Review
Liver and bone

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Abstract

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in cases with chronic cholestasis, hemochromatosis and alcohol abuse. The problem is more critical in transplant patients when bone loss is accelerated during the period immediately after transplantation, leading to a greater incidence of fractures. Advanced age, low body mass index and severity of the liver disease are the main risk factors for bone disease in patients with cholestasis. Mechanisms underlying osteoporosis in chronic liver disease are complex and poorly understood, but osteoporosis mainly results from low bone formation, related to the effects of retained substances of cholestasis, such as bilirubin and bile acids, or to the effects of alcohol on osteoblastic cells. Increased bone resorption has also been described in cholestatic women with advanced disease. Although there is no specific treatment, bisphosphonates associated with supplements of calcium and vitamin D are effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation. The outcome in reducing the incidence of fractures has not been adequately demonstrated essentially because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.

Introduction

For years “hepatic osteodystrophy”, including osteomalacia and osteoporosis, was used to describe the bone disorders observed in patients with different liver diseases. However, osteomalacia is very uncommon in patients with liver diseases, and it has been reported only in isolated patients with advanced primary biliary cirrhosis (PBC) and severe intestinal malabsorption in geographical areas with limited sunlight exposure [1].

Osteoporosis occurs in patients with chronic liver disease. However, there is certain heterogeneity regarding its prevalence, which depends on patient selection, liver disease etiology and additional risk factors for osteoporosis. Actually, most studies have been focused on bone disease in chronic cholestatic liver disease, mainly in patients with PBC, and in bone disease before and after liver transplantation. By contrast, few studies have evaluated bone disorders in other chronic liver diseases such as viral hepatitis, hemochromatosis and alcoholic liver disease.

In recent years there have been substantial advances in the identification of the risk factors and in the understanding of the pathogenetic mechanisms of osteoporosis in patients with chronic liver disease [2], [3], [4]. In spite of this, many issues remain to be elucidated.

This review describes the prevalence, risk factors, the current knowledge of the pathophysiology, and finally it focuses on the assessment and management of bone disorders in patients with liver disease.

Section snippets

Prevalence of osteoporosis

The prevalence of osteoporosis in chronic liver diseases is summarized in Table 1, which includes several relevant studies performed in patients with chronic cholestatic diseases, mainly primary biliary cirrhosis, and series of patients with mixed liver diseases. It should be taken into account, however, that because of the different densitometric criteria for osteoporosis, the table summarizes information on the studies with definite criteria for osteoporosis (T-score ⩽−2.5 in postmenopausal

Prevalence of fractures

The prevalence of fractures has been analyzed in few studies, mostly limited to short series as indicated in Table 1, which summarizes the available data on the studies where vertebral fractures were disclosed by spinal X-rays. Overall, the prevalence of fractures in patients with liver diseases ranges from 7% to 35% [5], [6], [7], [8], [11], [33], [42], [43], [44], [45]. We have recently assessed this issue in 170 patients with PBC, and the prevalence of vertebral (through X-rays of the

Risk factors for osteoporosis and fractures

Apart from the incomplete knowledge on the key mechanisms resulting in osteoporosis in PBC, some factors have been associated with the presence of low bone mass (Table 2). Several years ago, it was reported in a small series of PBC patients that osteoporosis was associated with the duration of liver disease, calcium malabsorption and the postmenopausal status [52]. Since most patients with PBC and osteoporosis are postmenopausal, it has been questioned whether the development of bone loss is

Pathogenesis of osteoporosis in liver diseases

The pathogenesis of osteoporosis in chronic liver diseases has been focused largely on PBC and on transplant recipients, and they have been scarcely studied in other liver disorders such as chronic hepatitis or alcoholic liver disease. However, some of these mechanisms are shared when cirrhosis or hyperbilirubinemia are involved in the course of liver disease.

The mechanisms resulting in osteoporosis in patients with PBC have not been completely elucidated since some studies indicate an

Diagnosis

The presence of risk factors for the development of osteoporosis should be evaluated in patients with chronic liver disease, including the following: chronic alcohol intake, smoking, body mass index lower than 19 kg/m2, male hypogonadism, early menopause, secondary amenorrhea of more than 6 months, family history of osteoporotic fracture and treatment with glucocorticoids (5 mg/d of prednisone or over for more than 3 months).

There has been some debate about the indications of bone densitometry in

Modification of risk factors and supportive measures for bone health

The factors contributing to bone loss should, as far as possible, be reduced to a minimum by stopping alcohol intake and smoking. As much physical activity as possible is advisable, as are exercises aimed at improving the mechanics of spine. However, the optimal exercise programme for osteoporosis in patients with chronic liver disease or after liver transplantation has not yet been determined. Specific recommendations should be given in patients with increased risk for falling.

Whenever

Summary and perspectives

Osteoporosis is a frequently observed complication in patients with chronic liver disease, especially in end-stages and in cases with chronic cholestasis, hemochromatosis and alcohol abuse. The problem is even more critical in transplant patients when bone loss is accelerated during the period immediately after transplantation, leading to a greater incidence of fractures. The pathogenesis of osteoporosis is mainly characterized by low bone formation, particularly related to the effect of

Acknowledgments

Supported in part by Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, and FIS-08/0105, Ministerio de Ciencia e Innovación, Spain.

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