Lviv clinical bulletin 2018, 1(21)-2(22): 46-56

Peculiarities of Calcium-Phosphorus Metabolism and Bone State in Patients with Liver Cirrhosis: Diagnosis and Principles of Differential Treatment (Literature Rewiev and Clinical Case Description)

N. Drobinska, O. Abrahamovych, U. Abrahamovych, M. Farmaha

Danylo Halytsky Lviv National Medical University

Introduction. The disorders of calcium-phosphorus metabolism and bone tissue state, which are the main cause of spontaneous fractures and motor activity disorders in patients with liver cirrhosis, they require deeper understanding of etiology and pathogenesis, the use of laboratory-instrumental methods of diagnosis, taking into account risk factors and prescribing of the effective treatment to improve the quality of life. Conducting the additional studies will give impetus to the search for new methods of treatment of not only individual nosolenias, but also co- and polymorbid diseases and will help to reduce the effect of radiation from the use of medications. Aim. To make the literature review devoted to the peculiarities of calcium-phosphorus metabolism and the state of bones in patients with liver cirrhosis, methods of diagnostics and the principles of differentiated treatment, to describe the clinical case.

Materials and Methods. The content analysis, the method of system and comparative analysis, the bibliosemantic method of studying the actual scientific studies of the peculiarities of calcium-phosphorus metabolism and the state of bones in patients with liver cirrhosis, methods of diagnostics and the principles of differentiated treatment are described.

Results. The review of the literature shows the importance and urgency of the problem of studying calcium-phosphorus metabolism and the state of bone tissue in patients with cirrhosis of the liver. Mechanisms leading to pathological changes in bone tissue in such patients has been insufficiently studied. Nevertheless, there are number of common factors affecting bone metabolism: malformation of calcium and vitamin D, vitamin K deficiency, hormonal disregulation, cytokine release, insulin-like growth factor 1 (IFR-1) deficiency, etc. All efforts in the treatment are aimed at minimizing the loss of bone mass, preventing the fractures and kneading bone pain. First of all, it’s important to persuade the patient to stop smoking and drink alcohol, exercise regularly, and maintain a balanced diet with high levels of calcium and vitamin D. In the described clinical case, the patient with cirrhosis of the liver is diagnosed with osteoporosis confirmed by ultrasound densitometry and examination of calcium-phosphorus metabolism and bone tissue state by measuring the content of total calcium, ionized calcium, phosphorus, vitamin D, parathyroid hormone and markers of bone metabolism (b- crossLaps, P1NP, osteocalcin).

Conclusions. The study of the state of calcium-phosphorus metabolism and the state of bone tissue in patients with liver cirrhosis requires the use of safe and informative diadynamic methods that will be used at any stage of the disease and will help in choosing the therapeutic tactics.


  1. Abrahamovych UО, Abrahamovych OО, Tsyhanyk LV, Synenkyi OV, Guta SI. Сomparative evaluation of bone mineral density based upon the results of ultrasound osteodensitometry, X-ray osteodensitometry, and dual-energy X-ray absorptiometry tests in premenopausal women with systemic lupus erythematosus. Lviv Clinical Bulletin. 2017;1(17):32-37. (Ukrainian).
  2. Bagrova SG. Osteoporosis in cancer practice and beyond: modern approaches to the drug treatment. Оncogynecology. 2015;1:55-62. (Russian)
  3. Borsukov AV, Moiseev DO. The opportunities of ultrasound densitometry in clinical assessment of the liver cirrhosis. Medical Alphabet. 2010;1(6):36-40. (Russian) 
  4. Volkov MM, Kayukov IG, Smirnov AV. Phosphorus­calcium metabolism and its regulation. Nephrology. 2010;14(1):91-103. (Russian)
  5. Golovach IYu. New goal of osteoporosis targeted therapy – the RANKL inhibitor denosumab. Ukrainian Rheumatologist Journal. 2013;1(51):12-20. (Ukrainan)
  6. Golovach IYu. Realization of the principle of individualization osteoporosis treatment for specific clinical scenarios. Ukrainian Rheumatologist Journal. 2015;3(61):4-9. (Ukrainan)  
  7. Golovach IYu. Sclerostin and its inhibitors – a new concept in the treatment of bone diseases: a well-known past, a promising future. Pharmateca. 2015;5(298):72-77. (Russian)   
  8. Goretskaya MV. Synthetic function of the liver and humoral factors of the immune system.  Еducational Establishment Grodno State Medical University. 2008;2(22):7-11. (Russian) 
  9. Drozdov V, Embutnieks Yu. Тhe efficiency and safety of biphosphonate treatment for osteopenia and osteoporosis. The Doctor. 2010;5:67-71. (Russian) 
  10. Karateev AE, Gontarenko NV, Tsurgan AV. Digestive comorbidity in patients with rheumatic diseases: not only NSAID-induced gastropathy. Rheumatology Science and Practice. 2016;54(4):382-389. (Russian) 
  11. Kovalenko VM, Povoroznyuk VV. Recommendations for diagnosis, prevention and treatment of systemic osteoporosis in postmenopausal women: methodological guidelines. K., 2010. 50 p. (Ukrainan)
  12. Masalova NN, Zakharenko RV. Normal calcium-phosphor and bone metabolism and its disorders in thyroid dysfunction. Dalnevostochnyi Meditsinslkiy Zhurnal. 2009;2:122-125. (Russian) 
  13. Mytnyk ZM, Golovach IYu. Calcium and phosphorus metabolism, bone turnover and the state of calcium regulated hormones in patients with alcoholic liver disease. Contemporary Gastroenterology. 2009;4(48):32-37. (Ukrainan)
  14. Mytnyk ZM, Golovach IYu. Development of secondary hyperparathyroidism in patients with cirrhosis of the liver and condition of mineral density of bone tissue. International Journal of Endocrinology. 2006;2(4):59-64. (Ukrainan)
  15. Povoroznyuk VV, Balacka NI. The role of markers of bone remodeling in diagnosing systemic osteoporosis. Art of Treatment. 2013;2-3(98-99):12-14. (Ukrainan)
  16. Povoroznyuk VV, Grygorieva NV, Povorozniuk VasV. Ultrasound densitometry in the evaluation of structural and functional status of bone tissue. Pain Joints Spine. 2013;4(12):5-12. (Ukrainan)
  17. Povoroznуuk VV, Grуgorieva NV, Kanis JA, McCloskey EV, Johansson H. Ukrainian version of FRAX: from creation to validation. Pain Joints Spine. 2016;3(23):5-14. (Ukrainan)
  18. Synenkyi OV. The influence of vitamin d deficiency on the rheumatoid arthritis activity and the ways of its corrections.  Lviv Clinical Bulletin. 2017;4(20):15-24. (Ukrainan)
  19. Topcheeva ON. The 2-nd place in the competition of young scientists of the NGO in 2010. Experimental and Clinical Gastroenterology. 2010;6:89-94. (Russian) 
  20. Chirkin AA. Molecular mechanisms of liver damage. Immunology, Allergology, Infectology. 2000;1:27-34. (Russian) 
  21. Baccaro LF, Boin IF, Pedro AO, Costa-Paiva L, Leal AL, Ramos CD, Pinto-Neto AM. Decrease in bone mass in women after liver transplantation: associated factors. Transplant Proc. 2011;43:1351-1356.
  22. Bansal RK, Kumar M, Sachdeva PRM, Kumar A. Prospective study of profile of hepatic osteodystrophy in patients with non-choleastatic liver cirrhosis and impact of bisphosphonate supplementation. United European Gastroenterol J. 2016;4(1):77-83.
  23. Bonewald LF. Osteocytes. In: Rosen CJ (ed). Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th edn. Wiley-Blackwell, Iowa. 2013;34-41.
  24. Capra F, Casaril M, Gabrielli GB, Stanzial A, Ferrari S, Gandini G et al. Plasma osteocalcin levels in liver cirrhosis. Ital J Gastroenterol. 1991;23(3):124-127.
  25. Chinnaratha MA, Chaudhary S, Doogue M, McCormick RJ, Woodman RJ, Wigg AJ. Prevalence of hepatic osteodystrophy and vitamin D deficiency in cirrhosis. Intern Med J. 2015;45(12):1230-1235.
  26. Collier J. Bone disorders. Cirrhosis: A practical guide to management (eds Lee SS, Moreau R). 2015;Chapter 25:283-290.
  27. Collier JD, Ninkovic M, Compston J E. Guidelines on the management of osteoporosis associated with chronic liver disease. Gut. 2002;50(1):i1-i9.
  28. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16)1532-1543.
  29. Culafic-Vojinovic V, Culafic D, Ignjatovic S, Petakov M, Nikolic Marina D et al. The clinical importance of biochemical bone markers in patients with alcoholic and viral liver cirrhosis. J Med Biochem. 2014;33(2):149-155.
  30. Dai J, Lin D, Zhang J, Habib P, Smith P, Murtha J et al. Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice. J Clin Invest. 2000;106(7):887-895.
  31. 3 Davies M, Mawer EB, Klass HJ, Lumb GA, Berry JL, Warnes TW. Vitamin D deficiency, osteomalacia, and primary biliary cirrhosis. Response to orally administered vitamin D3.   Dig Dis Sci.1983;28(2):145-153.
  32. Diamond T, Stiel D, Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med. 1989;110(6): 430-436.
  33. Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017;23(9):1072-1079.
  34. Fisher L, Fisher A. Relationship between serum gamma-glutamyltransferase (GGT) activity and indices of iron metabolism with bone-mineral parameters in orthogeriatric patients. J Biomedical Sci. 2016;5(4).
  35. 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):695-699.
  36. Gatta A, Verardo A, Pascoli MD, Giannini S, Bolognesi M. Hepatic osteodystrophy. Clin Cases Miner Bone Metab. 2014;11(3):185-191.
  37. Ge JR, Xie LH, Chen J, Li SQ, Xu HJ, Lai YL et al. Liuwei Dihuang Pill () treats postmenopausal osteoporosis with Shen (Kidney) yin deficiency via Janus kinase/signal transducer and activator of transcription signal pathway by up-regulating cardiotrophin-like cytokine factor 1 expression. Chin J Integr Med. 2016;1-8.
  38. Giouleme OI, Vyzantiadis TA, Nikolaidis NL, Vasiliadis TG, Papageorgiou AA, Eugenidis NP et al. Pathogenesis of osteoporosis in liver cirrhosis. Hepato-Gastroenterology. 2006;53(72):938-943.
  39. Goral V, Simsek M, Mete N. Hepatic osteodystrophy and liver cirrhosis. World J Gastroenterol. 2010;16(13):1639-1643.
  40. Grey A, Mitnick M-A, Masiukiewicz U, Sun BH, Rudikoff S, Jilka RL et al. A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology. 1999;140(10):4683-4690.
  41. Grossmann M, Hoermann R, Gani L, Chan I, Cheung A, Gow PJ et al. Low testosterone levels as an independent predictor of mortality in men with chronic liver disease. Clin Endocrinol. 2012;77(2):323-328.
  42. Guañabens N, Monegal A, Muxi A, Martinez-Ferrer A, Reyes R, Caballería J et al. Patients with cirrhosis and ascites have false values of bone density: implications for the diagnosis of osteoporosis. Osteoporos Int. 2012;23(4):1481-1487.
  43. Guañabens N, Monegal A, Cerdá D, Muxí Á, Gifre L, Peris P et al. Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis. Hepatology. 2013;58(6):2070-2078.
  44. Guañabens N, Parés A. Management of osteoporosis in liver disease. Clin Res Hepatol Gastroenterol. 2011;35(6):438-445.
  45. Guañabens N, Ruiz-Gaspà S, Gifre L, Miquel R, Peris P, Monegal A et al. Sclerostin expression in bile ducts of patients with chronic cholestasis may influence the bone disease in primary biliary cirrhosis. J Bone Miner Res. 2016;31(9):1725-1733.
  46. Guarino M, Loperto I, Camera S, Cossiga V, Di Somma C, Colao A et al. Osteoporosis across chronic liver disease. Osteoporos Int. 2016;27(6):1967-1977.
  47. Hajiabbasi A, Shafaghi A, Fayazi HS, Masooleh IS, Emami MHH, Parsa PG et al. The factors affecting bone density in cirrhosis. Hepat Mon. 2015;15(4):e26871.
  48. Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv Endocrinol Metab. 2016;7(3):128-135.
  49. Hiramatsu K, Asaba Y, Takeshita S Nimura Y, Tatsumi S, Katagiri N et al. Overexpression of γ-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis. Endocrinology. 2007;148(6):2708-2715.
  50. Janes CH, Dickson ER, Okazaki R, Bonde S, McDonagh AF, Riggs BL. Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice. J Clin Invest. 1995;95(6):2581-2586.
  51. Kawazoe Y, Miyauchi M, Nagasaki A, Furusho H, Yanagisawa S, Chanbora C et al. Osteodystrophy in Cholestatic liver diseases is attenuated by anti-γ-glutamyl transpeptidase antibody. PLoS ONE. 2015;10(9):e0139620.
  52. Kinyó Á, Belső N, Nagy N, Pálvölgyi A, Nagy I, Korom I et al. Strontium ranelate-induced DRESS syndrome with persistent autoimmune hepatitis. Acta Derm Venereol. 2011;91(2):205-206.
  53. Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology. 1991;13(2):267-276.
  54. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479-1491.
  55. Klein S, Rick J, Lehmann J, Schierwagen R, Schierwagen IG, Verbeke L et al. Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut. 2017;66(1):145-155.
  56. Knopp-Sihota JA, Cummings GG, Homik J, Voaklander D. The association between serious upper gastrointestinal bleeding and incident bisphosphonate use: a population-based nested cohort study. BMC Geriatr. 2013;13(1):36.
  57. Koshihara Y, Hoshi K, Okawara R, Ishibashi H, Yamamoto S. Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell culture. J Endocrinol. 2003;176(3):339-348.
  58. Krol C, Meiland D, Dekkers O, van der Veer E, Kroon H, Rabelink T et al. Pitfalls in the interpretation of bone turnover markers in liver transplantation. Endocrine Abstracts. 2015;37:EP226.
  59. Krzyżanowska P, Drzymała-Czyż S, Pogorzelski A, Duś-Żuchowska M, Skorupa W, Bober L et al. Vitamin K status in cystic fibrosis patients with liver cirrhosis. Dig Liver Dis. 2017; 49(6):672-675.
  60. Luger M, Kruschitz R, Kienbacher C, Traussnigg S, Langer FB, Schindler K et al. Prevalence of liver fibrosis and its association with non-invasive fibrosis and metabolic markers in morbidly obese patients with vitamin D deficiency. Obes Surg. 2016;26(10):2425-2432.
  61. Martinez-Ferrer A, Reyes R, Monegal A, Muxi A, Caballeria J, Peris P et al. Patients with ascites have false values of bone mineral density at the central skeleton. A prospective study. j Hepatol. 2010;52:S331.
  62. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9)1115-1117.
  63. McGee-Lawrence ME, Hamrick MW. Control of bone homeostasis by the Wnt inhibitor sclerostin. Curr Mol Bio Rep. 2016;2(3):141-148.
  64. Melkko J, Hellevik T, Risteli L, Risteli J, Smedsrød S. Clearance of NH2-terminal propeptides of types I and III Procollagen is a physiological function of the scavenger receptor in liver endothelial cells. J Exp Med. 1994;179(2):405-412.
  65. Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014;12(1):145.
  66. Monegal A, Navasa M, Guanabens N, Peris P, Pons F, De Osaba MM et al. Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos Int. 2001;12(6):484-492.
  67. Nakchbandi IA, Lang R, Kinder B, Insogna KL. The role of the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. J Clin Endocrinol Metab. 2008;93(3):967-973.
  68. Nakchbandi IA. Osteoporosis and fractures in liver disease: relevance, pathogenesis and therapeutic implications. World J Gastroenterol. 2014;20(28):9427-9438.
  69. Nakchbandi IA, Van Der Merwe SW. Current understanding of osteoporosis associated with liver disease. Nature Reviews Gastroenterology and Hepatology. 2009;6(11):660-670.
  70. Nishiguchi S, Shimoi S, Kurooka H, Tamori A, Habu D, Takeda T et al. Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol. 2001; 35(4):543-545.
  71. Okabe R, Inaba M, Nakatsuka K, Miki T, Naka H, Moriguchi A et al. Significance of serum CrossLaps as a predictor of changes in bone mineral density during estrogen replacement therapy; comparison with serum carboxyterminal telopeptide of type I collagen and urinary deoxypyridinoline. J Bone Miner Metab. 2004;22(2):127-131.
  72. Pan WL, Chen PL, Lin CY, Pan YC, Ju YR, Chan CP et al. Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: a case report. Clin Interv Aging. 2017;12:1089-1093.
  73. Parés A, Guañabens N. Bone disease in patients with cirrhosis. In Complications of Cirrhosis. 2015;295-305. Springer, Cham.
  74. Patel N, Muñoz SJ. Bone disease in cirrhosis. Clinical Liver Disease. 2015;6(4):96-99.
  75. Paternostro R, Wagner D, Reiberger T, Mandorfer M, Schwarzer R, Ferlitsch M et al. Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr. 2017;129(1-2):8-15.
  76. Pavel OR, Popescu M, Novac L, Mogoantă L, Pavel LP, Vicaş RM et al. Postmenopausal osteoporosis – clinical, biological and histopathological aspects. Rom J Morphol Embryol. 2016;57(1):121-130.
  77. Qvist P, Petersen KR, Jespersen J, Vinberg N, Christiansen C. Lack of hepatic metabolism of C-telopeptides of type I collagen. Clin Chim Acta. 2006;366(1):344-347.
  78. Raszeja-Wyszomirska J, Kucharski R, Kotarska K, Zalewska M, Miazgowski T. The impact of osteoporosis on health-related quality of life in patients after liver transplantation – a pilot study. Prz Gastroenterol. 2015;10(4):215-221.
  79. Rhee Y. Kim WJ, Han KJ, Lim SK, Kim SH. Effect of liver dysfunction on circulating sclerostin. J Bone Miner Metab. 2014;32(5):545-549.
  80. Ruellas O, Martins A, Peruzzo DC, Napimoga MH. Managing bisphosphonate-related osteonecrosis of the jaws with xenografts: a case report. Clin Case Rep. 2017;5(8):1395-1400.
  81. Santos LAA, Romeiro FG. Diagnosis and Management of Cirrhosis-Related Osteoporosis. Biomed Res Int. 2016;2016:1-12.
  82. Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 2014;3.
  83. Siris ES, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25(5):1439-1443.
  84. Smith DL, Shire NJ, Watts NB, Schmitter T, Szabo G, Zucker SD. Hyperbilirubinemia is not a major contributing factor to altered bone mineral density in patients with chronic liver disease. J Clin Densitom. 2006;9(1):105-113.
  85. Szalay F, Hegedus D, Lakatos PL, Tornai I, Bajnok E, Dunkel K et al. High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepat. 2003;38(4):395-400.
  86. Tanaka M, Itoh S, Yoshioka T, Yamashita K. The therapeutic effectiveness of the coadministration of weekly risedronate and proton pump inhibitor in osteoporosis treatment. J Osteoporos. 2014;2014:607145.
  87. Van Leeuwen J, van Driel M, van den Bemd G, Pols H. Vitamin D control of osteoblast function and bone extracellular matrix mineralization. Crit Rev Eukaryot Gene Expr. 2001;11(1-3):199-226.
  88. Veidal SS, Vassiliadis E, Bay-Jensen AC, Tougas G, Vainer B, Karsdal MA. Procollagen type I N-terminal propeptide (PINP) is a marker for fibrogenesis in bile duct ligation-induced fibrosis in rats. Fibrogenesis Tissue Repair. 2010;3(1):5.
  89. Wang D, Yin J, Dong R, Zhao J, Wang Q, Wang N et al. Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats. Dig Liver Dis. 2015;47(4);315-323.
  90. Wheater G, Elshahaly M, Tuck SP, Datta HK, van Laar JM. The clinical utility of bone marker measurements in osteoporosis. J Transl Med. 2013;11:201.
  91. Yurci A, Kalkan AO, Ozbakir O, Karaman A, Torun E, Kula M et al. Efficacy of different therapeutic regimens on hepatic osteodystrophy in chronic viral liver disease. Eur J Gastroenterol Hepatol. 2011;23(12):1206-1212.
  92. Zhou X, Gu Y, Xiao H, Kang N, Xie Y, Zhang G et al. Combining Vγ9Vδ2 T cells with a lipophilic bisphosphonate efficiently kills activated hepatic stellate cells. Front Immunol. 2017;8:1381.