Printer Friendly



Alterations of bone metabolism in patients with chronic liver diseases (CLD) represent an important complication that has been in the researchers' focus in recent years. This pathology is represented by osteoporosis or osteopenia, and seldom by osteomalacia, that may lead to morbidity (bone pain, skeletal deformities, immobilization, and fragility fractures) (1). All alterations of bone metabolism that appear in the evolution of CLD are defined as hepatic osteodystrophy (HO) (2). HO is a common complication of CLD and it involves impairment of bone mineral density (BMD). Therefore, assessment should be made in patients with CLD in order to preserve their quality of life and predict long-term prognosis (3). There are many factors that are involved in the etiology of HO but the pathogenesis of this form of secondary osteoporosis is still incompletely understood (2). Bone disorders may be found in viral, autoimmune or alcoholic CLD, but more frequently in CLD associated with cholestasis such as primary biliary cirrhosis and primary sclerosing cholangitis (4)' (5). This article provides an overview of this topic.

Material and Methods

For our narrative review, we searched medical literature using the following databases: PubMed, Google Scholar, Wiley, Science Direct, and Springer Link, and we collected English language articles from 1990 till 2015. We used the following keywords: "hepatic osteodystrophy", "cirrhosis", "hepatitis", "osteoporosis", "osteopenia", "bone density", "pathogenesis", "fracture", "antiviral therapy" and "bisphosphonates". We sorted out 148 papers (original articles and reviews) and we included in our review 100 papers which were more suitable and which met our review aim. All these articles included data on patients (older than 18 years) with CLD as: low BMD, pathogenesis and risk factors for low BMD, diagnosis, management, and treatment of HO.

Prevalence of Hepatic Osteodystrophy

Physiologically, peak bone density is achieved at around 30 years and then bone is lost at a rate of 0.5%-1% per year. In women, bone loss is accelerated in menopause, especially for 3-5 years of menopause onset. BMD also decreases with age, so the risk of fractures increases dramatically, mainly after the age of 60. Thus, osteoporotic fractures are known to impair the quality of life and daily activities, cause chronic pain and social isolation, increase the usage of pain killers and increase mortality (6).

The prevalence of osteoporosis in patients with CLD ranges from 3% to 48% (7-18), whereas the prevalence of osteopenia varies between 20% and 68%, depending on the etiology, pathogenesis and size of patient samples (8-10,13-18). The prevalence of fractures in patients with HO is between 5.3% in patients with chronic viral hepatitis or primary biliary cirrhosis and 23.7% in patients before orthotopic liver transplantation (Table 1) (8,13). Most of these studies used dual energy x-ray absorptiometry (DXA) to assess BMD (at lumbar spine and femoral neck) and to diagnose osteopenia and osteoporosis (except for the first study in Table 1, where spinal quantitative computed tomography and single photon absorptiometry were used). The etiology of HO in these studies varied from viral hepatitis and viral cirrhosis to primary biliary cirrhosis and end stage liver disease.

Pathogenesis of Hepatic Osteodystrophy

In pathologic conditions, BMD is reduced as a result of imbalance between bone formation and bone resorption. Some studies focused on bone resorption, especially in postmenopausal women, whereas other studies have reported decreased bone formation (19,20).

The risk of fractures in patients with CLD is determined by BMD, trabecular architecture and geometry, bone turnover, and risk factors (2). Many risk factors for HO have been reported such as genetic factors, vitamin D deficiency and calcium disorders, vitamin K deficiency, insulin-like growth factor 1 (IGF-1) deficiency, hyperbilirubinemia, hypogonadism, inadequate activity of the system of receptor activator of nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG), medication, fibronectin, hiperhomocysteinemia, leptin, and lifestyle (Table 2) (2).

Genetic factors

Genetic polymorphisms of vitamin D receptor and genetic polymorphisms of proteins that are implicated in vitamin D synthesis have been reported to play a role in CLD bone disorders, especially in primary biliary cirrhosis (21). Other genetic factors have also been reported to be involved in bone loss in patients with primary biliary cirrhosis, such as polymorphisms of collagen a 1 (I) gene, IGF-1, interleukin 1 (IL-1) receptor antagonist (IL1RA), and estrogen receptor a (ERa) (21,22). Data on vitamin D receptor and collagen a 1 (I) gene are discordant and no correlation has been found with an increased risk of osteoporosis for IL1RA or IGF-1 in the presence of ERa polymorphisms (23). Additionally, other known factors for osteoporosis may increase the risk of HO development. Female gender is a common risk factor for osteoporosis, including CLD osteoporosis. There has been reported that 21% of women aged 50-84 have osteoporosis (more than 12 million women from countries such as Germany, France, Italy, Spain and United Kingdom) (24). White and Asian races are those with lower BMD than other ethnic groups (25). Family risk of hip fracture has also been reported to be associated with the occurrence of osteoporosis and osteoporotic fractures in women, according to the study by Pinheiro et al? (6).

Vitamin D deficiency and calcium disorders

Previtamin [D.sub.3] (the first form of vitamin D which comes from the cholesterol metabolite 7-dehydrocholesterol under the effect of ultraviolet-B radiation) is transformed into vitamin [D.sub.3] in the skin. Only a very small part of vitamin D comes from diet. Vitamin [D.sub.3] becomes hydroxylated to vitamin D 25 in the liver and then the second hydroxylation process occurs in the kidney, which leads to vitamin D 1,25 (active metabolite). The role of this active form is to increase calcium resorption in the gastrointestinal tract, osteoclast activity (bone resorption) and osteoblast activity (bone mineralization) (27). In the study by Arteh et al., vitamin D deficiency has been reported in most patients with CLD (92%), and one-third of patients presented severe vitamin D deficiency (28). Vitamin D deficiency in CLD is caused by malnutrition, limited sun exposure, intestinal malabsorption, and decreasing skin synthesis (especially in patients with jaundice) (2). Nevertheless, the relationship between vitamin D and CLD remains unclear. A strong relationship has been reported in patients having undergone liver transplantation. Low serum vitamin D 25 levels have been correlated with osteoporosis post liver transplantation (29). However, after the first four months post liver transplantation, bone mass increased and higher serum vitamin D 25 levels were found (30). Vitamin D deficiency has recently been associated with high activity grade and stage of liver fibrosis in patients with chronic viral hepatitis C; in addition, vitamin D deficiency seems to be a risk factor in patients with no sustained virologic response when treated with peginterferon and ribavirin (31). In the study by Duarte et al., serum calcium was lower in patients with cirrhosis than non-cirrhotic ones; there was no proven connection between vitamin D deficiency and bone loss in chronic viral hepatitis (32). Verma et al. found that patients with primary biliary cirrhosis presented low spinal and femoral neck BMD and reduced fractional calcium absorption. However, additional studies are necessary to confirm that an increase in fractional calcium absorption may result in increased bone strength in patients with primary biliary cirrhosis (33).

Vitamin K deficiency

Vitamin K has an important role in the production of the bone matrix protein osteocalcin (a protein produced by osteoblast cells). Data have shown that in primary biliary cirrhosis, bone disorders were caused by vitamin K deficiency and that supplementation of vitamin K may prevent bone loss (34).

Insulin-like 1 growth factor deficiency

Osteoblasts and liver produce IGF-1, which is lower in the elderly and CLD patients. There are studies suggesting that low levels of IGF-1 may cause bone disorders, especially in CLD with cholestasis (4,12).


High bilirubin levels are often found in CLD, although the sequels of chronic cholestasis on bone tissue have not yet been established. Ruiz-Gaspa et al. studied the effects of bilirubin and serum from patients with jaundice on bone cells. They have reported that unconjugated bilirubin and serum from these patients affect osteoblast function and cause decreased bone formation, thus possibly contributing to the pathogenesis of HO (35).

Sex hormone deficiency

Normal bone metabolism requires normal sex hormone balance. In cirrhotic postmenopausal women, low levels of luteinizing hormone, follicle-stimulating hormone and estradiol, but normal testosterone levels were found (36). Deficiency of testosterone is a common factor for bone disorders in men with CLD, especially when liver disease is severe (end stage liver disease) and it is an independent predictor of mortality (37,38).

Receptor activator of nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) system

Inadequate activity of the RANKL/OPG system has been reported. This system includes cytokines that modulate osteoclast activity, since parathyroid hormone (PTH) does not have receptors on this type of cells. Usually, this system works as activating osteoclasts by RANKL (increasing bone resorption) and inhibiting osteoclast activity by osteoprotegerin; osteoprotegerin binds RANKL so that its activating power is stopped (decreasing bone resorption). Thus, any imbalance of this system such as increasing RANKL activity or decreasing osteoprotegerin activity leads to bone disorders (loss of bone mass) (39). This hypothesis is not yet clearly defined. In their study, Gaudio et al. did not confirm the fact that RANKL/OPG system could have a role in HO pathogenesis and they suggest that the increasing levels of osteoprotegerin may represent not only compensation for bone resorption but also a result of the inflammatory process in CL[D.sub.3] (8). Interleukin-6, a cytokine synthesized by osteoblasts, is an osteoclast activating factor. It may also stimulate osteoblasts to produce RANKL and thus promote bone resorption (40). There are studies which suggest that blockade of IL-6 receptor may lead to inhibition of the osteoclasts both in vitro and in vivo (5).


Glucocorticoid therapy may lead to drug-induced osteoporosis. The usage of glucocorticoids in CLD treatment (autoimmune and chronic cholestatic liver diseases) may accelerate development of osteoporosis. Glucocorticoids alter the balance between osteoclast and osteoblast activity in mineral bone metabolism (induce osteoblast apoptosis and prolong the lifespan of osteoclasts) (41,42).

Other drugs have been reported to interfere with calcium absorption, e.g., diuretics, antibiotics, and non-steroidal anti-inflammatory drugs (43). The use of benzodiazepine drugs has been found to correlate with fragility fractures in women (26). Cholestyramine is also a drug that may interfere with bone metabolism because of the adverse effect on the intestinal vitamin D absorption (4).

Regarding antiviral therapy little is known about the effect of the combination of ribavirin plus interferon (IFN) on BMD in patients with chronic hepatitis C, but back pain and bone fractures have been reported (44). Hofmann et al. have reported that BMD increased in patients administered pegylated interferon a and ribavirin, especially in those having achieved sustained virologic response (45). In their study, Solis-Herruzo et al. concluded that in patients with chronic hepatitis C the IFN-[alpha] and ribavirin therapy for 12 months could induce bone loss in almost all patients (46). Redondo-Cerezo et al. have reported recently that bone mass improved in hepatitis C patients who responded to antiviral therapy with ribavirin and pegylated IFN-[alpha] (47). The reduction of BMD in hepatitis B patients who received nucleoside (telbivudine, entecavir) and nucleotide (adefovir, tenofovir) analogs has also been studied but there are controversies. In a study of 319 chronic hepatitis B patients, the parameters such as age, gender, and nucleoside and nucleotide analog therapy correlated independently with bone loss (48). Buti et al. have recently shown data on long-term tenofovir disoproxil fumarate treatment in chronic hepatitis B infection, and no significant change in BMD was noticed in 7 years of the study (49). In another study, the prevalence of bone loss in chronic hepatitis B was similar in patients that were not treated with tenofovir and in those having received tenofovir for 12 months (50). Still, evaluation of BMD should be performed in patients receiving prolonged tenofovir treatment (51). Data are also limited about adefovir dipivoxil but lately many cases of osteomalacia due to adefovir treatment have been reported. Tanaka et al. have published a case of a patient who received adefovir depivoxil as treatment of lamivudine-resistant hepatitis B infection for 5 years and underwent total hip arthroplasty for osteomalacia and pathological hip fracture probably due to this treatment (52). Reduced BMD may be partially caused by CLD per se; also, low BMD may have existed prior to the introduction of antiviral therapy.

Other factors

Tumor necrosis factor (TNF) stimulates bone resorption and may cause bone disorders in patients with CLD (53). Elevated levels of soluble TNF receptor (sTN-FR-55) may also have a role in the pathogenesis of HO (47). Another factor involved in the pathophysiology of osteoporosis in CLD is leptin, a cytokine produced by adipocytes. Leptin plays a role both in hunger/satiety mechanisms and in bone metabolism. There is a hypothalamic central mechanism of leptin with anti-osteoporotic activity and also a peripheral leptin mechanism of increasing osteoblast proliferation, stimulating bone matrix synthesis and inhibiting RANKL activity (54,55). Data suggest that leptin levels are associated with BMD loss, especially in patients with primary biliary cirrhosis (56). Piche et al. have reported that high leptin levels are found in patients with chronic hepatitis C and these are correlated with the severity of liver fibrosis (57). In addition, it has been reported that there is an inverse association between serum leptin levels and BMD in patients with advanced liver disease (58). Pacifico et al. investigated the relationship between BMD and serum adipokines and high sensitivity C reactive protein levels in patients with nonalcoholic fatty liver disease, and found that low grade of systemic inflammation may decrease BMD (high sensitivity protein C was an independent factor associated with bone loss and low Z scores at lumbar spine) (59). Fibronectin is also a factor involved in bone metabolism. Fibronectin is a protein produced by a variety of cell types including cells of bone and liver. Fibronectin produced by liver goes to blood stream and its concentration is low in malnutrition and severe liver disease. The circulating isoform of fibronectin provided by the liver infiltrates the matrix of bone and increases matrix mineralization without affecting bone function and number of bone cells (60). An isoform of fibronectin named oncofetal fibronectin has been found in high levels in patients with primary biliary cirrhosis and it mediates bone loss by inhibiting bone formation (61). Homocysteine is also a player implicated in bone remodeling by increasing osteoclast activity, decreasing osteoblast activity, and it also has a direct effect on the bone matrix (62). Hyperhomocysteinemia has been reported to be associated with low BMD as an independent risk factor for osteoporosis and osteoporotic fractures (63). High levels of homocysteine have been found in patients with viral hepatitis C and can be reduced to normal range by standard antiviral therapy with IFN-[alpha] and ribavirin (64).

Lifestyle factors

In the pathogenesis of bone disorders due to CLD, behavioral factors such as alcoholism, cigarette smoking, malnutrition, low body mass index (BMI) and sedentary lifestyle have also been studied. Alcohol is an independent risk factor for osteoporosis; the hip fracture risk is 2.8 times higher than normal in alcoholic individuals (1). Kim et al. have reported that chronic alcohol consumption leads to low BMD in the femur Ward's triangle and trochanter (65). Cigarette smoking is also a risk factor that may be associated with osteoporosis in CLD (16,18,20,66). In postmenopausal women who have never smoked, passive smoking has been correlated with osteoporosis; also, the severity of lumbar and femoral neck osteoporosis has been positively associated with the number of cigarettes smoked by cohabitant smokers (67). Low BMI and malnutrition encountered in alcoholics are associated with bone loss, especially in those that have irregular feeding habits (68). Low BMI has been found to be associated with low BMD in patients with CLD (16,18,66). In the study by Pinheiro et al., 2420 individuals were investigated and sedentary lifestyle was found in women as a risk factor, along with age, family history of hip fracture, early menopause, poor quality of life, diabetes mellitus, use of benzodiazepine drugs, and recurrent falls. In the same study, the risk factors for osteoporosis in men were sedentary lifestyle, current smoking, poor quality of life, and diabetes mellitus (26).

Diagnosis of Hepatic Osteodystrophy

Osteoporosis is a systemic bone disease consisting of low bone mass and micro architectural disorders of bone tissue which leads to bone fragility and bone fractures (fragility fractures) (69). The gold standard in the diagnosis of HO is assessment of BMD by using DXA at lumbar vertebrae and femoral neck (70). According to the World Health Organization (WHO), osteoporosis is defined as T-score less than -2.5 (BMD less than 2.5 standard deviations compared to normal average score of young adults); osteopenia is defined as T-score between -1 and -2.5 (70). In individuals less than 50 years of age, the Z-score is used, which represents BMD of patient compared to mean BMD of age-, race- and sex-matched controls (71). These ranges refer only to BMD decrease, but there are many individual factors that should be assessed. Because of the individual risk, WHO has developed the Fracture Risk Assessment Tool (FRAX[R]), an instrument which takes into consideration many individual factors such as clinical factors and BMD at femoral neck. FRAX calculates the probability of hip fracture in ten years and the probability of major osteoporotic fracture (vertebral fractures, hip, humerus, forearm) in ten years (72,73).

In 2002, Collier et al. published guidelines for osteoporosis management in patients with CLD (1). Strong risk factors for osteoporosis require systematic BMD measurements and optimal treatment for prevention of fragility fractures, both in the absence and presence of CLD (associated with one or more risk factors) in every patient (Table 3) (1,6). Additionally, fragility fractures indicate severe osteoporosis and patients need immediate treatment without BMD scan (1).

In 2003, the American Gastroenterological Association (AGA) published guidelines for osteoporosis in liver and gastrointestinal disease (74). AGA recommends that vitamin D levels and BMD be assessed in all cirrhotic patients. Patients who have a history of personal fragility fracture, postmenopausal women and patients with long-term glucocorticoid therapy (>3 months) should have BMD evaluation. BMD measurement should also be performed in patients with primary biliary cirrhosis, cirrhosis, and patients undergoing liver transplantation. Patients who have risk factors and normal initial BMD test should be assessed after 2-3 years in order to exclude significant bone loss. A shorter interval for reevaluation of BMD (1 year) is recommended for patients on glucocorticoid therapy initiated recently and in high doses. In patients diagnosed with osteoporosis who have both elevated [gamma]-glutamyltransferase and serum alkaline phosphatase levels, screening for anti-mitochondrial antibodies should be performed because of the underlying cholestatic liver disease (which may have osteoporosis as the first clinical manifestation).

The 2003 World Gastroenterology Organization (WGO) Practice Guidelines for osteoporosis in gastrointestinal diseases recommend that repeated DXA scans should be performed at 12- to 18-month intervals (6). In addition, WGO recommends that fracture risk be assessed individually and decision should be made 'patient-by-patient'. If DXA scan is not available, patients at a high risk may be treated empirically (6).

Considering the high prevalence of HO, every patient with CLD should have complete evaluation of bone mass by detecting vitamin D and blood calcium levels, measuring BMD by DXA, besides using FRAX. The thyroid and gonadal functions should also be evaluated in patients to exclude other forms of osteoporosis (Table 4).

Vitamin D blood level should be determined in HO patients, especially those with possible low levels, for example, those receiving glucocorticoids.

Blood calcium level should be determined in patients with HO in order to exclude other causes of secondary endocrine osteoporosis. Evaluating the risk of osteoporosis at least once in the evolution of CLD should be considered (23). Patients with T-score less than -2.5 need immediate anti-osteoporotic treatment. Detection of T-score values between -1 and -2.5 indicates osteopenia and supplementation of calcium and vitamin D intake is required. In cirrhotic patients with ascites, paracentesis should be performed first, followed by BMD measurements because it has been demonstrated that fluid may erroneously reduce BMD values at lumbar spine during DXA scan (23,75,76).

In patients with bone disorders, bone turnover markers may also be detected; they are products of the bone remodeling process found in the blood and urine of these patients. The most widely used osteogenesis markers are osteocalcin, alkaline phosphatase (bone isoenzyme), procollagen type 1 carboxyterminal propeptide, and procollagen type 1 aminoterminal propeptide. Resorption markers are urinary pyridinoline, deoxypyridinoline, type 1 collagen amino-terminal telopeptide, and hidroxyprolinuria. All these markers are expressed related to urinary creatinine. There is little information in studies about bone turnover markers. In the study by Yenice et al., higher levels of urinary telopeptide were reported in postmenopausal women with chronic hepatitis B than in other groups (77). Schiefke et al. found elevated levels of alkaline phosphatase (bone isoenzyme) to be associated with histologically proven advanced viral chronic hepatitis (9). So far, there is no consensus regarding their use in clinical practice in CLD patients (1,2,13,77).

Management of Hepatic Osteodystrophy

Data on the management of patients with HO are insufficient and the best algorithm for diagnosis and treatment of patients with HO is individual management of every patient with CLD (1,74). According to the AGA, the management of osteoporosis in liver disease refers to three categories of patients who need BMD measurements using DXA: patients with CLD plus any of risk factors; patients with CLD undergoing liver transplantation; and patients with CLD and vertebral compression fractures in whom DXA scan is optional at baseline but treatment is mandatory (74). * For patients with normal T-score (T-score >-1), general prevention measures are recommended; for patients receiving long-term corticosteroid treatment and having normal T-score on DXA scan, both general measures and BMD reevaluation by DXA in one year are necessary.

* For osteopenia (T-score between -1 and -2.5), patients should follow general prevention measures and repeat DXA scan in two years; in patients with long-term glucocorticoid therapy and osteopenia, bisphosphonates should be considered and DXA scan performed in one year.

* Finally, for osteoporotic patients (T-score <-2.5), the recommendations are: general prevention measures, screening for other causes of osteoporosis and considering bisphosphonate therapy, otherwise they should be referred to a bone specialist.

Treatment of Hepatic Osteodystrophy

Treatment of HO patients includes general prevention measures and specific anti-osteoporotic therapy.

General prevention measures

Lifestyle measures involve reducing alcohol consumption, stopping smoking, having regular moderate physical exercise, and avoid falls (1,2). It is also recommended to limit the use of drugs such as diuretics, glucocorticoids and cholestyramine (78). Dietary measures refer to appropriate nutrition to avoid malnutrition and low BMI as risk factors for osteoporosis; dietary supplementation of calcium and vitamin D is recommended. The National Osteoporosis Foundation has established that adequate calcium intake is 1200 mg/day or more and vitamin D intake 800 -1000 IU/day; the optimal blood level of 25-hydroxyvitamin D is approximately 30-60 ng/mL (79). Serum level of 20-30 ng/mL of vitamin D indicates vitamin D insufficiency (80,81).

In their review of vitamin D and CLD, Kitson and Roberts have recommended that vitamin D status be investigated in all patients with CLD; if vitamin D is deficient, supplementation with vitamin [D.sub.3] in a dose of 1000-1400 IU/day is recommended (82). In the study by Yurci et al., patients with chronic viral hepatitis and cirrhosis who had reduced T-scores at DXA were treated for one year with different therapeutic regimens; one group of patients was treated only with 400 IU of vitamin D and their T-scores improved in the femoral neck region (83). So far, the role of calcium and vitamin D supplementation in preventing HO has not been established and clinical trials focused on this issue are required (1,2,74). However, data are discordant about optimal doses of vitamin D and calcium and their benefit; it is generally considered that patients with cirrhosis and low BMD should receive calcium and vitamin D supplementation. It is preferable to use parenteral high dose of vitamin D rather than oral low dose of vitamin D, but further research is needed to investigate this approach (84).

Specific anti-osteoporotic therapy

The agents used in osteoporosis treatment so far are hormone replacement therapy (HRT), selective estrogen receptor modulators, bisphosphonates, calcitonin, parathyroid hormone, and a combination of different therapies. The WGO recommends that if these drugs are not available for any reason, then vitamin D intake and sun exposure should be increased; the possibility to add vitamins in the food has also been discussed (6).

Currently, using HRT in HO treatment remains controversial. HRT with estrogens and progesterone is indicated as sequential or continuous combination therapy in women with liver disease and it can be administered orally or transdermally (1,85). This treatment should be used with caution because of its potential long-term risk to develop breast, gallbladder, endometrium or bladder cancers; however, HRT may have a protective effect against colorectal and liver cancers (6,86). HRT with testosterone in men without liver disease increased BMD (87). There are reports on the safety of these drugs in patients with liver disease (85). These drugs increased BMD by 5% and reduced the risk of fracture by 50% (6). The impact of HRT on BMD and fracture rate in postmenopausal or hypogonadal women with CLD was investigated in small studies (1). In patients with primary biliary cirrhosis, HRT improved lumbar spine BMD without impairing cholestasis (88).

Selective estrogen receptor modulators have beneficial effects on BMD at lumbar spine and femoral neck, and decrease vertebral fracture risk in postmenopausal women (2). Raloxifene improved BMD in osteopenic women with primary biliary cirrhosis (89). Also, raloxifene proved to be an adjuvant in standard treatment with pegylated IFNa2[alpha] and ribavirin in postmenopausal women with chronic hepatitis C (90).

Bisphosphonates are the most widely used drugs in postmenopausal osteoporosis reducing the rate of vertebral/hip fractures and height loss. They are antiresorptive agents that inhibit osteoclast activity and thus stop bone loss (91). They are also used in preventing glucocorticoid induced osteoporosis. In the study by Yurci et al., patients with chronic viral hepatitis and cirrhosis who had reduced DXA T-scores were treated for one year with different therapeutic regimens; three groups of patients were treated with alendronate 10 mg, alendronate 70 mg and risendronate 5 mg, respectively. T-scores improved significantly in all regions with alendronate 70 mg, and at lumbar spine and distal radius regions with alendronate 10 mg and risendronate 5 mg (83). Wolfhagen et al. have reported that cyclic etidronate seems to prevent osteoporosis induced by prednisone treatment in patients with primary biliary cirrhosis (92). Cyclic etidronate has also been reported to reduce the incidence of bone fractures in postmenopausal women with chronic hepatitis B and C (93). Pennisi et al. have suggested that pamidronate treatment decreases bone turnover and prevents bone loss after liver transplantation but the effect on bone at 12-month follow-up is limited to trabecular bone and not to cortical bone of the femur (94). In patients with primary biliary cirrhosis, alendronate has better antiresorptive effect than etidronate (95). Oral administration of alendronate should be avoided because of the risk of ulceration in esophageal mucosa (especially in cirrhosis patients with esophageal varices in whom variceal hemorrhage may appear). In contrast, risendronate has not been reported to have adverse effect on esophageal mucosa (1,96). Additionally, in another study, there were no adverse effects, including variceal hemorrhage (83). Zolendronic acid, another bisphosphonate, has been investigated in the last years and was found to prevent bone loss and reduce bone turnover and fractures in the first year after liver transplantation (97,98).

Currently, bisphosphonates are the most frequently used drugs for the treatment of HO, however, there is little information about their usage in liver diseases (74,78). They have been labeled as safe and most efficient ones, not only in preventing cortical bone loss but also in preventing trabecular bone loss, especially in chronic viral liver disease (83).

Calcitonin decreases bone loss and vertebral fracture rate in osteoporosis of postmenopausal women (1). Data on the efficacy of calcitonin in patients with CLD are discordant. Calcitonin and bisphosphonates have been reported to improve vertebral BMD after 12 months of treatment in patients having undergone liver transplantation (99). In the study by Yurci et al., patients with chronic viral hepatitis and cirrhosis who had reduced T-scores at DXA were treated with different therapeutic regimens; one patient group was treated with calcitonin 200 IU and their T-scores improved significantly in the lumbar spine region after one-year treatment (83). In patients with primary biliary cirrhosis, parenteral calcitonin administration had no effective results on bone loss when administered for 6 months (100). Additionally, 6-month calcitonin therapy had no effect on preventing or reducing bone loss or fractures occurring in the first year of liver transplantation in patients with primary biliary cirrhosis and primary sclerosing cholangitis (101). So far, this drug has been tested in a small number of studies and it remains as second line therapy after bisphosphonates.

Parathyroid hormone as a human recombinant form may be used to treat osteoporosis. It is administered subcutaneously and has been approved for the treatment of postmenopausal osteoporosis (74). PTH administration is very expensive and it is used in severe cases of osteoporosis (T-score < -3.5) (6). Recently, Leder et al. studied a novel synthetic peptide analog of PTH related protein named abaloparatide in postmenopausal women with osteoporosis. They concluded that abaloparatide increased BMD at lumbar spine, femoral neck and total hip in a dose dependent manner (102). There is little information about using PTH in osteoporosis due to liver disease. Recently, Anagnostis et al. have published a case of a liver transplant patient with severe osteoporosis who developed de novo autoimmune hepatitis after administration of PTH (1-34) and PTH (1-84) (103).


Hepatic osteodystrophy is a common complication in patients with CLD, which has attracted attention of many researchers from this field in the last years. This pathology involves osteoporosis or osteopenia, and sometimes osteomalacia, and may lead to morbidity (bone pain, skeletal deformities, immobilization, and fragility fractures) which affects the quality of life and survival. There are many factors that have been reported in the etiology of HO but the pathogenesis of this type of osteoporosis is still incompletely understood. Bone loss should be assessed in all patients with CLD. The management of bone disorders in CLD has not yet been established because of the lack of large therapeutic interventional trials in this field. Therefore, it is mandatory that the researchers keep their focus on HO in order to define better the pathogenesis, management of fracture risk, and treatment of this complication of CLD.


This work was supported by the Sectorial Operational Programme Human Resources Development (SOP HRD) financed by the European Social Fund and by the Romanian government under the contract number POSDRU/159/1.5/S/137390.


(1.) Collier JD, Ninkovic M, Compston JE. Guidelines on the management of osteoporosis associated with chronic liver disease. Gut. 2002;50:i1-9, doi: 10.1136/gut.50.suppl_1.i1.

(2.) Lopez-Larramona G, Lucendo AJ, Gonzalez-Castillo S, Tenias JM. Hepatic osteodystrophy: an important matter for consideration in chronic liver disease. World J Hepatol. 2013;3: 300-7, doi: 10.4254/wjh.v3.i12.300.

(3.) Marignani M, Angeletti S, Capurso G, Cassetta S, Delle Fave G. Bad to the bone: the effects of liver diseases on bone. Minerva Med. 2004;95:489-505.

(4.) Gasser RW. Cholestasis and metabolic bone disease--a clinical review. Wien Med Wochenschr. 2008;158:553-7, doi: org/10.1007/s10354-008-0594-z.

(5.) Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009; 60:2747-56, doi: 10.1002/art.24781.

(6.) Thomson ABR, Siminoski K, Fier M, et al. WGO Practice Guideline: Osteoporosis and gastrointestinal diseases 2003, revised 2004.

(7.) Diamond T, Stiel D, Lunzer M, Wilkinson M, Roche J, Posen S. Osteoporosis and skeletal fractures in chronic liver disease. Gut. 1990;31:82-7, doi: 10.1136/gut.31.1.82.

(8.) Carey EJ, Balan V, Kremers WK, Hay JE. Osteopenia and osteoporosis in patients with end-stage liver disease caused by hepatitis C and alcoholic liver disease: not just a cholestatic problem. Liver Transpl. 2003;9:1166-73, doi: 10.1053/jlts.2003.50242.

(9.) Schiefke I, Fach A, Wiedmann M, et al. Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection. World J Gastroenterol. 2005;11:1843-7, doi: 10.3748/wjg.v11.i12.1843.

(10.) George J, Ganesh HK, Acharya S, et al. Bone mineral density and disorders of mineral metabolism in chronic liver disease. World J Gastroenterol. 2009;15:3516-22, doi: 10.3748/wjg.15.3516.

(11.) Gonzalez-Calvin JL, Mundi JL, Casado-Caballero FJ, Abadia AC, Martin-Ibanez JJ. Bone mineral density and serum levels of soluble tumor necrosis factors, estradiol, and osteoprotegerin in postmenopausal women with cirrhosis after viral hepatitis. J Clin Endocinol Metab. 2009;94(12):4844-50, doi: 10.1210/jc.2009-0835.

(12.) Goral V, Simsek M, Mete N. Hepatic osteodystrophy and liver cirrhosis. World J Gantroenterol. 2010;16:1639-43.

(13.) Wariaghli G, Mounach A, Achemlal L, et al. Osteoporosis in chronic liver disease: a case-control study. Rheumatol Int. 2010;30:893-9, doi: F10.1007/s00296-009-1071-8.

(14.) Mitchell R, McDermid J, Ma MM, Chik CL. MELD score, insulin-like growth factor 1 and cytokines on bone density in end stage liver disease. World J Hepatol. 2011;3:157-63.

(15.) Soylu AR, Tuglu C, Arikan E, et al. The role of serum cytokines in the pathogenesis of hepatic osteodystrophy in male cirrhotic patients. Gastroenterol Res Pract. 2012;2012:425079, doi: 10.1155/2012/425079.

(16.) Orsini LGS, Pinheiro MM, Castro CHM, Silva AEB, Szejnfeld VL. Bone mineral density measurements, bone markers and serum vitamin D concentrations in men with chronic non-cirrhotic untreated hepatitis C. PLOS One. 2013;8:e81652, doi: 10.1371/journal.pone.0081652.

(17.) Abdelkader AH, Hegazy IM, Elbadrawy EG, et al. Osteoporosis in chronic hepatitis C. AJIED Afro-Egypt J Infect Endem Dis. 2014;4:126-35.

(18.) Barbu EC, Chitu-Tisu CE, Lazar M, et al. The effect of chronic viral hepatitis B and C on bone mineral density. Rom J Infect Dis. 2015;18(4):138.

(19.) Gallego-Rojo FJ, Gonzalez-Calvin JL, Munoz-Torres M, Mundi JL, Fernandez-Perez R, Rodrigo-Moreno D. Bone mineral density, serum insulin-like growth factor 1 and bone turnover markers in viral cirrhosis. Hepatology. 1998;28:695-9, doi: 10.1002/hep.510280315.

(20.) Nanda KS, Ryan EJ, Murray BF, et al. Effect of chronic hepatitis C virus infection on bone disease in postmenopausal women. Clin Gastroenterol Hepatol. 2009;7:894-9, doi: 10.1016/j.cgh.2009.01.011.

(21.) Pares A, Guanabens N, Rodes J. Gene polymorphisms as predictors of decreased bone mineral density and osteoporosis in primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2005; 17:311-5, doi: 10.1097/00042737-200503000-00009.

(22.) Lakatos LP, Bajnok E, Hegedeus D, Toth T, Lakatos P, Szalay F. Vitamin D receptor, oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2002;14:733-40, doi: 10.1097/00042737-200207000-00004.

(23.) Nakchbandi IA. Osteoporosis and fractures in liver disease: relevance, pathogenesis and therapeutic implications. World J Gastroenterol. 2014;20:9427-38.

(24.) Strom O, Borgstrom F, Kanis JA, et al. Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 2011;6:59-155, doi: 10.1007/s11657-011-0060-1.

(25.) Barrett-Connor E, Siris ES, Wehren LE, et al. Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res. 2005;20:185-94, doi: 10.1359/jbmr.041007.

(26.) Pinheiro MM, Ciconelli RM, Martini LA, Ferraz MB. Clinical risk factors for osteoporotic fractures in Brazilian women and men: the Brazilian Osteoporosis Study (BRAZOS). Osteoporos Int. 2009;20(3):399-408, doi: 10.1007/s00198-008-0680-5.

(27.) van Leeuwen JP, van Driel M, van den Bemd GJ, Pols HA. Vitamin D control of osteoblast function and bone extracellular matrix mineralization. Crit Rev Eukaryot Gene Expr. 2011; 11:199-226.

(28.) Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55:2624-8, doi: 10.1007/s10620-009-1069-9.

(29.) Crosbie OM, Freaney R, McKenna MJ, et al. Predicting bone loss following orthotopic liver transplantation. Gut. 1999;44: 1390-402, doi: 10.1136/gut.44.3.430.

(30.) Guichelaar MM, Kendall R, Malinchoc M, Hay JE. Bone mineral density before and after OLT: long term follow-up and predictive factors. Liver Transpl. 2006;12:1390-402, doi: 10.1002/lt.20874.

(31.) Lucaci C, Acalovschi M. The importance of vitamin D status in liver histological progression and response to antiviral therapy. HVM Bioflux. 2015;7:140-3.

(32.) Duarte MP, Farias ML, Coelho HS, et al. Calcium-parathyroid hormone-vitamin D axis and metabolic bone disease in chronic viral liver disease. J Gastroenterol Hepatol. 2001;16:1022-7, doi: 10.1046/j.1440-1746.2001.02561.x.

(33.) Verma A, Maxwell JD, Ang L, et al. Ursodeoxycholic acid enhances fractional calcium absorption in primary biliary cirrhosis. Osteoporos Int. 2002;13(8):677-82, doi: 10.1007/s001980200092.

(34.) Nishiguchi S, Shimoi S, Kurooka H, et al. Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol. 2001;35:543-5, doi: 10.1016/S0168-8278(01)00133-7.

(35.) Ruiz-Gaspa S, Martinez-Ferrer A, Guanabens N, et al. Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases. Hepatology. 2011;54(6):2104-13, doi: 10.1002/hep.24605.

(36.) Bell H, Raknerud N, Falch JA, Haug E. Inappropriately low levels of gonadotropins in amenorrhoeic women with alcoholic and non-alcoholic cirrhosis. Eur J Endocrinol. 1995;132(4): 444-9, doi: 10.1530/eje.0.1320444.

(37.) Grossmann M, Hoermann R, Gani L, et al. Low testosterone levels as an independent predictor of mortality in men with chronic liver disease. Clin Endocrinol (Oxf). 2012;77(2): 323-8, doi: 10.1111/j.365-2265.012.04347.x.

(38.) Gaudio A, Lasco A, Morabito N, et al. Hepatic osteodystrophy: does the osteoprotegerin/receptor activator of nuclear factor-kB ligand system play a role? J Endocrinol Invest. 2005;28 (8):677-82, doi: 10.1007/BF03347549.

(39.) Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res. 2000;15(1):2-12, doi: 10.1359/jbmr.2000.15.1.2.

(40.) Nakchbandi IA, Mitnick MA, Lang R, Gundberg C, Kinder B, Insogna K. Circulating levels of interleukin-6 soluble receptor predict rates of bone loss in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2002;87(11):4946-51, doi: 10.1210/jc.2001-011814.

(41.) Mitra R. Adverse effects of corticosteroids on bone metabolism: a review. Pm R. 2011;3(5):466-71, doi: 10.1016/j.pmrj.2011.02.017.

(42.) Pranic-Kragic A, Radie M, Martinovic-Kaliterna D, Radie J. Glucocorticoid induced osteoporosis. Acta Clin Croat. 2011; 50(4):563-6.

(43.) Ruppe MD. Medications that affect calcium. Endocr Pract. 2011;1:26-30, doi: 10.4158/EP10281.RA.

(44.) Goldstein SR, Martino FP, Cort S. Ribavirin capsules (SCH 18908) investigator's brochure. Schering-Plough Research Institute, 1997.

(45.) Hofmann WP, Kronenberger B, Bojunga J, et al. Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon alpha and ribavirin therapy. J Viral Hepat. 2008;15(11):790-6, doi: 10.1111/j.1365-2893.2008.01038.x.

(46.) Solis-Herruzo JA, 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(5):812-7, doi: 10.1016/S0168-8278(00)80314-1.

(47.) Redondo-Cerezo E, Casado-Caballero F, Martin-Rodriguez JL, Hernandez-Quero J, Escobar-Jimenez F, Gonzalez-Calvin JL. Bone mineral density and bone turnover in non-cirrhotic patients with chronic hepatitis C and sustained virological response to antiviral therapy with peginterferon-alfa and ribavirin. Osteoporos Int. 2014;25(6):1709-15, doi: 10.1007/s00198-014-2663-z.

(48.) Vigano M, Lampertico P, Eller-Vainicher C, et al. High prevalence of reduced bone mineral density in patients with chronic hepatitis B under nucleos(t)ides analogues treatment. Hepatology. 2010;52:526A.

(49.) Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci. 2014;60:1457-64, doi: 10.1007/s10620-014-3486-7.

(50.) Gill US, Al-Shamma S, Burke K, et al. Factors determining bone mineral density loss in chronic hepatitis B patients: is tenofovir disoproxil fumarate the main culprit? Gut. 2011;60: A230, doi: 10.1136/gut.2011.239301.486.

(51.) Ridruejo E, Silva MO. Safety of long-term nucleos(t)ide treatment in chronic hepatitis B. Expert Opin Drug Saf. 2012; 11(3):357-60, doi: 10.1517/14740338.2012.672972.

(52.) Tanaka M, Setoguchi T, Ishidou Y, et al. Pathological femoral fractures due to osteomalacia associated with adefovir dipivoxil treatment for hepatitis B: a case report. Diagn Pathol. 2012; 7(108):1746-56, doi: 10.1186/1746-1596-7-108.

(53.) Gonzalez-Calvin JL, Gallego-Rojo F, Fernandez-Perez R, Casado-Caballero F, Ruiz-Escolano E, Olivares EG. Osteoporosis, mineral metabolism, and serum soluble tumor necrosis factor receptor p55 in viral cirrhosis. J Clin Endocrinol Metab. 2004;89:4325-30, doi: 10.1210/jc.2004-0077.

(54.) Lucaci C, Acalovschi M. Hormonal and cytokine implications in the pathophysiology of osteoporosis occurring in chronic liver diseases. Maedica (Buchar). 2012;7(4):358-63.

(55.) Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197-207, doi: 10.1016/S0092-8674(00)81558-5.

(56.) Szalay F, Folhoffer A, Horvath A, et al. Serum leptin, soluble leptin receptor, free leptin index and bone mineral density in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2005;17:923-8, doi: 10.1097/00042737-200509000-00007.

(57.) Piche T, Vandenbos F, Abakar-Mahamat A, et al. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C. J Viral Hepat. 2004;11:91-6, doi: 10.1046/j.1365-2893.2003.00483.x.

(58.) Ormarsdottir S, Ljunggren O, Mallmin H, Olofsson H, Blum WF, Loof L. Inverse relationship between circulating levels of leptin and bone mineral density in chronic liver disease. J Gastroenterol Hepatol. 2001;16:1409-14, doi: 10.1046/j.1440-1746.2001.02631.x.

(59.) Pacifico L, Bezzi M, Lombardo CV, et al. Adipokines and C-reactive protein in relation to bone mineralization in pediatric nonalcoholic fatty liver disease. World J Gastroenterol. 2013; 19:4007-14, doi: 10.3748/wjg.v19.i25.4007.

(60.) Bentmann A, Kawelke N, Moss D, et al. Circulating fibronectin affects bone matrix, whereas osteoblast fibronectin modulates osteoblast function. J Bone Miner Res. 2010;25:706-15, doi: 10.1359/jbmr.091011.

(61.) Kawelke N, Bentmann A, Hackl N, et al. Isoform of fibronectin mediates bone loss in patients with primary biliary cirrhosis by suppressing bone formation. J Bone Miner Res. 2008;23: 1278-86, doi: 10.359/jbmr.080313.

(62.) Herrmann M, Widmann T, Herrmann W. Homocysteine--a newly recognised risk factor for osteoporosis. Clin Chem Lab Med. 2005;43:1111-7, doi: 10.1515/CCLM.2005.194.

(63.) Biagini MR, Tozzi A, Bongini E, et al. Association of plasma homocysteine with bone mineral density in postmenopausal women with osteoporosis or osteopenia affected by primary biliary cirrhosis. J Clin Gastroenterol. 2007;41:635, doi: 10.1097/01.mcg.0000225548.41998.c0.

(64.) Mustafa M, Hussain S, Qureshi S, Malik SA, Kazmi AR, Naeem M. Study of the effect of antiviral therapy on homocysteinemia in hepatitis C virus-infected patients. BMC Gastroenterol. 2012;12:117, doi: 10.1186/1471-230X-12-117.

(65.) Kim MJ, Shim MS, Kim MK, et al. Effect of chronic alcohol ingestion on bone mineral density in males without liver cirrhosis. Korean J Intern Med. 2003;18:174-80, doi: 10.3904/kjim.2003.18.3.174.

(66.) Barbu EC, Chitu-Tisu CE, Lazar M, Ion DA, Badarau IA. Osteodystrophy in chronic viral hepatitis C--an underdiagnosed pathology. J Intern Med Soc. 2015;XII(5):55-65.

(67.) Kim KH, Lee CM, Park SM, et al. Secondhand smoke exposure and osteoporosis in never-smoking postmenopausal women: the Fourth Korea National Health and Nutrition Examination Survey. Osteoporos Int. 2013;24:523-32, doi: 10.1007/s00198-012-1987-9.

(68.) Santolaria F, Gonzalez-Reimers E, Perez-Manzano JL, et al. Osteopenia assessed by body composition analysis is related to malnutrition in alcoholic patients. Alcohol. 2000;22:147-57, doi: 10.1016/S0741-8329(00)00115-4.

(69.) European Foundation for Osteoporosis and Bone Disease, the National Osteoporosis Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94(6):646-50, doi: 10.1016/0002-9343(93)90218-E.

(70.) World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. Tech Rep Ser. 1994;843: 1-129.

(71.) Fogelman I, Blake GM. Different approaches to bone densitometry. J Nucl Med. 2000;41:2015-25.

(72.) Kanis JA, on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary healthcare level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK; 2007.

(73.) WHO Fracture Risk Assessment Tool, FRAX[R], Available at: http://www.she[pounds sterling], Accessed on 28 March 2015.

(74.) Leslie WD, Bernstein CN, Leboff MS. AGA technical review on osteoporosis in hepatic disorders. Gastroenterology. 2003; 125:941-66, doi: 10.1016/s0016-5085(03)01062-x.

(75.) Labio ED, Del Rosario DB, Strasser SI, McCaughan GW, Crawford BA. Effect of ascites on bone density measurement in cirrhosis. J Clin Densitom. 2007;10:391-4, doi: 10.1016/j.jocd.2007.07.001.

(76.) Guanabens N, Monegal A, Muxi A, et al. Patients with cirrhosis and ascites have false values of bone density. Osteoporos Int. 2012;23:1481-7, doi: 10.1007/s00198-011-1756-1.

(77.) Yenice N, Gumrah M, Mehtap O, Kozan A, Turkmen S. Assessment of bone metabolism and mineral density in chronic viral hepatitis. Turk J Gastroenterol. 2006;17:260-6.

(78.) Mansueto P, Carroccio A, Seidita A, Di Fede G, Craxi A. Osteodystrophy in chronic liver diseases. Intern Emerg Med. 2013;8:377-88, doi: 10.1007/s11739-012-0753-5.

(79.) National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Washington, DC; 2008.

(80.) Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013;34(1):33-83,

(81.) Vukovic Arar Z, Knezevic Pravecek M, Miskic B, Vatavuk Z, Vukovic Rodriguez J, Sekelj S. Association between serum vitamin D level and glaucoma in women. Acta Clin Croat. 2016;55(2):203-8, doi:10.20471/acc.2016.55.02.04.

(82.) Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol. 2012;57:897-909, doi: 10.1016/j.jhep.2012.04.033.

(83.) Yurci A, Kalkan AO, Ozbakir O, et al. Efficacy of different therapeutic regimens on hepatic osteodystrophy in chronic viral liver disease. Eur J Gastroenterol Hepatol. 2011;23: 1206-12, doi: 10.097/MEG.0b013e32834cd6f6.

(84.) Crawford BA, Labio ED, Strasser SI, McCaughan GW. Vitamin D replacement for cirrhosis-related bone disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:689-99, doi: 10.1038/ncpgasthep0637.

(85.) O'Donohue J, Williams R. Hormone replacement therapy in women with liver disease. BJOG. 1997;104:1-3, doi: 10.1111/j.1471-0528.1997.tb10638.x.

(86.) Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C. Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer. 2003;105:408-12, doi: 10.1002/ijc.11083.

(87.) Behre HM, von Eckardstein S, Kliesch S, Nieschlag E. Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years. Clin Endocrinol (Oxf). 1999; 50:629-35, doi: 10.1046/j.1365-2265.1999.00705.x.

(88.) Crippin JS, Jorgensen RA, Dickson ER, Lindor KD. Hepatic osteodystrophy in primary biliary cirrhosis: effects of medical treatment. Am J Gastroenterol. 1994;89:47-50.

(89.) Levy C, Harnois DM, Angulo P, Jorgensen R, Lindor KD. Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis: results of a pilot study. Liver Int. 2005;25:117-21, doi: 10.1111/j.1478-3231.2005.01026.x.

(90.) Furusyo N, Ogawa E, Sudoh M, et al. Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: a randomized trial. J Hepatol. 2012;57(6):1186-92, doi: 10.016/j.jhep.2012.08.003.

(91.) Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008; 83(9):1032-45, doi: 10.4065/83.9.1032.

(92.) Wolfhagen FH, van Buuren HR, den Ouden JW, et al. Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis. A prospective, controlled pilot study. J Hepatol. 1997;26(2):325-30, doi: 10.1016/S0168-8278(97)80048-7.

(93.) Arase Y, Suzuki F, Suzuki Y, et al. Prolonged-efficacy of bisphosphonate in postmenopausal women with osteoporosis and chronic liver disease. J Med Virol. 2008;80(7):1302-7, doi: 10.1002/jmv.21195.

(94.) Pennisi P, Trombetti A, Giostra E, Mentha G, Rizzoli R, Fiore CE. Pamidronate and osteoporosis prevention in liver transplant recipients. Rheumatol Int. 2007;27(3):251-6, doi: 10.1007/s00296-006-0196-2.

(95.) Guanabens N, Pares A, Ros I, et al. Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol. 2003;98(10):2268-74, doi: 10.1111/j.1572-0241.2003.07639.x.

(96.) Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282(14):1344-52, doi: 10.1001/jama.282.14.1344.

(97.) Crawford BA, Kam C, Pavlovic J, et al. Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144(4):239-48, doi: 10.7326/0003-4819-144-4-200602210-00005.

(98.) Bodingbauer M, Wekerle T, Pakrah B, et al. Prophylactic bisphosphonate treatment prevents bone fractures after liver transplantation. Am J Transplant. 2007;7(7):1763-9, doi: 10.1111/j.1600-6143.2007.01844.x.

(99.) Valero MA, Loinaz C, Larrodera L, Leon M, Moreno E, Hawkins F. Calcitonin and bisphosphonates treatment in bone loss after liver transplantation. Calcif Tissue Int. 1995; 57(1):15-9, doi: 10.1007/BF00298990.

(100.) Camisasca M, Crosignani A, Battezzati PM, et al. Parenteral calcitonin for metabolic bone disease associated with primary biliary cirrhosis. Hepatology. 1994;20(3):633-7, doi: 10.1016/0270-9139(94)90098-1.

(101.) Hay JE, Malinchoc M, Dickson ER. A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2001; 34(2):292-8, doi: 10.1016/S0168-8278(00)00093-3.

(102.) Leder BZ, O'Dea LS, Zanchetta JR, et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2015;100(2): 697-706, doi: 10.1210/jc.2014-3718.

(103.) Anagnostis P, Efstathiadou ZA, Akriviadis E, Hytiroglou P, Kita M. De novo autoimmune hepatitis associated with PTH(1-34) and PTH(1-84) administration for severe osteoporosis in a liver transplant patient. Osteoporos Int. 2012; 23(9):2387-91, doi: 10.1007/s00198-011-1848-y.



E. C. Barbu, C. E. Chi?u-Ti?u, M. Lazar, C. Olariu, M. Bojinca, R. A. Ionescu, D. A. Ion i I. A. Badarau

Jetrena osteodistrofi ja je cesta i nerijetko nelijecena komplikacija koja se manifestira kao osteoporoza ili osteopenija, a susrece se u bolesnika s kronicnim bolestima jetre. Ovaj narativni pregled jetrene osteodistrofi je preispituje ucestalost, patofi ziologiju, dijagnostiku i lijecenje jetrene osteodistrofi je. Proveli smo pretragu medicinske literature u bazama podataka PubMed, Google Scholar, Wiley, Science Direct i Springer Link pomocu prikladnih kljucnih rijeci kako bismo dobili podatke o niskoj mineralnoj gustoci kosti povezanoj s kronicnim bolestima jetre. Mnoga istrazivanja izvjestavaju o povecanoj ucestalosti osteoporoze/osteopenije u bolesnika s kronicnim jetrenim bolestima. Patogeneza je multifaktorijalna i ukljucuje genetske cimbenike, pomanjkanje raznih vitamina, proupalne citokine, hipogonadizam, hiperbilirubinemiju, protuvirusnu terapiju, kortikosteroidne lijekove te cimbenike povezane s nacinom zivota. Lijecenje ovih bolesnika treba obuhvatiti individualiziranu procjenu cimbenika rizika za prijelome te mineralnu gustocu kosti. Svim bolesnicima s kronicnim bolestima jetre i osteoporozom treba preporuciti uzimanje dodataka vitamina C i kalcija. Bisfosfonati su najucinkovitiji lijekovi za lijecenje jetrene osteodistrofi je. Potrebno je bolje defi nirati zbrinjavanje i specifi cno lijecenje jetrene osteodistrofi je kako bi se sprije cili prijelomi zbog krhkih kosti te poboljsala kvaliteta zivota ovih bolesnika.

Kljucne rijeci: Kostane bolesti, metabolicke--dijagnostika; Kostane bolesti, metabolicke--patofi ziologija; Osteoporoza, jetrene bolesti; Ucestalost, kost, gustoca; Rizicni cimbenici; Prijelomi kosti; Protuvirusna sredstva; Bisfosfonati

Ecaterina-Constanta Barbu (1,2,3), Cristina-Emilia Chitu-Tisu (1,2,3), Mihai Lazar (1,2), Cristina Olariu (1,2), Mihai Bojinca (1,3), Razvan Adrian Ionescu (1,4), Daniela Adriana Ion (1) and Ioana Anca Badarau (1)

(1) Carol Davila University of Medicine and Pharmacy, (2) Matei Bals National Institute for Infectious Diseases' (3) I. Cantacuzino Clinical Hospital, (4) Colentina Clinical Hospital, Bucharest, Romania

Correspondence to: Ecaterina-Constanta Barbu, MD, PhD student, Carol Davila University of Medicine and Pharmacy, Matei Bals National Institute for Infectious Diseases, European Academy of HIV/AIDS and Infectious Diseases, Dr. Calistrat Grozovici Str. 1, 2nd District, Bucharest, 021105, Romania


Received May 19, 2016, accepted October 24, 2016
Table 1. Prevalence (%) of osteoporosis, osteopenia and fractures in
chronic liver diseases

Author,               Osteoporosis      Osteopenia        Fracture
year                  prevalence        prevalence        prevalence

Diamond               30%-48%           -                 12%-18%
et al.,
1990 (7)
Carey                 13.8%-28.1%       36.8%-41.5%       23.7%
et al.,                                                   (before OLT)
2003 (8)                                                  17% (first
                                                          year after
Schierke              26%               51%
et al.,
2005 (9)
George                                  68%
et al.,
2009 (10)
Gonzalez--Calvin      30.8%-46%
et al.,
2009 (11)
Goral                 37%
et al.,
2010 (12)
Wariaghli             45.3%             39.1%-50%          5.3%
et al.,
2009 (13)
Mitchell              21.4%             47%
et al.,
2011 (14)
Soylu                  1.9% -13%        20%
et al.,
2012 (15)
Orsini                 3%-36%           32%
et al.,
2013 (16)
Abdel-                 6.7%-10%         36.7% -43.3%
et al.,
Barbu                 11.6%             46.6%
et al.,
2015 (18)

Author,            Factors             CLD                Demographic
year               associated          etiology           data
                   with low

Diamond            Hypogonadism        Mixed              N=115
et al.,                                etiology           M/F: 72/43
1990 (7)                                                  Mean age 49.8
                                                          (range 20-74)
Carey              Increased           OLT                N=207
et al.,            bilirubin levels,   (alcoholic,        M/F: 131/76
2003 (8)           CTP, MELD           viral--HCV)        Mean age 51
                   score                                  (range 32-68)
Schierke           Increased PTH,      Hepatitis B, C     N=43
et al.,            BALP levels                            M/F: 12/31
2005 (9)                                                  Mean age 49
                                                          (range 26-77)
George             Hypogonadism,       Cirrhosis          N=72
et al.,            vitamin D           alcoholic,         Ethnicity:
2009 (10)          deficiency,         viral)             Indian
                   decreased                              M/F: 63/9
                   IGF-1 levels                           Mean age 45
                                                         (range 22-50)
Gonzalez--Calvin   Increased           Viral cirrhosis,   N=84
et al.,            sTNFr, estradiol    postmenopausal     Ethnicity:
2009 (11)          and OPG levels      women              Caucasian
                                                          M/F: 0/84
                                                          Mean age 65.1
                                                          (range 55-80)
Goral              Increased           Mixed              N=55
et al.,            TNF[alpha], IL-6,   etiology           M/F: 38/17
2010 (12)          IL-1 levels                            Mean age 44.8
Wariaghli          Cholestasis,        PBC,               N=64
et al.,            female sex,         Hepatitis B, C     M/F: 16/48
2009 (13)          lower weight                           Mean age 51.6
                   and height                             (range 26-76)
Mitchell           Decreased           ESLD               N=117
et al.,            IGF-1 levels                           M/F: 74/43
2011 (14)                                                 Mean age 50.4
                                                          (range 18-73)
Soylu              Increased IL-2,     Cirrhosis          N=44
et al.,            IL-6 serum          (alcoholic,        M/F: 44/0
2012 (15)          levels              viral)             Mean age 50.8
Orsini                                 Chronic            N=60
et al.,                                hepatitis C        M/F: 60/0
2013 (16)                                                 Mean age 41.5
Abdel-             Decreased           Chronic C          N=60
kader              testosterone        hepatitis          M/F: 52/8
et al.,            levels              and cirrhosis      Mean age 39.3
                                                          (range 22-55)
Barbu              Smoking, low        Chronic B,         N=60
et al.,            BMI, liver          C hepatitis        Ethnicity:
2015 (18)          fibrosis                               Caucasian
                                                          M/F: 40/20
                                                          Mean age 44.9
                                                          (range 20-70)

BALP = bone specific alkaline phosphatase; BMD = bone mineral density;
BMI = body mass index; CLD = chronic liver diseases; CTP =
Child-Turcotte-Pugh; ESLD = end stage liver disease; F = female;
HCV = hepatitis C virus; IGF-1 = insulin-like growth factor 1;
IL-1 = interleukin 1; IL-2 = interleukin 2; IL-6 = interleukin 6;
M = male; MELD = Model for End Stage Liver Disease; N = number;
OLT = orthotopic liver transplantation; OPG = osteoprotegerin;
PBC = primary biliary cirrhosis; PTH = parathyroid hormone;
sTNFr = soluble tumor necrosis factor receptor; TNF[alpha] = tumor
necrosis factor [alpha]; yrs = years

Table 2. Factors involved in bone loss in chronic liver diseases

Genetic factors:
 Vitamin D receptor (VDR) polymorphisms
 Collagen a1 (I) gene polymorphisms
 IL-1 receptor agonist (IL1RA) polymorphisms
 Estrogen receptor a (ERa) polymorphisms
 IGF-1 polymorphisms
Vitamin deficiencies:
 Vitamin D deficiency and calcium disorders
 Vitamin K deficiency
IGF-1 deficiency
Sex hormone deficiency
RANKL/OPG system
 Antiviral therapies (IFNa plus RBV, nucleos(t)ide
Other factors:
 C-reactive protein
Lifestyle factors:
 Cigarette smoking
 Low BMI
 Sedentary lifestyle

BMI = body mass index; IFN[alpha] = interferon [alpha]; IGF-1 =
insulin-like growth factor 1; RANKL/OPG system = receptor activator of
nuclear factor kappa B ligand/osteoprotegerin system; RBV = ribavirin;
TNF[alpha] = tumor necrosis factor [alpha]

Table 3. Risk factors strongly associated with osteoporosis in the
presence or absence of liver disease (1,6)

History of premature maternal hip fracture (<60 years)
Hypogonadism (primary hypogonadism,
early menopause (age <45 years), secondary
amenorrhea >6 months)
5 mg prednisolone (or equivalent)/day (>3 months)
Osteopenia evidenced by x-ray scan
Height loss >4 cm
Low body mass index (<19 kg/[m.sup.2])

Table 4. Diagnosis of hepatic osteodystrophy

Blood vitamin D level
Blood calcium level
Assessment of risk factors for osteoporosis FRAX
calculation--estimates risk fracture in ten years
T-score, Z-score and BMD assessment using DXA

BMD = bone mineral density; DXA=dual energy x-ray absorptiometry;
FRAX = WHO Fracture Risk Assessment Tool (FRAX[R]), (73)
COPYRIGHT 2017 Klinicki bolnicki centar Sestre milosrdnice
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Barbu, Ecaterina-Constanta; Chitu-Tisu, Cristina-Emilia; Lazar, Mihai; Olariu, Cristina; Bojinca, Mi
Publication:Acta Clinica Croatica
Article Type:Report
Date:Sep 1, 2017

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |