett-Connor E, Ensrud K, Lau EM, Orwoll ES, Mr OSRG (2005) Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 16:1525–1537CrossRefPubMedCentralGoogle Scholar
  41. 41.
    May H, Murphy S, Khaw KT (1995) Alcohol consumption and bone mineral density in older men. Gerontology 41:152–158CrossRefPubMedCentralGoogle Scholar
  42. 42.
    Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP (1995) Alcohol intake and bone mineral density in elderly men and women. The Framingham study. Am J Epidemiol 142:485–492CrossRefPubMedCentralGoogle Scholar
  43. 43.
    Orwoll ES, Bauer DC, Vogt TM, Fox KM (1996) Axial bone mass in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 124:187–196CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Nguyen TV, Kelly PJ, Sambrook PN, Gilbert C, Pocock NA, Eisman JA (1994) Lifestyle factors and bone density in the elderly: implications for osteoporosis prevention. J Bone Miner Res 9:1339–1346CrossRefPubMedCentralGoogle Scholar
  45. 45.
    Williams FM, Cherkas LF, Spector TD, MacGregor AJ (2005) The effect of moderate alcohol consumption on bone mineral density: a study of female twins. Ann Rheum Dis 64:309–310CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, Longcope C, Speizer FE (1995) Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 87:1297–1302CrossRefGoogle Scholar
  47. 47.
    Purohit V (1998) Moderate alcohol consumption and estrogen levels in postmenopausal women: a review. Alcohol Clin Exp Res 22:994–997CrossRefPubMedCentralGoogle Scholar
  48. 48.
    Ginsburg ES, Mello NK, Mendelson JH, Barbieri RL, Teoh SK, Rothman M, Gao X, Sholar JW (1996) Effects of alcohol ingestion on estrogens in postmenopausal women. JAMA 276:1747–1751CrossRefPubMedCentralGoogle Scholar
  49. 49.
    Nielsen NR, Schnohr P, Jensen G, Gronbaek M (2004) Is the relationship between type of alcohol and mortality influenced by socio-economic status? J Intern Med 255:280–288CrossRefPubMedCentralGoogle Scholar
  50. 50.
    Rimm EB (1996) Alcohol consumption and coronary heart disease: good habits may be more important than just good wine. Am J Epidemiol 143:1094–1098 (discussion 1099)CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Burgess S, Davies NM, Thompson SG (2016) Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol 40:597–608CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OrthopaedicsShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology CenterVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations