• Jelena S Rudic, Vanja Giljaca, Miodrag N Krstic, Goran Bjelakovic, and Christian Gluud.
• Department of Hepatology, Clinic of Gastroenterology, Clinical Centre of Serbia, Koste Todorovica 2, Belgrade, Serbia, 11000.
• Cochrane Db Syst Rev. 2011 Jan 1(12):CD009144.

BackgroundBisphosphonates 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.ObjectivesTo assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis.Search MethodsThe 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.Selection CriteriaAll randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug.Data Collection And AnalysisTwo 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).Main ResultsSix 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.Authors' ConclusionsWe 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.

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