The prevalence of osteoporosis in patients with chronic liver disease is variable and depends on patient selection and diagnostic criteria [4–26] (Table 31.1). Nevertheless, around 30 % of patients have osteoporosis, with a higher prevalence in patients with primary biliary cirrhosis [4–12]. The prevalence of osteoporosis in patients with cirrhosis related to chronic alcohol intake or resulting from chronic hepatitis C virus infection ranges from 12 to 39 % of cases [14–23]. In a recent study assessing bone disease in patients awaiting liver transplantation, the prevalence of osteoporosis was still very high (30 %) [23]. Additionally, around 30 % of patients with hemochromatosis may have osteoporosis [24–26].

The prevalence of fractures in liver patients ranges between 7 and 35 % [4, 8, 10–13, 15–18, 20, 22, 23). Fractures are more prevalent in postmenopausal women than in males and young women [15], and in patients with autoimmune hepatitis treated with glucocorticoids [27]. In women with primary biliary cirrhosis, vertebral fractures are associated with osteoporosis and osteopenia with a T-score lower than −1.5, whereas osteoporosis and osteopenia are associated with the severity of liver damage [12]. The clear-cut correlation between vertebral fracture and a T-score < −1.5, observed in these patients may indicate that this densitometric measurement is a useful guide for considering therapy.

Osteoporosis with high risk for fracture represents an additional concern in patients who are candidates for liver transplantation. Thus, most liver transplant patients have a rapid bone loss within the first 6 months after transplantation [28]. This is associated with an incidence of fractures between 25 and 35 % within the first year of transplantation, being more frequent in women, the elderly, cholestatic [29] and alcoholic patients, and particularly in those with osteoporosis and fragility fractures before transplantation [30]. However, these numbers may have become lower in recent years because of the advances in the management of patients following transplantation [31].

The mechanisms resulting in osteoporosis in liver disease have not been completely clarified, in part because the amount of bone mass depends on the balance between two opposite processes: bone resorption modulated by osteoclasts, and bone formation induced by osteoblasts (Fig. 31.2) [1]. Up to now, most studies point towards a decreased bone formation, whereas few studies have reported an increased resorption. Impaired osteoblast function resulting in lower mean wall thickness and a defect in matrix synthesis [32], as well as a low bone formation rate have been reported in some studies [32, 33]. These data are consistent with the decreased serum levels of osteocalcin [34], a biochemical marker of bone formation. Furthermore, the noxious effects of bilirubin and retained bile acids as a consequence of cholestasis may also play a role, since deleterious consequences on osteoblast viability, differentiation, and mineralization and increased apoptosis have been reported in different experiments [35–37]. Osteoblast dysfunction may result from reduced trophic factors such as insulin growth factor-1 (IGF-1). Thus, serum IGF-1 levels are decreased in patients with cirrhosis [38] and low doses of IGF-1 increase bone mass in cirrhotic rats [39]. A role for proinflammatory cytokines has been suggested in the pathogenesis of osteoporosis in liver diseases [40]. Thus, serum concentrations of soluble tumor necrosis factor receptor p55 are significantly higher in cirrhotic patients with osteoporosis and are inversely correlated with BMD [41].

Despite the previous data on osteoblasts and subsequent effects on bone formation , past histomorphometric reports have revealed increased bone resorption and turnover even in the absence of osteoporosis as an early feature of bone disease in patients with primary biliary cirrhosis [42]. Reduced trabecular wall thickness and increased bone turnover have been found to be proportional to the severity of hepatic dysfunction and cholestasis [43]. Overt or slight calcium and vitamin D deficiencies leading to secondary hyperparathyroidism have been proposed as the cause of increased bone turnover found in some patients with cholestasis [44]. Moreover, in human osteoblasts, serum from jaundiced patients significantly upregulates the RANKL/OPG (receptor activator of nuclear factor-κB ligand/osteoprotegerin) gene expression ratio, which activates the differentiation of osteoclasts and maintains their function [36]. These effects may partially explain the increased bone resorption described in some patients, particularly in those with chronic cholestasis.

Other conditions including low vitamin D levels, hypogonadism, and poor nutrition may be contributing factors to the full picture of bone disease in liver patients. Thus, hypogonadism, which is frequent in hemochromatosis [25], cirrhosis, and alcoholic liver disease [45], may result in increased bone remodeling and bone loss. Likewise, a reduction in bone formation has been observed in alcoholic patients, with low serum levels of osteocalcin during alcohol intake, which normalizes with abstinence [46]. Deposits of iron may be responsible for low bone formation, due to the direct lesion-producing effects of iron on osteoblast activity in hemochromatosis [47]. Vitamin K deficiency has also been considered as another ancillary factor in the pathogenesis of osteoporosis in liver disease, since vitamin K mediates the carboxylation of glutamyl residues in bone protein such as osteocalcin [1].

Genetic susceptibility for osteoporosis in liver diseases has been assessed with uncertain results. Taken together, gene polymorphisms either do not influence or have a very small effect on the development of osteoporosis in these patients [48].

Because of the high prevalence of osteoporosis and thus, increased risk for fractures in patients with chronic cholestasis and end-stage cirrhosis of different etiologies, it seems reasonable to establish guidelines for the diagnosis of bone disease that results in very high morbidity. This is even more important given that patients with advanced cirrhosis may be eligible for liver transplantation. However, there is scarce information about the steps to follow in terms of diagnosis and treatment, as bone disease in patients with cirrhosis has received little attention, except for conditions associated with chronic cholestasis and after liver transplantation [49]. It seems realistic to establish the same recommendations as in patients with other processes that are associated with osteoporosis.