Osteoporosis In Primary Biliary Cirrhosis Research Articles

Osteoporosis in primary biliary cirrhosis of the liver.

Osteoporosis is a metabolic bone disease associated with a reduction in bone mass and deterioration of bone architecture, leading to increased fragility and subsequent low-trauma fractures in the vertebral column, hip, forearm and other bones. In literature, metabolic bone diseases such as osteoporosis and osteomalacia have been recognised as a complication of chronic liver disease, although the mechanisms of this association remain unclear. An increasing body of research data indicates a strong relationship between osteoporosis and primary biliary cirrhosis (PBC), which mainly results from early diagnosis of the disease, usually when it is still asymptomatic. The incidence of osteoporosis in PBC ranges from 20% to 44% and increases with the progression of the disease. Similarly, the incidence of bone fractures is high in this group of patients (10–20%). In this article, current knowledge on risk factors, pathogenesis, diagnosis and treatment of osteoporosis in PBC is reviewed.

Strengthening the bones in primary biliary cirrhosis

Strengthening the bones in primary biliary cirrhosis

Bisphosphonates for osteoporosis in primary biliary cirrhosis

Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis in patients with primary biliary cirrhosis. To assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis. The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted for additional studies during the conductance of the review. All randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug. Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95% confidence intervals (CI). Methodological components were used to assess risk of systematic errors (bias). Trial sequential analysis was also used to control for random errors (play of chance). Six trials were included. Three trials with 106 participants, of which two trials with high risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95% CI -0.12 to 0.12, I² = 0%), fractures (RR 0.87; 95% CI 0.29 to 2.66, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04). Two trials with 62 participants with high risk of bias compared one bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95% CI -0.14 to 0.07, I² = 0%), fractures (RR 0.95; 95% CI 0.18 to 5.06, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04, I² = 0%). Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates had no significant effect on bone mineral density compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95% CI -23.77 to -10.10; 2 trials with 88 patients; I² = 0%) and serum osteocalcin (SMD -0.81; 95% CI -1.22 to -0.39; 3 trials with 100 patients; I² = 34 %) concentration. The former result was supported by trial sequential analysis, but not the latter. Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95% CI -9.41 to 2.18; 2 trials with 47 patients; I² = 82%) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95% CI -6.75 to -2.05; 2 trials with 47 patients; I² = 82%), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95% CI -15.96 to -1.63; 2 trials with 47 patients; I² = 38%), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95% CI -24.23 to -3.90; 2 trials with 46 patients; I²=0%) in a fixed-effect model. The latter two results were not supported by trial sequential analyses. There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95% CI -0.21 to 0.12; 2 trials with 46 patients; I² = 0%), or another bisphosphonate (RR 0.56; 95% CI 0.14 to 2.17; 2 trials with 62 patients; I² = 0%). One trial with 32 participants and with high risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or bone mineral density. Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration. We did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis. The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error. There is need for more randomised clinical trials assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in primary biliary cirrhosis.

High osteoprotegerin serum levels in primary biliary cirrhosis are associated with disease severity but not with the mRNA gene expression in liver tissue

The influence of osteoprotegerin and RANKL as regulators of osteoclastogenesis and bone remodeling in liver disease and in the development of osteoporosis in primary biliary cirrhosis (PBC) is uncertain. Therefore, 68 women with PBC and 20 healthy females were studied by assessing circulating osteoprotegerin and RANKL. Bone mineral density and markers of bone turnover were measured as well. Osteoprotegerin-mRNA expression was also assessed in liver tissue from 16 patients and 5 controls. Osteoprotegerin was higher in PBC than in controls (5.4 +/- 0.2 vs. 2.9 +/- 0.2 pM/l, P < 0.0001), whilst RANKL was lower in patients than in controls (0.39 +/- 0.06 vs. 1.40 +/- 0.16 pM/l, P < 0.0001). Osteoprotegerin was more elevated in patients with more advanced disease, as defined by bilirubin above 1.2 mg/dl (6.6 +/- 0.6 vs. 5.2 +/- 0.2 pM/l, P = 0.02) or by Mayo over 4 (5.9 +/- 0.3 vs. 4.8 +/- 0.2 pM/l, P = 0.02). Osteoprotegerin and RANKL were unrelated with osteoporosis, and no associations were found with markers of bone remodeling, except for RANKL, which was particularly decreased in patients with low osteocalcin. This marker of bone formation was also higher in patients with elevated circulating osteoprotegerin. Liver osteoprotegerin gene expression was similar in patients and controls, and no correlation was found between liver osteoprotegerin-mRNA and patients' respective circulating levels. In conclusion, osteoprotegerin and RANKL are abnormal in patients with PBC, regardless of osteoporosis. The elevated circulating osteoprotegerin is associated with the severity of disease, but not with gene expression in the liver.

Human Parathyroid Hormone 1–34 Prevents Bone Loss in Experimental Biliary Cirrhosis in Rats

Reduced bone mass and increased fracture rate are complications of primary biliary cirrhosis (PBC). The effect of intermittent administration of human parathyroid hormone (hPTH) 1-34 on bone mass and architecture in bile duct-ligated (BDL) rats was studied. Six-month-old male rats were subjected to BDL or sham operation (SO) and were treated from the second postoperative week intermittently with either hPTH 1-34 40 microg/kg per day, 80 microg/kg per day, or a vehicle for 4 weeks. Femoral and tibial bones were evaluated ex vivo by dual x-ray absorptiometry, microcomputed tomography, and histomorphometry. Serum osteocalcin and urinary deoxypyridinoline cross-links (DPD) were determined. BDL rats had decreased bone mass compared with SO rats as indicated by a 6% decrease in femoral and tibial bone mineral density (BMD), 18% reduction in femoral trabecular bone volume (bone volume/total volume [BV/TV]), 17% decrease in trabecular thickness, and 10% decrease in tibial cortical thickness. The administration of hPTH 1-34 at 40 microg/kg per day increased femoral and tibial BMD (9% and 9%), femoral trabecular BV/TV (50%), trabecular thickness (50%), tibial cortical thickness (17%), and serum osteocalcin (82%). On the other hand, hPTH 1-34 80 microg/kg per day had no effect on BMD and tibial cortical thickness, was associated with a smaller increase in trabecular BV/TV (24%), and had a higher osteoclast number and DPD compared with untreated BDL rats and the lower hPTH 1-34 dose treatment group. BDL rats exhibit loss of bone mass and structure, which can be prevented by the intermittent administration of hPTH 1-34, a potential therapy for osteoporosis in PBC.

Osteoporosis in Primary Biliary Cirrhosis: A Randomized Trial of the Efficacy and Feasibility of Estrogen/Progestin

The optimal therapy for the prevention and treatment of osteoporosis in primary biliary cirrhosis (PBC) is unknown. Hormone replacement therapy (HRT) prevents osteoporosis, but may promote cholestasis. We performed a double-blind, randomized, placebo-controlled trial of transdermal estrogen/progestin in postmenopausal women with PBC. The 24-month study enrolled 31 patients, but trial uptake was limited and treatment arm dropout was significant. Placebo-treated patients had a higher percentage loss in femoral neck bone mineral density than actively treated patients (-3.76 +/- 1.37% versus 0.21 +/- 1.01%, respectively, P = .058). New fractures occurred in 2 patients on placebo, and in no patients on treatment. The mean monthly increase in bilirubin was not significantly different between groups, but individual data suggest HRT may worsen cholestasis. In conclusion, women with PBC have strong feelings about HRT, and recruitment for this intervention is difficult. Transdermal estrogen/progestin likely provides protection against bone loss in PBC patients, but may worsen cholestasis.

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.

Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis

Since primary biliary cirrhosis (PBC) is usually diagnosed in postmenopausal women with minor cholestasis, it has been questioned whether PBC itself represents a further risk for osteoporosis. To assess the prevalence and risk factors for osteoporosis in an unselected series of women with PBC. 142 women with PBC (age: 54.3+/-0.8 years) and an age-matched control group. Osteoporosis was established by densitometry (bone mineral density below -2.5 T-score). Age, duration and severity of PBC, body mass index, menopausal status, histological stage and markers of bone turnover were assessed. Prevalence of osteoporosis was higher in PBC (32.4%) than in normal women (11. 1%) (RR: 3.83, 95%CI: 2.59-5.67, P<0.001). Osteoporosis was associated with older age, menopausal status, body mass index, longer PBC duration, advanced histological stage, high bilirubin and alkaline phosphatase, and low albumin and prothrombin index. Regression analysis identified older age, higher Mayo risk score, lower body mass index and advanced histological stage but not menopause as the independent risk factors for osteoporosis. Osteoporosis is more prevalent in women with PBC than in the general population. Age and severity of the disease, but not menopausal status, are the main risk factors for osteoporosis in this liver disease.

Duration and severity of the disease but not menopausal status are the main risk factors for osteoporosis in primary biliary cirrhosis

Duration and severity of the disease but not menopausal status are the main risk factors for osteoporosis in primary biliary cirrhosis

Osteoporosis in primary biliary cirrhosis revisited

BACKGROUNDPrimary biliary cirrhosis (PBC) is increasingly being diagnosed in the earlier non-cholestatic stages of disease. Accepted wisdom has been that PBC is frequently complicated by osteoporosis. Whether this association holds...

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

Background/Aim: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis. Methods: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score <−2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate. Results: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density. Conclusions: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.

Management of osteoporosis in primary biliary cirrhosis

Osteoporosis is not a significant problem in the majority of patients with primary biliary cirrhosis (PBC). However, substantial bone-related morbidity may occur in patients with advanced disease, in particular after liver transplantation. The cause of osteoporosis in PBC is multifactorial, and pathophysiological mechanisms specifically related to PBC have not been defined. In general, the principles of management followed in post-menopausal osteoporosis also apply in chronic liver disease. Dual energy X-ray absorptiometry is currently the method of choice for monitoring bone mineral density. Avoidance of conditions with potential negative effects on bone mass, and maintaining adequate serum vitamin D levels and calcium intake form the cornerstone in preventing osteoporosis. Bisphosphonates are the most logical choice when specific medical treatment of PBC-associated osteoporosis is indicated, as well as for preventing bone loss during glucocorticoid treatment and after liver transplantation. Recent studies suggest that active vitamin D analogues are effective alternatives in the post-transplant setting.

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.

Cyclical etidronate versus sodium fluoride for treatment of osteoporosis in primary biliary cirrhosis. Preliminary results after two years

Cyclical etidronate versus sodium fluoride for treatment of osteoporosis in primary biliary cirrhosis. Preliminary results after two years

Primary biliary cirrhosis and bone disease

Primary biliary cirrhosis and bone disease

Hepatic osteodystrophy in primary biliary cirrhosis: a possible defect in Kupffer cell mediated cleavage of parathyroid hormone.

Twelve of fourteen female patients with primary biliary cirrhosis, receiving vitamin D supplementation, exhibited unequivocal signs of osteoporosis but not of osteomalacia. Vitamin D treatment reproduced normal 25-hydroxyvitamin D levels in all but two patients and the 1,25 and 24,25-dihydroxyvitamin D metabolic pathways appeared to be unimpaired. A possible mechanism for the vitamin D resistant osteoporosis has been identified following the observation that, in those patients with severe cirrhosis, the circulating concentration of intact PTH was elevated. The increase in intact hormone appears to be at the expense of the carboxyl-regional PTH produced by hepatic Kupffer cell mediated cleavage of intact PTH. As a defect in Kupffer cell function is documented in primary biliary cirrhosis we postulate that the increased intact PTH/decreased carboxyl-regional PTH concentrations arise as a result of diminished Kupffer cell mediated cleavage. The reduced generation of cleaved PTH, due to this loss of Kupffer cell activity, would thus contribute to the development of osteoporosis in primary biliary cirrhosis.

Osteoporosis in Primary Biliary Cirrhosis: Effects of 25-Hydroxyvitamin D3 Treatment

Bone histology, bone mineral content, and calcium absorption were evaluated in 10 patients with primary biliary cirrhosis and osteopenia, before and after 1 yr of treatment with oral 25-hydroxycholecalciferol. Before treatment, quantitative histomorphometric analysis of full-thickness iliac crest bone biopsy specimens with double-tetracycline labeling demonstrated that 9 of 10 patients had osteoporosis. None had osteomalacia. Fasting intestinal calcium absorption correlated well with trabecular bone volume (r = 0.85). Bone mineral content measured by 125I-photon absorption was low in 6 of 10 patients, and it correlated poorly with iliac crest trabecular bone volume. After 1 yr of treatment with oral 25-hydroxyvitamin D3, bone mineral content fell in all 8 patients who were restudied. Iliac crest trabecular bone volume increased in 3 patients, 2 of whom had the greatest pretreatment impairment in calcium absorption, but fell in 5. Bone fractures continued to occur in 3 of 5 patients who were alive after 1 yr and developed for the first time in a sixth patient. We conclude that 25-hydroxyvitamin D3 is ineffective in reversing the bone thinning in the majority of primary biliary cirrhosis patients, but it may be helpful in a few selected patients.