Compromised bone strength in patients with alcoholic liver cirrhosis
Keywords:
Osteoporosis, Alcoholic liver cirrhosis, Bone fragility, Fracture risk, Bone Mineral Density
Abstract
Osteoporosis and/or osteopenia are frequently observed complications in alcoholic liver disease patients, especially in it’s irreversible stage (alcoholic liver cirrhosis – ALC). Current literature review regarding osteoporosis incidence, increased fracture risk, bone mineral density changes, micro-structural alteration and pathogenetic mechanisms leading to ALC - induced decrease in bone quality is presented. It has been reported that osteoporosis is influencing a significant number of ALC patients, with a particular accent on the lumbar spine as most commonly affected skeletal site. Several risk factors and ethio-pathogenic mechanisms have been associated with the loss of bone mineral density in patients with ALC and other cirrhosis. Certain authors claim that the dominant mechanism in ALC-induced bone loss is a decrease in bone formation and osteoblastic function, while other results suggest increased bone remodelling as underlying cause of increased bone fragility in ALC patients. Increase bone fragility and susceptibility to osteoporotic fractures significantly affect life expectancy and quality of life in patients with ALC. Thus, osteological screening and individual fracture risk assessment are highly recommended for all patients with alcoholic liver cirrhosis.
References
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22. Campbell MS, Lichtenstein GR, Rhim AD, Pazianas M, Faust T. Severity of liver disease does not predict osteopenia or low bone mineral density in primary sclerosing cholangitis. Liver Int. 2005;25(2):311–6.
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24. Ulhøi 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. J Forensic Sci. 2017;62(1):131–6.
25. Alvisa-Negrín J, González-Reimers E, Santolaria-Fernández F, García-Valdecasas-Campelo E, Valls MRA, Pelazas-González R, et al. Osteopenia in alcoholics: Effect of alcohol abstinence. Alcohol Alcohol. 2009;44(5):468–75.
26. Kim Jin Mi, Shim Suk Myung, Kim Kyu Moon, Lee Yeon, Shin Goo Young, Chung Hee Choon KOS. Effect of Chronic Alcohol Ingestion on Bone Mineral Density in Males without Liver Cirrhosis. Korean J Intern Med. 2003;18:174–80.
27. Berg KM, Kunins H V., Jackson JL, Nahvi S, Chaudhry A, Harris KA, et al. Association Between Alcohol Consumption and Both Osteoporotic Fracture and Bone Density. Am J Med. 2008;121(5):406–18.
28. Carey EJ, Balan V, Kremers WK, Hay JE. Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: Not just a cholestatic problem. Liver Transplant. 2003;9(11):1166–73.
29. Díez-Ruiz A, García-Saura PL, García-Ruiz P, González-Calvin JL, Gallego-Rojo F, Fuchs D. Bone mineral density, bone turnover markers and cytokines in alcohol-induced cirrhosis. Alcohol Alcohol. 2010;45(5):427–30.
30. Mahmoudi A, Sellier N, Reboul-Marty J, Chalès G, Lalatonne Y, Bourcier V, et al. Bone mineral density assessed by dual-energy X-ray absorptiometry in patients with viral or alcoholic compensated cirrhosis. A prospective study. Clin Res Hepatol Gastroenterol [Internet]. 2011;35(11):731–7. Available from: http://dx.doi.org/10.1016/j.clinre.2011.07.009
31. Culafić D, Djonic D, Culafic-Vojinovic V, Ignjatovic S, Soldatovic I, Vasic J, et al. Evidence of degraded BMD and geometry at the proximal femora in male patients with alcoholic liver cirrhosis. Osteoporos Int. 2014;26(1):253–9.
32. Guichelaar MMJ, Malinchoc M, Sibonga J, Clarke BL, Hay JE. Bone metabolism in advanced cholestatic liver disease: Analysis by bone histomorphometry. Hepatology. 2002;36(4I):895–903.
33. Schnitzler CM, Mesquita JM, Shires R. Cortical and trabecular bone microarchitecture and turnover in alcohol-induced chronic pancreatitis: A histomorphometric study. J Bone Miner Metab. 2010;28(4):456–67.
34. Jorge-Hernandez JA, Gonzalez-Reimers CE, Torres-Ramirez A, Santolaria-Fernandez F, Gonzalez-Garcia C, Batista-Lopez JN, et al. Bone changes in alcoholic liver cirrhosis - A histomorphometrical analysis of 52 cases. Dig Dis Sci. 1988;33(9):1089–95.
35. Wakolbinger R, Muschitz C, Scheriau G, Bodlaj G, Kocijan R, Feichtinger X, et al. Bone microarchitecture and bone turnover in hepatic cirrhosis. Osteoporos Int. 2019;30(6):1195–204.
36. Schmidt T, Schmidt C, Schmidt FN, Butscheidt S, Mussawy H, Hubert J, et al. Disease Duration and Stage Influence Bone Microstructure in Patients With Primary Biliary Cholangitis. J Bone Miner Res. 2018;33(6):1011–9.
37. 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 [Internet]. 2020; Available from: https://doi.org/10.1007/s00198-020-05509-7
38. Wakolbinger R, Muschitz C, Wallwitz J, Bodlaj G, Feichtinger X, Schanda JE, et al. Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis. Wien Klin Wochenschr. 2020;132(1–2):19–26.
39. Crilly RG, Anderson C, Hogan D, Delaquerrière-Richardson L. Bone histomorphometry, bone mass, and related parameters in alcoholic males. Calcif Tissue Int. 1988;43(5):269–76.
40. Malik P, Gasser RW, Moncayo R, Kemmler G, Wolfgang Fleischhacker W. Markers of Bone Resorption and Formation During Abstinence in Male Alcoholic Patients. Alcohol Clin Exp Res. 2012;36(12):2059–64.
41. Emkey GR. Secondary osteoporosis. Encycl Endocr Dis. 2018;39(3):253–69.
42. Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc [Internet]. 2002;77(5):453–68. Available from: http://dx.doi.org/10.4065/77.5.453
43. Kawelke N, Bentmann A, Hackl N, Hager HD, Feick P, Geursen A, et al. Isoform of fibronectin mediates bone loss in patients with primary biliary cirrhosis by suppressing bone formation. J Bone Miner Res. 2008;23(8):1278–86.
44. Parés A, Guañabens N. Primary biliary cholangitis and bone disease. Best Pract Res Clin Gastroenterol. 2018;34–35:63–70.
45. Hegedus D, Ferencz V, Lakatos PL, Meszaros S, Lakatos P, Horvath C, et al. Decreased bone density, elevated serum osteoprotegerin, and β-cross-laps in Wilson disease. J Bone Miner Res. 2002;17(11):1961–7.
46. Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int. 2009;20(4):549–55.
47. Corazza GR, Trevisani F, Di Stefano M, De Notariis S, Veneto G, Cecchetti L, et al. Early increase of bone resorption in patients with liver cirrhosis secondary to viral hepatitis. Dig Dis Sci. 2000;45(7):1392–9.
48. 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.
49. Moschen AR, Kaser A, Stadlmann S, Millonig G, Kaser S, Mühllechner P, et al. The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol. 2005;43(6):973–83.
50. Fábrega E, Orive A, Garciá-Suarez C, Gaciá-Unzueta M, Amado JA, Pons-Romero F. Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Liver Int. 2005;25(2):305–10.
51. Bihari C, Lal D, Thakur M, Sukriti S, Mathur D, Patil AG, et al. Suboptimal Level of Bone‐Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy. Hepatol Commun. 2018;2(9):1095–110.
52. 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.
53. Mitchell R, McDermid J, Ma MM, Chik CL. MELD score, insulin-like growth factor 1 and cytokines on bone density in end-stage liver disease. World J Hepatol. 2011;3(6):157–63.
54. 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.
55. Sens C, Altrock E, Rau K, Klemis V, von Au A, Pettera S, et al. An O-Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through α4β1 Integrin. J Bone Miner Res. 2017;32(1):70–81.
56. González-Reimers E, Martín-González C, De la vega-Prieto MJ, Pelazas-González R, Fernández-Rodríguez C, López-Prieto J, et al. Serum sclerostin in alcoholics: A pilot study. Alcohol Alcohol. 2013;48(3):278–82.
2. Crawford BAL, Kam C, Donaghy AJ, McCaughan GW. The heterogeneity of bone disease in cirrhosis: A multivariate analysis. Osteoporos Int. 2003;14(12):987–94.
3. Mansueto P, Carroccio A, Seidita A, Di Fede G, Craxì A. Osteodystrophy in chronic liver diseases. Intern Emerg Med. 2013;8(5):377–88.
4. Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism [Internet]. 2016;65(8):1017–25. Available from: http://dx.doi.org/10.1016/j.metabol.2016.01.012
5. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: A review of available epidemiological data. J Hepatol [Internet]. 2013;58(3):593–608. Available from: http://dx.doi.org/10.1016/j.jhep.2012.12.005
6. Guañabens N, Parés A. Osteoporosis in chronic liver disease. Liver Int. 2018;38(5):776–85.
7. Nakchbandi IA, van der Merwe SW. Current understanding of osteoporosis associated with liver disease. Nat Rev Gastroenterol Hepatol [Internet]. 2009;6(11):660–70. Available from: http://dx.doi.org/10.1038/nrgastro.2009.166
8. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Prim [Internet]. 2018;4(1). Available from: http://dx.doi.org/10.1038/s41572-018-0014-7
9. Maurel DB, Boisseau N, Benhamou CL, Jaffre C. Alcohol and bone: Review of dose effects and mechanisms. Osteoporos Int. 2012;23(1):1–16.
10. Wibaux C, Legroux-Gerot I, Dharancy S, Boleslawski E, Declerck N, Canva V, et al. Assessing bone status in patients awaiting liver transplantation. Jt Bone Spine. 2011;78(4):387–91.
11. Ninkovic M, Love SA, Tom B, Alexander GJM, Compston JE. High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif Tissue Int. 2001;69(6):321–6.
12. Bang UC, Benfield T, Bendtsen F, Hyldstrup L, Beck Jensen JE. The risk of fractures among patients with cirrhosis or chronic pancreatitis. Clin Gastroenterol Hepatol [Internet]. 2014;12(2):320–6. Available from: http://dx.doi.org/10.1016/j.cgh.2013.04.031
13. López-Larramona G, Lucendo AJ, González-Castillo S, Tenias JM. Hepatic osteodystrophy: An important matter for consideration in chronic liver disease. World J Hepatol. 2011;3(12):300–7.
14. Otete H, Deleuran T, Fleming KM, Card T, Aithal GP, Jepsen P, et al. Hip fracture risk in patients with alcoholic cirrhosis: A population-based study using English and Danish data. J Hepatol [Internet]. 2018;69(3):697–704. Available from: https://doi.org/10.1016/j.jhep.2018.04.002
15. Liang J, Meng WD, Yang JM, Li SL, Zhong MN, Hou XX, et al. The association between liver cirrhosis and fracture risk: A systematic review and meta-analysis. Clin Endocrinol (Oxf). 2018;89(4):408–13.
16. López-Larramona G, Lucendo AJ, González-Delgado L. Alcoholic liver disease and changes in bone mineral density. Rev Española Enfermedades Dig. 2013;105(10):609–21.
17. Nakchbandi IA. Osteoporosis and fractures in liver disease: Relevance, pathogenesis and therapeutic implications. World J Gastroenterol. 2014;20(28):9427–38.
18. Milovanovic P, Vukovic Z, Antonijevic D, Djonic D, Zivkovic V, Nikolic S, et al. Porotic paradox: distribution of cortical bone pore sizes at nano- and micro-levels in healthy vs. fragile human bone. J Mater Sci Mater Med [Internet]. 2017;28(5):1–7. Available from: http://dx.doi.org/10.1007/s10856-017-5878-7
19. Mounach A, Ouzzif Z, Wariaghli G, Achemlal L, Benbaghdadi I, Aouragh A, et al. Primary biliary cirrhosis and osteoporosis: A case-control study. J Bone Miner Metab. 2008;26(4):379–84.
20. Gallego-Rojo FJ, Gonzalez-Calvin JL, Muñoz-Torres M, Mundi JL, Fernandez-Perez R, Rodrigo-Moreno D. Bone mineral density, serum insulin-like growth factor I, and bone turnover markers in viral cirrhosis. Hepatology. 1998;28(3):695–9.
21. González-Calvin JL, Mundi JL, Casado-Caballero FJ, Abadia AC, Martin-Ibañez JJ. Bone mineral density and serum levels of soluble tumor necrosis factors, estradiol, and osteoprotegerin in postmenopausal women with cirrhosis after viral hepatitis. J Clin Endocrinol Metab. 2009;94(12):4844–50.
22. Campbell MS, Lichtenstein GR, Rhim AD, Pazianas M, Faust T. Severity of liver disease does not predict osteopenia or low bone mineral density in primary sclerosing cholangitis. Liver Int. 2005;25(2):311–6.
23. Bang CS, Shin IS, Lee SW, Kim JB, Baik GH, Suk KT, et al. Osteoporosis and bone fractures in alcoholic liver disease: A meta-analysis. World J Gastroenterol. 2015;21(13):4038–47.
24. Ulhøi 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. J Forensic Sci. 2017;62(1):131–6.
25. Alvisa-Negrín J, González-Reimers E, Santolaria-Fernández F, García-Valdecasas-Campelo E, Valls MRA, Pelazas-González R, et al. Osteopenia in alcoholics: Effect of alcohol abstinence. Alcohol Alcohol. 2009;44(5):468–75.
26. Kim Jin Mi, Shim Suk Myung, Kim Kyu Moon, Lee Yeon, Shin Goo Young, Chung Hee Choon KOS. Effect of Chronic Alcohol Ingestion on Bone Mineral Density in Males without Liver Cirrhosis. Korean J Intern Med. 2003;18:174–80.
27. Berg KM, Kunins H V., Jackson JL, Nahvi S, Chaudhry A, Harris KA, et al. Association Between Alcohol Consumption and Both Osteoporotic Fracture and Bone Density. Am J Med. 2008;121(5):406–18.
28. Carey EJ, Balan V, Kremers WK, Hay JE. Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: Not just a cholestatic problem. Liver Transplant. 2003;9(11):1166–73.
29. Díez-Ruiz A, García-Saura PL, García-Ruiz P, González-Calvin JL, Gallego-Rojo F, Fuchs D. Bone mineral density, bone turnover markers and cytokines in alcohol-induced cirrhosis. Alcohol Alcohol. 2010;45(5):427–30.
30. Mahmoudi A, Sellier N, Reboul-Marty J, Chalès G, Lalatonne Y, Bourcier V, et al. Bone mineral density assessed by dual-energy X-ray absorptiometry in patients with viral or alcoholic compensated cirrhosis. A prospective study. Clin Res Hepatol Gastroenterol [Internet]. 2011;35(11):731–7. Available from: http://dx.doi.org/10.1016/j.clinre.2011.07.009
31. Culafić D, Djonic D, Culafic-Vojinovic V, Ignjatovic S, Soldatovic I, Vasic J, et al. Evidence of degraded BMD and geometry at the proximal femora in male patients with alcoholic liver cirrhosis. Osteoporos Int. 2014;26(1):253–9.
32. Guichelaar MMJ, Malinchoc M, Sibonga J, Clarke BL, Hay JE. Bone metabolism in advanced cholestatic liver disease: Analysis by bone histomorphometry. Hepatology. 2002;36(4I):895–903.
33. Schnitzler CM, Mesquita JM, Shires R. Cortical and trabecular bone microarchitecture and turnover in alcohol-induced chronic pancreatitis: A histomorphometric study. J Bone Miner Metab. 2010;28(4):456–67.
34. Jorge-Hernandez JA, Gonzalez-Reimers CE, Torres-Ramirez A, Santolaria-Fernandez F, Gonzalez-Garcia C, Batista-Lopez JN, et al. Bone changes in alcoholic liver cirrhosis - A histomorphometrical analysis of 52 cases. Dig Dis Sci. 1988;33(9):1089–95.
35. Wakolbinger R, Muschitz C, Scheriau G, Bodlaj G, Kocijan R, Feichtinger X, et al. Bone microarchitecture and bone turnover in hepatic cirrhosis. Osteoporos Int. 2019;30(6):1195–204.
36. Schmidt T, Schmidt C, Schmidt FN, Butscheidt S, Mussawy H, Hubert J, et al. Disease Duration and Stage Influence Bone Microstructure in Patients With Primary Biliary Cholangitis. J Bone Miner Res. 2018;33(6):1011–9.
37. 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 [Internet]. 2020; Available from: https://doi.org/10.1007/s00198-020-05509-7
38. Wakolbinger R, Muschitz C, Wallwitz J, Bodlaj G, Feichtinger X, Schanda JE, et al. Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis. Wien Klin Wochenschr. 2020;132(1–2):19–26.
39. Crilly RG, Anderson C, Hogan D, Delaquerrière-Richardson L. Bone histomorphometry, bone mass, and related parameters in alcoholic males. Calcif Tissue Int. 1988;43(5):269–76.
40. Malik P, Gasser RW, Moncayo R, Kemmler G, Wolfgang Fleischhacker W. Markers of Bone Resorption and Formation During Abstinence in Male Alcoholic Patients. Alcohol Clin Exp Res. 2012;36(12):2059–64.
41. Emkey GR. Secondary osteoporosis. Encycl Endocr Dis. 2018;39(3):253–69.
42. Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc [Internet]. 2002;77(5):453–68. Available from: http://dx.doi.org/10.4065/77.5.453
43. Kawelke N, Bentmann A, Hackl N, Hager HD, Feick P, Geursen A, et al. Isoform of fibronectin mediates bone loss in patients with primary biliary cirrhosis by suppressing bone formation. J Bone Miner Res. 2008;23(8):1278–86.
44. Parés A, Guañabens N. Primary biliary cholangitis and bone disease. Best Pract Res Clin Gastroenterol. 2018;34–35:63–70.
45. Hegedus D, Ferencz V, Lakatos PL, Meszaros S, Lakatos P, Horvath C, et al. Decreased bone density, elevated serum osteoprotegerin, and β-cross-laps in Wilson disease. J Bone Miner Res. 2002;17(11):1961–7.
46. Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int. 2009;20(4):549–55.
47. Corazza GR, Trevisani F, Di Stefano M, De Notariis S, Veneto G, Cecchetti L, et al. Early increase of bone resorption in patients with liver cirrhosis secondary to viral hepatitis. Dig Dis Sci. 2000;45(7):1392–9.
48. 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.
49. Moschen AR, Kaser A, Stadlmann S, Millonig G, Kaser S, Mühllechner P, et al. The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol. 2005;43(6):973–83.
50. Fábrega E, Orive A, Garciá-Suarez C, Gaciá-Unzueta M, Amado JA, Pons-Romero F. Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Liver Int. 2005;25(2):305–10.
51. Bihari C, Lal D, Thakur M, Sukriti S, Mathur D, Patil AG, et al. Suboptimal Level of Bone‐Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy. Hepatol Commun. 2018;2(9):1095–110.
52. 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.
53. Mitchell R, McDermid J, Ma MM, Chik CL. MELD score, insulin-like growth factor 1 and cytokines on bone density in end-stage liver disease. World J Hepatol. 2011;3(6):157–63.
54. 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.
55. Sens C, Altrock E, Rau K, Klemis V, von Au A, Pettera S, et al. An O-Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through α4β1 Integrin. J Bone Miner Res. 2017;32(1):70–81.
56. González-Reimers E, Martín-González C, De la vega-Prieto MJ, Pelazas-González R, Fernández-Rodríguez C, López-Prieto J, et al. Serum sclerostin in alcoholics: A pilot study. Alcohol Alcohol. 2013;48(3):278–82.