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.

Fatigue is common in primary biliary cirrhosis (PBC). Altered central serotonergic neurotransmission may be involved in its pathogenesis. This multicenter, randomized, doubleblind, placebo-controlled, crossover trial evaluated the efficacy of ondansetron, a selective 5-HT3 receptor subtype antagonist, for treating fatigue in PBC. A crossover design was chosen, allowing subjects to serve as their own controls-appropriate to evaluate fatigue, a subjective symptom. Sixty patients with clinically stable PBC, a Fatigue Severity Score (FSS) > 4, and no other identifiable cause for fatigue were enrolled. Subjects were randomized to receive ondansetron (4 mg) or placebo orally 3 times daily for 4 weeks (period 1). Subjects then crossed over, after a minimum 1-week washout period, for a further 4 weeks of ondansetron or placebo (period 2). Fatigue was measured at the beginning and end of each period by using the FSS and Fatigue Impact Scale (FIS). Six patients withdrew; the remaining 54 subjects had a mean baseline FSS of 5.55 (؎0.1). Response to study medication in period 1 versus period 2 was not uniform; thus, it was necessary to analyze the trial periods separately. In period 1, there was no significant additional fatigue reduction on ondansetron over placebo. During period 2, FSS and FIS decreased significantly on ondansetron versus placebo (P ‫؍‬ .001). However, period 2 results were invalidated because drug side effects unblinded subjects (constipation affected 63.0% of patients taking ondansetron, versus 13.3% on placebo). In conclusion, ondansetron administration did not confer clinically significant fatigue reduction when compared with placebo in our study population. F atigue is common in primary biliary cirrhosis (PBC), affecting between 55% and 85% of patients. 1-3 It diminishes quality of life and interferes with many activities of daily living. 2,4 No known treatment exists for fatigue in PBC. Previously investigated drugs, including ursodeoxycholic acid, 5 cyclosporine, 6 thalidomide, 7 and antioxidants, 8 were not effective in ameliorating this debilitating symptom.The pathogenesis of fatigue in PBC is unclear. Fatigue in patients with PBC may be centrally mediated and not peripheral in origin. 9 The mechanisms proposed for this centrally mediated fatigue include abnormal neuroendocrine function and altered serotonergic neurotransmission. These mechanisms have been demonstrated in a bile duct-ligated rat model simulating acute cholestasis 10,11 as well as in humans. 12,13 In the rat model, repeated administration of a serotonin-1a receptor agonist relieved fatigue as measured by activity scores during a swim tank test. 11 In humans, administration of the serotonin reuptake inhibitor paroxetine resulted in decreased exercise endurance time in recreationally active young males. 13 Questionnaire studies conducted in individuals with PBC have consistently found an association of fatigue with depression. 1-3 Abnormalities in central serotonin transmission are thought to be key to the pathogenesis of