Skip to main content

Advertisement

Log in

Making Sense of the Highly Variable Effects of Alcohol on Bone

  • Review Paper
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Alcohol consumption is often reported to influence bone health in a dose-dependent manner where moderate alcohol intake is deemed beneficial and heavy drinking detrimental. However, this relationship may not be valid for individual alcohol consumers, as small quantities of alcohol can have detrimental skeletal effects and not all studies report clinically relevant bone loss with long-duration alcohol abuse. These discrepant findings suggest that factors beyond quantity of alcohol consumed contribute to the observed skeletal response. We propose that the interplay between intrinsic factors (e.g., age, sex, skeletal site) and extrinsic factors (e.g., age of onset of drinking, duration of drinking, comorbidities) influence the precise impact of alcohol consumption on bone health. In this review, we summarize literature reporting the effects of alcohol on the human skeleton. Based on the finding that alcohol alters the circulating levels of dozens of peptides shown to influence bone metabolism, we arrive at the conclusion that no single unifying mechanism adequately explains the diversity of reports or successfully predicts individuals most likely to be impacted favorably or unfavorably by alcohol consumption. We propose that a more holistic approachin which drinking pattern and intrinsic factors are accounted foris required to better understand and respond to the end-organ effects of alcohol on the skeleton.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Arranz S, Chiva-Blanch G, Valderas-Martinez P, Medina-Remon A, Lamuela-Raventos RM, Estruch R. Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer. Nutrients. 2012;4(7):759–81. https://doi.org/10.3390/nu4070759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. CDC. Alcohol use and alcohol use disorders in the United States: mail finding from the 2012–2013 National Epidemiologic Survey on alcohol related conditions-III (NESARC-III). Alcohol Epidemiol Data Ref Manual. 2014;10.

  3. Fung TT, Mukamal KJ, Rimm EB, Meyer HE, Willett WC, Feskanich D. Alcohol intake, specific alcoholic beverages, and risk of hip fractures in postmenopausal women and men age 50 and older. Am J Clin Nutr. 2019;110(3):691–700. https://doi.org/10.1093/ajcn/nqz135

    Article  PubMed  PubMed Central  Google Scholar 

  4. Santori C, Ceccanti M, Diacinti D, Attilia ML, Toppo L, D’Erasmo E, et al. Skeletal turnover, bone mineral density, and fractures in male chronic abusers of alcohol. J Endocrinol Invest. 2008;31(4):321–6. https://doi.org/10.1007/BF03346365

    Article  CAS  PubMed  Google Scholar 

  5. Sommer I, Erkkila AT, Jarvinen R, Mursu J, Sirola J, Jurvelin JS, et al. Alcohol consumption and bone mineral density in elderly women. Public Health Nutr. 2013;16(4):704–12. https://doi.org/10.1017/S136898001200331X

    Article  PubMed  Google Scholar 

  6. Roy DK, O’Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, et al. Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2003;14(1):19–26. https://doi.org/10.1007/s00198-002-1317-8

    Article  CAS  Google Scholar 

  7. Fini M, Giavaresi G, Salamanna F, Veronesi F, Martini L, De Mattei M, et al. Harmful lifestyles on orthopedic implantation surgery: a descriptive review on alcohol and tobacco use. J Bone Miner Metab. 2011;29(6):633–44. https://doi.org/10.1007/s00774-011-0309-1

    Article  PubMed  Google Scholar 

  8. Jung MK, Callaci JJ, Lauing KL, Otis JS, Radek KA, Jones MK, et al. Alcohol exposure and mechanisms of tissue injury and repair. Alcohol Clin Exp Res. 2011;35(3):392–9. https://doi.org/10.1111/j.1530-0277.2010.01356.x

    Article  CAS  PubMed  Google Scholar 

  9. Ronis MJ, Mercer K, Chen JR. Effects of nutrition and alcohol consumption on bone loss. Curr Osteoporos Rep. 2011;9(2):53–9. https://doi.org/10.1007/s11914-011-0049-0

    Article  PubMed  PubMed Central  Google Scholar 

  10. Maurel DB, Boisseau N, Benhamou CL, Jaffre C. Alcohol and bone: review of dose effects and mechanisms. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2012;23(1):1–16. https://doi.org/10.1007/s00198-011-1787-7

    Article  CAS  Google Scholar 

  11. Turner RT, Doran E, Iwaniec UT. Detrimental effects of alcohol on bone growth. INTECH Open Access Publisher. 2012.

  12. Abukhadir SS, Mohamed N, Mohamed N. Pathogenesis of alcohol-induced osteoporosis and its treatment: a review. Curr Drug Targets. 2013;14(13):1601–10. https://doi.org/10.2174/13894501113146660231

    Article  CAS  PubMed  Google Scholar 

  13. Gaddini GW, Turner RT, Grant KA, Iwaniec UT. Alcohol: a simple nutrient with complex actions on bone in the adult skeleton. Alcohol Clin Exp Res. 2016;40(4):657–71. https://doi.org/10.1111/acer.13000

    Article  PubMed  PubMed Central  Google Scholar 

  14. Luo Z, Liu Y, Liu Y, Chen H, Shi S, Liu Y. Cellular and molecular mechanisms of alcohol-induced osteopenia. Cell Mol Life Sci. 2017;74(24):4443–53. https://doi.org/10.1007/s00018-017-2585-y

    Article  CAS  PubMed  Google Scholar 

  15. Eby JM, Sharieh F, Callaci JJ. Impact of alcohol on bone health, homeostasis, and fracture repair. Curr Pathobiol Rep. 2020;8:75–86. https://doi.org/10.1007/s40139-020-00209-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dempster DW. Osteoporosis and the burden of osteoporosis-related fractures. Am J Manag Care. 2011;17(Suppl 6):S164–9.

    PubMed  Google Scholar 

  17. Viswanathan HN, Curtis JR, Yu J, White J, Stolshek BS, Merinar C, et al. Direct healthcare costs of osteoporosis-related fractures in managed care patients receiving pharmacological osteoporosis therapy. Appl Health Econ Health Policy. 2012;10(3):163–73. https://doi.org/10.2165/11598590-000000000-00000

    Article  PubMed  Google Scholar 

  18. Mello NK, Mendelson JH. A quantitative analysis of drinking patterns in alcoholics. Arch Gen Psychiatry. 1971;25(6):527–39.

    Article  CAS  PubMed  Google Scholar 

  19. Baker EJ, Farro J, Gonzales S, Helms C, Grant KA. Chronic alcohol self-administration in monkeys shows long-term quantity/frequency categorical stability. Alcohol Clin Exp Res. 2014;38(11):2835–43. https://doi.org/10.1111/acer.12547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hoidrup S, Gronbaek M, Gottschau A, Lauritzen JB, Schroll M. Alcohol intake, beverage preference, and risk of hip fracture in men and women. Copenhagen Centre for Prospective Population Studies. Am J Epidemiol. 1999;149(11):993–1001. https://doi.org/10.1093/oxfordjournals.aje.a009760

  21. Tucker KL, Jugdaohsingh R, Powell JJ, Qiao N, Hannan MT, Sripanyakorn S, et al. Effects of beer, wine, and liquor intakes on bone mineral density in older men and women. Am J Clin Nutr. 2009;89(4):1188–96. https://doi.org/10.3945/ajcn.2008.26765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ganry O, Baudoin C, Fardellone P. Effect of alcohol intake on bone mineral density in elderly women: the EPIDOS study. Epidemiologie de l'Osteoporose. Am J Epidemiol. 2000;151(8):773–80.

  23. Marrone JA, Maddalozzo GF, Branscum AJ, Hardin K, Cialdella-Kam L, Philbrick KA, et al. Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women. Menopause. 2012;19(9):974–9. https://doi.org/10.1097/gme.0b013e31824ac071

    Article  PubMed  Google Scholar 

  24. Jadzic J, Cvetkovic D, Milovanovic P, Tomanovic N, Zivkovic V, Nikolic S, et al. The micro-structural analysis of lumbar vertebrae in alcoholic liver cirrhosis. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2020. https://doi.org/10.1007/s00198-020-05509-7

    Article  Google Scholar 

  25. Berg KM, Kunins HV, Jackson JL, Nahvi S, Chaudhry A, Harris KA Jr, et al. Association between alcohol consumption and both osteoporotic fracture and bone density. Am J Med. 2008;121(5):406–18. https://doi.org/10.1016/j.amjmed.2007.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP. Alcohol intake and bone mineral density in elderly men and women. The Framingham Study. Am J Epidemiol. 1995;142(5):485–92.

  27. Holbrook TL, Barrett-Connor E. A prospective study of alcohol consumption and bone mineral density. BMJ. 1993;306(6891):1506–9. https://doi.org/10.1136/bmj.306.6891.1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jang HD, Hong JY, Han K, Lee JC, Shin BJ, Choi SW, et al. Relationship between bone mineral density and alcohol intake: a nationwide health survey analysis of postmenopausal women. PLoS ONE. 2017;12(6). https://doi.org/10.1371/journal.pone.0180132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Laitinen K, Karkkainen M, Lalla M, Lamberg-Allardt C, Tunninen R, Tahtela R, et al. Is alcohol an osteoporosis-inducing agent for young and middle-aged women? Metab: Clin Exp. 1993;42(7):875–81.

  30. Mukamal KJ, Robbins JA, Cauley JA, Kern LM, Siscovick DS. Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2007;18(5):593–602. https://doi.org/10.1007/s00198-006-0287-7

    Article  CAS  Google Scholar 

  31. Rapuri PB, Gallagher JC, Balhorn KE, Ryschon KL. Alcohol intake and bone metabolism in elderly women. Am J Clin Nutr. 2000;72(5):1206–13. https://doi.org/10.1093/ajcn/72.5.1206

    Article  CAS  PubMed  Google Scholar 

  32. Wosje KS, Kalkwarf HJ. Bone density in relation to alcohol intake among men and women in the United States. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2007;18(3):391–400. https://doi.org/10.1007/s00198-006-0249-0

    Article  CAS  Google Scholar 

  33. Seo S, Chun S, Newell MA, Yun M. Association between alcohol consumption and Korean young women's bone health: a cross sectional study from the 2008 to 2011 Korea National Health and Nutrition Examination Survey. BMJ Open. 2015;5(10). https://doi.org/10.1136/bmjopen-2015-007914

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sung DJ, Singh H, Oh SB, Kim S. Bone-loading physical activity and alcohol intake but not BMI affect areal bone mineral density in young college-aged Korean women: a cross-sectional study. Int J Environ Res Public Health. 2019;16(24). https://doi.org/10.3390/ijerph16245063

  35. Diamond T, Stiel D, Lunzer M, Wilkinson M, Posen S. Ethanol reduces bone formation and may cause osteoporosis. Am J Med. 1989;86(3):282–8. https://doi.org/10.1016/0002-9343(89)90297-0

    Article  CAS  PubMed  Google Scholar 

  36. Ulhoi MP, Meldgaard K, Steiniche T, Odgaard A, Vesterby A. Chronic alcohol abuse leads to low bone mass with no general loss of bone structure or bone mechanical strength<sup/> J Forensic Sci. 2017;62(1):131–6. https://doi.org/10.1111/1556-4029.13256

    Article  PubMed  Google Scholar 

  37. Gonzalez-Reimers E, Martin-Gonzalez C, de la Vega-Prieto MJ, Pelazas-Gonzalez R, Fernandez-Rodriguez C, Lopez-Prieto J, et al. Serum sclerostin in alcoholics: a pilot study. Alcohol Alcohol. 2013;48(3):278–82. https://doi.org/10.1093/alcalc/ags136

    Article  CAS  PubMed  Google Scholar 

  38. Paccou J, Edwards MH, Ward K, Jameson K, Moon R, Dennison E, et al. Relationships between bone geometry, volumetric bone mineral density and bone microarchitecture of the distal radius and tibia with alcohol consumption. Bone. 2015;78:122–9. https://doi.org/10.1016/j.bone.2015.05.002

    Article  CAS  PubMed  Google Scholar 

  39. Pumarino H, Gonzalez P, Oviedo S, Lillo R, Bustamante E. Assessment of bone status in intermittent and continuous alcoholics, without evidence of live damage. Revista medica de Chile. 1998;124:423–30.

  40. Hefferan TE, Kennedy AM, Evans GL, Turner RT. Disuse exaggerates the detrimental effects of alcohol on cortical bone. Alcohol Clin Exp Res. 2003;27(1):111–7. https://doi.org/10.1097/01.ALC.0000047348.23797.6E

    Article  PubMed  Google Scholar 

  41. Johnson TL, Gaddini G, Branscum AJ, Olson DA, Caroline-Westerlind K, Turner RT, et al. Effects of chronic heavy alcohol consumption and endurance exercise on cancellous and cortical bone microarchitecture in adult male rats. Alcohol Clin Exp Res. 2014;38(5):1365–72. https://doi.org/10.1111/acer.12366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Reed AH, McCarty HL, Evans GL, Turner RT, Westerlind KC. The effects of chronic alcohol consumption and exercise on the skeleton of adult male rats. Alcohol Clin Exp Res. 2002;26(8):1269–74. https://doi.org/10.1097/01.ALC.0000023984.47311.6E

    Article  CAS  PubMed  Google Scholar 

  43. Iwaniec UT, Turner RT. Intraperitoneal injection of ethanol results in drastic changes in bone metabolism not observed when ethanol is administered by oral gavage. Alcohol Clin Exp Res. 2013;37(8):1271–7. https://doi.org/10.1111/acer.12105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sampson HW, Gallager S, Lange J, Chondra W, Hogan HA. Binge drinking and bone metabolism in a young actively growing rat model. Alcohol Clin Exp Res. 1999;23(7):1228–31. https://doi.org/10.1111/j.1530-0277.1999.tb04282.x

    Article  CAS  PubMed  Google Scholar 

  45. Turner RT, Evans GL, Zhang M, Sibonga JD. Effects of parathyroid hormone on bone formation in a rat model for chronic alcohol abuse. Alcohol Clin Exp Res. 2001;25(5):667–71.

    Article  CAS  PubMed  Google Scholar 

  46. Callaci JJ, Juknelis D, Patwardhan A, Sartori M, Frost N, Wezeman FH. The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment. Alcohol Clin Exp Res. 2004;28(1):182–91. https://doi.org/10.1097/01.ALC.0000108661.41560.BF

    Article  PubMed  PubMed Central  Google Scholar 

  47. Foger-Samwald U, Knecht C, Stimpfl T, Szekeres T, Kerschan-Schindl K, Mikosch P, et al. Bone effects of binge alcohol drinking using prepubescent pigs as a model. Alcohol Clin Exp Res. 2018;42(11):2123–35. https://doi.org/10.1111/acer.13874

    Article  PubMed  PubMed Central  Google Scholar 

  48. LaBrie JW, Boyle S, Earle A, Almstedt HC. Heavy episodic drinking is associated with poorer bone health in adolescent and young adult women. J Stud Alcohol Drugs. 2018;79(3):391–8. https://doi.org/10.15288/jsad.2018.79.391

    Article  PubMed  PubMed Central  Google Scholar 

  49. Laitinen K, Lamberg-Allardt C, Tunninen R, Harkonen M, Valimaki M. Bone mineral density and abstention-induced changes in bone and mineral metabolism in noncirrhotic male alcoholics. Am J Med. 1992;93(6):642–50.

    Article  CAS  PubMed  Google Scholar 

  50. Prabhakaran A, Bhasin DK, Rana SS, Bhadada SK, Bhansali A, Rao C, et al. Bone mineral metabolism and bone mineral density in alcohol related and idiopathic chronic pancreatitis. Trop Gastroenterol. 2014;35(2):107–12. https://doi.org/10.7869/tg.189

    Article  PubMed  Google Scholar 

  51. Hogan HA, Argueta F, Moe L, Nguyen LP, Sampson HW. Adult-onset alcohol consumption induces osteopenia in female rats. Alcohol Clin Exp Res. 2001;25(5):746–54.

    Article  CAS  PubMed  Google Scholar 

  52. Kahler-Quesada AM, Grant KA, Walter NAR, Newman N, Allen MR, Burr DB, et al. Voluntary chronic heavy alcohol consumption in male Rhesus Macaques suppresses cancellous bone formation and increases bone marrow adiposity. Alcohol Clin Exp Res. 2019;43(12):2494–503. https://doi.org/10.1111/acer.14202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim MJ, Shim MS, Kim MK, Lee Y, Shin YG, Chung CH, et al. Effect of chronic alcohol ingestion on bone mineral density in males without liver cirrhosis. Korean J Intern Med. 2003;18(3):174–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM, Lewis R, et al. The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016;27(4):1281–386. https://doi.org/10.1007/s00198-015-3440-3

    Article  CAS  Google Scholar 

  55. Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, Wright JK et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest. 1994;93(2):799–808. https://doi.org/10.1172/JCI117034

  56. Seibel MJ, Cooper MS, Zhou H. Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol. 2013;1(1):59–70. https://doi.org/10.1016/S2213-8587(13)70045-7

    Article  CAS  PubMed  Google Scholar 

  57. Sibonga JD. Spaceflight-induced bone loss: is there an osteoporosis risk? Curr Osteoporos Rep. 2013;11(2):92–8. https://doi.org/10.1007/s11914-013-0136-5

    Article  PubMed  Google Scholar 

  58. Nordin BE, Need AG, Steurer T, Morris HA, Chatterton BE, Horowitz M. Nutrition, osteoporosis, and aging. Ann N Y Acad Sci. 1998;854:336–51. https://doi.org/10.1111/j.1749-6632.1998.tb09914.x

    Article  CAS  PubMed  Google Scholar 

  59. Cabral HW, Andolphi BF, Ferreira BV, Alves DC, Morelato RL, Chambo AF, et al. The use of biomarkers in clinical osteoporosis. Rev Assoc Med Bras (1992). 2016;62(4):368–76. https://doi.org/10.1590/1806-9282.62.04.368

  60. Kuo TR, Chen CH. Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives. Biomark Res. 2017;5:18. https://doi.org/10.1186/s40364-017-0097-4

    Article  PubMed  PubMed Central  Google Scholar 

  61. Qvist P, Christgau S, Pedersen BJ, Schlemmer A, Christiansen C. Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone. 2002;31(1):57–61. https://doi.org/10.1016/s8756-3282(02)00791-3

    Article  CAS  PubMed  Google Scholar 

  62. van der Spoel E, Oei N, Cachucho R, Roelfsema F, Berbee JFP, Blauw GJ, et al. The 24-hour serum profiles of bone markers in healthy older men and women. Bone. 2019;120:61–9. https://doi.org/10.1016/j.bone.2018.10.002

    Article  CAS  PubMed  Google Scholar 

  63. Gonzalez-Calvin JL, Garcia-Sanchez A, Bellot V, Munoz-Torres M, Raya-Alvarez E, Salvatierra-Rios D. Mineral metabolism, osteoblastic function and bone mass in chronic alcoholism. Alcohol Alcohol. 1993;28(5):571–9.

    CAS  PubMed  Google Scholar 

  64. Laitinen K, Lamberg-Allardt C, Tunninen R, Karonen SL, Ylikahri R, Valimaki M. Effects of 3 weeks' moderate alcohol intake on bone and mineral metabolism in normal men. Bone Miner. 1991;13(2):139–51. https://doi.org/10.1016/0169-6009(91)90081-a

    Article  CAS  PubMed  Google Scholar 

  65. Bikle DD, Stesin A, Halloran B, Steinbach L, Recker R. Alcohol-induced bone disease: relationship to age and parathyroid hormone levels. Alcohol Clin Exp Res. 1993;17(3):690–5. https://doi.org/10.1111/j.1530-0277.1993.tb00821.x

    Article  CAS  PubMed  Google Scholar 

  66. Chappard D, Plantard B, Petitjean M, Alexandre C, Riffat G. Alcoholic cirrhosis and osteoporosis in men: a light and scanning electron microscopy study. J Stud Alcohol. 1991;52(3):269–74.

    Article  CAS  PubMed  Google Scholar 

  67. Diamond TH, Stiel D, Lunzer M, McDowall D, Eckstein RP, Posen S. Hepatic osteodystrophy. Static and dynamic bone histomorphometry and serum bone Gla-protein in 80 patients with chronic liver disease. Gastroenterology. 1989;96(1):213–21.

  68. Diez A, Puig J, Serrano S, Marinoso ML, Bosch J, Marrugat J, et al. Alcohol-induced bone disease in the absence of severe chronic liver damage. J Bone Miner Res: J Am Soc Bone Miner Res. 1994;9(6):825–31. https://doi.org/10.1002/jbmr.5650090608

    Article  CAS  Google Scholar 

  69. Nyquist F, Ljunghall S, Berglund M, Obrant K. Biochemical markers of bone metabolism after short and long time ethanol withdrawal in alcoholics. Bone. 1996;19(1):51–4. https://doi.org/10.1016/8756-3282(96)00110-x

    Article  CAS  PubMed  Google Scholar 

  70. Pepersack T, Fuss M, Otero J, Bergmann P, Valsamis J, Corvilain J. Longitudinal study of bone metabolism after ethanol withdrawal in alcoholic patients. J Bone Miner Res: J Am Soc Bone Miner Res. 1992;7(4):383–7. https://doi.org/10.1002/jbmr.5650070405

    Article  CAS  Google Scholar 

  71. Garcia-Valdecasas-Campelo E, Gonzalez-Reimers E, Santolaria-Fernandez F, De la Vega-Prieto MJ, Milena-Abril A, Sanchez-Perez MJ, et al. Serum osteoprotegerin and RANKL levels in chronic alcoholic liver disease. Alcohol and Alcoholism. 2006;41(3):261–6. https://doi.org/10.1093/alcalc/agl004.

    Article  CAS  PubMed  Google Scholar 

  72. Turner RT, Kidder LS, Kennedy A, Evans GL, Sibonga JD. Moderate alcohol consumption suppresses bone turnover in adult female rats. J Bone Miner Res: J Am Soc Bone Miner Res. 2001;16(3):589–94. https://doi.org/10.1359/jbmr.2001.16.3.589

    Article  CAS  Google Scholar 

  73. Turner RT, Wronski TJ, Zhang M, Kidder LS, Bloomfield SA, Sibonga JD. Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for matrix proteins, skeletal growth factors, and cytokines are followed by reductions in bone formation. Alcohol Clin Exp Res. 1998;22(7):1591–9. https://doi.org/10.1111/j.1530-0277.1998.tb03953.x

    Article  CAS  PubMed  Google Scholar 

  74. Sripanyakorn S, Jugdaohsingh R, Mander A, Davidson SL, Thompson RP, Powell JJ. Moderate ingestion of alcohol is associated with acute ethanol-induced suppression of circulating CTX in a PTH-independent fashion. J Bone Miner Res: J Am Soc Bone Miner Res. 2009;24(8):1380–8. https://doi.org/10.1359/jbmr.090222

    Article  CAS  Google Scholar 

  75. Sibonga JD, Iwaniec UT, Shogren KL, Rosen CJ, Turner RT. Effects of parathyroid hormone (1–34) on tibia in an adult rat model for chronic alcohol abuse. Bone. 2007;40(4):1013–20. https://doi.org/10.1016/j.bone.2006.11.002

    Article  CAS  PubMed  Google Scholar 

  76. Shankar K, Hidestrand M, Liu X, Chen JR, Haley R, Perrien DS, et al. Chronic ethanol consumption inhibits postlactational anabolic bone rebuilding in female rats. J Bone Miner Res: J Am Soc Bone Miner Res. 2008;23(3):338–49. https://doi.org/10.1359/jbmr.071023

    Article  CAS  Google Scholar 

  77. Turner RT, Sibonga JD. Effects of alcohol use and estrogen on bone. Alcohol Res Health: the journal of the National Institute on Alcohol Abuse and Alcoholism. 2001;25(4):276–81.

    CAS  Google Scholar 

  78. Malik P, Gasser RW, Kemmler G, Moncayo R, Finkenstedt G, Kurz M, et al. Low bone mineral density and impaired bone metabolism in young alcoholic patients without liver cirrhosis: a cross-sectional study. Alcohol Clin Exp Res. 2009;33(2):375–81. https://doi.org/10.1111/j.1530-0277.2008.00847.x

    Article  CAS  PubMed  Google Scholar 

  79. Yin J, Winzenberg T, Quinn S, Giles G, Jones G. Beverage-specific alcohol intake and bone loss in older men and women: a longitudinal study. Eur J Clin Nutr. 2011;65(4):526–32. https://doi.org/10.1038/ejcn.2011.9

    Article  CAS  PubMed  Google Scholar 

  80. Alvisa-Negrin J, Gonzalez-Reimers E, Santolaria-Fernandez F, Garcia-Valdecasas-Campelo E, Valls MR, Pelazas-Gonzalez R, et al. Osteopenia in alcoholics: effect of alcohol abstinence. Alcohol Alcohol. 2009;44(5):468–75. https://doi.org/10.1093/alcalc/agp038

    Article  CAS  PubMed  Google Scholar 

  81. Peris P, Pares A, Guanabens N, Del Rio L, Pons F, Martinez de Osaba MJ, et al. Bone mass improves in alcoholics after 2 years of abstinence. J Bone Miner Res: J Am Soc Bone Miner Res. 1994;9(10):1607–12. https://doi.org/10.1002/jbmr.5650091014

  82. Song TH, Shim JC, Jung DU, Moon JJ, Jeon DW, Kim SJ, et al. Increased bone mineral density after abstinence in male patients with alcohol dependence. Clin Psychopharmacol Neurosci. 2018;16(3):282–9. https://doi.org/10.9758/cpn.2018.16.3.282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lauing K, Himes R, Rachwalski M, Strotman P, Callaci JJ. Binge alcohol treatment of adolescent rats followed by alcohol abstinence is associated with site-specific differences in bone loss and incomplete recovery of bone mass and strength. Alcohol. 2008;42(8):649–56. https://doi.org/10.1016/j.alcohol.2008.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Di Rocco G, Baldari S, Pani G, Toietta G. Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells. Cell Mol Life Sci. 2019;76(2):231–44. https://doi.org/10.1007/s00018-018-2931-8

    Article  CAS  PubMed  Google Scholar 

  85. Natoli RM, Yu H, Meislin MC, Abbasnia P, Roper P, Vuchkovska A, et al. Alcohol exposure decreases osteopontin expression during fracture healing and osteopontin-mediated mesenchymal stem cell migration in vitro. J Orthop Surg Res. 2018;13(1):101. https://doi.org/10.1186/s13018-018-0800-7

    Article  PubMed  PubMed Central  Google Scholar 

  86. Turner RT, Rosen CJ, Iwaniec UT. Effects of alcohol on skeletal response to growth hormone in hypophysectomized rats. Bone. 2010;46(3):806–12. https://doi.org/10.1016/j.bone.2009.10.027

    Article  CAS  PubMed  Google Scholar 

  87. Galliera E, Locati M, Mantovani A, Corsi MM. Chemokines and bone remodeling. Int J Immunopathol Pharmacol. 2008;21(3):485–91. https://doi.org/10.1177/039463200802100301

    Article  CAS  PubMed  Google Scholar 

  88. Shankar K, Liu X, Singhal R, Chen JR, Nagarajan S, Badger TM, et al. Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3–24-hydroxylase (CYP24A1). Endocrinology. 2008;149(4):1748–56. https://doi.org/10.1210/en.2007-0903

    Article  CAS  PubMed  Google Scholar 

  89. Turner RT, Aloia RC, Segel LD, Hannon KS, Bell NH. Chronic alcohol treatment results in disturbed vitamin D metabolism and skeletal abnormalities in rats. Alcohol Clin Exp Res. 1988;12(1):159–62. https://doi.org/10.1111/j.1530-0277.1988.tb00152.x

    Article  CAS  PubMed  Google Scholar 

  90. Freeman WM, Salzberg AC, Gonzales SW, Grant KA, Vrana KE. Classification of alcohol abuse by plasma protein biomarkers. Biol Psychiatry. 2010;68(3):219–22. https://doi.org/10.1016/j.biopsych.2010.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Freeman WM, Vanguilder HD, Guidone E, Krystal JH, Grant KA, Vrana KE. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. Int J Neuropsychopharmacol. 2011;14(7):899–911. https://doi.org/10.1017/S1461145711000046

    Article  CAS  PubMed  Google Scholar 

  92. Helms CM, Messaoudi I, Jeng S, Freeman WM, Vrana KE, Grant KA. A longitudinal analysis of circulating stress-related proteins and chronic ethanol self-administration in cynomolgus macaques. Alcohol Clin Exp Res. 2012;36(6):995–1003. https://doi.org/10.1111/j.1530-0277.2011.01685.x

    Article  CAS  PubMed  Google Scholar 

  93. Pedersen KB, Osborn ML, Robertson AC, Williams AE, Watt J, Denys A, et al. Chronic ethanol feeding in mice decreases expression of genes for major structural bone proteins in a Nox4-independent manner. J Pharmacol Exp Ther. 2020;373(3):337–46. https://doi.org/10.1124/jpet.119.264374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Watt J, Alund AW, Pulliam CF, Mercer KE, Suva LJ, Chen JR, et al. NOX4 deletion in male mice exacerbates the effect of ethanol on trabecular bone and osteoblastogenesis. J Pharmacol Exp Ther. 2018;366(1):46–57. https://doi.org/10.1124/jpet.117.247262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Watt J, Schuon J, Davis J, Ferguson TF, Welsh DA, Molina PE, et al. Reduced serum osteocalcin in high-risk alcohol using people living with HIV does not correlate with systemic oxidative stress or inflammation: data from the New Orleans alcohol use in HIV study. Alcohol Clin Exp Res. 2019;43(11):2374–83. https://doi.org/10.1111/acer.14186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Iwaniec UT, Turner RT. Animal models for osteoporosis. Osteoporosis. 4th ed. Elsevier; 2013. p. 939–61.

  97. FDA. FDA Osteoporosis: nonclinical evaluation of drugs intended for treatment guidance for industry.

  98. Gaddini GW, Grant KA, Woodall A, Stull C, Maddalozzo GF, Zhang B, et al. Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling. Bone. 2015;71:227–36. https://doi.org/10.1016/j.bone.2014.10.025

    Article  CAS  PubMed  Google Scholar 

  99. Daunais JB, Davenport AT, Helms CM, Gonzales SW, Hemby SE, Friedman DP, et al. Monkey alcohol tissue research resource: banking tissues for alcohol research. Alcohol Clin Exp Res. 2014;38(7):1973–81. https://doi.org/10.1111/acer.12467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shnitko TA, Liu Z, Wang X, Grant KA, Kroenke CD. Chronic alcohol drinking slows brain development in adolescent and young adult nonhuman primates. eNeuro. 2019;6(2). https://doi.org/10.1523/ENEURO.0044-19.2019

  101. Sureshchandra S, Rais M, Stull C, Grant K, Messaoudi I. Transcriptome profiling reveals disruption of innate immunity in chronic heavy ethanol consuming female rhesus macaques. PLoS ONE. 2016;11(7). https://doi.org/10.1371/journal.pone.0159295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cheng HJ, Grant KA, Han QH, Daunais JB, Friedman DP, Masutani S, et al. Up-regulation and functional effect of cardiac beta3-adrenoreceptors in alcoholic monkeys. Alcohol Clin Exp Res. 2010;34(7):1171–81. https://doi.org/10.1111/j.1530-0277.2010.01194.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ivester P, Roberts LJ 2nd, Young T, Stafforini D, Vivian J, Lees C, et al. Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis. Alcohol Clin Exp Res. 2007;31(1):144–55. https://doi.org/10.1111/j.1530-0277.2006.00276.x

    Article  CAS  PubMed  Google Scholar 

  104. Barr T, Sureshchandra S, Ruegger P, Zhang J, Ma W, Borneman J, et al. Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates. Gut Microbes. 2018;9(4):338–56. https://doi.org/10.1080/19490976.2018.1441663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rivas P, Moore S, Iwaniec U, Turner R, Grant K, Baker E. Optimizing support vector machine analysis in low density biological data sets. Int Conf Comput Sci Comput Intell (CSCI). 2018;2018:1357–61. https://doi.org/10.1109/CSCI46756.2018.00263

    Article  Google Scholar 

  106. Laitinen K, Tahtela R, Luomanmaki K, Valimaki MJ. Mechanisms of hypocalcemia and markers of bone turnover in alcohol-intoxicated drinkers. Bone Miner. 1994;24(3):171–9. https://doi.org/10.1016/s0169-6009(08)80134-1

    Article  CAS  PubMed  Google Scholar 

  107. Blower S, Dowlatabadi H. Sensitivity and uncertainty analysis of complex-models of disease transmission - an HIV model, as an example. Int Stat Rev. 1994;62:229–43.

    Article  Google Scholar 

  108. Gerasimchuk I, Kovalev A. Localization of nonlinear waves in layered media. Low Temp Phys. 2000;26:586–93.

    Article  Google Scholar 

  109. Naves Diaz M, O'Neill TW, Silman AJ. The influence of alcohol consumption on the risk of vertebral deformity. European Vertebral Osteoporosis Study Group. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 1997;7(1):65–71. https://doi.org/10.1007/BF01623463

  110. Isales CM, Zaidi M, Blair HC. ACTH is a novel regulator of bone mass. Ann N Y Acad Sci. 2010;1192:110–6. https://doi.org/10.1111/j.1749-6632.2009.05231.x

    Article  CAS  PubMed  Google Scholar 

  111. Abbott MJ, Roth TM, Ho L, Wang L, O’Carroll D, Nissenson RA. Negative skeletal effects of locally produced adiponectin. PLoS ONE. 2015;10(7). https://doi.org/10.1371/journal.pone.0134290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gavish H, Bab I, Tartakovsky A, Chorev M, Mansur N, Greenberg Z, et al. Human alpha 2-macroglobulin is an osteogenic growth peptide-binding protein. Biochemistry. 1997;36(48):14883–8. https://doi.org/10.1021/bi971670t

    Article  CAS  PubMed  Google Scholar 

  113. Menaa C, Esser E, Sprague SM. Beta2-microglobulin stimulates osteoclast formation. Kidney Int. 2008;73(11):1275–81. https://doi.org/10.1038/ki.2008.100

    Article  CAS  PubMed  Google Scholar 

  114. Henriksen K, Bay-Jensen AC, Christiansen C, Karsdal MA. Oral salmon calcitonin–pharmacology in osteoporosis. Expert Opin Biol Ther. 2010;10(11):1617–29. https://doi.org/10.1517/14712598.2010.526104

    Article  CAS  PubMed  Google Scholar 

  115. Li H, Lu Y, Qian J, Zheng Y, Zhang M, Bi E, et al. Human osteoclasts are inducible immunosuppressive cells in response to T cell-derived IFN-gamma and CD40 ligand in vitro. J Bone Miner Res: J Am Soc Bone Miner Res. 2014;29(12):2666–75. https://doi.org/10.1002/jbmr.2294

    Article  CAS  Google Scholar 

  116. Alblowi J, Tian C, Siqueira MF, Kayal RA, McKenzie E, Behl Y, et al. Chemokine expression is upregulated in chondrocytes in diabetic fracture healing. Bone. 2013;53(1):294–300. https://doi.org/10.1016/j.bone.2012.12.006

    Article  CAS  PubMed  Google Scholar 

  117. Collins FL, Williams JO, Bloom AC, Singh RK, Jordan L, Stone MD, et al. CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss. Bone. 2017;97:94–104. https://doi.org/10.1016/j.bone.2017.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ruddy MJ, Shen F, Smith JB, Sharma A, Gaffen SL. Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment. J Leukoc Biol. 2004;76(1):135–44. https://doi.org/10.1189/jlb.0204065

    Article  CAS  PubMed  Google Scholar 

  119. Liu C, Liu Y, Zhang W, Liu X. Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model. J Orthop Surg Res. 2017;12(1):8. https://doi.org/10.1186/s13018-017-0510-6

    Article  PubMed  PubMed Central  Google Scholar 

  120. Matsuoka K, Park KA, Ito M, Ikeda K, Takeshita S. Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J Bone Miner Res: J Am Soc Bone Miner Res. 2014;29(7):1522–30. https://doi.org/10.1002/jbmr.2187

    Article  CAS  Google Scholar 

  121. Schneider MR, Sibilia M, Erben RG. The EGFR network in bone biology and pathology. Trends Endocrinol Metab. 2009;20(10):517–24. https://doi.org/10.1016/j.tem.2009.06.008

    Article  CAS  PubMed  Google Scholar 

  122. Roedel EK, Schwarz E, Kanse SM. The factor VII-activating protease (FSAP) enhances the activity of bone morphogenetic protein-2 (BMP-2). J Biol Chem. 2013;288(10):7193–203. https://doi.org/10.1074/jbc.M112.433029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lazary A, Kosa JP, Tobias B, Lazary J, Balla B, Bacsi K, et al. Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk. Eur J Endocrinol. 2008;159(2):187–96. https://doi.org/10.1530/EJE-08-0021

    Article  CAS  PubMed  Google Scholar 

  124. Linsley C, Wu B, Tawil B. The effect of fibrinogen, collagen type I, and fibronectin on mesenchymal stem cell growth and differentiation into osteoblasts. Tissue Eng Part A. 2013;19(11–12):1416–23. https://doi.org/10.1089/ten.TEA.2012.0523

    Article  CAS  PubMed  Google Scholar 

  125. Sordet C, Cantagrel A, Schaeverbeke T, Sibilia J. Bone and joint disease associated with primary immune deficiencies. Joint Bone Spine. 2005;72(6):503–14. https://doi.org/10.1016/j.jbspin.2004.07.012

    Article  PubMed  Google Scholar 

  126. Fulzele K, Clemens TL. Novel functions for insulin in bone. Bone. 2012;50(2):452–6. https://doi.org/10.1016/j.bone.2011.06.018

    Article  CAS  PubMed  Google Scholar 

  127. Bouxsein ML, Rosen CJ, Turner CH, Ackert CL, Shultz KL, Donahue LR, et al. Generation of a new congenic mouse strain to test the relationships among serum insulin-like growth factor I, bone mineral density, and skeletal morphology in vivo. J Bone Miner Res: J Am Soc Bone Miner Res. 2002;17(4):570–9. https://doi.org/10.1359/jbmr.2002.17.4.570

    Article  CAS  Google Scholar 

  128. Zhang Q, Chen B, Yan F, Guo J, Zhu X, Ma S, et al. Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases. Biomed Res Int. 2014;2014. https://doi.org/10.1155/2014/284836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yoshimatsu M, Kitaura H, Fujimura Y, Kohara H, Morita Y, Eguchi T, et al. Inhibitory effects of IL-12 on experimental tooth movement and root resorption in mice. Arch Oral Biol. 2012;57(1):36–43. https://doi.org/10.1016/j.archoralbio.2011.07.006

    Article  CAS  PubMed  Google Scholar 

  130. Yamada A, Takami M, Kawawa T, Yasuhara R, Zhao B, Mochizuki A, et al. Interleukin-4 inhibition of osteoclast differentiation is stronger than that of interleukin-13 and they are equivalent for induction of osteoprotegerin production from osteoblasts. Immunology. 2007;120(4):573–9. https://doi.org/10.1111/j.1365-2567.2006.02538.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Schneider GB, Relfson M. Effects of interleukin-2 on bone resorption and natural immunity in osteopetrotic (ia) rats. Lymphokine Cytokine Res. 1994;13(6):335–41.

    CAS  PubMed  Google Scholar 

  132. Aguila HL, Mun SH, Kalinowski J, Adams DJ, Lorenzo JA, Lee SK. Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice. J Bone Miner Res: J Am Soc Bone Miner Res. 2012;27(5):1030–42. https://doi.org/10.1002/jbmr.1553

    Article  CAS  Google Scholar 

  133. Lotinun S, Evans GL, Turner RT, Oursler MJ. Deletion of membrane-bound steel factor results in osteopenia in mice. J Bone Miner Res: J Am Soc Bone Miner Res. 2005;20(4):644–52. https://doi.org/10.1359/JBMR.041209

    Article  CAS  Google Scholar 

  134. Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, et al. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology. 1998;139(3):1338–45. https://doi.org/10.1210/endo.139.3.5818

    Article  CAS  PubMed  Google Scholar 

  135. Kim JO, Han SH, Lee YH, Ahn TK, Lim JJ, Chung YS et al. Association of plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with osteoporotic vertebral compression fractures (OVCFs) in postmenopausal women. Int J Mol Sci. 2016;17(12). https://doi.org/10.3390/ijms17122062

  136. Orwoll ES, Lapidus J, Wang PY, Vandenput L, Hoffman A, Fink HA, et al. The limited clinical utility of testosterone, estradiol, and sex hormone binding globulin measurements in the prediction of fracture risk and bone loss in older men. J Bone Miner Res: J Am Soc Bone Miner Res. 2017;32(3):633–40. https://doi.org/10.1002/jbmr.3021

    Article  CAS  Google Scholar 

  137. Bethel M, Barnes CL, Taylor AF, Cheng YH, Chitteti BR, Horowitz MC, et al. A novel role for thrombopoietin in regulating osteoclast development in humans and mice. J Cell Physiol. 2015;230(9):2142–51. https://doi.org/10.1002/jcp.24943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sobue T, Hakeda Y, Kobayashi Y, Hayakawa H, Yamashita K, Aoki T, et al. Tissue inhibitor of metalloproteinases 1 and 2 directly stimulate the bone-resorbing activity of isolated mature osteoclasts. J Bone Miner Res: J Am Soc Bone Miner Res. 2001;16(12):2205–14. https://doi.org/10.1359/jbmr.2001.16.12.2205

    Article  CAS  Google Scholar 

  139. Huang H, Ma L, Kyrkanides S. Effects of vascular endothelial growth factor on osteoblasts and osteoclasts. Am J Orthod Dentofacial Orthop. 2016;149(3):366–73. https://doi.org/10.1016/j.ajodo.2015.09.021

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the National Institutes of Health (AA02689 to UTI and AA013510, AA13641, and AA109431 to KAG).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Urszula T. Iwaniec.

Ethics declarations

Research Involving Human and Animals Participants

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

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Turner, R.T., Sattgast, L.H., Jimenez, V.A. et al. Making Sense of the Highly Variable Effects of Alcohol on Bone. Clinic Rev Bone Miner Metab 19, 1–13 (2021). https://doi.org/10.1007/s12018-021-09277-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12018-021-09277-8

Keywords

Navigation