Hepatic osteodystrophy: An important matter for consideration in chronic liver disease

Hepatic osteodystrophy (HO) is the generic term defining the group of alterations in bone mineral metabolism found in patients with chronic liver disease. This paper is a global review of HO and its main pathophysiological, epidemiological and therapeutic aspects. Studies examining the most relevant information concerning the prevalence, etiological factors, diagnostic and therapeutic aspects involved in HO were identified by a systematic literature search of the PubMed database. HO generically defines overall alterations in bone mineral density (BMD) (osteoporosis or osteopenia) which appear as a possible complication of chronic liver disease. The origin of HO is multifactorial and its etiology and severity vary in accordance with the underlying liver disease. Its exact prevalence is unknown, but different studies estimate that it could affect from 20% to 50% of patients. The reported mean prevalence of osteoporosis ranges from 13%-60% in chronic cholestasis to 20% in chronic viral hepatitis and 55% in viral cirrhosis. Alcoholic liver disease is not always related to osteo-penia. HO has been commonly studied in chronic cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis). Several risk factors and pathogenic mechanisms have been associated with the loss of BMD in patients with chronic liver disease. However, little information has been discovered in relationship to most of these mechanisms. Screening for osteopenia and osteoporosis is recommended in advanced chronic liver disease. There is a lack of randomized studies assessing specific management for HO.     

Osteoporosis in chronic liver disease

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end‐stages and in chronic cholestasis, in addition to non‐alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/β‐catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease.     

Osteoporosis in patients with primary biliary cirrhosis

Metabolic bone disease has been recognized as an important complication of chronic liver disease particularly in cholestatic disorders [primary biliary cirrhosis (PBC) and primary sclerosing cholangitis] and after liver transplantation. It includes osteoporosis and more rarely osteomalacia, which is more frequent in severe malabsorption and advanced liver disease. The pathogenesis of this disorder is complex and is likely to be multifactorial. Regardless of the etiology of osteoporosis in PBC patients, they have an increased risk of spontaneous or low-trauma fracturing leading to significant patient morbidity, deterioration of quality of life, and even patient mortality. The development of bone densitometry has allowed assessment of bone mass and then contributed in estimating the fracture risk. The gold standard of bone mineral density measurement is currently the dual- energy X-ray absorptiometry. Recommendations formulated by the World Health Organization have reported the diagnostic ranges of osteoporosis based on the t-score: patient with osteoporosis has a t-score less than -2.5 SD, osteopenia has a t-score between -1.0 and -2.5 SD and a normal individual has a t-score more than -1.0 SD. The risk of fracture shows a correlation with bone mineral density but no fracture threshold was determined and the best site of characterizing the hip fracture risk is the measure of the bone mineral density of the proximal femur. The treatment of osteoporosis in patients with PBC is largely based on trials of patients with postmenopausal osteoporosis as there are a few and smaller studies of osteoporotic patients with PBC. Bisphosphonates seem to be effective in biliary disease and are more tolerated.     

Osteoporosis in liver cirrhosis

Osteoporosis is a common complication of chronic liver disease, especially in the final stages. This entity is more critical in liver transplant recipients, when bone loss accelerates during the immediate postoperative period. The main mechanism involved in the development of osteoporosis in liver disease is deficient bone formation due to the harmful effects of substances such as bilirubin and bile acids or the toxic effect of alcohol or iron on osteoblasts. To prevent and treat osteoporosis, good nutrition and calcium and vitamin D supplementation are required. There are no specific recommendations on drug treatment but bisphosphonates are effective in increasing bone mass in patients with chronic cholestasis and have a good safety profile.     

Osteoporosis in liver cirrhosis

BACKGROUND: Osteoporosis is still an underestimated complication of liver cirrhosis (LC). AIM. To study the prevalence of osteoporosis and osteopenia in patients with LC and to identify the principal risk factors associated. MATERIAL AND METHODS: The prevalence of osteoporosis and osteopenia was studied in 150 patients with alcoholic or viral LC who were admitted to the Institute of Gastroenterology and Hepatology, Iasi in 2003. Osteoporosis was diagnosed by measuring their bone density using dual energy X-ray absorptiometry (DXA). Patients with liver disease due to multiple aetiologies or with other liver conditions (primary biliary cirrhosis, autoimmune or metabolic causes, etc.) as well post menopausal women were excluded from the study. The variables taken into consideration were: gender, nutritional status (body mass index - BMI), etiology of liver disease, presence of cholestasis, severity and duration of disease. RESULTS: Fifty-seven patients with LC (38%) were found to have osteoporosis or osteopenia. There was a statistically significant correlation between the presence of bone changes and a BMI of <20 kg/m2, cholestasis, Child class C and long duration of disease (>10 years). During the study period, despite the relatively high rate of bone metabolism abnormalities, there were no pathological fractures in the patients group. CONCLUSIONS: Osteoporosis has a raised prevalence in patients with LC. It is important to be diagnosed and treated early, especially when risk factors such as malnutrition, cholestasis and a severe liver disease are present for a long period of time.     

Osteoporosis in patients with inflammatory bowel disease: risk factors, prevention, and treatment

Patients with inflammatory bowel disease (IBD) are at increased risk for osteoporotic fracture. Bone density testing and osteoporosis management are recommended for IBD patients at greater risk for fracture (ie, postmenopausal women, men aged . 60 years, and those with low body mass indices, glucocorticoid use, family history of osteoporosis, and malabsorption). Patient management includes modification of osteoporosis risk factors, such as calcium and vitamin D supplementation, hormone deficiency correction, and smoking cessation. When indicated, bisphosphonates, such as risedronate and alendronate, have been shown to increase bone mass and reduce fracture risk in patients with glucocorticoid-induced osteoporosis. Infliximab, an anti-tumor necrosis factor a antibody, increases bone mineral density, but this effect has not as yet translated into reduced fracture risk.     

Bone health and vitamin D status in alcoholic liver disease

Alcohol consumption is harmful to many organs and tissues, including bones, and it leads to osteoporosis. Hepatic osteodystrophy is abnormal bone metabolism that has been defined in patients with chronic liver disease (CLD), including osteopenia, osteoporosis, and osteomalacia. Decreased bone density in patients with CLD results from decreased bone formation or increased bone resorption. The prevalence of osteopenia in alcoholic liver disease (ALD) patients is between 34 % and 48 %, and the prevalence of osteoporosis is between 11 % and 36 %. Cirrhosis is also a risk factor for osteoporosis. The liver has an important role in vitamin D metabolism. Ninety percent of patients with alcoholic liver cirrhosis have vitamin D inadequacy (<80 nmol/L). The lowest serum vitamin D levels were observed in patients with Child–Pugh class C. Bone densitometry is used for the definitive diagnosis of osteoporosis in ALD. There are no specific controlled clinical studies on the treatment of osteoporosis in patients with ALD. Alcohol cessation and abstinence are principal for the prevention and treatment of osteoporosis in ALD patients, and the progression of osteopenia can be stopped in this way. Calcium and vitamin D supplementation is recommended, and associated nutritional deficiencies should also be corrected. The treatment recommendations of osteoporosis in CLD tend to be extended to ALD. Bisphosphonates have been proven to be effective in increasing bone mineral density (BMD) in chronic cholestatic disease and post-transplant patients, and they can be used in ALD patients. Randomized studies assessing the management of CLD-associated osteoporosis and the development of new drugs for osteoporosis may change the future. Here, we will discuss bone quality, vitamin D status, mechanism of bone effects, and diagnosis and treatment of osteoporosis in ALD.     

Bone disorders in chronic liver disease

Osteomalacia rarely occurs in adult patients with chronic liver disease despite a low serum vitamin D level being reported in up to two-thirds of patients with cirrhosis. In contrast, osteoporosis, which increases the risk of vertebral fractures, occurs in 12%-55% of patients with cirrhosis. Although the prevalence is probably falling, as shown by a fall from 57%-26% in patients with biliary disease requiring liver transplantation over the last 2 decades, it still accounts for significant patient morbidity. Bone density also falls in the first 3 months after liver transplantation, and pretransplant fractures are predictive of posttransplant fractures. Many of the known risk factors for postmenopausal osteoporosis exist in the cirrhotic population, such as excess alcohol intake, steroid use, poor nutrition, and hypogonadism. There is also an increased risk of osteoporosis in patients without cirrhosis, particularly those with hemochromatosis and biliary disease. The diagnosis is made with bone density measurements. The effective treatment is largely based on evidence from postmenopausal osteoporosis as there have been only a few small clinical trials of patients with chronic liver disease. Bisphosphonates are the mainstay of treatment; they have been shown to be effective in biliary disease and are well tolerated.     

Advances in renal bone disease: Osteoporosis and chronic kidney disease

Osteoporosis is a common bone disease characterized by low bone density, microarchitectural deterioration of bone tissue, and a consequent increase in fracture risk. Recent decades have seen major advances in the understanding of the pathophysiology, prevention, and treatment of this disorder. Chronic kidney disease (CKD) affects more than 20 million Americans and is associated with unique metabolic mineral disorders related to low bone density and increased fractures. Because many patients with low bone density may have CKD, and the combination of osteoporosis and CKD may further increase fracture risk with increased morbidity and mortality, appropriate identification is necessary for effective management. The clinical, laboratory, and imaging studies currently used to diagnose osteoporosis in the general population inadequately detect the complex bone and metabolic changes that occur with CKD. This review focuses on the pathophysiology of osteoporosis and CKD and discusses problems with current diagnostic tools and considerations for treatment regimens.     

Prevention and Treatment of Postmenopausal Osteoporosis

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of the skeleton leading to enhanced bone fragility and an increased risk of fracture. Prior to fracture, diagnosis is established by documenting low bone mass. In the first section of this article we review the clinical use of bone mass measurements and biochemical markers of bone remodeling in selecting patients most in need of preventive therapy at menopause. Women with high bone turnover lose bone at menopause more rapidly than those with normal bone turnover and are more likely to derive benefit from the several preventive therapies available. The second section addresses the available technologies used to diagnose osteoporosis and/or establish fragility fracture risk using noninvasive bone mass measurement and biochemical markers of bone remodeling separately or in combination. In the third section we review the several treatment options available for patients with osteoporosis, including alendronate (alendronic acid), risendronate (risedronic acid), calcitonin, teriparatide, and raloxifene, and the approaches to monitoring the therapeutic response. The final section deals with fall protection--an often forgotten aspect of management of the patient at risk for sustaining and osteoporotic fragility fracture.     

Evaluation of bone mineral density in women with chronic liver diseases during perimenopausal period

Osteoporosis is the most frequently occurring metabolic diseases of bones, observed especially in women after menopause. The goal of the paper was a comparison of bone mineral density (BMD) of health women with that in perimenopausal patients with chronic liver diseases. The study was performed in 47 patients with chronic liver diseases, aged: 37-56 years. Qualification criteria included chronic type B hepatitis, chronic type C hepatitis and cirrhosis of viral aetiology. The control group consisted of 15 healthy, age-matched women. All the women had been examined in order to identify other risk factors of osteoporosis development. RESULTS: The incidence of decreased BMD was statistically higher in the group of patients with chronic hepatic diseases, compared to the group of healthy subjects. No bone fracture was found in any of the examined patients. CONCLUSIONS: Routine densitometric examinations should be performed in all women in perimenopausal age with chronic liver diseases. Results of our studies indicate that in patients with liver diseases, the lowest BMD values are found in the group of patients with cirrhosis or chronic type C hepatitis. These women constitute a large risk group for secondary osteoporosis development.     

Bone loss in chronic liver diseases: Could healthy liver be a requirement for good bone health?

Given that the liver is involved in many metabolic mechanisms, it is not surprising that chronic liver disease (CLD) could have numerous complications. Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients. Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis. Recent publications indicated that CLD-induced bone fragility depends on the etiology, duration, and stage of liver disease. Therefore, the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention, diagnosis, and treatment measures. The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood, especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals. It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals. Bone mineral density is widely used as the “golden standard” in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk. Therefore, microscale bone alterations (bone microstructure, mechanical properties, and cellular indices) were analyzed in CLD individuals. These studies further support the thesis that bone strength could be compromised in CLD individuals, implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients. However, more well-designed studies are required to solve the bone fragility puzzle in CLD patients.     

Treatment of osteoporosis in patients with chronic liver disease and in liver transplant recipients

Opinion statement The pathogenesis of osteoporosis in chronic liver disease and post-liver transplantation is complex and heterogeneous. The development of hepatic osteodystrophy may be related to both increased bone resorption and decreased bone formation. Available medical treatments can be broadly classified into antiresorptive and bone-stimulating agents. Most published studies on the treatment of osteoporosis in patients with liver disease have used the commonly prescribed antiosteoporosis drugs approved for postmenopausal osteoporosis. These studies have included a small number of subjects and used bone mineral density (BMD) changes rather than fracture occurrence as an endpoint because of the short follow-up. Although the increases in BMD are promising, no intervention is proven to have antifracture efficacy in hepatic osteodystrophy. The natural history of bone disease following liver transplantation has not been fully investigated, although studies suggest that bone mineral loss is transient and generally reverses within a year following transplantation. The approach to treatment in liver transplant recipients should be targeted at preventing the early bone loss without interfering with the later recovery. Based on the available data, no single available agent can be considered as first-line therapy. In our opinion, the best treatment approach involves the elucidation of modifiable risk factors and the selection of agents targeted at the underlying derangements.     

Bone disease after orthotopic liver transplantation

After orthotopic liver transplantation (OLT), not infrequently a deterioration of bone disease leading to compression fractures of vertebrae is seen. In a consecutive series of 36 adult OLT patients, we studied, clinically and radiologically, the incidence and degree of bone disease before and after OLT; we also studied whether clinical, radiological and laboratory findings were related to the event of postoperative vertebral collapse. Before OLT, radiological signs of mostly slight osteoporosis were seen in a minority of patients. After OLT, 38% of patients developed vertebral collapse, mainly in the second trimester. Collapse occurred in both previously normal and abnormal vertebrae. Of the preoperative parameters sex, age, menopause, intake of prednisolone, duration and diagnosis of liver disease, duration and degree of cholestasis, bone radiology and urinary calcium, only a low urinary calcium was related to postoperative collapse. Of the postoperative parameters duration of cholestasis, urinary calcium, duration of hospital stay, prednisolone dose and outcome in terms of life and death, none was related to collapse. We conclude that vertebral collapse after OLT occurs frequently and is not easily predicted. Early prevention of bone disease in patients with chronic liver disease before OLT and a low steroid-containing immunosuppressive regimen after OLT are advocated.     

Management of primary biliary cirrhosis

Opinion statement Primary biliary cirrhosis is a chronic, progressive disease for which there is no definitive treatment. Ursodeoxycholic acid, however, is of benefit for delaying progression to irreversible end-stage liver disease and prolonging survival free of transplantation. It is, therefore, the standard medical therapy for primary biliary cirrhosis. Orthotopic liver transplantation can be offered for patients with end-stage disease. Other important endpoints of treatment in this condition include management of the long-term complications of cholestasis such as pruritus, osteoporosis, and fat-soluble vitamin deficiencies. Pruritus is best treated with cholestyramine; rifampicin, antihistaminics, opioid-antagonists, and ondansetron can also be tried. Osteoporosis should be treated with calcium and vitamin D supplementation. Bisphosphonates or vitamin K2 may be of additional benefit to decrease the risk of fractures, but this is unproved as of yet. Deficiencies of vitamins A, D, E, and K should be treated with appropriate replacement. Finally, orthotopic liver transplant is indicated for cases of liver failure, intractable pruritus, or severe osteoporosis.     

Bone health as a co-morbidity of chronic kidney disease

Chronic kidney disease and osteoporosis commonly co-exist in aged patients. Chronic kidney disease affects bone health because of its effect on mineral metabolism in the syndrome, Chronic Kidney Disease Mineral and Bone Disorder, resulting in an increased risk of fractures. Hip fracture risk may be as much as four-fold higher in the worst affected. Tools to estimate fracture risk such as FRAX® and measuring bone density can be used in patients with chronic kidney disease; however, bone density may underestimate fracture risk in this population as it does not give information on bone quality. While osteoporosis treatment in patients with chronic kidney disease stage 1–3 does not differ from the general population, in the absence of Chronic Kidney Disease Mineral and Bone Disorder, patients with disease stage 4–5 require special consideration. It is, however, of the utmost importance that these patients receive pharmacological treatment because of their high risk of fractures.     

Bone Disorders in Chronic Liver Diseases

Bone disease is a major complication of chronic liver disease. Osteomalacia is quite uncommon despite low vitamin D levels in the majority of patients with cirrhosis. In contrast, osteoporosis is quite common, occurring in up to 50% of patients. Osteoporosis can result in spontaneous or low-impact fractures in patients with chronic liver diseases, adversely affecting morbidity, quality of life, and survival. The general biology of osteoporosis, including its pathogenesis, diagnostic tools, and rationale for treatment, have been determined largely empirically from studies of postmenopausal women with osteoporosis. Treatment regimens with modification of risk factors, use of vitamin D, and supplementation with calcium and bisphosphonates have been shown to be effective in select groups of patients with chronic liver diseases.     

Avances en la valoración de la salud ósea en el trasplantado renal

Bone disease related to chronic kidney disease and, particularly, to kidney transplant patients is a common cause or morbidity and mortality, especially due to a higher risk of osteoporotic fractures. Despite the fact that this has been known for decades, to date, an appropriate diagnostic strategy has yet to be established. Apart from bone biopsy, which is invasive and scarcely used, no other technique is available to accurately establish the risk of fracture in kidney patients. Techniques applied to the general population, such as bone densitometry, have not been subjected to sufficient external validation and their use is not systematic. This means that the identification of patients at risk of fracture and therefore those who are candidates for preventive strategies is an unmet need.Bone strength, defined as the ability of the bone to resist fracture, is determined by bone mineral density (measured by bone densitometry), trabecular architecture and bone tissue quality. The trabecular bone score estimates bone microarchitecture, and low values have been described as an independent predictor of increased fracture risk. Bone microindentation is a minimally invasive technique that measures resistance of the bone to micro-cracks (microscopic separation of mineralised collagen fibres), and therefore bone tissue biomechanical properties. The superiority over bone densitometry of the correlation between the parameters measured by trabecular bone score and microindentation with the risk of fracture in diverse populations led us to test its feasibility in chronic kidney disease and kidney transplant patients.     

Osteoporosis in chronic liver disease: a case–control study

Osteoporosis has become an increasingly recognized complication among patients with chronic liver disease (CLD). The aim of the present study was to assess the prevalence and risk factors of osteoporosis in patients with CLD (primary biliary cirrhosis and chronic viral hepatitis B or C patients) in comparison with a group of age- and sex-matched controls. Sixty-four patients with CLD (mean age 51.66 ± 11.54 years), 48 females and 16 males were included. Age- and sex-matched individuals from the general population served as controls. Osteoporosis was evaluated by dual energy X-ray absorptiometry (bone mineral density below ?2.5 T score) at the lumbar spine (LS) and total hip (TH). Vertebral fractures were established by densitometric morphometry (vertebral fracture assessment). Bone turnover was assessed by intact parathyroid hormone, osteocalcin and C-telopeptides of type I collagen in the serum. Prevalence of osteoporosis in either the LS or the TH was 45.3%, twice as high as in the controls (19.6%) (RR 2.31, 95% CI 1.42–3.75, P < 0.001). Age, menopausal status, cirrhosis and advanced histological stage are not determinant factors for developing osteoporosis in patients with CLD. However, female sex, cholestasis, lower weight and height but not body mass index seem to play predominant role. Three (5.3%) patients had dorsal and LS fractures. It was concluded that osteoporosis is effectively a complication of CLD. Cholestasis in addition to female sex and lower weight and height are risk factors of osteoporosis in CLD.     

Gene polymorphisms as predictors of decreased bone mineral density and osteoporosis in primary biliary cirrhosis

Osteoporosis is a common complication observed in patients with primary biliary cirrhosis (PBC), with a prevalence of around 25%. The pathogenesis of bone loss in PBC is not well understood, since low bone formation and high resorption have been described. Bone disease is influenced by the duration and severity of the disease and oestrogen deficiency secondary to menopause. Genetic susceptibility has also been considered for osteoporosis in PBC, including vitamin D receptor genotypes, the gene encoding collagen type I alpha1 and insulin growth factor 1 gene microsatellite repeat polymorphism. Based on current evidence, the proposed genotypes either do not influence the development of osteoporosis in PBC or play only a minor role in it. The duration as well the severity of cholestasis are the main factors for such a disturbance since they are associated with the degree of bone loss. These features may exceed the potential effect of gene polymorphisms on osteoporosis in PBC.