Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis

BACKGROUND Several studies have been conducted to explore the association between the use of proton pump inhibitors (PPIs) and hepatic encephalopathy (HE) risk in patients with liver cirrhosis. However, their results are controversial. AIM To perform a systematic review and meta-analysis to evaluate the HE risk among PPI users. METHODS A systematic search on PubMed, Web of Science, EMBase, and ScienceDirect databases was conducted up to December 31, 2018 for eligible studies involving PPI use and HE risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed or random effects model. Publication bias was evaluated using Begg’s test, Egger’s test, and trim-and-fill method. RESULTS Seven studies with 4574 patients were included in the present meta-analysis. The meta-analysis results indicated a significant association between the PPI use and HE risk (OR = 1.50;95%CI: 1.25-1.75) with low heterogeneity (I2 = 14.2%, P = 0.321). Although publication bias existed when Egger’s tests were used (P = 0.005), the trim-and-fill method verified the stability of the pooled result. Sensitivity analyses suggested that the results of this meta-analysis were robust. CONCLUSION The current evidence indicates that PPI use increases HE risk in patients with liver cirrhosis. Further studies with a large data set and well-designed models are needed to validate our findings.     

Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis

BACKGROUND Several studies have explored the association between the use of proton pump inhibitors (PPIs) and the risk of developing hepatic encephalopathy (HE) in patients with advanced liver disease. However, the evidence-based conclusions are controversial. We hypothesized that using PPIs may increase the risk of HE in patients with advanced liver disease. If confirmed, clinicians must strictly adhere to the indications for PPI treatment in this population. AIM To evaluate the pooled risk of HE in patients with advanced liver disease who use PPIs. METHODS Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from the date of database inception through January 8, 2019 to identify comparative studies evaluating the association between PPI use and the risk of HE. Data from the included studies were extracted. The random-effects model was used for pooling risk estimates and the corresponding 95% confidence intervals (CIs). Subgroup and sensitivity analyses were also performed. RESULTS In total, 4342 patients from five case-control studies and 188053 patients from four cohort studies were included in this analysis. In patients with advanced liver disease, PPI use was associated with an elevated risk of developing HE, with significant heterogeneity. The pooled odds ratio for case-control studies was 2.58 (95%CI: 1.68-3.94, I2 = 72%). The pooled RR for cohort studies was 1.67 (95%CI: 1.30-2.14, I2 = 67%). The results of the subgroup analyses suggested that the heterogeneity may be the result of differences in the study designs and the definitions of PPI use. The sensitivity and subgroup analyses did not alter our findings. CONCLUSION In patients with advanced liver disease, PPI use is associated with an elevated risk of HE. Future large prospective studies are needed to confirm this association.     

Mental status impairment in patients with West Haven grade zero hepatic encephalopathy: the role of HCV infection

Background In patients with cirrhosis, subclinical hepatic encephalopathy, which negatively affects the activity of daily living, is often unidentified. In a multicenter observational study, we investigated the possibility of detecting minimal neurological changes consistent with subclinical hepatic encephalopathy by using the Trail Making Test in a cohort of patients with liver cirrhosis at hospital admission. Methods Seventy-seven consecutive patients with liver cirrhosis were studied (mean age, 69.5 ± 9.1; 95% confidence interval, 67.5–71.6 years). In all patients, possible encephalopathy was investigated according to the West Haven criteria. All those free of any sign of encephalopathy (West Haven 0) were also studied by the Trail Making Test forms A and B. The Child-Pugh score was determined in all patients, and results were compared with the West Haven stage. Exclusion criteria were use of benzodiazepine, beta adrenergic blockers, alcohol, or antiepileptic drugs, or coexistence of depression, dementia, Parkinson's disease, or chronic or acute cerebral vasculopathy. Results Of the 77 patients, 44 (57.1%, 23 men and 21 women) had West Haven score 0, but among these, 26 (59.1%) were diagnosed with mental impairment likely linked to minimal hepatic encephalopathy. Severity of liver disease correlated with the presence of likely minimal hepatic encephalopathy, because the prevalence of abnormal Trail Making Test results increased from 22.2% in Child-Pugh A, to 63.4% and 74.0% in Child-Pugh B and C, respectively. Conclusions The investigation of patients with cirrhosis by the West Haven test is not sufficient to identify subclinical forms of encephalopathy. The Trail Making Test (a simple, inexpensive test) in our series evidenced poor psychometric performance in more than half of the patients who were free of manifest encephalopathy. Subclinical hepatic encephalopathy was present mostly in patients with HCV-related cirrhosis. Detecting minimal hepatic encephalopathy in patients with cirrhosis may help improve their quality of life.     

Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites

BACKGROUND:

There are data suggesting a link between proton pump inhibitor (PPI) use and the development of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites; however, these data are controversial.

OBJECTIVE:

To assess whether the use of PPIs in cirrhotic patients with ascites is associated with an increased risk for SBP.

METHODS:

A retrospective case-control study (June 2004 to June 2010) was conducted at the Centre Hospitalier de l’Université de Montréal in Montreal, Quebec. Fifty-one cirrhotic patients admitted with paracentesis-proven SBP (≥250 neutrophils/mm³), occurring within seven days of hospital admission, met the inclusion criteria. These patients were matched 1:2 (for age, Child-Pugh class and year of admission) with 102 comparable cirrhotic patients with ascites who were admitted for conditions other than SBP.

RESULTS:

Patients with SBP had a significantly higher rate of pre-hospital PPI use (60.8%) compared with cirrhotic patients without SBP (42.2%; P=0.03). On multivariate analysis, PPI use was the only factor independently associated with SBP (OR 2.09 [95% CI 1.04 to 4.23]; P=0.04). Thirty-five (35%) patients in both groups had no documented indication for PPI use in their charts. Forty-five percent of the remaining cirrhotic patients with SBP had an inappropriate indication, as defined in the protocol, for PPI use compared with 25% of controls.

CONCLUSIONS:

Cirrhotic patients with SBP were twice as likely to have taken PPIs than patients without SBP. These findings reinforce the association between PPI use and SBP observed in other studies. A high percentage of cirrhotic patients were taking a PPI without any documented indication.     

The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors: A multicenter retrospective study in Japan

Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan.A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010–2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively.A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066–4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702–1.726).This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.     

Proton pump inhibitor administration delays rebleeding after endoscopic gastric variceal obturation

AIM:To clarify the efficacy of proton pump inhibitors(PPIs)after endoscopic variceal obturation(EVO)with N-butyl-2-cyanoacrylate.METHODS:A retrospective study was performed on16 liver cirrhosis patients with gastric variceal bleeding that received EVO with injections of N-butyl-2-cyanoacrylate at a single center(Kyung Hee University Hospital at Gangdong)from January 2008 to December 2012.Medical records including patient characteristics and endoscopic findings were reviewed.Treatment results,liver function,serum biochemistry and cirrhosis etiology were compared between patients receiving PPIs and those that did not.Furthermore,the rebleeding interval was compared between patients that received PPI treatment after EVO and those who did not.RESULTS:The patient group included nine males and seven females with a mean age of 61.8±11.7years.Following the EVO procedure,eight of the 12patients that received PPIs and three of the four nonPPI patients experienced rebleeding.There were no differences between the groups in serum biochemistry or patient characteristics.The rebleeding rate was not significantly different between the groups,however,patients receiving PPIs had a significantly longer rebleeding interval compared to non-PPI patients(22.2±11.2mo vs 8.5±5.5 mo;P=0.008).The duration of PPI use was not related to the rebleeding interval.A total of six patients,who had ulcers at the injection site,exhibited a shorter rebleeding interval(16.8±5.9 mo)than patients without ulcers(19.9±3.2 mo),though this difference was not statistically significant.CONCLUSION:PPI therapy can extend the rebleeding interval,and should therefore be considered after EVO treatment for gastric varices.     

质子泵抑制剂对老年急性呼吸窘迫综合征患者发生应激性溃疡的治疗效果分析

目的:分析质子泵抑制剂(PPI)预防老年急性呼吸窘迫综合征(ARDS)患者发生应激性溃疡(SU)效果及影响短期死亡风险的相关因素。方法:多中心回顾性队列研究。连续性纳入2017年11月至2019年12月在北大国际医院、北京安贞医院和鄂州市中心医院诊治的老年ARDS患者200例,均为入重症监护室后48 h内应用PPI(奥...     

Proton-pump inhibitors for prevention of upper gastrointestinal bleeding in patients undergoing dialysis

AIM:To investigate the preventive effects of low-dose proton-pump inhibitors(PPIs) for upper gastrointestinal bleeding(UGIB) in end-stage renal disease.METHODS:This was a retrospective cohort study that reviewed 544 patients with end-stage renal disease who started dialysis at our center between 2005 and 2013.We examined the incidence of UGIB in 175 patients treated with low-dose PPIs and 369 patients not treated with PPIs(control group).RESULTS:During the study period, 41 patients developed UGIB, a rate of 14.4/1000 person-years.The mean time between the start of dialysis and UGIB events was 26.3 ± 29.6 mo.Bleeding occurred in only two patients in the PPI group(2.5/1000 person-years) and in 39 patients in the control group(19.2/1000 person-years).Kaplan-Meier analysis of cumulative non-bleeding survival showed that the probability of UGIB was significantly lower in the PPI group than in the control group(log-rank test, P 0.001).Univariate analysis showed that coronary artery disease, PPI use, anti-coagulation, and anti-platelet therapy were associated with UGIB.After adjustments for the potential factors influencing risk of UGIB, PPI use was shown to be significantly beneficial in reducing UGIB compared to the control group(HR = 13.7, 95%CI:1.8-101.6; P = 0.011).CONCLUSION:The use of low-dose PPIs in patients with end-stage renal disease is associated with a low frequency of UGIB.     

Association of Proton Pump Inhibitor Therapy with Hepatic Encephalopathy in Hepatitis B Virus-related Acute-on-Chronic Liver Failure

Background:

Hepatic encephalopathy (HE) is an important neuropsychiatry complication of acute-on-chronic liver failure (ACLF). PPI therapy may increase the intestinal bacterial overgrowth and infections.

Objectives:

The aim of this study was to assess whether PPI use in ACLF is associated with HE.

Patients and Methods:

A retrospective case-control study was performed. Fifty five admitted patients with hepatitis B virus (HBV)-related ACLF complicated by Stage II-IV HE developed after admission between January 2008 and December 2012 were matched (by sex, age, and MELD score) with comparable HBV-related ACLF patients (n = 110) who did not develop this complication during hospitalization. We excluded combined HE upon admission and other neurological disorders in patients with ACLF. Univariate and multivariate analyses of 30 variables (laboratory examination, predisposition, treatment, etc.) before the occurrence of HE were carried out to identify the factors predictive of HE.

Results:

In univariate analysis, patients with HE in ACLF had a significantly higher rate of PPI use (89.1%) compared with non-HE (63.6%, P = 0.001). In addition, clinical and standard laboratory variables were significantly different between the two groups regarding the infection rate, hyponatremia, alpha-fetoprotein (AFP), Arginine Hydrochloride use and Lactulose use. Logistic regression analysis was used to examine the combined effects of the variables with HE as the outcome. HE in ACLF was associated with hyponatremia (odds ratio (OR) = 6. 318, 95% confidence interval (CI) = 2. 803-14.241; P = 0. 000), PPI use was independently associated with HE (OR = 4. 392, CI = 1. 604-12.031; P = 0. 004), and lactulose use was protective (OR = 0. 294, CI = 0. 136-0.675; P = 0. 003).

Conclusions:

The occurrence of HE is associated with hyponatremia and PPI use in patients with ACLF.     

Oral Proton Pump Inhibitors Are as Effective as Endoscopic Treatment for Bleeding Peptic Ulcer: A Prospective,Randomized, Controlled Trial

In managing patients with bleeding peptic ulcers, it has been reported that pharmacologic treatment can be an alternative to endoscopic treatment. We compared the hemostasis rates of the endoscopic treatment, hemoclipping, and the phamacologic treatment, oral proton pump inhibitors (PPIs), in bleeding peptic ulcer. A randomized prospective study was performed on 129 bleeding peptic ulcer patients with hematemesis or melena. Sixty-two patients were treated by endoscopic hemoclipping and subsequently H₂ receptor antagonists were injected intravenously (hemoclipping group), and 67 patients were treated with an oral PPI without endoscopic treatment (PPI group). The 24-hr gastric pH test was performed sequentially following the treatment. The initial hemostasis rate of the hemoclipping group was 93.5% (58/62) and the rebleeding rate was 6.9% (4/58), and the hemostasis rate of the PPI group was 92.5% (62/67) and the rebleeding rate was 7.5% (5/67), which were not different. The 24-hr gastric pH was 4.54 ± 2.56 in the hemoclipping group and 5.97 ± 1.30 in the PPI group (P < 0.037). In the bleeding peptic ulcer patients, the hemostasis rate with the oral administration of PPIs was not different from that with the endoscopic hemoclipping treatment.     

Correlation between ammonia levels and the severity of hepatic encephalopathy

PURPOSE: Because the correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, we prospectively evaluated the correlation in 121 consecutive patients with cirrhosis. METHODS: The diagnosis of hepatic encephalopathy was based on clinical criteria, and the severity of hepatic encephalopathy was based on the West Haven Criteria for grading of mental status. Arterial and venous blood samples were obtained from each patient. Four types of ammonia measurements were analyzed: arterial and venous total ammonia, and arterial and venous partial pressure of ammonia. Spearman rank correlations (r(s)) were calculated. RESULTS: Of the 121 patients, 30 (25%) had grade 0 encephalopathy (no signs or symptoms), 27 (22%) had grade 1, 23 (19%) had grade 2, 28 (23%) had grade 3, and 13 (11%) had grade 4 (the most severe signs and symptoms). Each of the four measures of ammonia increased with the severity of hepatic encephalopathy: arterial total ammonia (r(s) = 0.61, P < or = 0.001), venous total ammonia (r(s) = 0.56, P < or = 0.001), arterial partial pressure of ammonia (r(s) = 0.55, P < or = 0.001), and venous partial pressure of ammonia (r(s) = 0.52, P < or = 0.001). CONCLUSION: Ammonia levels correlate with the severity of hepatic encephalopathy. Venous sampling is adequate for ammonia measurement. There appears to be no additional advantage of measuring the partial pressure of ammonia compared with total ammonia levels.     

Olfactory Function is Affected in Patients with Cirrhosis Depending on the Severity of Hepatic Encephalopathy

Introduction and aim. Olfactory functions are altered to a variable degree by chronic liver disease. Few studies including only small populations of patients emphasized the possibility of hepatic encephalopathy (HE) influencing olfactory nervous tasks. So far, no study has explicitly focused on olfactory function depending on the severity of HE as assessed by objective diagnostic procedures. Thus we performed a study using the “Sniffin’ Sticks” test system, critical flicker-fusion frequency (CFF) and clinical West Haven criteria.Material and methods. 54 cirrhotic patients with liver cirrhosis were included. Furthermore, 43 adult volunteers participating as a non-cirrhotic control group. Olfactory testing was performed using the “Sniffin’ Stick” test battery (Burghart Medizintechnik, Wedel, Germany) which renders a widely-used tool both in clinical and research settings for the assessment of olfactory threshold, odor identification and discrimination. Several complications of cirrhosis were diagnosed by reference methods. Statistical analysis of cirrhosis-associated complications and their relation to olfactory function was performed. Assessment of HE and classification of different stages were performed according to clinical criteria (West- Haven criteria) and according to CFF, which was determined using a portable analyzer.Results. Olfactory function was significantly reduced in cirrhotic patients (in 61.1%) compared to controls (p < 0.001). Among cirrhotics patients, the prevalence of olfactory deficits (hyposmia, anosmia) increased with the severity of HE as assessed by CFF and clinical criteria (p = 0.008 and p = 0.097, respectively). No correlation was observed between olfactory deficits and severity of liver disease as assessed by Child-Pugh-Score, etiology of cirrhosis and complications of cirrhosis such as ascites and portal venous hypertension.Conclusions. Olfactory testing serves as a screening tool for HE and may faciliate grading of HE-severity.     

A meta-analysis of impact of proton pump inhibitors on antiplatelet effect of clopidogrel

Previous mechanistic studies have suggested a possible interaction between proton pump inhibitor (PPIs) and clopidogrel. However, the results of clinical trials about the effects of PPIs on safety and efficacy of clopidogrel are controversial. The study sought to estimate the impact of PPIs on antiplatelet effect of clopidogrel. The study performed a meta-analysis of comparative concomitant use of clopidogrel with PPIs versus clopidogrel without PPIs studies published or presented to October 2010. Cardiovascular death, readmission for myocardial infarction/readmission for acute coronary syndrome, and nonfatal stroke were set as clinical endpoints. In randomized control trials (RCTs), the clinical endpoints risk ratio for clopidogrel with PPIs versus clopidogrel without PPIs was 1.20 (P= 0.34) in the random-effects model and 1.03 (P= 0.63) in the fixed-effects model. In observational studies, the risk ratio for the clinical endpoints for clopidogrel with PPI versus clopidogrel without PPI was 1.40 (P < 0.001) in the random-effects model and 1.49 (P < 0.001) in the fixed-effects model. Different assay methods showed that coadministration of clopidogrel with PPIs was associated with attenuation of clopidogrel's antiplatelet effect in vitro. This meta-analysis indicated an obvious discrepancy between RCTs and observational studies with respect to the interaction between PPIs and clopidogrel.     

Intravenous Versus High-Dose Oral Proton Pump Inhibitor Therapy After Endoscopic Hemostasis of High-Risk Lesions in Patients with Acute Nonvariceal Upper Gastrointestinal Bleeding

Intravenous proton pump inhibitors (IV PPIs) decrease rebleeding following endoscopic hemostasis of bleeding peptic ulcers. Oral PPIs may be equally efficacious and may significantly reduce health care costs. This study aimed to compare outcomes in patients receiving oral versus IV PPI therapy following endoscopic hemostasis in patients with acute nonvariceal upper gastrointestinal bleeding (ANVUGIB). We performed a retrospective review of all patients who received PPI therapy following endoscopic hemostasis for ANVUGIB. The primary outcome was the adverse gastrointestinal event rate. One hundred sixty-two patients met the entry criteria (72 oral PPIs, 90 IV PPIs). The difference in the rate of adverse gastrointestinal events between the two groups was 1% (P = 0.85). Postendoscopic IV PPI use was associated with an odds ratio of 1.01 for developing an adverse outcome versus oral PPIs (95% CI: 0.44–2.33). We conclude that oral PPIs are probably equivalent to IV PPIs for preventing rebleeding in ANVUGIB patients.     

氨甲酰磷酸合成酶-Ⅰ和鸟氨酸氨基甲酰转移酶与肝性脑病的关系

目的 探讨血清氨甲酰磷酸合成酶Ⅰ(CPS-Ⅰ)和鸟氨酸氨基甲酰转移酶(OCT)在肝性脑病(HE)发生中的作用.方法 2008年1月-2009年12月在我院住院的120例肝硬化患者,其中HE患者25例,非肝性脑病(非HE)患者95例.对照组为我院健康体检正常者60例.收集研究对象的血清和血浆,采用酶联免疫吸附试验方法测定血清CPS-Ⅰ、OCT,VITROS-250干化学分析仪测定血氨.分析HE组、非HE组、对照组CPS-Ⅰ和OCT水平;分析肝硬化患者CPS-Ⅰ、OCT与肝功能及血氨的相关性;分析CPS-Ⅰ、OCT水平与肝硬化患者Child-Pugh分级之间的相关性.应用SPSS15.0软件进行数据分析,采用x2和t检验,计量资料两组间比较采用成组t检验,多组间的比较采用方差分析、q检验,两变量相关分析采用Pearson相关分析法.结果 HE组血清CPS-Ⅰ、OCT水平分别为(143.3±48.5)U/L和(297.0±102.6)×10 U/L,非HE组分别为(180.3±51.5)U/L和(351.8±109.0)×10 U/L,t值分别为2.53和2.78,P值均＜0.01;HE组、非HE组血清CPS-Ⅰ、OCT水平均低于正常对照组,t值分别为3.21、4.16和2.12、3.15,P值均＜0.05.CPS-Ⅰ与OCT相关性好,r=0.946,P＜0.05;CPS-Ⅰ、OCT与ALT、AST呈负相关,r值分别为-0.284、-0.239、-0.303、-0.322,P值均＜0.05.肝硬化患者CPS-Ⅰ、OCT水平和Child分级密切相关,F值分别为10.13,20.28,P值均＜0.01.结论 肝硬化患者CPS-Ⅰ和OCT活性影响血氨水平,CPS-Ⅰ和OCT与肝性脑病的发生密切相关.     

Association between Proton Pump Inhibitor Use and Spontaneous Bacterial Peritonitis

Proton pump inhibitors (PPIs) increase enteric bacterial colonization, overgrowth, and translocation, all effects which might predispose to spontaneous bacterial peritonitis. We investigated whether PPI usage is associated with spontaneous bacterial peritonitis. Our retrospective case-control study included 116 consecutive cirrhotic patients with ascites who underwent diagnostic paracentesis upon hospital admission (2002–2005). Spontaneous bacterial peritonitis was defined as paracentesis yielding ≥250 polymorphonuclear leukocytes/ml. We performed logistic regression to determine the risk of spontaneous bacterial peritonitis by PPI usage. Of the 116 subjects, 32 had spontaneous bacterial peritonitis. Patient characteristics were similar between groups with and without infection, with the exception of the Model for End-Stage Liver Disease score (median: 23 and 18, respectively; P = 0.002). Crude and adjusted odds ratios for the development of spontaneous bacterial peritonitis by exposure to PPIs were 1.22 (95% confidence interval: 0.52–2.87) and 1.05 (0.43–2.57), respectively. In conclusion, we did not find a positive association between PPI use and spontaneous bacterial peritonitis. Mical S. Campbell and Keith Obstein contributed equally to this work. The study was not funded. Dr. Y.-X. Yang has served as a consultant to AstraZeneca.     

A Proton Pump Inhibitor’s Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study

Background/AimsProton pump inhibitors (PPIs) act by irreversibly binding to the H⁺-K⁺-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H⁺-ATPase in osteoclasts.MethodsWe investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H⁺-K⁺-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period.ResultsTwenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age ≥60 years was an independent predictor for the changes in serum calcium and urine DPD.ConclusionsIn elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H⁺-ATPase in osteoclasts.