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Osteoporosis International
Published in: Osteoporosis International 6/2016

01-06-2016 | Review

Osteoporosis across chronic liver disease

Authors: M. Guarino, I. Loperto, S. Camera, V. Cossiga, C. Di Somma, A. Colao, N. Caporaso, F. Morisco

Published in: Osteoporosis International | Issue 6/2016

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Abstract

Osteoporosis is a complication of chronic liver disease, with impact on morbidity, quality of life, and survival. The progress of medicine and the new therapies stretched the disease’s natural history and improved the survival of patients with liver disease. So, it is fundamental to make better the quality of life and to prevent complications. Metabolic bone disorders are common complications of chronic liver disease (CLD). Patients with CLD have an increased risk of bone fractures, with significant impact on morbidity, quality of life, and even on survival. Bone diseases, including osteomalacia, osteoporosis, and osteopenia, are frequently observed in many types of liver disease. The pathogenesis of damage and the mechanisms of bone loss are different in relation to the specific liver disease. The relevance of these conditions induced many authors to create a new nosographic entity known as “hepatic osteodystrophy”, although this term is rarely used anymore and it is now commonly referred to as osteopenia or osteoporosis associated with chronic liver disease. This review is based on the personal experiences of the authors and upon research done of the available literature on this subject matter. The authors searched the PubMed database for publications containing the term “liver disease” in combination with “bone disease”, “hepatic osteodistrophy”, “osteoporosis”, “osteopenia”, “osteomalacia”, and “fractures”. They selected publications from the past 10 years but did not exclude older seminal publications, especially for colestatic liver diseases. This review of literature shows that osteoporosis crosses all CLD. It is important to underline that the progress of medicine and the new therapies stretched the disease’s natural history and improved the survival of patients with CLD. It is fundamental to make better the quality of life and it is mandatory to prevent complications and in particular the osteoporotic ones, especially fractures.
Literature
1.
Blachier M, Leleu H, Peck-Radosavljevic M et al (2013) The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 58(3):593–608CrossRefPubMed
2.
3.
Christodoulou S, Goula T, Ververidis A et al (2013) Vitamin D and bone disease. Biomed Res Int 2013:396–541CrossRef
4.
Arteh J, Narra S, Nair S (2010) Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci 55(9):2624–2628CrossRefPubMed
5.
6.
7.
Krawitt EL, Grundman MJ, Mawer EB (1977) Absorption, hydroxylation, and excretion of vitamin D3 in primary biliary cirrhosis. Lancet 2(8051):1246–1249CrossRefPubMed
8.
WHO (2003) Prevention and management of osteoporosis. World Health Organ Tech Rep Ser 921:1–164
9.
Dontas IA, Yiannakopoulos CK (2007) Risk factors and prevention of osteoporosis-related fractures. J Musculoskelet Nueronal Interact 7(3):268–272
10.
Collier JD, Ninkovic M, Compston JE (2002) Guidelines on the management of osteoporosis associated with chronic liver disease. Gut 50(Suppl 1):1–9CrossRef
11.
Lucaci C, Acalovschi M (2012) Hormonal and cytokine implications in the pathophysiology of osteoporosis occurring in chronic liver diseases. Maedica (Buchar) 7(4):358–363
12.
Aubin JE, Triffitt JT (2002) Mesenchymal stem cells and osteoblast differentiation. Princ Bone Biol 1:59–81CrossRef
13.
Moschen AR, Kaser A, Stadlmann S et al (2005) The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol 43(6):973–983CrossRefPubMed
14.
15.
Fede G, Spadaro L, Tomaselli T et al (2012) Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 55(4):1282–1291CrossRefPubMed
16.
Kim CH, Takai E, Zhou H et al (2003) Trabecular bone response to mechanical and parathyroid hormone stimulation: the role of mechanical microenvironment. J Bone Miner Res 18(12):2116–2125CrossRefPubMed
17.
Lombardi G, Di Somma C, Rubino M et al (2011) The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics. J Endocrinol Investig 34(7 Suppl):18–22
18.
Nuzzo V, Zuccoli A, De Terlizzi F et al (2013) Low 25-hydroxyvitamin d levels and low bone density assessed by quantitative ultrasonometry in a cohort of postmenopausal Italian nuns. J Clin Densitom 16(3):308–312CrossRefPubMed
19.
Autier P, Boniol M, Pizot C et al (2014) Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2(1):76–89CrossRefPubMed
20.
Chaney A, Heckman MG, Diehl NN et al (2015) Effectiveness and outcomes of current practice in treating vitamin D deficiency in patients listed for liver transplantation. Endocr Pract 21(7):761–769CrossRefPubMed
21.
Artaza JN, Norris KC (2009) Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. J Endocrinol 200(2):207–221CrossRefPubMedPubMedCentral
22.
Nobili V, Reif S (2015) Vitamin D and liver fibrosis: let’s start soon before it’s too late. Gut 64(5):698–699CrossRefPubMed
23.
Beilfuss A, Sowa JP, Sydor S et al (2015) Vitamin D counteracts fibrogenic TGF-beta signaling in human hepatic stellate cells both receptor-dependently and independently. Gut 64(5):791–799CrossRefPubMed
24.
Wang J, Zhou J, Cheng CM et al (2004) Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 180(2):247–255CrossRefPubMed
25.
Weinstein RS, Jilka RL, Parfitt AM et al (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Investig 102(2):274–282CrossRefPubMedPubMedCentral
26.
Mirza F, Canalis E (2015) Management of endocrine disease: secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 173(3):R131–R151CrossRefPubMed
27.
Gupte AA, Sabek OM, Fraga D et al (2014) Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 155(12):4697–4705CrossRefPubMed
28.
Ducy P, Amling M, Takeda S et al (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197–207CrossRefPubMed
29.
Caetano-Lopes J, Canhao H, Fonseca JE (2009) Osteoimmunology—the hidden immune regulation of bone. Autoimmun Rev 8(3):250–255CrossRefPubMed
30.
Hackl NJ, Bersch C, Feick P et al (2010) Circulating fibronectin isoforms predict the degree of fibrosis in chronic hepatitis C. Scand J Gastroenterol 45(3):349–356CrossRefPubMed
31.
Wariaghli G, Mounach A, Achemlal L et al (2010) Osteoporosis in chronic liver disease: a case–control study. Rheumatol Int 30(7):893–899CrossRefPubMed
32.
Benetti A, Crosignani A, Varenna M et al (2008) Primary biliary cirrhosis is not an additional risk factor for bone loss in women receiving regular calcium and vitamin D supplementation: a controlled longitudinal study. J Clin Gastroenterol 42(3):306–311PubMed
33.
Guanabens N, Pares A, Ros I et al (2005) Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis. J Hepatol 42(4):573–577CrossRefPubMed
34.
Solaymani-Dodaran M, Card TR, Aithal GP et al (2006) Fracture risk in people with primary biliary cirrhosis: a population-based cohort study. Gastroenterology 131(6):1752–1757CrossRefPubMed
35.
Pares A, Guanabens N (2008) Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment. Clin Liver Dis 12(2):407–424CrossRefPubMed
36.
Guañabens N, Cerdá D, Monnegal A et al (2010) Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis. Gastroenterology 138(7):2348–2356CrossRefPubMed
37.
Mounach A, Ouzzif Z, Wariaghli G et al (2008) Primary biliary cirrhosis and osteoporosis: a case–control study. J Bone Miner Metab 26(4):379–384CrossRefPubMed
38.
39.
Menon KV, Angulo P, Weston S et al (2011) Bone disease in primary biliary cirrhosis: independent indicators and rate of progression. J Hepatol 35(3):316–323CrossRef
40.
Raszeja-Wyszomirska J, Kucharski R, Zygmunt M et al (2015) The impact of fragility fractures on health-related quality of life in patients with PSC. Hepat Mon 15(4):e25539CrossRefPubMedPubMedCentral
41.
Reiter FP, Hohenester S, Nagel JM et al (2015) 1,25-(OH)2-vitamin D3 prevents activation of hepatic stellate cells in vitro and ameliorates inflammatory liver damage but not fibrosis in the Abcb4(−/−) model. Biochem Biophys Res Commun 459(2):227–233CrossRefPubMed
42.
Guggenbuhl P, Deugnier Y, Boisdet JF et al (2005) Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 16(12):1809–1814CrossRefPubMed
43.
Valenti L, Varenna M, Fracanzani AL et al (2009) Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 20(4):549–555CrossRefPubMed
44.
Schiefke I, Fach A, Wiedmann M (2005) Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection. World J Gastroenterol 11:1843–1847CrossRefPubMedPubMedCentral
45.
Corey KE, Zheng H, Mendez-Navarro J et al (2012) Serum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis. PLoS One 7(2):e27144CrossRefPubMedPubMedCentral
46.
Morisco F, Colao A, Guarino M et al (2013) Vitamin D levels and chronic hepatitis C. e-SPEN J 4(8):e169–e174CrossRef
47.
Fisher L, Fisher A (2007) Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol 5(4):513–520CrossRefPubMed
48.
Petta S, Grimaudo S, Marco VD et al (2013) Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients. J Viral Hepatol 20(7):486–493CrossRef
49.
Petta S, Grimaudo S, Tripodo C et al (2015) The hepatic expression of vitamin D receptor is inversely associated with the severity of liver damage in genotype 1 chronic hepatitis C patients. J Clin Endocrinol Metabol 100(1):193–200CrossRef
50.
Villar LM, Ronchal I, Del Campo JA (2012) Vitamin D supplementation influences sustained virological response rate in hepatitis C: a systematic review and meta-analysis. Hepatology 256(supplement 2):1024A
51.
Kitson MT, Dore GJ, George J et al (2013) Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection. J Hepatol 58(3):467–472CrossRefPubMed
52.
Esmat G, El Raziky M, Elsharkawy A et al (2015) Impact of vitamin D supplementation on sustained virological response in chronic hepatitis C genotype 4 patients treated by pegylated interferon/ribavirin. J Interferon Cytokine Res 35(1):49–54CrossRefPubMed
53.
Mandorfer M, Payer BA, Schwabl P et al (2015) Revisiting liver disease progression in HIV/HCV-coinfected patients: the influence of vitamin D, insulin resistance, immune status, IL28B and PNPLA3. Liver Int 35(3):876–885CrossRefPubMed
54.
Di Carlo P, Siracusa L, Mazzola G et al (2015) Vitamin D and osteoporosis in HIV/HCV coinfected patients: a literature review. Int J Endocrinol 2015:969040CrossRefPubMedPubMedCentral
55.
Bang CS, Shin IS, Lee SW et al (2015) Osteoporosis and bone fractures in alcoholic liver disease: a meta-analysis. World J Gastroenterol 21(13):4038–4047CrossRefPubMedPubMedCentral
56.
57.
González-Reimers E, García-Valdecasas-Campelo E, Santolaria-Fernández F et al (2005) Rib fractures in chronic alcoholic men: relationship with feeding habits, social problems, malnutrition, bone alterations, and liver dysfunction. Alcohol 37(2):113–117CrossRefPubMed
58.
Moore JB (2010) Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc 69(2):211–220CrossRefPubMed
59.
Fabbrini E, Sullivan S, Klein S (2010) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51(2):679–689CrossRefPubMedPubMedCentral
60.
Yaturu S, Humphrey S, Landry C et al (2009) Decreased bone mineral density in men with metabolic syndrome alone and with type 2 diabetes. Med Sci Monit 15(1):CR5–CR9PubMed
61.
Szulc P, Varennes A, Delmas PD et al (2010) Men with metabolic syndrome have lower bone mineral density but lower fracture risk—the MINOS study. J Bone Miner Res 25(6):1446–1454CrossRefPubMed
62.
Jeon YK, Lee YG, Kim SS et al (2011) Association between bone mineral density and metabolic syndrome in pre and postmenopausal women. Endocr J 58(2):87–93CrossRefPubMed
63.
Targher G, Lonardo A, Rossini M (2015) Nonalcoholic fatty liver disease and decreased bone mineral density: is there a link? J Endocrinol Investig 38(8):817–825CrossRef
64.
Li M, Xu Y, Xu M et al (2012) Association between nonalcoholic fatty liver disease (NAFLD) and osteoporotic fracture in middle-aged and elderly Chinese. J Clin Endocrinol Metab 97(6):2033–2038CrossRefPubMed
65.
Moon SS, Lee YS, Kim SW (2012) Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women. Endocrine 42(2):423–429CrossRefPubMed
66.
Skoien R, Richardson MM, Jonsson JR et al (2013) Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. Liver Int 33:624–632CrossRefPubMed
67.
Nobili V, Giorgio V, Liccardo D et al (2014) Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol 170:547–553CrossRefPubMed
68.
Monegal A, Navasa M, Guanabens N et al (2001) Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos Int 12(6):484–492CrossRefPubMed
69.
70.
Chinnaratha MA, Chaudhary S, Doogue M et al (2015) Prevalence of hepatic osteodystrophy and vitamin D deficiency in cirrhosis. Int Med J. doi:10.​1111/​imj.​12866
71.
Trépo E, Ouziel P, Pradat P (2013) Severe vitamin D deficiency is associated with complications of portal hypertension and a worse prognosis in alcoholic cirrhosis. J Hepatol 58:S54CrossRef
72.
Kulak CA, Borba VZ, Kulak Júnior J et al (2014) Bone disease after transplantation: osteoporosis and fractures risk. Arq Bras Endocrinol Metab 58(5):484–492CrossRef
73.
Loria I, Albanese C, Giusto M et al (2010) Bone disorders in patients with chronic liver disease awaiting liver transplantation. Transplant Proc 42(4):1191–1193CrossRefPubMed
74.
Galtieri PA, Lattanzi B, Giusto M (2013) Bone disorders before and after liver transplantation. J Hepatol 58:S70CrossRef
75.
Ninkovic M, Love SA, Tom B (2001) High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif Tissue Int 69(6):321–326CrossRefPubMed
76.
Corey RL, Whitaker MD, Crowell MD et al (2014) Vitamin D deficiency, parathyroid hormone levels, and bone disease among patients with end-stage liver disease and normal serum creatinine awaiting liver transplantation. Clin Transpl 28(5):579–584CrossRef
77.
Guichelaar M, Malinchoc M, Sibonga J et al (2004) Immunosuppressive and postoperative effects of orthotopic liver transplantation on bone metabolism. Liver Transpl 10(5):638–647CrossRefPubMed
78.
Guichelaar M, Schmoll J, Malinchoc M et al (2007) Fractures and avascular necrosis before and after orthotopic liver transplantation: long-term follow-up and predictive factors. Hepatology 46(4):1198–1207CrossRefPubMed
79.
Guichelaar M, Kendall R, Malinchoc M et al (2006) Bone mineral density before and after OLT: long-term follow-up and predictive factors. Liver Transpl 12(9):1390–1402CrossRefPubMed
80.
Chaney A (2015) Primary care management of vitamin D deficiency and liver disease. J Am Assoc Nurse Pract 27(8):415–419PubMed
81.
Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (2013) Guidelines for the diagnosis, prevention and treatment of osteoporosis. Minerva Endocrinol 38:1–30
82.
Maimoun L, Sultan C (2011) Effects of physical activity on bone remodeling. Metabolism 60(3):373–388CrossRefPubMed
83.
Zelber-Sagi S, Ratziu V, Oren R (2011) Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol 17(29):377–389CrossRef
84.
Peng L, Wang J, Li F (2011) Weight reduction for non-alcoholic fatty liver disease. Cochrane Database Syst Rev 15(6):CD003619
85.
Brandi ML (2012) Evaluation of fracture risk and fracture prevention: an Italian picture. Clin Cases Miner Bone Metab 9(2):73–75PubMedPubMedCentral
86.
Otaka Y (2013) Fall risk and fracture. Secondary prevention of falls after sustaining a fall-related fracture. Clin Calcium 23(5):739–744PubMed
87.
Asano S, Suzuki A (2013) Assessment of the treatment of glucocorticoid-induced osteoporosis. Clin Calcium 23(3):401–408PubMed
88.
Pereira RM, Carvalho JF, Paula AP et al (2012) Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Rev Bras Reumatol 52(4):580–593CrossRefPubMed
89.
Hagino H (2015) Vitamin D3 analogs for the treatment of osteoporosis. Can J Physiol Pharmacol 93(5):327–332CrossRefPubMed
90.
91.
Guanabens N, Pares A, Ros I et al (2003) Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol 98(10):2268–2274CrossRefPubMed
92.
Zein CO, Jorgensen RA, Clarke B et al (2005) Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology 42(4):762–771CrossRefPubMed
93.
Monegal A, Guanabens N, Suarez MJ et al (2009) Pamidronate in the prevention of bone loss after liver transplantation: a randomized controlled trial. Transpl Int 22(2):198–206CrossRefPubMed
94.
Atamaz F, Hepguler S, Karasu Z et al (2006) The prevention of bone fractures after liver transplantation: experience with alendronate treatment. Transplant Proc 38(5):1448–1452CrossRefPubMed
95.
Shane E, Cohen A, Stein EM (2012) Zoledronic acid versus alendronate for the prevention of bone loss after heart or liver transplantation. J Clin Endocrinol Metab 97:4481–4490CrossRefPubMedPubMedCentral
96.
97.
O'Donohue J, Williams J (1997) Hormone replacement therapy in women with liver disease. B J Obstet Gynaecol 104(1):1–3CrossRef
98.
Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C (2011) Hormone replacement for osteoporosis in women with primary biliary cirrhosis. Cochrane Database Syst Rev 7(12):CD009146
99.
Ormarsdottir S, Mallmin H, Naessen T et al (2004) An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis. J Intern Med 256(1):63–69CrossRefPubMed
Metadata
Title
Osteoporosis across chronic liver disease
Authors
M. Guarino
I. Loperto
S. Camera
V. Cossiga
C. Di Somma
A. Colao
N. Caporaso
F. Morisco
Publication date
01-06-2016
Publisher
Springer London
Published in
Osteoporosis International / Issue 6/2016
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-016-3512-z

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