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• W2034626585 abstract "1. IntroductionOsteoporosis is a common complication of chronic liver disease from cholestatic disorders to autoimmune, alcoholic and posthepatitic cirrhosis. Its aetiology is poorly understood and may vary in different liver diseases. Most symptomatic bone diseases in patients with liver disease are revealed only after liver transplantation (OLT) when early rapid bone loss leads to a high rate of fracturing in the first postoperative year. Reduced bone mass before OLT is the main risk factor for posttransplant fracturing and, therefore, its understanding and management are of prime importance. Optimal management of posttransplant osteopenia requires consideration of pre- and posttransplant factors.By WHO criteria, osteoporosis is defined as bone of reduced density to less than 2.5 standard deviations below normal adult peak bone mass, adjusted for male or female sex, i.e. T-score of less than −2.5. Implicit in this definition is that the bone, albeit of small volume, is normally mineralised (no osteomalacia) and has no other pathological changes. Reduced bone density of T-score of −1.0 to −2.5 is called osteopenia. Osteopenia is also used as a collective term for both osteopenia and osteoporosis.2. Aetiology of osteopenia before and after liver transplantationBone undergoes continuous remodelling by a sequence of events whereby old bone undergoes resorption and is then replaced by new bone formation which must be mineralised by adequate calcium ([[1]Dempster D. Lindsay R. Pathogenesis of osteoporosis.Lancet. 1993; 341: 797-805Abstract PubMed Scopus (205) Google Scholar], #103, [[2]Manolagas S. Jilka R. Bone marrow, cytokins, and bone remodeling.N Engl J Med. 1995; 332: 305-311Crossref PubMed Scopus (1092) Google Scholar], #102). Bone mass is maintained by a balance between resorption and formation, a process regulated by many hormones and growth factors (Fig. 1) ([[2]Manolagas S. Jilka R. Bone marrow, cytokins, and bone remodeling.N Engl J Med. 1995; 332: 305-311Crossref PubMed Scopus (1092) Google Scholar], #102, [[3]Eriksen E. Kassem M. Langdahl B. Growth hormone, insulin-like growth factors and bone remodelling.Eur J Clin Invest. 1996; 26: 525-534Crossref PubMed Google Scholar], #342). The major influences on bone metabolism are genetic, but also essential are mechanical stress (exercise and muscle activity), good nutrition, adequate calcium and vitamin D and a normal hormonal environment. The patient with chronic liver disease has many potential causes for thin bones (Table 1) but the importance of different aetiologic factors in different liver diseases is poorly defined.Table 1Potential causes of bone loss in liver diseases and after transplantationGenetic factors Female sex Small body frame ?Vitamin D receptor phenotypeAbnormalities of calcium and vitamin DPoor nutrition Poor oral intake of protein/calories Low body mass indexLack of mechanical stress to bone Immobility Poor muscle massHormonal abnormalities in males and females Hypothalamic hypogonadism Primary gonadal failure PostmenopausalLifestyle effects Alcoholism SmokingDrugs Corticosteroids Other immunosuppressive agentsLiver-related factors Chronic cholestasis Iron overload ?Effects of cirrhosis, e.g. IGF-1, osteoprotegerin Open table in a new tab 2.1 Abnormalities of calcium and vitamin D metabolismThe potential for osteomalacia or rickets due to deficiencies of vitamin D and calcium exists in any jaundiced patient with intraluminal deficiency of bile salts and fat malabsorption, particularly in children with severe chronic cholestasis. Many abnormalities of calcium and vitamin D are indeed seen in the osteopenia associated with chronic cholestatic liver diseases – reduced absorption of both calcium and vitamin D and low serum levels of 25-hydroxyvitamin D ([[4]Compston J. Thompson R. Intestinal absorption of 25-hydroxyvitamin D and osteomalacia in primary biliary cirrhosis.Lancet. 1977; i: 721-724Abstract Google Scholar], #82, [[5]Kehayoglou A. Holdsworth C. Agnew J. Whelton J. Sherlock S. Bone disease and calcium absorption in primary biliary cirrhosis.Lancet. 1968; i: 715-719Abstract Google Scholar], #88, [[6]Kaplan M. Goldberg M. Matloff D. Neer R. Goodman D. Effect of 25-hydroxyvitamin D3 on vitamin D metabolites in primary biliary cirrhosis.Gastroenterology. 1981; 81: 681-685PubMed Google Scholar], #77). However, 1,25-dihydroxyvitamin D is often normal ([[6]Kaplan M. Goldberg M. Matloff D. Neer R. Goodman D. Effect of 25-hydroxyvitamin D3 on vitamin D metabolites in primary biliary cirrhosis.Gastroenterology. 1981; 81: 681-685PubMed Google Scholar], #77), 25-hydroxylation of vitamin D by the liver is usually preserved ([[7]Skinner R. Long R. Sherlock S. Wills M. 25-Hydroxylation of vitamin D in primary biliary cirrhosis.Lancet. 1977; i: 720-721Abstract Google Scholar], #83) and no correlation has ever been identified between osteopenia and low levels of vitamin D or calcium or parathyroid dysfunction ([[8]Hay J. Bone disease in cholestatic liver disease.Gastroenterology. 1995; 108: 276-283Abstract Full Text PDF PubMed Scopus (83) Google Scholar], #19, [[9]Menon K. Angulo P. Weston S. Dickson E. Lindor K. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.J Hepatol. 2001; 35: 316-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], #5). Histomorphometric studies have shown no evidence of osteomalacia ([[10]Guichelaar M, Malinchoc M, Sibonga J, Clarke B, Hay J. Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Hepatology 2002;36:895–903.Google Scholar], #399). Even more compelling against a pathogenic role for vitamin D in cholestatic osteopenia, are two trials ([[11]Herlong H. Recker R. Maddrey W. Bone disease in primary biliary cirrhosis: histologic features and response to 25-hydroxyvitamin D.Gastroenterology. 1982; 83: 103-108Abstract Full Text PDF PubMed Google Scholar], #74, [[12]Matloff D. Kaplan M. Neer R. Goldberg J. Bitman W. Wolfe H. Osteoporosis in primary biliary cirrhosis: effects of 25-hydroxyvitamin D3 treatment.Gastroenterology. 1982; 83: 97-102Abstract Full Text PDF PubMed Google Scholar], #75) in which vitamin D therapy did not prevent ongoing bone loss in primary biliary cirrhosis (PBC) despite normalising serum vitamin D levels. Similarly, children with chronic cholestasis generally show no correlation between osteopenia and serum levels of vitamin D ([[13]Argao E. Specker B. Heubi J. Bone mineral content in infants and children with chronic cholestatic liver disease.Pediatrics. 1993; 91: 1151-1154PubMed Google Scholar], #35) or between osteopenia and calcium malabsorption ([[14]Bucuvalas J. Heubi J. Specker B. Gregg D. Yergey A. Vieira N. Calcium absorption in bone disease associated with chronic cholestasis during childhood.Hepatology. 1990; 12: 1200-1205Crossref PubMed Scopus (20) Google Scholar], #46).In alcoholic cirrhosis, hemochromatosis and autoimmune hepatitis, osteoporosis and low vitamin D levels are both common but no consistent correlation of osteopenia and indices of calcium or vitamin D metabolism has been found and most histomorphometric studies fail to show osteomalacia ([[15]Diamond T. Stiel D. Lunzer M. McDowall D. Eckstein R. Posen S. Hepatic osteodystrophy: static and dynamic bone histomorphometry and serum bone gla-protein in 80 patients with chronic liver disease.Gastroenterology. 1989; 96: 213-221PubMed Google Scholar], #385, [[16]Diamond T. Stiel D. Lunzer M. Wilkinson M. Roche J. Posen S. Osteoporosis and skeletal fractures in chronic liver disease.Gut. 1990; 31: 82-87Crossref PubMed Google Scholar], #386, [[17]Jorge-Hernandez J. Gonzalez-Reimers C. Torres-Ramirez A. Santolaria-Fernandez F. Gonzalez-Garcia C. Batista-Lopez J. et al.Bone changes in alcoholic liver cirrhosis. A histomorphometrical analysis of 52 cases.Dig Dis Sci. 1988; 33: 1089-1095Crossref PubMed Google Scholar], #59, [[18]Mobarhan S. Russell R. Recker R. Posner D. Iber F. Miller P. Metabolic bone disease in alcoholic cirrhosis: a comparison of the effect of vitamin D2, 25-hydroxyvitamin D, or supportive treatment.Hepatology. 1984; 4: 266-273Crossref PubMed Google Scholar], #72, [[19]Monegal A. Navasa M. Guanabens N. Peris P. Pons F. Martinez de Osaba M. et al.Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.Calcif Tissue Int. 1997; 60: 148-154Crossref PubMed Scopus (119) Google Scholar], #332). However, in patients with posthepatitic cirrhosis due to hepatitis B or C, bone mineral density (BMD) has correlated with vitamin D levels ([[20]Tsuneoka K. Tameda Y. Takase K. Nakano T. Osteodystrophy in patients with chronic hepatitis and liver cirrhosis.J Gastroenterol. 1996; 31: 669-678Crossref PubMed Scopus (63) Google Scholar], #320, [[21]Chen C.-C. Wang S.-S. Jeng F.-S. Lee S.-D. Metabolic bone disease of liver cirrhosis: is it parallel to the clinical severity of cirrhosis?.J Gastroenterol Hepatol. 1996; 11: 417-421Crossref PubMed Google Scholar], #319).2.2 Body mass index, other nutritional factors and alcohol ingestionOsteopenia in PBC has been shown to correlate with low body mass index (BMI) suggesting the importance of nutrition and/or muscle mass to normal bone density ([[9]Menon K. Angulo P. Weston S. Dickson E. Lindor K. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.J Hepatol. 2001; 35: 316-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], #5, [[22]Ormarsdottir S. Ljunggren O. Mallmin H. Brahm H. Loof L. Low body mass index and use of corticosteroids, but not cholestasis, are risk factors for osteoporosis in patients with chronic liver disease.J Hepatol. 1999; 31: 84-90Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar], #317). Osteocalcin, a bone matrix protein synthesised by osteoblasts, is vitamin K-dependent but studies in PBC patients have shown no aetiologic link between osteopenia and vitamin K deficiency. Vitamin K therapy prevented bone loss in cirrhotic females with viral hepatitis ([[23]Shiomi S. Nishiguchi S. Kubo S. Tamori A. Habu D. Takeda T. et al.Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver.Am J Gastroenterol. 2002; 97: 578-581Crossref Google Scholar], #353) but the mechanism of this beneficial effect is unknown. Although suggested in children with cholestatic disease ([[24]Heubi J. Hollis B. Specker B. Tsang R. Bone disease in chronic childhood cholestasis. I Vitamin D absorption and metabolism.Hepatology. 1989; 9: 258-264Crossref PubMed Google Scholar], #55), no correlation of magnesium deficiency and osteopenia has been seen in adults. Skeletal copper content may be increased in Wilson disease with multiple skeletal complications including osteoporosis and osteomalacia ([[25]Bikle D. Genant H. Cann C. Recker R. Halloran B. Strewler G. Bone disease in alcohol abuse.Ann Intern Med. 1985; 103: 42-48Crossref PubMed Google Scholar]). Chronic alcohol ingestion, even with normal hepatic and gonadal function, may be detrimental to bone metabolism, inducing osteoporosis, fracturing and low bone turnover ([[26]Feitelberg S. Epstein S. Ismail F. D'Amanda C. Deranged bone mineral metabolism in chronic alcholism.Metabolism. 1987; 36: 322-326Abstract Full Text PDF PubMed Google Scholar], #60, [[27]Lalor B. France M. Powell D. Adams P. Counihan T. Bone and mineral metabolism and chronic alcohol abuse.Q J Med. 1986; 59: 497-511PubMed Google Scholar], #65, [[28]Diamond T. Stiel D. Lunzer M. Wilkinson M. Posen S. Ethanol reduces bone formation and may cause osteoporosis.Am J Med. 1989; 86: 282-288Abstract Full Text PDF PubMed Google Scholar], #52), by a direct effect of alcohol on osteoblast function ([[29]Jilka R. Cytokines, bone remodeling, and estrogen deficiency: a 1998 update.Bone. 1998; 23: 75-81Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar], #343). Reduced intestinal calcium absorption occurs in chronic alcoholics but no other consistent abnormality of calcium homeostasis has been identified ([[26]Feitelberg S. Epstein S. Ismail F. D'Amanda C. Deranged bone mineral metabolism in chronic alcholism.Metabolism. 1987; 36: 322-326Abstract Full Text PDF PubMed Google Scholar], #60, [[27]Lalor B. France M. Powell D. Adams P. Counihan T. Bone and mineral metabolism and chronic alcohol abuse.Q J Med. 1986; 59: 497-511PubMed Google Scholar], #65, [[28]Diamond T. Stiel D. Lunzer M. Wilkinson M. Posen S. Ethanol reduces bone formation and may cause osteoporosis.Am J Med. 1989; 86: 282-288Abstract Full Text PDF PubMed Google Scholar], #52, [[29]Jilka R. Cytokines, bone remodeling, and estrogen deficiency: a 1998 update.Bone. 1998; 23: 75-81Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar], #343). Fracture risk increases with heavy drinking ([[28]Diamond T. Stiel D. Lunzer M. Wilkinson M. Posen S. Ethanol reduces bone formation and may cause osteoporosis.Am J Med. 1989; 86: 282-288Abstract Full Text PDF PubMed Google Scholar], #52).2.3 HypogonadismHormonal abnormalities and hypogonadism are common in males and females with chronic liver disease due to reduced gonadotrophin release from the hypothalamus and primary gonadal dysfunction. Hypogonadism is a risk factor for ‘high-turnover’ osteoporosis ([[30]Pignata S. Daniele B. Galati M. Esposito G. Vallone P. Fiore F. et al.Oestradiol and testosterone blood levels in patients with viral cirrhosis and hepatocellular carcinoma.Eur J Gastroenterol Hepatol. 1997; 9: 283-286Crossref PubMed Google Scholar], #379) but, although it certainly contributes to osteopenia in some patients, it is not the only factor for bone loss in patients with liver disease. Low serum testosterone levels are common in males with alcoholic cirrhosis but correlation with osteopenia in uncertain ([[16]Diamond T. Stiel D. Lunzer M. Wilkinson M. Roche J. Posen S. Osteoporosis and skeletal fractures in chronic liver disease.Gut. 1990; 31: 82-87Crossref PubMed Google Scholar], #386, [[17]Jorge-Hernandez J. Gonzalez-Reimers C. Torres-Ramirez A. Santolaria-Fernandez F. Gonzalez-Garcia C. Batista-Lopez J. et al.Bone changes in alcoholic liver cirrhosis. A histomorphometrical analysis of 52 cases.Dig Dis Sci. 1988; 33: 1089-1095Crossref PubMed Google Scholar], #59). In males with posthepatitic cirrhosis due to hepatitis B or C, serum testosterone and oestrogen levels were within the normal range but with worsening cirrhosis, testosterone decreased and oestrogen increased ([[31]Diamond T. Stiel D. Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency or other factors?.Ann Intern Med. 1989; 110: 430-436Crossref PubMed Google Scholar], #53). Osteopenia in hemochromatosis is associated with low serum testosterone levels; increased iron overload may also play a role here, as bone formation markers are greater in those undergoing venesection ([[32]Diamond T. Stiel D. Posen S. Effects of testosterone and venesection on spinal and peripheral bone mineral in six hypogonadal men with hemochromatosis.J Bone Miner Res. 1991; 6: 39-43Crossref PubMed Google Scholar], #369, [[33]Bell H. Raknerud N. Falch J. Haug E. Inappropriately low levels of gonadotrophins in amenorrhoeic women with alcoholic and non-alcoholic cirrhosis.Eur J Endocrinol. 1995; 132: 444-449Crossref PubMed Google Scholar], #396). Amenorrhoeic females with cirrhosis and both cirrhotic and non-cirrhotic alcoholic liver disease, commonly have decreased hypothalamic function with low levels of luteinising and follicle-stimulating hormones (LH and FSH); serum levels of sex hormone-binding globulin and testosterone are normal with low oestradiol ([[34]Pares A. Guanabens N. Ros I. Caballeria L. Pons F. Vidal S. et al.Duration and severity of the disease but not menopausal status are the main risk factors for osteoporosis in primary biliary cirrhosis.J Hepatol. 2002; 36: 154-155Abstract Full Text PDF Google Scholar], #381). Despite the frequency of hormonal abnormalities in advanced liver disease, no correlation between osteopenia and menopausal status has been established in the large studies of PBC patients ([[9]Menon K. Angulo P. Weston S. Dickson E. Lindor K. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.J Hepatol. 2001; 35: 316-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], #5, [[35]Adler R. Rosen C. Glucocorticoids and osteoporosis.Endocrinol Metab Clin North Am. 1994; 23: 641-654Abstract Full Text PDF PubMed Google Scholar], #339).2.4 Corticosteroids and other drugsCorticosteroids have many effects on bone ([[36]Olsson R. Johansson C. Lindstedt G. Mellstrom D. Risk factors for bone loss in chronic active hepatitis and primary biliary cirrhosis.Scand J Gastroenterol. 1994; 29: 753-756Crossref PubMed Google Scholar], #27), all of which cause bone loss – increased resorption, decreased formation and calcium malabsorption. This seems a likely aetiologic factor in the osteopenia of autoimmune hepatitis ([[37]Clements D. Compston J. Rhodes J. Evans W. Smith P. Low-dose corticosteroids in chronic active hepatitis do not adversely affect spinal bone.Eur J Gastroenterol Hepatol. 1993; 5: 543-547Google Scholar], #33) though some studies have shown no or weak correlation with steroid dose ([[38]Stellon A. Davies A. Compston J. Williams R. Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy.Gastroenterology. 1985; 89: 1078-1083PubMed Google Scholar], #69, [[39]Stellon A. Webb A. Compston J. Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis.Gut. 1988; 29: 378-384Crossref PubMed Google Scholar], #56); advanced liver disease with cirrhosis seems to be at least as important a determinant for osteopenia in these patients. Decreased bone formation is seen histomorphometrically in the osteoporosis of corticosteroid-treated autoimmune hepatitis ([[40]Solis-Herruzo J. Castellano G. Fernandez I. Munoz R. Hawkins F. Decreased bone mineral density after therapy with alpha interferon in combination with ribavirin for chronic hepatitis C.J Hepatol. 2000; 33: 812-817Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar], #392) but the effects of steroids and liver disease cannot be separated. A small randomised trial of prednisolone therapy in 36 patients with PBC suggested increased bone loss in some treated patients ([[41]Porayko M. Wiesner R. Hay J. Krom R. Dickson E. Beaver S. et al.Bone disease in liver transplant recipients: incidence, timing and risk factors.Transplant Proc. 1991; 23: 1462-1465PubMed Google Scholar], #40). Combination therapy of ribavirin and interferon for hepatitis C has recently been implicated in bone loss ([[42]Shiomi S. Kuroki T. Massaki K. Takeda T. Nishiguchi S. Nakajima S. et al.Osteopenia in primary biliary cirrhosis and cirrhosis of the liver in women, evaluated by dual-energy X-ray absorptiometry.J Gastroenterol. 1994; 29: 605-609Crossref PubMed Scopus (24) Google Scholar], #28) but these data need confirmation before any firm conclusions can be reached.2.5 Chronic cholestasisMany studies have shown that osteopenia and fracturing are most severe in chronic cholestatic disease, particularly in advanced disease ([[43]Hay J. Guichelaar M. Egan K. Therneau T. Bone mineral density in the first decade after liver transplantation.Hepatology. 2000; 32 (abstract): 239ACrossref PubMed Google Scholar], #346, [[44]Newton J. Francis R. Prince M. James O. Bassendine M. Rawlings D. et al.Osteoporosis in primary biliary cirrhosis revisited.Gut. 2001; 49: 282-287Crossref PubMed Scopus (61) Google Scholar], #355). In 646 consecutive patients undergoing OLT ([[45]Floreani A. Osteoporosis is not a specific complication of primary biliary cirrhosis (PBC).Gut. 2002; 50: 898-899Crossref PubMed Scopus (11) Google Scholar], #356), the pretransplant T-score of the lumbar spine in PBC and primary sclerosing cholangitis (PSC) was significantly lower than in chronic active hepatitis (CAH) or alcoholic cirrhosis (Table 2). Females with PBC, only 30% of whom were cirrhotic, had lower bone density than an older group of patients with posthepatitic cirrhosis ([[44]Newton J. Francis R. Prince M. James O. Bassendine M. Rawlings D. et al.Osteoporosis in primary biliary cirrhosis revisited.Gut. 2001; 49: 282-287Crossref PubMed Scopus (61) Google Scholar], #355). The studies failing to show increased osteopenia in PBC generally have patients with earlier disease ([[22]Ormarsdottir S. Ljunggren O. Mallmin H. Brahm H. Loof L. Low body mass index and use of corticosteroids, but not cholestasis, are risk factors for osteoporosis in patients with chronic liver disease.J Hepatol. 1999; 31: 84-90Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar], #317, [[46]Eastell R. Dickson E. Hodgson S. Wiesner R. Porayko M. Wahner H. et al.Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis.Hepatology. 1991; 14: 296-300Crossref PubMed Google Scholar], #44) or small numbers ([[47]Hay J. Lindor K. Wiesner R. Dickson E. Krom R. LaRusso N. The metabolic bone disease of primary sclerosing cholangitis.Hepatology. 1991; 14: 257-261Crossref PubMed Google Scholar], #43).Table 2Pretransplant bone density of the lumbar spine in patients with advanced cholestatic, posthepatitic and alcoholic cirrhosis [43]Hay J. Guichelaar M. Egan K. Therneau T. Bone mineral density in the first decade after liver transplantation.Hepatology. 2000; 32 (abstract): 239ACrossref PubMed Google ScholarLiver disease# PatientsT-score of lumbar spine (mean)Primary biliary cirrhosis129−2.22Primary sclerosing cholangitis160−1.93Chronic active hepatitis199−1.23Alcoholic cirrhosis59−0.86 Open table in a new tab In addition, increasing osteopenia is seen as PBC and PSC advance in severity with progressive jaundice ([[9]Menon K. Angulo P. Weston S. Dickson E. Lindor K. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.J Hepatol. 2001; 35: 316-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], #5, [[13]Argao E. Specker B. Heubi J. Bone mineral content in infants and children with chronic cholestatic liver disease.Pediatrics. 1993; 91: 1151-1154PubMed Google Scholar], #35, [[35]Adler R. Rosen C. Glucocorticoids and osteoporosis.Endocrinol Metab Clin North Am. 1994; 23: 641-654Abstract Full Text PDF PubMed Google Scholar], #339, [[48]Guanabens N. Pares A. Marinoso L. Brancos M. Piera C. Serrano S. et al.Factors influencing the development of metabolic bone disease in primary biliary cirrhosis.Am J Gastroenterol. 1990; 85: 1356-1362PubMed Google Scholar], #47, [[49]Hodgson S. Dickson E. Wahner H. Johnson K. Mann K. Riggs B. Bone loss and reduced osteoblast function in primary biliary cirrhosis.Ann Intern Med. 1985; 103: 855-860Crossref PubMed Google Scholar], #70). An inverse relationship between BMD of the lumbar spine and serum bilirubin was seen in 210 ambulatory PBC patients ([[48]Guanabens N. Pares A. Marinoso L. Brancos M. Piera C. Serrano S. et al.Factors influencing the development of metabolic bone disease in primary biliary cirrhosis.Am J Gastroenterol. 1990; 85: 1356-1362PubMed Google Scholar], #47). The severity of osteopenia in 176 PBC patients was most severe in patients with stages 3 or 4 disease and the rate of bone loss correlated with bilirubin; osteopenia here correlated with patient age and BMI and males had as much osteopenia as their female counterparts ([[9]Menon K. Angulo P. Weston S. Dickson E. Lindor K. Bone disease in primary biliary cirrhosis: independent indicators and rate of progression.J Hepatol. 2001; 35: 316-323Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], #5). Similarly, 142 women with PBC showed correlation between osteoporosis and disease severity, as assessed by bilirubin and histologic stage, but not menopausal status ([[35]Adler R. Rosen C. Glucocorticoids and osteoporosis.Endocrinol Metab Clin North Am. 1994; 23: 641-654Abstract Full Text PDF PubMed Google Scholar], #339). Clearly, the above studies show that cholestatic osteopenia is not simply an age-related or menopausal phenomenon and that the severity of osteopenia increases with advancing liver disease and jaundice.The connection between cholestasis and osteopenia is unexplained. Histomorphometric studies have generally shown low bone formation ([[10]Guichelaar M, Malinchoc M, Sibonga J, Clarke B, Hay J. Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Hepatology 2002;36:895–903.Google Scholar], #399, [[50]Stellon A. Webb A. Compston J. Williams R. Low bone turnover state in primary biliary cirrhosis.Hepatology. 1987; 7: 137-142Crossref PubMed Google Scholar], #62, [[51]Cuthbert J. Pak C. Zerwekh J. Glass K. Combes B. Bone disease in primary biliary cirrhosis: increased bone resorption and turnover in the absence of osteoporosis or osteomalacia.Hepatology. 1984; 4: 1-8Crossref PubMed Google Scholar], #73, [[52]Hodgson S. Dickson E. Eastell R. Eriksen E. Bryant S. Riggs B. Rates of cancellous bone remodeling and turnover in osteopenia associated with primary biliary cirrhosis.Bone. 1993; 14: 819-827Abstract Full Text PDF PubMed Scopus (59) Google Scholar], #32) but some also show evidence of increasing bone turnover ([[10]Guichelaar M, Malinchoc M, Sibonga J, Clarke B, Hay J. Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Hepatology 2002;36:895–903.Google Scholar], #399, [[53]Janes C. Dickson E. Okazaki R. Bonde S. McDonagh A. Riggs B. Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice.J Clin Invest. 1995; 95: 2581-2586Crossref PubMed Google Scholar], #341, [[54]Gallego-Rojo F. Gonzalez-Calvin J. Munoz-Torres M. Mundi J. 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: 695-699Crossref PubMed Google Scholar], #305). Unfortunately, no correlation has ever been found between any histomorphometric abnormality and bilirubin, hepatic synthetic function or indices of calcium and vitamin D. Osteoblast proliferation was inhibited by unconjugated bilirubin in vitro and by the serum of jaundiced patients, suggesting that bilirubin may have a direct effect on bone metabolism ([[55]Hattori N. Kurahachi H. Ikekubo K. Ishihara T. Moridera K. Hino M. Serum growth hormone-binding protein, insulin-like growth factor-I, and growth hormone in patients with liver-cirrhosis.Metabolism. 1992; 41: 377-381Abstract Full Text PDF PubMed Scopus (69) Google Scholar], #336).2.6 CirrhosisA correlation of osteoporosis with the severity of chronic liver disease itself, independent of other identified risk factors, has been seen, not only in cholestatic disease as above, but also in alcoholic cirrhosis, CAH, hemochromatosis and posthepatitic cirrhosis ([[16]Diamond T. Stiel D. Lunzer M. Wilkinson M. Roche J. Posen S. Osteoporosis and skeletal fractures in chronic liver disease.Gut. 1990; 31: 82-87Crossref PubMed Google Scholar], #386, [[54]Gallego-Rojo F. Gonzalez-Calvin J. Munoz-Torres M. Mundi J. 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: 695-699Crossref PubMed Google Scholar], #305, [[19]Monegal A. Navasa M. Guanabens N. Peris P. Pons F. Martinez de Osaba M. et al.Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.Calcif Tissue Int. 1997; 60: 148-154Crossref PubMed Scopus (119) Google Scholar], #332, [[56]Cemborain A. Castilla-Cortazar I. Garcia M. Quiroga J. Muguerza B. Picardi A. et al.Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-I treatment.J Hepatol. 1998; 28: 122-131Abstract Full Text PDF PubMed Scopus (57) Google Scholar], #316). Low levels of insulin-like growth factor (IGF-1), which is trophic for bone and stimulates osteoblast proliferation, have been described in patients with cirrhosis and osteoporosis ([[56]Cemborain A. Castilla-Cortazar I. Garcia M. Quiroga J. Muguerza B. Picardi A. et al.Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-I treatment.J Hepatol. 1998; 28: 122-131Abstract Full Text PDF PubMed Scopus (57) Google Scholar], #316, [[57]Simonet W. Lacey D. Dunstan C. Kelley M. Chang M.-S. Luthy R. et al.Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Cell. 1997; 89: 309-319Abstract Full Text Full Text PDF PubMed Google Scholar], #360), children with cholestatic disease ([[14]Bucuvalas J. Heubi J. Specker B. Gregg D. Yergey A. Vieira N. Calcium absorption in bone disease associated with chronic cholestasis during childhood.Hepatology. 1990; 12: 1200-1205Crossref PubMed Scopus (20) Google Scholar], #46) and in experimental animal models of osteopenia ([[58]Cooper G. Umbach D. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis.J Bone Miner Res. 1996; 11: 1841-1849Crossref PubMed Google Scholar], #373); low serum levels of growth hormone-binding protein and elevated levels of growth hormone have also been described ([[57]Simonet W. Lacey D. Dunstan C. Kelley M. Chang M.-S. Luthy R. et al.Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Cell. 1997; 89: 309-319Abstract Full Text Full Text PDF PubMed Google Scholar], #360). Low levels of osteoprotegerin (which regulates osteoclast activity) in liver disease has been postulated as a potential cause for increased bone resorption ([[59]Gennari L. Becherini L. Masi L. Gonnelli S. Cepollaro C. Martini S. et al.Vi" @default.
• W2034626585 created "2016-06-24" @default.
• W2034626585 creator A5008493167 @default.
• W2034626585 date "2003-06-01" @default.
• W2034626585 modified "2023-09-25" @default.
• W2034626585 title "Osteoporosis in liver diseases and after liver transplantation" @default.
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