Review

Nature Reviews Gastroenterology and Hepatology 6, 660-670 (November 2009) | doi:10.1038/nrgastro.2009.166

Subject Category: Liver

Current understanding of osteoporosis associated with liver disease

Inaam A. Nakchbandi1 & Schalk W. van der Merwe2  About the authors

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Osteoporosis is a common complication of many types of liver disease. Research into the pathogenesis of osteoporosis has revealed that the mechanisms of bone loss differ between different types of liver disease. This Review summarizes our current understanding of osteoporosis associated with liver disease and the new advances that have been made in this field. The different mechanisms by which cholestatic and parenchymal liver disease can lead to reduced bone mass, the prevalence of osteopenia and osteoporosis in patients with early and advanced liver disease, and the influence of osteoporotic fractures on patient survival are discussed along with the advances in our understanding of the molecular pathways associated with bone loss. The role of the CSF1–RANKL system and that of the liver molecule, oncofetal fibronectin, a protein that has traditionally been viewed as an extracellular matrix protein are also discussed. The potential impact that these advances may have for the treatment of osteoporosis associated with liver disease is also reviewed.

Key points

  • Metabolic bone disease is a common complication of chronic liver disease; patients with chronic liver disease have an increased risk of bone fractures, which affects patient survival and well being
  • Osteoporosis is uncommon in patients with early liver disease but affects up to 50% of patients with cirrhosis
  • The cause of bone loss in patients with chronic liver disease is multifactorial and differs between types of liver diseases
  • Levels of osteoprotegerin are elevated and levels of RANKL are decreased in patients with liver disease and osteoporosis
  • Factors that may contribute to bone loss include oncofetal fibronectin and CSF1 in patients with cholestatic liver disease, and TNF in patients with viral hepatitis and alcoholic liver disease
  • Current therapy for bone loss relies on supportive measurements with calcium and vitamin D supplementation; bisphosphonate therapy is efficacious and safe for patients with primary biliary cirrhosis

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Introduction

Osteoporosis is a common complication of chronic liver disease.1, 2, 3 Like senile osteoporosis, liver-disease-associated osteoporosis results from an imbalance between bone formation and resorption that leads to a net decrease in bone mass. The factors responsible for reduced bone formation and/or increased bone resorption in liver-disease-associated osteoporosis remain incompletely understood. However, advances made over the past decade have shed some light on the potential pathogenic mechanisms involved in this process.

This Review focusses on two central themes. First, the prevalence and risk factors associated with osteopenia in patients with liver disorders and how knowledge of these factors may increase our understanding of the cause and onset of bone loss in these patients, and second, how new insights into the role of mediators involved in orchestrating bone loss in patients with liver disease can be contrasted with the traditional views of the bone remodeling process.

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Normal bone physiology

Numerous studies have contributed to our understanding of how signaling between the two main cellular elements in bone, the osteoclasts and the osteoblasts, is regulated to continuously remodel the skeleton (Figure 1). Osteoclasts are multinucleated cells that are derived from circulating monocytes and degrade bone matrix. Osteoblasts are cells of mesenchymal origin that are cardinal to the production of bone matrix proteins and mineralization of the osteoid seam to replace bone after osteoclastic resorption. Hence, the activities of these two cell types must remain tightly coupled to maintain a constant bone mass. Factors that are released by osteoclasts during the resorption phase are thought to signal the recruitment of osteoblasts. In addition, osteoblasts provide essential signals for the differentiation of osteoclasts via the synthesis and secretion of RANKL, CSF1 (otherwise known as M-CSF) and other co-stimulatory signals.4, 5 RANKL is known to be the key osteoclastogenic cytokine that regulates bone turnover in health and in many disease states.4 RANKL binds to its receptor, RANK on osteoclast precursors and osteoclasts to induce the differentiation and activation of these cells into mature bone resorbing osteoclasts. Osteoblasts also secrete osteoprotegerin, which acts as a soluble decoy receptor by scavenging RANKL and preventing RANKL–RANK interaction.4 Thus, within the bone microenvironment, the tightly coupled signaling between osteoclasts and osteoblasts provides an important mechanism by which bone turnover is controlled.4 However, hormones, cytokines and vitamins also act within this microenvironment on the osteoblast and osteoclast to regulate different aspects of bone formation, mineralization and resorption.

Figure 1 | Factors that affect bone turnover in patients with liver disease.
Figure 1 : Factors that affect bone turnover in patients with liver disease. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comSolid arrows indicate established pathways and interrupted arrows indicate pathways for which limited evidence is available. Osteoclast precursors are activated by proinflammatory cytokines such as TNF, the levels of which are increased in patients with viral hepatitis and alcoholic liver disease. CSF1 binds to its receptor c-fms to induce osteoclastogenesis. Increased CSF1 levels have been shown in patients with cholestatic liver disease, and could be induced by the inflamed liver environment. IL-17 is produced by a subset of T lymphocytes (TH17 cells), is increased in patients with alcohol-associated liver disease and potentially induces bone loss. RANKL is a key regulator of osteoclast function that binds to its receptor RANK to induce osteoclastogenesis. OPG is a decoy receptor that inhibits RANKL. The RANKL–RANK–OPG axis might not have a role in the bone loss associated with chronic liver disease. Vitamin D, PTH, IGF-I, and oncofetal fibronectin affect osteoblast formation. Oncofetal fibronectin produced by activated stellate cells suppresses osteoblasts and bone formation in patients with primary biliary cirrhosis. Intermittent hPTH1–34 stimulates osteoblast function but has not been studied in patients with liver disease. Abbreviations: OPG, osteoprotegerin; PTH, parathyroid hormone; Vit D, vitamin D.

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Osteoporosis

Osteoporosis is defined by the WHO as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture risk. The clinical significance rests with the fractures that arise as a consequence of the condition and their attendant morbidity and mortality.6 Osteoporosis is further defined by the WHO criteria as a reduction of bone mineral density (BMD) to less than 2.5 standard deviations below normal adult peak bone mass. This equates to a T-score of less than or equal to -2.5 as assessed by dual X-ray absorptiometry (DEXA). Osteopenia, which represents a milder degree of bone loss, is defined as a T-score between -1.0 and -2.5.7 Of note, risk of fracture increases dramatically with decreasing BMD.1 The application of the WHO criteria has enabled the noninvasive assessment of bone mineral status in patients with liver disease and enabled comparisons to be made between various populations of these patients.8

Osteoporosis in patients with liver disease

The incidence of osteoporosis and skeletal fractures in patients with chronic liver disease varies widely and has been extensively reviewed elsewhere.8 Pooled data for the studies reviewed by Leslie et al. are shown in Table 1.8 The prevalence of osteoporosis and skeletal fractures in these patients depends on the etiology of the underlying liver disease, the severity of the liver disease, and the patient population studied, for example postmenopausal women tend to have more severe disease because of the compounding effect of the loss of estrogen. These measurements are also highly dependent on the study methodology used, as can be seen by the different values reported in uncontrolled, controlled and longitudinal studies (Table 1).


Cholestatic liver disease

Metabolic bone disease has been extensively studied in patients with cholestatic liver disease.9, 10, 11, 12, 13 Osteoporosis is uncommon in patients with early primary biliary cirrhosis and in those with early primary sclerosing cholangitis in the absence of cirrhosis.7 However, osteoporosis is common in patients with advanced forms of these liver diseases. In fact, two large studies in Europe and the US found that osteopenia is common in patients with advanced primary biliary cirrhosis; the presence of bone disease correlated with higher values of the Mayo risk scores and advanced histological stage.11, 14 In the Mayo clinic study, the severity of liver disease contributed significantly to the degree and rate of progression of bone loss; this effect was independent of other risk factors of bone loss in the general population.14 By contrast, another European study found no difference in the yearly rate of bone loss between patients with primary biliary cirrhosis and the general population, and no association between bone mass and histological severity of liver disease in patients with primary biliary cirrhosis.10 The discrepancies between these studies remain difficult to explain.

A 2006 study from the Mayo clinic confirmed the clinical relevance of metabolic bone disorders in patients with primary biliary cirrhosis and primary sclerosing cholangitis. At the time these patients were assessed for liver transplantation, 77% had an abnormal BMD value, 38% had established osteoporosis, and osteoporotic fractures had occurred in 19%.12 Almost all these patients were ambulatory at the time of assessment and no difference in the incidence of metabolic bone disease was observed between patients with primary biliary cirrhosis and those with primary sclerosing cholangitis, or between females and males.12

In another study from the same group at the Mayo clinic, static and dynamic histomorphometric parameters were studied in bone specimens from 50 patients with cholestatic liver disease at the time of liver transplantation.15 Parameters of bone formation were decreased and parameters of bone resorption, such as osteoclast number and percentage of eroded surfaces increased compared with those of a normal reference population. These histomorphometric changes correlated with decreased BMD, and were similar between patients with primary biliary cirrhosis and those with primary sclerosing cholangitis. In another histomorphometry study, bone formation was decreased, while resorption was minimally affected in patients with cholestatic liver disease.16 The findings of these studies collectively indicate that decreased bone formation is a key mechanism in the loss of bone associated with primary biliary cirrhosis. These findings also raise the possibility that a common etiological factor may lead to bone loss under these cholestatic conditions.15, 16

Parenchymal liver disease

Osteoporosis has also been reported in patients with parenchymal liver disease. In pretransplantation patients with cirrhotic viral hepatitis, the prevalence of osteoporosis varies between 20–53%.17, 18, 19 A large, Japanese, longitudinal study of patients with chronic hepatitis C found that only women over 60 years of age were at significant risk of osteopenia compared with the general population, which suggests that this disease may work in concert with other risk factors to exacerbate bone loss.20 A 2005 study assessed the prevalence of osteoporosis in patients with non-cirrhotic viral hepatitis.21 Patients with chronic HBV or HCV infection without cirrhosis already had significantly reduced BMD that correlated with the degree of fibrosis, indicating that bone loss may occur early in patients with viral hepatitis.21

New evidence has also emerged with regard to the impact of chronic viral hepatitis and cirrhosis on bone fracture and survival in postmenopausal females. Arase and colleagues demonstrated the cumulative incidence of skeletal fractures in these individuals to be 12.2% at 10 years after their initial presentation, which correlated with low albumin levels and older age. Strikingly, however, the presence of a skeletal fracture was associated with increased mortality in this population. The cumulative survival rate after a bone fracture was severely reduced (57.6%), which underscores the importance of osteoporotic fracture prevention in individuals with liver disease.22

Metabolic bone disease is also frequently found in patients with other parenchymal liver diseases, such as alcohol-associated liver disease, in whom the severity of bone disease correlates with the severity of liver disease and the presence of cirrhosis.8, 23, 24 Bone disease is also common in patients with genetic hemochromatosis and autoimmune hepatitis.8, 24, 25, 26

No new studies on the histomorphometric characteristics of bone disease associated with parenchymal liver injury exist. A 1989 study demonstrated a significant decrease in osteoblast surface and bone formation rate in all types of chronic disease studied compared with that of normal controls.27 A major issue of such studies is the difficulty in discerning the compounding effects of alcohol on osteoblasts in patients with alcohol-associated liver disease, the effects of inflammation on osteoclasts in patients with viral-associated liver disease, and the effects of corticosteroids on both osteoblasts and osteoclasts in patients receiving corticosteroid treatment.27

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Risk factors

An individual's peak bone mass is determined by many factors; however, constant remodeling of bone occurs throughout life in all individuals.1, 3 Bone integrity is dependent on the availability of certain factors (Box 1). Bone microarchitecture and mass is also modulated by mechanical stress through weight bearing and exercise.

A number of factors in patients with liver disease increase susceptibility to bone loss. For instance, malnutrition or dietary deficiencies occur frequently in these individuals,7 partly because nutritional requirements are increased due to the presence of ascites or other complications,1 and exercise levels are often reduced compared with levels of healthy individuals. In addition, the presence of parenchymal damage in patients with chronic liver disease can influence various pathways, such as the hypothalamic–pituitary–gonadal axis, which causes hypogonadism.28 Furthermore, medications, such as corticosteroids and the antiviral agent ribavirin affect bone metabolism, and long-term alcohol abuse suppresses bone formation. Advanced age or postmenopausal status may independently cause bone loss as in the general population.

Factors that have traditionally been associated with the pathogenesis of bone disease and their association with liver disease are described in further detail in the following sections.

Vitamin D and calcium

Vitamin D3 that is synthesized in the skin or absorbed through the gut is hydroxylated in the liver by the enzyme 25-hydroxylase. Further metabolism in the kidney results in the formation of the active metabolite 1,25(OH)2 vitamin D3 (calcitriol). This molecule is critical for bone health, and affects bone mineralization and intestinal absorption of calcium. Studies in a bile-duct-ligated rat model suggest that decreased 25-hydroxylase activity might be responsible for the bone loss associated with chronic liver disease.24 Studies in humans with chronic cholestatic liver disease, however, confirmed that 25-hydroxylase activity is preserved and that levels of 1,25(OH)2 vitamin D3 remain normal even in patients with cirrhosis.29 A study in patients with primary biliary cirrhosis has also shown normal circulating levels of 25(OH) vitamin D3 can be achieved if sufficient substrate is provided.30 In another study, histomorphometric analyses were performed on bone specimens from patients with primary biliary cirrhosis before and after receiving oral 25(OH) vitamin D3 therapy for 1 year. The purpose of the analysis was to differentiate the bone features associated with 1,25(OH)2 vitamin D3 deficiency from those related to liver disease-associated bone loss. Bone histomorphometry at baseline showed decreased bone formation in both men and women, and evidence for increased bone resorption in women, which indicated the presence of osteoporosis despite normalization of 25(OH) vitamin D3 levels. Furthermore histomorphometric analysis after 1 year of therapy showed progressive bone loss despite early correction of 25(OH) vitamin D3 levels.31

Studies involving vitamin D and calcium treatment in patients with liver disease are scant. The studies that are available often include low numbers of patients, heterogeneous diseases, and are often nonrandomized and grossly underpowered. Nevertheless, these studies have generally shown that 25(OH) vitamin D3 and calcium therapy alone has no effect on reducing bone loss in patients with cholestatic liver disease.31, 32 However, studies have also investigated the effects of the administration of the active metabolite, 1,25(OH)2 vitamin D3, that does not require activation by 25-hydroxylase in the liver in patients with primary biliary cirrhosis and liver cirrhosis. In these studies, administration of 1,25(OH)2 vitamin D3 increased BMD as assessed by DEXA in males with cirrhosis and slowed bone loss in females with cirrhosis and in patients with primary biliary cirrhosis.33, 34 The efficacy of vitamin D and calcium therapy for the prevention and treatment of osteoporotic fractures in postmenopausal women has been assessed in large community-based studies where the benefit of this treatment was found to be modest at best and possibly limited only to individuals with vitamin D and calcium deficiency.35 Despite the lack of adequately powered studies in patients with liver disease, by extrapolation of data from community-based osteoporosis studies, it seems reasonable to advise vitamin D and calcium therapy as an adjunct therapy for the prevention and treatment of osteoporosis in these patients.

Malnutrition, muscle wasting and BMI

Malnutrition, muscle wasting and low BMI are commonly observed in patients with chronic liver disease. When assessed carefully, malnutrition occurs in as many as 12% of patients evaluated for liver transplantation.12 The frequency of muscle wasting is even more common, and the wasting of muscle mass independent of malnutrition may be a feature of liver cirrhosis.36 A low BMI often correlates with low BMD in the general population and in patients with chronic liver disease.1, 7, 37

Studies over the past decade have indicated an important role for the adipokine leptin, in the control of bone mass. Leptin is mainly produced by adipocytes and has long been known to be involved in the regulation of energy homeostasis through the suppression of appetite and by increasing energy expenditure.38 Peripheral leptin acts in bone to increase osteoblast proliferation and the synthesis of bone matrix, which leads to increased bone formation. Leptin also suppresses RANKL production, which leads to decreased bone resorption. The net effect of these actions is an increase in bone mass. Leptin also has complex immunomodulatory effects and may act as a proinflammatory cytokine that is able to activate inflammatory cells and promote the secretion of other proinflammatory cytokines such as IL-1, TNF and IFN-gamma.4 Leptin production is increased in activated stellate cells,39 and leptin levels are elevated in patients with chronic hepatitis C in whom they correlate with fibrosis scores.40 However, most studies of patients with cholestatic liver disease have found decreased leptin levels in these individuals.41, 42 As levels of leptin strongly correlate with BMI, low leptin levels may merely reflect the diminished nutritional status of these patients. In summary, although proinflammatory and bone modulatory effects of leptin are recognized, the contribution of leptin to bone loss in patients with liver disease remains unclear.

Hypogonadism

Sex hormones are important for the maintenance of bone mass. Gonadal function is affected in patients with cirrhosis and clinical features of hypogonadism are often evident in patients with advanced liver disease. The pathogenesis of hypogonadism in patients with cirrhosis is complex and may involve both hypothalamic–pituitary and gonadal dysfunction. Patients with cirrhosis have increased levels of sex-hormone-binding globulin (SHBG), which can lead to overestimations of bioavailable estrogen and testosterone levels.28 Sex hormone replacement therapy increases bone mass in patients with liver disease;3, 4, 7 however, low levels of testosterone do not consistently correlate with bone loss in patients with alcoholic liver disease even though the main cause of hypogonadism seems to be secondary to defective hypothalamic–pituitary–gonadal signaling in this disease.3, 28 Early studies suggested that hypogonadism is particularly common in osteoporotic patients with hemochromatosis, but the study by Guggenbuhl and co-workers in 2005 of 38 men with hemochromatosis found only 13% to be hypogonadal, whereas 34% were osteoporotic.43 These findings suggest that iron levels, rather than testosterone deficiency were responsible for the bone loss in these patients.43 Although one large study of patients with primary biliary cirrhosis did not find postmenopausal status to be an independent predictor of osteoporosis,11 another study reported contradicting findings.44 Of note, however, although the benefit and safety of hormone replacement therapy in hypogonodal patients with liver disease and osteoporosis has been established, some concerns exist with regard to the promotion of hepatocellular carcinoma by testosterone replacement.7

Genetic factors

Peak bone mass in healthy adults is, in general, determined by genetic factors,1 and thus, susceptibility of patients with liver disease to osteoporosis may also be mediated by genetic factors. The association of polymorphisms in the gene that encodes the vitamin D receptor (VDR) with bone density in populations without liver disease has been established. Restriction fragment length polymorphism analysis showed that the BB and tt genotypes of VDR are associated with low BMD at the lumbar spine and femoral neck in postmenopausal females of different ethnic backgrounds.45 Likewise, COL1A1, the gene that encodes alpha-1 type 1 collagen, also regulates BMD since type I collagen is the most important structural protein present in bone matrix.3 The influence of certain polymorphisms of these genes on risk of osteoporosis in patients with chronic liver disease has been studied with conflicting results.13, 45, 46, 47 One study demonstrated VDR genotype to predict low BMD in Canadian patients with primary biliary cirrhosis.47 Patients in this study who were homozygous or heterozygous for the b allele of VDR had a lower BMD than individuals with other VDR genotypes. This finding is in contrast to studies in healthy young females in whom this allele did not confer increased susceptibility to low bone mass.47, 48 By contrast, two European studies found no association between VDR genotype and risk of osteoporosis in patients with primary biliary cirrhosis.46, 49 Studies that have assessed polymorphisms of the COL1A1 gene in patients with primary biliary cirrhosis have found either no association of COL1A1 genotype with osteoporosis,50 or an association only with the Z-score at the lumbar spine.13

No association between the frequency of IGF-I gene microsatellite repeats or IL-1 receptor antagonist (IL1RA) gene polymorphisms and osteoporosis has been found in patients with primary biliary cirrhosis. Interestingly, polymorphisms in the gene that encodes estrogen receptor alpha are more common in patients with primary biliary cirrhosis and osteoporosis than in healthy controls or those without osteoporosis.50

Thus, the extent to which mutations or polymorphisms in VDR and COL1A1 or other genes confer independent genetic susceptibility to bone loss in patients with liver disease remains uncertain. However, current data suggest these genes either have no or a very modest association with bone status in these patients.3, 45

Iron and copper

The accumulation of iron or copper may directly affect bone formation. As mentioned previously, hemochromatosis is frequently associated with osteoporosis, especially in patients with cirrhosis.51 A 2005 study showed that osteopenia is common in patients with hemochromatosis but without cirrhosis, which suggests that iron accumulation may directly affect osteoblast function.43 Indeed, a correlation between iron overload, as measured by serum ferritin levels, and BMD has been identified.52 Conditions that are characterized by iron overload, such as thalasemia, and siderosis, are also associated with osteoporosis,53, 54 which supports the notion that iron can directly affect osteoblast function even in the absence of cirrhosis or hypogonadism.54 A 1991 study that assessed iron accumulation in bone by use of histomorphometry in patients with liver disease showed iron content was increased only in the bones of patients with reduced bone formation.55 Despite these findings, the value of measures to reduce iron levels to influence BMD and osteoporosis in these patients have not been assessed.

Osteoporosis has also been observed in patients with Wilson disease. In one study of patients with a mean age of 31 years, osteoporosis occurred in 43% but did not correlate with severity of liver dysfunction. These findings suggest that copper might also directly affect bone formation.56

Bilirubin

Lumbar BMD of patients with cholestatic liver disease is lower than in patients with viral hepatitis or alcohol-associated cirrhosis at the time of assessment for liver transplantation.6 Bilirubin and bile acids are the two major components that accumulate in patients with cholestasis. Culture studies showed that unconjugated bilirubin, but not bile salts inhibited osteoblast proliferation.57 Some clinical studies have shown an inverse correlation between BMD and bilirubin levels,11 whereas others have not.12, 14 For example, a 2006 study found no correlation between serum bilirubin levels (either conjugated or unconjugated), and reduced BMD in patients with end-stage liver disease.58 This study also assessed the effects of chronic unconjugated hyperbilirubinemia on BMD and bone turnover in Gunn rats. BMD and bone turnover was not different between hyperbilirubinemic Gunn rats and wildtype animals, which suggested that unconjugated bilirubin does not uncouple bone remodeling.58 Furthermore, bone biopsy samples from pretransplant patients with cholestatic liver disease and osteopenia assessed by histomorphometry, also showed no correlation between low rates of bone formation and serum bilirubin levels in these patients.15

Ursodeoxycholic acid therapy in patients with primary biliary cirrhosis has a profound effect, causing a 50% decrease in the production of endogenous bile acids and a 26% decrease in levels of total circulating bile acids in these patients.59 Treatment of such patients with ursodeoxycholic acid improved biochemical parameters of cholestasis, but failed to improve bone density, again suggesting that excess levels of bilirubin and bile acids do not affect bone mass in patients with primary biliary cirrhosis.60 Thus, despite evidence from in vitro data that suggest an inhibitory effect of bilirubin on osteoblasts, in vivo data from animal and clinical studies have failed to conclusively support such an inhibitory role.

Corticosteroid therapy

Osteoporosis is frequently associated with long-term corticosteroid therapy; BMD is decreased in approximately 50% of individuals treated with corticosteroids for >1 year.61 Corticosteroid therapy also exacerbates existing osteopenia caused by underlying liver disease.62 Corticosteroid-induced bone loss is often more pronounced in the spine than other regions because of the high trabecular bone content and turnover at this site.61 Evidence that the use of bisphosphonate therapy in the solid organ transplantation setting may prevent corticosteroid-induced osteoporosis is also accumulating.61 Although speculative at present, the early use of bisphosphonates after liver transplantation or in patients with autoimmune hepatitis may protect such individuals from corticosteroid-induced bone loss, even in those with normal BMD.

Cirrhosis

As mentioned earlier, osteoporosis is more common in patients with cholestatic and parenchymal liver disease with cirrhosis than in those with early liver disease. In fact, osteoporosis is rare in most patients with early forms of liver disease but affects up to 38% of patients with cholestatic liver disease and 53% of patients with viral hepatitis at the time of their assessment for liver transplantation.4, 5, 17, 18 In animal models, the presence of a portasystemic shunt, but not the presence of isolated portal hypertension or early cirrhosis, is associated with bone loss even when BMD is corrected for malnutrition and decreased muscle mass.63, 64 The precise feature of cirrhosis that leads to bone loss is at present unclear, but the metabolic dysfunction that accompanies cirrhosis as well as the inflamed liver environment may contribute to bone loss associated with chronic liver disease.

Insulin-like growth factor I

The liver microenvironment of patients with chronic liver disease undergo changes that involve inflammation, altered blood flow, activation of stellate cells and loss of normal hepatic function A loss of synthetic function is common in patients with advanced liver disease, and can affect the production of factors such as IGF-I, which may impact bone formation. IGF-I is produced mainly in the liver in response to growth hormone. In the circulation, IGF-I is typically bound to one of six IGF binding proteins (IGFBP 1–6). IGF-I often exists in a 150-kDa complex that comprises an IGF-I molecule, IGFBP-3, and the insulin-like growth factor-binding protein complex acid labile chain (ALS).65 This ternary complex regulates the biological activities of IGF-I at the bone interface. Importantly, the liver is not only the principal source of circulating IGF-I, but is also the source of IGFBP-3, and ALS.65 The binding of IGF-I to osteoblasts results in increased bone formation (Figure 1).66 Studies in mice demonstrated that selective deletion of IgfI from hepatocytes causes abrogation of liver IgfI mRNA, which results in a 75% reduction in circulating levels of IGF-I, a 9% decrease in total BMD, and a 6% decrease in cortical bone density.65, 66 Additional deletion of the gene that encodes ALS resulted in a 10% loss of cortical bone.66 Of note, rats with cirrhosis show an improvement in BMD when treated with IGF-I.67

Reduced serum levels of IGF-I are associated with idiopathic osteoporosis in men.68 The role of IGF-I in osteopenia associated with chronic liver disease has been extensively investigated; however, although one study identified a correlation between decreased levels of circulating IGF-I and reduced bone mass in patients with viral hepatitis,18 other studies in patients with primary biliary cirrhosis and a variety of other liver diseases found no correlation between IGF-I levels and bone mass.50, 69 Although IGF-I levels have been assessed in patients with chronic liver disease the importance of the ALS and IGFBP-3 subunits in osteopenia associated with liver disease remains to be established.

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Recent advances: mechanisms of bone loss

Fundamental differences in the pathogenesis of osteoporosis associated with the menopause and that associated with liver disease exist. Postmenopausal osteoporosis is caused by the loss of estrogen, which seems to act as an inhibitory switch at the level of the osteoclast.70 After menopause, or in situations that affect estrogen production, a variety of cytokines, such as IL-6 and RANKL are upregulated, which results in an increase in the number and activity of osteoclasts and leads to increased bone resorption.71, 72 Loss of the stimulatory effects of estrogen on osteoblasts also contributes to bone loss, but the relevance of this remains unclear.73 In patients with chronic cholestatic liver disease, bone loss seems to relate to decreased osteoblast function (Box 2), with some effect on osteoclast numbers and surface erosion.15, 74, 75, 76 Similarly, in a cholestatic animal model, a reduction in bone formation and osteoblast number was observed in male bile-duct-ligated rats.77 In addition, bone formation and trabecular bone volume in this model could be increased by administration of parathyroid hormone (PTH), which predominantly affects the osteoblast.77 Histomorphometry studies in patients with parenchymal liver disease are scant but the available studies have demonstrated decreased trabecular bone volume as in patients with cholestatic liver disease.27, 78 Histomorphometry that assesses bone turnover at a specific site may not reflect total skeletal bone turnover. Despite their limitations,79 serum and urinary markers of bone formation and resorption have been applied in various liver disease populations, with findings that often reflect decreased bone formation and increased resorption contributing to bone loss.17, 19, 80 The dominant effect of cholestatic liver disease on osteoblasts is in contrast to the predominant activation of osteoclasts associated with postmenopausal osteoporosis.15, 16 The overriding effect of cholestatic liver disease on osteoblasts may, therefore, offer a unique opportunity for the identification of methods to modify osteoblast function.

Role of the immune system

A strong link between dysregulation of the immune system and increased bone turnover has emerged over the past 10 years.4 Two key concepts support the interaction between the immune system and bone turnover. First, RANKL is produced by several types of immune cells, including circulating monocytes, macrophages and lymphocytes.81 Second, stimulation of the immune system associated with chronic inflammatory states (for example, IBD), autoimmunity (for example, rheumatoid arthritis), or infectious diseases (for example, HIV infection or AIDS), has been shown to induce osteoclast differentiation and bone resorption.4, 82, 83, 84 Activation of inflammatory cells in patients with these conditions induces the production of proinflammatory cytokines such as TNF, IL-1, IL-13, IL-6, IL-7, IL-11, IL-15 and IL-17, which are capable of inducing bone loss. These cytokines can increase bone loss either by the direct activation of osteoclast precursors, or by inducing the production of RANKL by osteoblasts.4

Activated T cells are able to produce RANKL and, therefore, support osteoclastogenesis.85 The effects of activated, RANKL-producing T cells can be counter-balanced by regulatory T (TREG) cells, which inhibit bone resorption suppressing osteoclast formation by inhibiting osteoclast precursor differentiation into mature osteoclasts.63, 86 In their normal state, however, T cells are anti-osteoclastogenic, and produce cytokines such as IFN-gamma that are potent inhibitors of bone resorption.4 In 2006, a T-helper (TH) cell subset that expressed high levels of RANKL and proinflammatory cytokines, and low levels of IFN-gamma was identified in patients with autoimmune arthritis.87 These cells, known as TH17 cells, produced IL-17 and were linked to bone matrix degradation and bone loss.87 In a study of alcoholic liver disease, peripheral TH17 cells that secrete IL-17 were identified. This study also showed that the liver is extensively infiltrated by this cell population.88 The high levels of IL-17 in patients with alcohol-associated liver disease and the known effects of TH17 cells in the regulation of bone loss may represent an interesting additional pathway by which bone may be lost in patients with alcohol-associated liver disease.

Immune function in chronic liver disease

The finding that osteoprotegerin is produced by the liver initiated interest in the association of chronic liver disease with deregulation of the RANKL–RANK–osteoprotegerin axis.89 Depending on the patient population and stage of liver disease studied, levels of RANKL have been shown to be either decreased,90 increased,91 or not different from those of the normal population.92 However, most studies have found no correlation between RANKL levels and BMD,24, 90, 91, 92, 93 which suggests that the occasional increase in bone resorption is not related to this key osteoclast stimulating factor. Most studies have found circulating osteoprotegerin levels to be increased in patients with both cholestatic and parenchymal liver disease, compared with levels of healthy controls,24, 90, 91, 92, 93 although no consistent correlation between osteoprotegerin levels and decreased BMD has been identified.24, 92, 93 However, as increased levels of osteoprotegerin would be expected to result in increased BMD, this finding further underlines the limited role of the RANKL–osteoprotegerin system in bone loss secondary to liver disease.

The inconclusive data with regard to the role of the RANKL–osteoprotegerin system in osteoporosis associated with liver disease, led to an extensive characterization of peripheral monocytes in patients with chronic cholestatic liver disease with and without osteoporosis.94 In this study, RANKL was not expressed by the T cells of osteoporotic patients with cholestatic liver disease. Rather, peripheral blood mononuclear cells of patients with liver disease and osteopenia formed a greater number of osteoclast-like cells than patients with liver disease but without osteopenia. When cultured in the presence of CSF1 and RANKL, these osteoclast-like cells were functionally active and resorbed bone in vitro. These data suggest that an early step in the formation of osteoclasts may be affected in patients with chronic cholestatic liver disease. Also in this study, circulating levels of CSF1 were increased in patients with cholestatic liver disease and osteoporosis compared with levels in patients without osteoporosis, raising the possibility that CSF1 may be responsible for priming a larger number of monocytes to form osteoclasts in these patients. This study, therefore, suggests that a RANKL-independent pathway is operative in patients with cholestatic liver disease in whom bone resorption is increased.94 Several important questions, however, remain unanswered. For example, why are levels of CSF1 increased in patients with cholestatic liver disease, what is the potential role of the inflammatory liver microenvironment in the production of this cytokine, and what is the nature of the interplay between the CSF1 and RANKL-mediated induction and osteoprotegerin-mediated inhibition of osteoclastogenesis in these patients, particularly with regard to the elevated levels of this decoy receptor in patients with chronic liver disease? Whether these findings can be extrapolated to patients with parenchymal liver disease also remains to be established.

TNF is a potent proinflammatory cytokine that induces bone resorption.95 Levels of TNF are increased in patients with alcohol-associated liver disease and in those with viral hepatitis where serum levels of the soluble TNF receptor, TNF-R1, correlate with severity of liver disease, Child–Turcotte–Pugh status and presence of endotoxemia.24, 96, 97 Activated tissue macrophages and monocytes are major sources of TNF.98 In patients with viral liver disease, levels of TNF-R1 are inversely correlated with BMD,80 which suggests a role for this potent cytokine in the loss of bone associated with this condition. By contrast, levels of TNF vary widely and do not correlate with osteopenia in patients with cholestatic liver disease.94

Liver dysfunction: a question of bad molecules?

The possibility that the diseased liver could alter the production of factors that may affect osteoblasts to cause decreased bone formation led to the proposal of a novel mechanism by which liver diseases causes loss of bone mass. The presence of plasma fibronectin, which is normally produced by the liver, is critical for osteoblast function in vitro.99, 100 In patients with liver injury, however, activated stellate cells produce a glycosylated isoform of this protein, called oncofetal fibronectin.101, 102 A study that assessed circulating levels of oncofetal fibronectin in patients with primary biliary cirrhosis found a significant correlation between increased levels of oncofetal fibronectin and decreased levels of the marker of bone formation, osteocalcin.101 This finding suggested that elevated levels of oncofetal fibronectin resulted in decreased bone formation. Injection of oncofetal fibronectin in mice had a similar outcome; osteoblast number and bone formation rate were decreased, resulting in decreased BMD.101 However, a comparable relationship between oncofetal fibronectin and BMD in patients with viral hepatitis could not be detected,101 which suggested that this mechanism is specific to primary biliary cirrhosis. Collectively, these findings demonstrate that an extracellular matrix protein can function as a hormone to affect bone metabolism, and that an altered isoform of fibronectin produced by the inflamed liver is, at least in part, responsible for inhibition of osteoblast function associated with primary biliary cirrhosis.101

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Implications for therapy

Increased understanding of the mechanisms involved in bone loss associated with liver disease will enable the development of targeted and specific therapies for patients with this condition. In addition to general measures such as vitamin D and calcium supplementation, hormone replacement therapy in hypogonodal patients, mild weight bearing exercise and cessation of alcohol intake and cigarette smoking,1, 3, 7 several targeted approaches that may potentially benefit these patients are discussed below.

Stimulation of osteoblast function

Human parathyroid hormone 1–34 (hPTH1–34) is the only anabolic agent approved by the FDA for the treatment of osteoporosis. In an animal model of biliary cirrhosis, daily injections of hPTH1–34 increased bone formation by enhancing the recruitment, proliferation, and differentiation of osteoblasts.77 Human PTH1–34 might, therefore, be an attractive therapeutic option for osteoporosis in patients with liver disease. The applicability and the pharmacokinetics of hPTH1–34 in patients with chronic liver disease, however, need to be established.

Administration of IGF-I in rats with cirrhosis improved their BMD.67 Evidence from the past decade indicates that the IGFBP-3 and ALS subunits of the IGF-I complex are of particular importance to the bioactivity of IGF-I because deletion of these subunits led to greater bone loss than did deletion of IGF-I alone in transgenic animals.65, 66 Additional research is needed to understand the potential contribution of the IGFBP-3 and ALS subunits to bone mass in patients with chronic liver disease before these molecules can be assessed as a target to improve BMD.

Strontium ranelate increases bone formation, decreases bone resorption and increases bone mass in osteoporotic patients.103 This drug is mainly excreted by the kidneys but may accumulate in patients with chronic renal failure, and lead to osteomalacia.104 Strontium ranelate has not been evaluated in patients with liver disease, but may also benefit patients with chronic liver disease and osteopenia, although concerns would exist with regard to the use of this agent in patients with liver disease and impaired renal function.

RANKL pathway and inhibition of osteoclast function

The RANKL–RANK pathway has been extensively investigated with limited evidence that this pathway is important for the bone loss associated with chronic liver disease. On the basis of our current knowledge, there is no scientific rationale for the evaluation of therapeutic monoclonal anti-RANKL antibodies for these patients. Osteoclastogenesis induced by CSF1 has been linked to bone loss associated with cholestatic liver disease.94 Although no inhibitors of CSF1 are available, a surrogate intervention could involve the downstream inhibition of osteoclast function by means of bisphosphonate therapy. The use of bisphosphonate therapy for patients with liver disease has been evaluated in small clinical trials mainly in patients with cholestatic liver disease in whom the efficacy and safety of these agents has been established.3, 4 Bisphosphonate therapy is also effective for patients with steroid-induced osteoporosis and in patients undergoing transplantation. The use of bisphosphonate therapy for the prevention of bone loss in high-risk patients with liver disease or in situations where corticosteroid use is planned requires further exploration.

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Conclusions

Patients with chronic liver disease are at increased risk of osteoporosis and osteoporotic fractures. The pathophysiology of osteoporosis associated with liver disease is multifactorial and seems to differ between various liver diseases. Factors that suppress bone formation, increase osteoclastogenesis and activate the immune system all contribute in various combinations to the loss of bone commonly observed in these patients. Suppression of bone formation may result from altered production of fibronectin, altered levels of IGF-I or by the actions of other factors. The production of cytokines including TNF, CSF1 and IL-17 can increase osteoclastogenesis and bone loss. How the inflamed liver microenvironment and associated immune components interact with cellular elements at the bone interface are only beginning to be unraveled. Further research is required to elucidate the cytokines and signaling pathways and the role of the inflamed liver in liver disease-associated bone loss. Until targeted therapies are available, non-targeted approaches such as the use of bisphosphonate therapy to inhibit bone resorption are reasonable. Advances in the development of new osteoporosis therapies may also be useful for the treatment of bone loss associated with liver disease.

Review criteria

This Review is based on the personal experience of the authors and literature accumulated over their years working on hepatic osteodystrophy. Both authors compiled their literature lists independently, and searched the PubMed database between 2000 and 2009 using the search term "hepatic osteodystrophy", and the terms "bone", "osteopenia" and "osteoporosis" with the terms "liver", "hepatic", "chronic cholestatic liver disease", and "primary biliary cirrhosis". Only full text papers in English were reviewed. The reference lists of selected papers were examined for leads to relevant older literature.

Competing interests statement

The authors declare no competing interests.

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Author affiliations

Max-Planck Institute for Biochemistry, Martinsried, Germany. (I. A. Nakchbandi).Hepatology and Gastrointestinal Research Laboratory, Department of Immunology, University of Pretoria, South Africa. (S. W. van der Merwe).

Correspondence to: S. W. van der Merwe Email: svdmerwe1@doctors.netcare.co.za

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