Bone disease in primary biliary cirrhosis: increased bone resorption and turnover in the absence of osteoporosis or osteomalacia

The role of vitamin D in hepatic osteodystrophy was examined. Eleven unselected patients with primary biliary cirrhosis (PBC) were assessed for disorders of mineral and vitamin D metabolism. Six were not receiving supplementary vitamin D, and five were being treated with oral vitamin D (50,000 IU daily). Serum levels of 25-hydroxyvitamin D were normal in all patients receiving oral therapy and in 4 of 6 untreated patients. Levels of serum 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D were normal or near normal in all patients. Studies were repeated after 6 months of therapy with parenteral vitamin D2 (100,000 IU i.m. monthly) in 7 patients. Initial bone histomorphometry revealed no evidence of osteomalacia or osteoporosis. However, the bone resorption surface of trabecular bone was increased. This abnormality was no longer present on repeat bone biopsies obtained after parenteral vitamin D therapy, and bone formation had decreased. In addition, trabecular bone volume remained normal in the face of the lower rate of bone formation. Increased bone resorption surface in the absence of osteoporosis or osteomalacia has not been previously described in PBC. Improvement in this bone parameter, associated with the finding of a decrease in the formation of bone and in hydroxyproline excretion in urine after parenteral vitamin D, suggests that increased turnover may be an early feature of the bone disease which complicates PBC and that parenteral vitamin D may retard the rate at which hepatic osteodystrophy develops in chronic cholestatic liver disease.     

Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis

Opinion statement Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients’ well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.     

Vitamin D replacement for cirrhosis-related bone disease

The osteoporotic fracture rate in patients with chronic liver disease is approximately twice that of age-matched, control individuals. About 66% of patients with moderately severe cirrhosis and 96% of patients awaiting liver transplantation have vitamin D deficiency. Studies have shown a strong correlation between vitamin D deficiency and bone density, particularly in the hip. Previous studies of vitamin D therapy in cirrhosis-related bone disease have had major design flaws. Most reports and guidelines on the treatment of hepatic bone disease have concluded that vitamin D deficiency does not have a significant pathogenetic role in the development of osteoporosis in cirrhosis, and that there is no evidence for a therapeutic effect of vitamin D supplementation. Conversely, it is generally recommended that patients with cirrhosis and low bone density should receive calcium and vitamin D supplementation; yet there is a paucity of reliable data on the optimal doses to use, as well as a lack of clearly demonstrated benefit. We believe that clinical trials of vitamin D therapy in these patients with liver disease are warranted. As low-dose oral supplementation often will not normalize vitamin D levels or suppress parathyroid hormone activity in cirrhotic patients, high-dose, parenteral vitamin D might be preferable, but further long-term studies are required to assess the benefits and safety of this approach.     

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.     

Prevention and treatment of osteoporosis in primary biliary cirrhosis.

Osteoporosis is not a feature unique to primary biliary cirrhosis (PBC) but is also found in other categories of liver disease. The principles developed for monitoring and treating postmenopausal osteoporosis can also be followed for patients with PBC. Monitoring of dietary intake of calcium and vitamin D serum levels is essential, and the threshold for initiating supplementation should be low. Bisphosphonates can be considered the most rational choice when specific therapy is required.     

Advantages of active vitamin D metabolites in the treatment of osteoporosis as compared with calciferol

Vitamin D is one of the most important regulating agents in the development of bone mass. Therefore administration of calciferol along with calcium in patients with nutritional vitamin D deficiency leads to improvement of bone density. In patients with osteoporosis who do not respond to vitamin D, insensitivity of osseous tissue to the active metabolite of vitamin D--1,25(OH)2 D3--is involved or inadequate synthesis of active metabolites in the liver or kidneys. Administration of 1alpha-OH vitamin D3 and in particular 1,25(OH) 2D3 improves the general calcium balance in the organism and increases by direct osteoforming action the value of bone mass and improves its quality. Administration of active vitamin D metabolites is unequivocally better in treatment of involutional osteoporosis, either along with calcium or in combination with some antiresorption substance, in osteoporosis associated with chronic inflammatory diseases, after organ transplantation or glukcocorticoid treatment. Even patients with postmenopausal osteoporosis respond better to 1,25(OH)2D3.     

Pamidronate and osteoporosis prevention in liver transplant recipients

Osteoporosis is a common complication in patients with end-stage liver disease and after orthotopic liver transplantation (LT), with resulting increasing fracture rate. In this study, we investigated the role of treatment with pamidronate in preventing further bone loss after LT. Eighty-five patients with end-stage liver disease were included in the study. Pamidronate 30 mg was given intravenously every 3 months after LT for the duration of 1 year to 43 patients with osteopenia or osteoporosis prior LT. The remainders served as controls. All patients received a supplementation of calcium and vitamin D. Bone mineral density (BMD) at the lumbar spine and the femoral neck, and markers of bone metabolism were measured before and 12 months after LT. Sixty-two BMD were available at 12 months; only paired BMD were evaluated. A significant increase in lumbar spine BMD was observed in pamidronate treated patients. No change was evident in controls. Femoral neck BMD decreased in both treated and untreated patients. Osteocalcin serum levels and deoxypyridinoline urinary excretion were significantly reduced by treatment. Our study suggests that pamidronate decreases bone turnover and is effective in preventing the course of bone loss after LT, however the efficacy, at the dosage regimen employed and in a follow-up of 12 months, appears to be limited to trabecular bone, with no effect on the cortical structure of the femur.     

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.     

Osteoporosis after solid organs transplantation

Osteoporosis is a common complication following kidney, heart, liver and lung transplantation. Immunosuppressive regimens to prevent graft rejection after transplantation commonly include glucocorticoids, cyclosporin A and tacrolimus which are detrimental to bone and mineral homeostasis and are superimposed on an already compromised skeleton. Additional factors likely to contribute to post-transplantation osteoporosis pathogenesis are vitamin D insufficiency, secondary hyperparathyroidism and hypogonadism. Measures should be taken to optimize bone health prior transplantation: bone mineral density and spinal X-rays should be performed, and vitamin D and gonadal status assessed. Prophylaxis against bone loss after transplantation should be considered for all patients. Data from clinical trials suggest that bisphosphonates are the most promising agents for the prevention and treatment of post-transplantation osteoporosis.     

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.     

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.     

Autoimmune chronic active hepatitis and primary biliary cirrhosis

Autoimmune CAH is important to recognize, since it is highly responsive to treatment which undoubtedly prolongs life. Autoimmune CAH can rarely be cured; complete withdrawal of treatment leads to relapse in over 80% of patients. Prednisolone and azathioprine are the major drugs of choice, the former inducing remission while the latter maintains remission, either alone or in combination with prednisolone. Since both drugs are associated with substantial side-effects which tend to be dose-related, the object of treatment must be to induce and maintain remission with the minimum risk of relapse together with an acceptably low incidence of complications. Although PBC shares many features in common with autoimmune CAH, treatment of the underlying disease is generally unsuccessful. To date no drug has been shown to induce remission or to prolong survival. The main aim of treatment should be directed towards the complications of PBC, of which pruritus and osteoporosis are the two major complaints. Cholestyramine and antihistamines are the drugs of choice, but when these fail a variety of other therapies are also available, although many have only been shown to be effective on an anecdotal basis. No treatment has yet been shown to reverse the bone demineralization which occurs in PBC, but early calcium supplementation is recommended in this disorder. Osteomalacia is uncommon and can be prevented by prophylactic calcium and vitamin D supplementation in jaundiced patients. Liver transplantation is effective in treating PBC, and when successful leads to complete restoration of health with the prospects of increasingly long survival. Recurrence of PBC does not appear to be a significant problem.     

Sodium fluoride prevents bone loss in primary biliary cirrhosis

Low-bone-turnover osteoporosis is a common complication of primary biliary cirrhosis (PBC). Since sodium fluoride stimulates bone formation we assessed the effect of this drug on bone mass in a 2-year, prospective, double-blind trial including 22 women with PBC who were randomly assigned to receive sodium fluoride (50 mg/day) or placebo. All received calcium supplements and low doses of vitamin D. Bone mineral density of the lumbar spine was measured by dual-photon absorptiometry initially and every 6 months. Vertebral fractures were evaluated in thoracic and lumbar spine initially, and after 1 and 2 years. Seven patients in the fluoride group and eight in the placebo group completed the trial. In the fluoride group, bone mineral density did not change after 2 years (initial 1.05 +/- 0.07, final 1.07 +/- 0.06 g/cm2; p = n.s.). In the placebo group, however, bone mineral density decreased significantly (initial 1.00 +/- 0.07, final 0.93 +/- 0.06 g/cm2; p = 0.03). Moreover, in the fluoride group bone mineral density increased by 2.9 +/- 3.6%, and in the placebo group decreased by 6.6 +/- 2.6% (p = 0.04). None of the patients developed new vertebral or non-vertebral fractures. Treatment with sodium fluoride did not impair liver function or cholestasis in PBC. These results indicate that sodium fluoride prevents bone loss in PBC and therefore might be considered as a possible therapeutic agent for osteoporosis associated with this liver disease. Since a small number of patients completed the trial, further studies are required.     

Primary biliary cirrhosis is not an additional risk factor for bone loss in women receiving regular calcium and vitamin D supplementation: a controlled longitudinal study

BACKGROUND AND GOALS: Alterations in bone metabolism in primary biliary cirrhosis (PBC) are generally considered to be highly prevalent and severe, but no data are available from prospective studies with adequate control groups. The aims of this study were: (1) to measure changes in bone mineral density (BMD) over time; (2) to correlate the degree of bone loss with the severity of liver disease; and (3) to characterize bone disease in PBC patients receiving regular calcium and vitamin D supplementation. STUDY: We enrolled 118 women with PBC (mean age+/-SD: 56+/-11 y; 72% postmenopausal; 43% with cirrhosis), and measured BMD (lumbar spine, DXA-Hologic) at entry and serially over the following 5 years. The controls were 472 healthy women selected from a large observational group matched for age and menopausal status (mean age+/-SD: 55+/-10 y; 73% postmenopausal). RESULTS: Mean BMD was 0.851+/-0.142 g/cm2 in the PBC group and 0.857+/-0.158 g/cm2 in the control group; the prevalence of osteoporosis was 28% and 29%, respectively. BMD significantly correlated with age and postmenopausal status, but not with liver cirrhosis or serum bilirubin levels. The biochemical markers of bone turnover were high in about 50% of the patients. The yearly bone loss in the PBC group was 0.008 g/cm2 (95% confidence interval: 0.014-0.003) similar to that calculated in the control group. CONCLUSIONS: Among patients with PBC, the prevalence of osteoporosis and the yearly rate of BMD loss are similar to those observed in the general population, and are not associated with the severity of liver disease.     

Management of osteoporosis in liver disease

Osteoporosis resulting in a high risk for fracture is a common complication in patients with liver disease, particularly in those with chronic cholestasis and with end-stage cirrhosis. The pathogenesis of bone loss in liver patients is poorly understood but it mainly results from low bone formation as a consequence of cholestasis or the harmful effects of alcohol or iron on osteoblasts. Increased bone resorption has also been described in cholestatic women with advanced disease. The management of bone disease in liver patients is addressed to reduce or avoid the risk factors for osteoporosis and fracture. Bisphosphonates associated with supplements of calcium and vitamin D are safe and effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation, though no clear achievements in descreasing the incidence of fractures have been described, probably because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.     

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.     

原发性胆汁性胆管炎肝移植术后预后研究现状与挑战

原发性胆汁性胆管炎(PBC)是一种病因尚不明确的慢性胆汁淤积性肝病。熊去氧胆酸、奥贝胆酸等药物治疗不佳的患者最终发展为肝硬化,甚至肝衰竭。目前,肝移植是治疗PBC的唯一有效手段。主要阐述了PBC患者进行肝移植的概况、肝移植术后生存期、并发症、PBC复发以及肝移植治疗前景及挑战,为PBC移植术后的临床转归及治疗提供参考。     

Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines

Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.     

An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis

Objectives. The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. Subjects/interventions. Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 μg 24 h^?1 two times per week + medroxyprogesterone 2.5 mg day^?1 + alfacalcidol 0.25 μg day^?1 and calcium 1 g day^?1 or (ii) alfacalcidol 0.25 μg day^?1 and calcium 1 g day^?1. Dual‐energy X‐ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment. Results. BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen‐treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver‐related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups. Conclusion. Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver.     

Osteoporosis in primary biliary cholangitis

Primary biliary cholangitis(PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from Pub Med, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.