Osteoporosis is a frequent complication in

Randomized Trial Comparing Monthly Ibandronate and Weekly Alendronate for Osteoporosis in Patients With Primary Biliary Cirrhosis Nuria Gua~nabens, 1,2 Anna Monegal, 1 Dacia Cerda, 1 Africa Muxı, 3 Laia Gifre, 1 Pilar Peris, 1,2 and Albert Pares 2,4 Osteoporosis resulting in bone fractures is a complication in patients with primary biliary cirrhosis (PBC). Once-weekly alendronate improves bone mass and is well tolerated in these patients, but there is a concern because of poor compliance. Therefore, the efficacy, adherence, and safety of monthly ibandronate (150 mg) with weekly alendronate (70 mg) were compared in a randomized, 2-year study in 42 postmenopausal women with PBC and osteoporosis. Bone mineral density (BMD) of the lumbar spine and proximal femur (by DXA), liver function, and bone markers were measured at entry and every 6 months over 2 years. Adherence to therapy was assessed by the Morisky- Green score. At enrollment, the two groups were similar with respect to age, BMD, severity of cholestasis, previous fractures, and bone markers. Thirty-three patients, 14 in the ibandronate group and 19 in the alendronate group, completed the trial. At 2 years both treatments resulted in a significant increase in BMD at the lumbar spine (from 0.875 6 0.025 to 0.913 6 0.026 g/cm 2, P < 0.001 with alendronate, and from 0.898 6 0.024 to 0.949 6 0.027 g/cm 2, P < 0.001 with ibandronate). The mean percentage change was 4.5% and 5.7%, respectively (P 5 not significant). BMD increased at the total hip by 2.0% and 1.2%, respectively. Changes in bone markers were similar in both groups and one patient with alendronate developed a new vertebral fracture. Adherence to therapy was higher with ibandronate (P 5 0.009). Neither treatment impaired liver function or cholestasis. Conclusion: Both regimens, weekly alendronate and monthly ibandronate, improve bone mass and are comparable in safety for osteoporosis therapy in patients with PBC, although adherence is higher with the monthly regimen. Further larger studies are needed to assess fracture prevention. (HEPATOLOGY 2013;58:2070-2078) See Editorial on Page 1871 Osteoporosis is a frequent complication in patients with primary biliary cirrhosis (PBC), with a reported prevalence of 37% in a series of 185 Spanish female patients 1 and up to 20% in a large series from the Mayo Clinic. 2 This metabolic bone disease results in an increased risk of fracture particularly at the spine, forearm, and hip. Recently, we reported that the risk of fracture in this population is associated with low bone mass and indirectly, through this condition, with the severity and duration of liver disease. Furthermore, patients with a bone mineral density (BMD) T- score lower than 21.5 have a higher risk of fragility fractures, particularly vertebral fractures and, therefore, may benefit from evaluation and be considered for therapy. 1 Up to now, there has been no definite treatment for osteoporosis in patients with PBC. Most drugs used for postmenopausal osteoporosis have been evaluated in PBC patients in the last 20 years. They include Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; PBC, primary biliary cirrhosis; PTH, parathyroid hormone. From the 1 Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clınic, IDIBAPS, University of Barcelona, Barcelona, Spain; 2 Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, CIBERehd, Barcelona, Spain; 3 Service of Nuclear Medicine, Hospital Clınic, IDIBAPS, Barcelona, Spain; 4 Liver Unit, Hospital Clınic, IDIBAPS, University of Barcelona, Barcelona, Spain. Supported, in part, by Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, and FIS-08/0105, Ministerio de Ciencia e Innovacion, Spain. Received January 22, 2013; accepted April 11, 2013. 2070

HEPATOLOGY, Vol. 58, No. 6, 2013 GUA ~NABENS ET AL. 2071 calcitonin, 3 sodium fluoride, 4 hormone replacement, 5,6 raloxifene, 7 and various bisphosphonates, 8-12 along with calcium and vitamin D supplementation. Oral bisphosphonates are at present the standard of care of postmenopausal osteoporosis, since as many as one in seven postmenopausal women in the United States have been treated with a bisphosphonate at some time. 13 For this reason, it is interesting to evaluate their efficacy and safety in patients with PBC. A recent Cochrane review of bisphosphonates for osteoporosis in PBC patients included only six randomized trials with 106 participants, after assessing the risk of bias from 77 initial reports. The six trials evaluated the efficacy and safety of etidronate (three trials), alendronate (two trials), and ibandronate (one trial), the last report showing preliminary data from our group. 14 These trials assessed one bisphosphonate versus another bisphosphonate or versus placebo, and in one case versus sodium fluoride. 15 Etidronate was licensed for use in many countries for patients with established vertebral osteoporosis, 16 but at present it is barely used in the treatment of primary and secondary osteoporosis. By contrast, alendronate is a worldwide-approved drug and it is well established for the treatment of osteoporosis. 17 However, its weekly administration has prompted researchers to search a bisphosphonate with less frequent dosing intervals, such as a once-monthly oral regimen. This strategy could have an impact on adherence and persistence with treatment, since a growing body of evidence suggests that adherence with daily and weekly oral bisphosphonates is suboptimal 18,19 with an impaired therapeutic efficacy. Thus, a less frequent intermittent administration may help to overcome these deficiencies. 20 The aim of this study was to evaluate the efficacy, safety, and adherence of monthly ibandronate with weekly alendronate in a randomized study in postmenopausal women with PBC and osteoporosis. Patients and Methods Study Design and Patients This randomized controlled trial was conducted between February 2007 to December 2011 in a single center. Inclusion criteria were: (1) primary biliary cirrhosis, (2) postmenopausal women, and (3) osteoporosis, according to the WHO criteria, which is a BMD T-score of 22.5 21 or with osteopenia (BMD T-score between 21 and 22.5) and at least one fragility fracture. Exclusion criteria were the use of oral bisphosphonates within 12 months or hormone replacement within 6 months. Women were also excluded if they had previous gastrointestinal bleeding, known peptic ulcer, symptomatic hiatus hernia, renal failure (serum creatinine >1.5 mg/dl), total bilirubin levels >6 mg/ dl, ascites, or hepatic encephalopathy. Patients were randomly assigned to receive either monthly ibandronate 150 mg or weekly alendronate 70 mg for 2 years, using computer-generated random numbers. Patients were instructed to take their medication with 250 ml water, in an upright position, on an empty stomach in the morning; for ibandronate at least 60 minutes before breakfast, or 30 minutes for alendronate. In addition, all patients received supplementation with oral calcium (1,000 mg/day) and vitamin D (266 lg of 25-hydroxyvitamin D every 2 weeks). All patients received 14-16 mg/kg/day of ursodeoxycholic acid during the study. Patients were evaluated at entry and every 6 months over 2 years. All adverse events, as well as liver transplantation and deaths that occurred during the study, were recorded. Adherence to therapy was assessed by the self-reported 4-item Morisky-Green scale at all timepoints. Questions include whether individuals sometimes forgot to take their medications, whether they were sometimes careless with their medications, and whether they sometimes stopped taking their medications when they felt better or worse. Each question has a yes/no answer and scores 1 for every affirmative answer. 22 The study, with EudraCT application number 2006-003764-56, was approved by the Ethical Committee of the institution, and informed written consent was obtained from all participants. Study Measurements Biochemical and Hormonal Determinations. Blood and second morning urine samples were obtained between 8:00 and 10:00 a.m. after an overnight fast. Samples were stored at 220 C until assay. In addition to liver function tests, serum levels of calcium, Address reprint requests to: Nuria Gua~nabens, Service of Rheumatology, Hospital Clınic, Villarroel 170, 08036 Barcelona, Spain. E-mail: nguanabens@ub.edu. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26466 Potential conflict of interest: Nothing to report.

2072 GUA ~NABENS ET AL. HEPATOLOGY, December 2013 phosphate, and creatinine were measured by standard procedures at entry and every 6 months. Biochemical markers of bone turnover, including serum osteocalcin (OC), bone alkaline phosphatase (bone ALP), and procollagen type I N propeptide (PINP) as markers of bone formation, and serum cross-linked C-telopeptides of type I collagen (bctx) and urinary cross-linked N-telopeptides of type I collagen (NTx) as markers of bone resorption, were also measured at the same timepoints. Serum OC was assayed with an immunoradiometric method (Cis Elsa-Osteo, Gif-sur-Yvette, France), bone ALP was measured by enzyme-linked immunosorbent assay (ELISA) (Octeia Ostase BAP (IDS, Bolton, UK), PINP and bctx were measured by Elecsys Autoanalyzer (Roche, Basel, Switzerland), and NTx was measured by ELISA (Ostex, Seattle, WA) and expressed as a ratio of urinary creatinine. Serum 25 hydroxyvitamin D (25(OH) D) and parathyroid hormone (PTH) levels were measured by the Liason DiaSorin chemiluminescent immunoassay system (Saluggia, Italy). BMD and Fracture Assessment. BMD at the lumbar spine (L1-L4) and proximal femur (femoral neck and total hip) was measured at entry and every 6 months by dual-x-ray absorptiometry (DXA) (Lunar Prodigy, Madison, WI). The coefficients of variation were 0.8, 2.3, and 0.6 for the lumbar spine, femoral neck, and total hip, respectively. Lateral radiographs of the thoracic and lumbar spine were obtained at entry and after 24 months in all patients to disclose vertebral fractures. In patients with clinical symptoms suggestive of incident vertebral fracture, a control vertebral x-ray was performed. Radiographs were evaluated by an observer who did not know the patient s treatment group. Vertebral fracture was defined as a reduction of 20% in the anterior, middle, or posterior height of the vertebral body. Fractures attributable to major trauma were not recorded. Development of new peripheral fractures was also recorded throughout the study. Sample Size Calculation and Statistical Analysis Given that we presume there would not be different effects of both regimens in increasing bone mass during the trial, the sample size calculation was done assuming a percentage of self-declared nonadherence to the bisphosphonate treatment, assessed by the Morisky- Green scale for the four 6-month periods of evaluation. An expected poor adherence (failure in at least one item in one of the four study periods) of 50% was estimated from the literature in the alendronate weekly regimen, while in the monthly ibandronate regimen the assumed nonadherence was considered to be 5%. Based on these assumptions, a total sample size of 38 (19 patients per group) would provide 80% power to detect a significant difference of adherence between the two groups at 2 years. The alpha level was set at 0.05. To allow for an estimated dropout rate of 10%, a total sample size of 42 patients was projected. Results are expressed as mean 6 standard error of the mean. The two regimens were compared for their effects on clinical, biochemical, and BMD measurements. Analysis of variance for repeated measures was used to analyze differences within a group, introducing treatment as the between-subjects factor. Moreover, a paired Student t test was used to assess differences between timepoints and the baseline values for each treatment arm, and an unpaired Student t test was used to analyze changes at each timepoint between groups. The chi-square test was used to analyze differences in noncontinuous variables between both regimens. A two-tailed P-value 0.05 was considered to indicate a significant difference. Results Figure 1 shows the flow chart of patient participation in the trial. Of the 101 screened patients from February 2007 to December 2009, 53 did not accomplish the inclusion criteria, and six were excluded because of bisphosphonate consumption 4 or endstage PBC. 2 From the eligible remaining 42 patients (mean age 64.4 6 1.4 years), 20 were randomly assigned to receive monthly ibandronate and 22 weekly alendronate. The groups were similar at baseline with respect to age, severity of cholestasis, BMD values, and previous fractures (Table 1). Thirty-three patients (78.6%), 14 in the ibandronate group and 19 in the alendronate group, completed the 2-year trial. The reasons for discontinuation were loss to follow-up (two patients), breast cancer (one patient), mild adverse effects (three patients) in the ibandronate group, and personal reasons (one patient) and mild adverse effects (two patients) in the alendronate group (Fig. 1). The clinical and biochemical features, as well as the baseline BMD measurements and previous fractures of the patients who completed the trial, were similar in both groups (Table 2). After 24 months, both monthly ibandronate and weekly alendronate were associated with a significant relative increase in BMD at the lumbar spine from baseline of 5.7% and 4.5%, respectively (Fig. 2). BMD at the lumbar spine increased from 0.899 6 0.02 to 0.949 6 0.03 g/cm 2 (P < 0.001) with ibandronate and from 0.875 6 0.02 to 0.913 6 0.03

HEPATOLOGY, Vol. 58, No. 6, 2013 GUA ~NABENS ET AL. 2073 Fig. 1. Patients flow diagram. g/cm 2 (P < 0.001) with alendronate (Table 3). At the femoral neck, BMD increased by 1.2% and 2.7% in the ibandronate and alendronate groups, respectively (P 5 n.s.). By contrast, a greater increase in total hip BMD from baseline was observed among patients treated with alendronate, with changes from 0.805 6 0.02 to 0.822 6 0.02 g/cm 2 (P 5 0.04), than in those treated with ibandronate, although the percentage change was not significantly different between the groups (2.0% and 1.2%, P 5 not significant) (Fig. 3). The increase in BMD at the total hip in the alendronate group was significantly higher in those patients with baseline values of 25(OH) D higher than 30 ng/ ml, which is considered the optimal serum 25(OH)D concentration threshold. In these patients total hip BMD increased from 0.800 6 0.02 to 0.820 6 0.02 g/cm 2 (P < 0.01), while no significant changes were observed in the six patients with insufficient baseline Table 1. Baseline Clinical, Analytical, and Densitometric Data of Patients at Randomization Ibandronate N 5 20 Alendronate N 5 22 Age (years) 65.5 6 2.3 63.6 6 1.6 BMI (kg/m 2 ) 26.6 6 0.8 26.5 6 0.9 Total bilirubin (mg/dl) 0.6 6 0.1 0.5 6 0.1 Albumin (g/l) 43.7 6 0.6 44.9 6 0.6 ALT (u/l) 37 6 6 356 5 Alkaline phosphatase (u/l) 359 6 76 305 6 48 c-glutamyl transferase (u/l) 100 6 41 84 6 28 Prothrombin ratio (%) 95 6 2 976 1 BMD T-score Lumbar 22.56 6 0.15 22.61 6 0.19 Femoral neck 21.67 6 0.18 21.83 6 0.16 Total hip 21.29 6 0.17 21.65 6 0.17 Previous fractures 5 (25%) 13 (59%) vertebral 4 (20%) 4 (18%) peripheral 4 (20%) 10 (45%) Abbreviations: BMD, bone mineral density; BMI, body mass index. Table 2. Baseline Clinical, Analytical, and Densitometric Data of Patients Who Completed 2 Years of Treatment Ibandronate N 5 14 Alendronate N 5 19 Age (years) 64.8 6 2.3 63.1 6 1.8 BMI (kg/m 2 ) 26.6 6 0.9 26.6 6 1.0 Total bilirubin (mg/dl) 0.6 6 0.1 0.5 6 0.1 Albumin (g/l) 43.5 6 0.8 45.2 6 0.7 ALT (u/l) 37 6 8 346 3 Alkaline phosphatase (u/l) 367 6 65 306 6 55 c-glutamyl transferase (u/l) 70 6 22 83 6 32 Prothrombin ratio (%) 94 6 2 976 1 BMD T-score Lumbar 22.38 6 0.19 22.63 6 0.21 Femoral neck 21.60 6 0.11 21.75 6 0.17 Total hip 21.31 6 0.15 21.62 6 0.19 Previous fractures 5 (36%) 10 (53%) vertebral 3 (21%) 1 (5%) peripheral 3 (21%) 9 (47%) Abbreviations: BMD, bone mineral density; BMI, body mass index.

2074 GUA ~NABENS ET AL. HEPATOLOGY, December 2013 Fig. 2. Percent changes in lumbar BMD with respect to baseline values for patients with PBC treated with ibandronate (broken line) or alendronate (solid line). No significant differences in BMD change were observed between treatments for each time period, but the increase in BMD was significant in each arm from 6 months. 25(OH) D levels. One patient in the alendronate group who already had previous fractures developed a new vertebral fracture (5%), while no patient developed nonvertebral fractures. The changes in bone turnover markers over 24 months are shown as a percentage change from baseline (Fig. 4). There were no significant differences in the magnitude of the decreases between the groups of treatment at any timepoint. However, significant changes in most bone turnover markers were seen as early as 6 months, except for NTx, which was less prominent in the ibandronate group. Moreover, Fig. 3. Percent changes in total hip BMD with respect to baseline values for patients with PBC treated with ibandronate (broken line) or alendronate (solid line). No significant differences in BMD change were observed between treatments for each time period, but the increase in BMD was significant at 24 months in patients under alendronate (P 5 0.04). changes in PTH were particularly apparent in patients treated with ibandronate (table 3). Adherence to therapy, evaluated by the self-reported 4-item Morisky-Green scale, was good in both groups, as recorded in each of the four 6-month assessment periods. However, when comparing adherence to ibandronate and alendronate treatment, the Morisky- Green scale showed a significantly higher adherence to ibandronate. Thus, failure in at least one item was recorded in 3 of the 56 study periods, (5.3%) in the ibandronate group, and in 18 of the 76 study periods Table 3. Changes in the Bone Mineral Density and Markers of Bone Mineral Metabolism in Patients With Primary Biliary Cirrhosis Who Received Ibandronate (N 5 14) or Alendronate (N 5 19) for 2 Years Baseline 6 12 18 24 F P Bone mineral density Lumbar (g/cm 2 ) I 0.898 6 0.024 0.926 6 0.025 0.932 6 0.027 0.932 6 0.027 0.949 6 0.027 5.72 0.012 A 0.875 6 0.025 0.902 6 0.025 0.915 6 0.027 0.916 6 0.026 0.913 6 0.026 5.82 0.005 Femoral Neck (g/cm 2 ) I 0.788 6 0.014 0.789 6 0.015 0.796 6 0.016 0.802 6 0.015 0.797 6 0.019 0.32 n.s. A 0.771 6 0.021 0.782 6 0.021 0.782 6 0.023 0.779 6 0.022 0.790 6 0.021 1.22 n.s. Total hip (g/cm 2 ) I 0.844 6 0.018 0.852 6 0.020 0.856 6 0.024 0.859 6 0.020 0.854 6 0.019 2.75 n.s. A 0.805 6 0.023 0.820 6 0.024 0.819 6 0.024 0.823 6 0.024 0.822 6 0.023 3.21 0.04 Markers of bone mineral metabolism PTH (pg/ml) I 49.3 6 3.8 65.0 6 6.1 62.2 6 5.6 69.1 6 6.5 71.1 6 6.9 10.0 0.002 A 53.6 6 5.5 57.4 6 4.4 55.3 6 4.7 62.0 6 7.1 62.4 6 5.2 2.46 n.s. 25OH D (ng/ml) I 34.6 6 3.7 35.9 6 6.7 31.8 6 4.4 29.4 6 2.8 37.6 6 4.3 1.39 n.s. A 42.7 6 5.5 34.5 6 4.0 28.5 6 2.3 38.0 6 2.6 33.7 6 2.5 2.43 n.s. OC (ng/ml) I 21.2 6 1.8 14.4 61.2 11.6 6 1.3 14.3 6 2.1 14.1 6 1.7 9.84 0.002 A 19.3 6 2.1 13.3 6 1.4 11.9 6 1.3 12.6 6 1.3 11.9 6 1.2 5.01 0.009 BAP (ng/ml) I 24.3 6 2.3 17.0 6 2.2 16.7 6 3.0 16.3 6 2.4 14.4 6 1.6 4.87 0.019 A 18.1 6 1.4 14.9 6 1.2 13.3 6 1.3 13.0 6 1.6 13.6 6 1.3 6.28 0.004 PINP (ng/ml) I 45.1 6 3.4 25.1 6 3.5 23.4 6 3.7 22.9 6 2.8 24.4 6 3.4 11.57 0.001 A 39.7 6 3.8 24.0 6 2.2 21.3 6 2.5 19.7 6 1.9 21.9 6 2.2 11.44 0.001 NTx (nm/mm) I 57.1 6 7.6 40.4 6 4.0 43.3 6 7.9 32.3 6 3.7 28.3 6 3.7 9.94 0.002 A 54.6 6 5.0 33.8 6 3.4 31.4 6 2.9 32.2 6 3.3 27.8 6 2.4 9.85 <0.001 CTx (ng/ml) I 0.42 6 0.04 0.23 6 0.05 0.17 6 0.03 0.17 6 0.03 0.18 6 0.04 6.31 0.011 A 0.38 6 0.04 0.19 6 0.03 0.15 6 0.03 0.14 6 0.03 0.14 6 0.02 9.43 0.001 Abbreviations: 25-OH-D, 25 hydroxyvitamin D; A, weekly alendronate; BAP, bone alkaline phosphatase; CTx, serum cross-linked C-telopeptides of type I collagen; I, monthly ibandronate; NTx, cross-linked N-telopeptides of type I collagen; OC, osteocalcin; PINP, procollagen type I N propeptide; PTH, parathyroid hormone. Month

HEPATOLOGY, Vol. 58, No. 6, 2013 GUA ~NABENS ET AL. 2075 (23.6%) in the alendronate group (P 5 0.009). This lower adherence did not result in differences in the course of BMD or bone turnover markers. The overall incidence of adverse events was similar in both treatment groups. There were no serious adverse events throughout the study, and the incidence of discontinuations because of adverse events included upper gastrointestinal symptoms such as dyspepsia or nausea with vomiting (two cases in each treatment group) and arthralgia (one case in the ibandronate group). These adverse events came out near the beginning of the trial in the two groups, resulting in treatment discontinuation. Neither treatment impaired liver function or cholestasis, nor did any patient develop events of progressive disease. Fig. 4. Effects of monthly ibandronate or weekly alendronate over 2 years on markers of bone mineral metabolism (OC: osteocalcin; BAP: bone alkaline phosphatase; PINP: procollagen type I N propeptide; NTx: cross-linked N-telopeptides of type I collagen; CTx: serum crosslinked C-telopeptides of type I collagen). Percent changes with respect to baseline values for patients treated with ibandronate (broken line) or alendronate (solid line). In the two groups, significant decreases of all markers, except for NTx in the ibandronate group were observed after 6 months of treatment. Discussion The results of this study show that both ibandronate and alendronate increase bone mass and are well tolerated in postmenopausal women with PBC and osteoporosis or severe osteopenia, without impairment of liver function or cholestasis. The monthly regimen of ibandronate may be more convenient for patients who are taking multiple medications and, in fact, adherence to therapy was slightly, although significantly, higher for ibandronate than for alendronate. By contrast, alendronate increased BMD more consistently at the total hip and a significant decrease in most bone turnover markers was seen as early as at 6 months. Although few data are available from randomized, controlled clinical trials, at present the treatment of osteoporosis in patients with PBC mostly relies on oral bisphosphonates, particularly weekly alendronate. 23-26 In the current and previous studies it has been shown that this drug increases BMD and is safe when stringent dosing procedures are followed and known risk factors for upper gastrointestinal side effects are avoided. Importantly, alendronate did not impair liver function when it was assayed in patients with PBC and after liver transplantation. 8-11,27 To the best of our knowledge, this is the first trial assessing once-monthly ibandronate in patients with PBC and osteoporosis. This bisphosphonate, which allows dosing with extended intervals, may enhance patient adherence. Poor adherence with bisphosphonates is considered the main problem in the realworld setting, since 50% of patients discontinue daily therapy within a year, and although weekly dosage improves adherence, levels are still suboptimal. 28 Thus, when analyzing adherence and persistence with weekly bisphosphonates, a review of seven studies

2076 GUA ~NABENS ET AL. HEPATOLOGY, December 2013 showed a suboptimal mean medication possession ratio ranging from 0.58 to 0.76 and a percentage of persistent patients at the end of the follow-up period of only 35.7% to 69.7%. 29 In the present study, the Morisky-Green scale showed a high rate of adherence in both groups, although it was significantly higher for ibandronate, reinforcing the message that less frequent dosing intervals may improve the use of bisphosphonate therapy and, therefore, its clinical benefit. 30 The lack of significant differences in the course of BMD measurements and bone turnover marker levels between fully adherent and mildly adherent patients can be explained by the persisting effect of bisphosphonates on bone. In other words, discontinuing treatment for a short period may not result in significant changes in BMD and bone markers. The magnitude of the increase in BMD at the lumbar spine observed in patients with PBC under weekly alendronate and monthly ibandronate was similar to that reported in postmenopausal women with osteoporosis. In this sense, the gains in lumbar BMD at 2 years with ibandronate 150 mg once-monthly and alendronate 70 mg once-weekly in PBC patients were 5.7% and 4.5%, respectively; similar to the reported increase of 6.6% at 2 years with the monthly regimen 31 and 4.2% to 5.1% with the weekly regimen, at 1 year. 32,33 However, when comparing the current results with a previous trial using once-weekly alendronate in PBC patients, lower gains in BMD at the lumbar spine were observed. Thus, in one study from the Mayo Clinic, 34 patients were randomized to alendronate or placebo over 1 year. The mean percent BMD change from baseline in the 17 patients of the alendronate group was 10.4% at the lumbar spine and 1.4% at the proximal femur. 11 The greater gains in lumbar BMD observed in this study may be in part attributed to the concomitant estrogen treatment in 11 out of 17 patients. In a previous study from our group, 32 PBC patients were randomly assigned to receive daily alendronate 10 mg or cyclical etidronate for 2 years. 9 In this latter trial, a slightly greater increase in BMD at the lumbar spine was observed when compared with the present study (5.8% versus 4.5%). Both drugs induced a decrease in all markers of bone turnover, without significant differences in the magnitude of the change between treatment groups, although changes in the alendronate group were seen earlier than in the ibandronate group, particularly for NTx, a marker of bone resorption. The consistent decrease in the levels of bone turnover markers reinforces the proper adherence and persistence to therapy in the current trial. 34 On the other hand, higher increases in PTH levels were observed in the ibandronate group, with no precise consequences on BMD changes, or resulting from lower 25 (OH) D levels. It should be noted that all the patients were supplemented with oral vitamin D. An interesting observation of our study was that the increase in BMD at the total hip in the alendronate group was statistically significant in those patients with baseline levels of 25(OH)D above 30 ng/ml. This finding is in agreement with a recent study in postmenopausal osteoporosis, showing that 25(OH)D levels influence adequate response to bisphosphonate therapy, since postmenopausal women with vitamin D insufficiency had more frequent incident fragility fractures or a decrease in lumbar or total hip BMD than those with vitamin D levels higher than 30 ng/ml during the last year of treatment. 35 This fact is relevant in patients with PBC, since low 25(OH) D levels are frequent in this liver disease, particularly in patients with more severe cholestasis and, therefore, with higher risk for osteoporosis. 24,26 This observation reinforces the importance of measuring vitamin D serum levels in PBC patients and the use of supplements to achieve vitamin D repletion. The low incidence of fractures over the study is another relevant result taken from this trial. Actually, only one patient under alendronate developed a new vertebral fracture and no peripheral fractures were recorded in the patients included in the two arms. This is in contrast with higher rates of fractures observed in previous trials, even in patients with better BMD measurements and a lower rate of osteoporosis, 9,11 thus suggesting a favorable effect of bisphosphonates in PBC patients with osteoporosis or severe osteopenia, which are those with a high risk for fracture. In spite of these data, the scarce number of patients included in the trial diminishes the power of such an issue, thus questioning the preventive effect on fracture development. An important issue with the use of oral bisphosphonates in patients with PBC is safety. It is known that oral nitrogen-containing bisphosphonates may be associated with upper gastrointestinal side effects, particularly in their postmarket use. 36 Gastritis with antral erosions was found in one patient with PBC under treatment with once-weekly alendronate. 11 In our series, there were only two cases in each treatment group. These patients discontinued because of mild gastrointestinal adverse effects, such as dyspepsia or nausea with vomiting. This is particularly interesting, since the risk of serious adverse gastrointestinal effects has precluded the use of oral bisphosphonates in

HEPATOLOGY, Vol. 58, No. 6, 2013 GUA ~NABENS ET AL. 2077 patients with liver diseases, mainly in those who may have esophageal varices. 23 We did not perform esophagogastroduodenoscopy to rule out esophageal varices before starting therapy because our patients did not have signs of portal hypertension, and no serious upper gastrointestinal symptoms were reported during treatment with once-weekly alendronate and oncemonthly ibandronate over 2 years. Importantly, stringent dosing procedures must be followed by the patient, 36 and digestive disorders that make oral bisphosphonate administration inappropriate must be considered. When the tolerability profile is poor or a recent esophageal banding/sclerotherapy has been performed 37 other therapeutic options like parenteral bisphosphonates may be considered. 38 Our study has some limitations, such as the nonblinding design and not being powered to differentiate between these two drugs in terms of fracture risk reduction because of the small sample size and the use of two active agents that have been shown to reduce the risk of vertebral fractures. However, it has several strengths. The design of this direct comparative study was randomized and includes a number of patients that, although small, constitutes one of the largest therapeutic trials for improving low bone mass in PBC patients. In addition, the absence of ascites in our series makes the results of BMD measurements reliable by DXA. 39 Moreover, the clear-cut effects on decreasing bone markers support the correct adherence to therapy in the two groups. 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