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Comparison of renal safety and bone mineral density of tenofovir and entecavir in patients with chronic hepatitis B: a systematic review and meta-analysis

Open AccessPublished:September 15, 2022DOI:https://doi.org/10.1016/j.ijid.2022.09.021

      Highlights

      • Provides insights into the drug use for patients with chronic hepatitis B.
      • Tenofovir disoproxil fumarate (TDF) is more harmful to renal function than entecavir (ETV) at 24 months or less.
      • The effects of TDF and ETV on renal function were not different over 24 months.
      • There was no significant difference in the effects of TDF and ETV on bone density.

      Abstract

      Objectives

      Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are recommended as first-line treatments for chronic hepatitis B (CHB). However, the safety of these two drugs remains controversial. This study aimed to evaluate and compare renal function and bone mineral density in patients with CHB who took TDF or ETV.

      Methods

      The electronic databases of the Cochrane Library, PubMed, and Embase were searched. The keywords were: “CHB”, “tenofovir”, and “entecavir”. Heterogeneity and subgroups were analyzed.

      Results

      A total of 16 studies met the inclusion criteria. There was no significant difference in serum creatinine levels between the TDF and the ETV group. There was a significant standardized mean difference (SMD) in the serum estimated glomerular filtration rate between months (12 months: SMD [95% confidence interval] = -0.07 [-0.12, -0.01]; 18-24 months: SMD [95% confidence interval] = -0.11 [-0.17, -0.05]), but no significant difference emerged in the long-term drug use for over 24 months. There was no significant difference in the incidence of osteopenia/osteoporosis (I2 = 41%, risk ratio [95% confidence interval] = 1.29 [0.93, 1.77], P-value = 0.13 >0.05).

      Conclusion

      Compared with the ETV group, a greater reduction in estimated glomerular filtration rate and serum phosphorus levels was observed in the TDF group. There was no significant difference in the incidence of osteopenia/osteoporosis between the two groups.

      Keywords

      Introduction

      Hepatitis B virus (HBV) infection is considered one of the most critical public health problems worldwide, with an estimated 257 million people worldwide infected with HBV (

      World Health Organization, Global hepatitis report, 2017. Available at: https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/, 2017. Accessed June 10, 2022.

      ). More than 686,000 people die yearly from end-stage chronic hepatitis B (CHB) and CHB-related complications, such as decompensated cirrhosis and hepatocellular carcinoma (

      World Health Organization, Hepatitis B. Available at: http://www.who.int/mediacentre/factsheets/fs204/en/, 2022. Accessed June 10, 2022.

      ). Oral antiviral drugs are regarded as first-line treatments for HBV, considering the health care conditions, adherence, and cost. Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have been recommended as the drugs of the first choice for HBV treatment in long-term clinical trials. However, recent years have seen the rise of concern about the safety of TDF and ETV, especially the safety of TDF regarding its impacts on renal function.
      The safety of these two drugs remains controversial. The guidelines published by the European Association for the Study of the Liver recommend consideration of ETV in patients with CHB with underlying renal disease and an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or switching from TDF to ETV or tenofovir alafenamide fumarate. Nevertheless, the American Association for the Study of Liver Diseases has no preference between TDF and ETV, considering their effects on the kidney.
      Some studies suggest that glomerular disease may be the underlying cause of renal insufficiency. Other studies indicate that a history of drugs other than nucleoside (acid) analogs, hypertension, diabetes, and baseline renal function are all causes of renal impairment during the therapy with oral nucleos(t)ide analog drugs (
      • Lai KN
      • Li PK
      • Lui SF
      • Au TC
      • Tam JS
      • Tong KL
      • Lai FM.
      Membranous nephropathy related to hepatitis B virus in adults.
      ;
      • Fontana RJ.
      Side effects of long-term oral antiviral therapy for hepatitis B.
      ).
      In addition, studies in animal models have found that using TDF reduces bone mineral density (
      • Van Rompay KK
      • Brignolo LL
      • Meyer DJ
      • Jerome C
      • Tarara R
      • Spinner A
      • Hamilton M
      • Hirst LL
      • Bennett DR
      • Canfield DR
      • Dearman TG
      • Von Morgenland W
      • Allen PC
      • Valverde C
      • Castillo AB
      • Martin RB
      • Samii VF
      • Bendele R
      • Desjardins J
      • Marthas ML
      • Pedersen NC
      • Bischofberger N.
      Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.
      ). TDF may affect the ability of cells to synthesize DNA, resulting in altered expression of genes involved in bone maintenance and thus, loss of bone density. Some studies have revealed that renal insufficiency caused by TDF may be the cause of bone density loss that may lead to osteoporosis, hypophosphorus osteomalacia, etc. (
      • Lucey JM
      • Hsu P
      • Ziegler JB.
      Tenofovir-related Fanconi's syndrome and osteomalacia in a teenager with HIV.
      ). The kidneys are mainly responsible for the calcium and phosphorus metabolism that upholds bone metabolism. The kidney and bone are closely related. Due to the long-term use of antiviral drugs and even life-long medication, more individuals have begun to perceive the influence of antiviral drugs on the human kidney and bone health.
      To the best of our knowledge, four systematic reviews have compared the efficacy and safety of TDF and ETV. Among them,
      • Ke W
      • Liu L
      • Zhang C
      • Ye X
      • Gao Y
      • Zhou S
      • Yang Y.
      Comparison of efficacy and safety of tenofovir and entecavir in chronic hepatitis B virus infection: a systematic review and meta-analysis.
      and
      • Han Y
      • Zeng A
      • Liao H
      • Liu Y
      • Chen Y
      • Ding H.
      The efficacy and safety comparison between tenofovir and entecavir in treatment of chronic hepatitis B and HBV related cirrhosis: a systematic review and meta-analysis.
      focused on efficacy rather than renal safety.
      • Ke W
      • Liu L
      • Zhang C
      • Ye X
      • Gao Y
      • Zhou S
      • Yang Y.
      Comparison of efficacy and safety of tenofovir and entecavir in chronic hepatitis B virus infection: a systematic review and meta-analysis.
      did not find a significant difference in the safety between the two drugs, whereas
      • Han Y
      • Zeng A
      • Liao H
      • Liu Y
      • Chen Y
      • Ding H.
      The efficacy and safety comparison between tenofovir and entecavir in treatment of chronic hepatitis B and HBV related cirrhosis: a systematic review and meta-analysis.
      suggested that patients treated with TDF may have underlying renal impairment compared with those treated with ETV. However, neither study provided precise data on continuous variables of renal function.
      • Chan HL
      • Shaikh J
      • Gupta S
      • Hamed K.
      Renal function in nucleos(t)ide analog-treated patients with chronic hepatitis B: a systematic literature review and network meta-analysis.
      performed a network analysis to compare the effects of various nucleos(t)ide analogs on renal function, but only three of all the included articles directly compared TDF and ETV.
      • Lee HY
      • Oh H
      • Park CH
      • Yeo YH
      • Nguyen MH
      • Jun DW.
      Comparison of renal safety of tenofovir and entecavir in patients with chronic hepatitis B: systematic review with meta-analysis.
      indicated that TDF increased serum creatinine levels and decreased eGFR compared with ETV over 6-24 months, but the difference was minimal. The observation time of the above four studies did not exceed 24 months, and the changes in bone mineral density in patients with HBV were not analyzed and compared. Despite a growing body of research efforts to elucidate the differences between the two drugs in renal and bone damage, the safety of TDF and ETV has not been determined. In this study, we performed a meta-analysis to investigate the effects of TDF and ETV on renal function and bone mineral density in patients infected with HBV.

      Materials and methods

      This study follows the Preferred Reporting Items for Systematic Review and Meta-analyses statement and preregistered the research protocol on the International Prospective Register of Systematic Reviews (#CRD 42022333445).

      Data and literature sources

      Two authors independently performed a systematic search in PubMed, EMBASE, and Cochrane library databases, without restrictions on language. The following keywords, medical subject headings, and free text were searched: tenofovir, entecavir, chronic hepatitis B, and multiple synonyms. Then, relevant articles and bibliographies were manually identified based on the reference list of included studies.

      Inclusion and exclusion criteria

      Two authors independently identified eligible articles for inclusion based on a two-level screening using the population, intervention, comparison, outcome framework. Differences among reviewers were resolved by consensus with the third author.
      The inclusion criteria were as follows: (i) human subjects; randomized controlled trials, and nonrandomized controlled trials with more than two arms; (ii) CHB infection; (iii) interventions with ETV or TDF monotherapy; (iv) treatment for more than 6 months; and (v) patients aged over 18 years.
      The exclusion criteria were as follows: (i) co-infection with other hepatitis viruses (A, C, D, or E), human immunodeficiency virus, cytomegalovirus, or Epstein-Barr virus; (ii) alcoholic liver disease, autoimmune hepatitis, drug-induced liver injury, Wilson disease, and other liver diseases; (iii) acute hepatitis and acute exacerbations.; (iv) combination therapy or sequential therapy; and (v) not reporting any efficacy measures or not conveying sufficient statistical information.

      Data extraction

      Two authors independently extracted data with predefined data extraction tables to minimize random and biased errors. A third author independently reviewed any disagreements or unresolved issues. The following variables were extracted from selected studies: (i) we compared changes in eGFR and levels of serum creatinine, calcium, and phosphorus at 12 months, 18-24 months, and >24 months and the incidence of osteopenia/osteoporosis in the TDF and the ETV group. Outcomes were reported as mean ± SD, and risk ratio (RR). (ii) When studies presented data using graphs rather than measured numerical data, we extracted comparable data from graphs. (iii) If necessary, we would modify the data (merging two data or converting standard error to standard deviation) for better comparison.

      Assessment of methodological quality

      Two authors used the Newcastle-Ottawa scale for nonrandomized studies to assess the quality of included cohort studies and the National Institutes of Health Study Quality Assessment Tools to assess the quality of included cross-sectional studies.

      Statistical analysis

      The primary outcomes were changes in serum creatinine level, eGFR, and the incidence of osteopenia/osteoporosis at 12 months, 18-24 months, and >24 months in the TDF and the ETV group. Secondary outcomes were changes in levels of serum calcium and serum phosphorus.
      We derived the mean differences in eGFR and levels of serum creatinine, serum calcium, and serum phosphorus between the aforementioned time points and baseline. The mean differences between the TDF and ETV groups were estimated and pooled using a fixed/random-effects model. The incidence of osteopenia/osteoporosis between the TDF and ETV groups was obtained, and the RR values were pooled. A significant difference was defined as a P-value of the Z-score less than 0.05. Publication bias was assessed when more than 10 studies were included for an outcome measure. Because eGFR is estimated by a different formula (e.g., Modification of Diet in Renal Disease or The Chronic Kidney Disease Epidemiology Collaboration), we synthesized standardized mean differences (SMDs) for continuous variables with potential differences in such measures. A subgroup analysis of patients with decompensated cirrhosis and liver transplantation was performed, and a meta-analysis was performed using Review Manager (RevMan version 5.3).

      Results

      Identification of studies

      Figure 1 shows details of the literature search and study selection. A total of 2770 articles were identified from databases. First, 708 duplicates were excluded, 498 non-English and nonclinical studies were excluded, 1474 publications were excluded because they did not meet the selection criteria after screening the title and abstract, and four were unavailable. Then, we reviewed the remaining 86 articles by reading full texts. A total of 16 reports (four prospective cohort studies [
      • Kahraman R
      • Şahin A
      • Öztürk O
      • Çalhan T
      • Sayar S
      • Kanat E
      • Doğanay L
      • Özdil K.
      Effects of long-term tenofovir and entecavir treatment on bone mineral density in patients with chronic hepatitis B.
      ;
      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      ;
      • Koksal AR
      • Alkim H
      • Boga S
      • Iyisoy MS
      • Sen I
      • Tekin Neijmann ST
      • Alkim C.
      Value of cystatin C-based e-GFR measurements to predict long-term tenofovir nephrotoxicity in patients with hepatitis B.
      ;
      • Riveiro-Barciela M
      • Tabernero D
      • Calleja JL
      • Lens S
      • Manzano ML
      • Rodríguez FG
      • Crespo J
      • Piqueras B
      • Pascasio JM
      • Comas C
      • Gutierrez ML
      • Aguirre A
      • Suárez E
      • García-Samaniego J
      • Rivero M
      • Acero D
      • Fernandez-Bermejo M
      • Moreno D
      • Sánchez-Pobre P
      • de Cuenca B
      • Moreno-Palomares JJ
      • Esteban R
      • Buti M
      Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma.
      ], 10 retrospective cohort studies [
      • Chon YE
      • Park SY
      • Kim SU
      • Hong HP
      • Lee JS
      • Lee HW
      • Kim MN
      • Park JY
      • Kim DY
      • Ahn SH
      • Kim BK.
      Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: a multicenter study.
      ;
      • Huang PY
      • Chiu SYH
      • Chang KC
      • Tseng PL
      • Yen YH
      • Tsai MC
      • Wang JH
      • Kee KM
      • Chen CH
      • Hung CH
      • Chiu KW
      • Hu TH.
      A novel evidence of serial changes of bone mineral density in chronic hepatitis B patients treated with entecavir.
      ;
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      ;
      • Kim SJ
      • Rhu J
      • Lee SH
      • Kim JM
      • Choi GS
      • Kim K
      • Joh JW.
      Tenofovir does not induce renal dysfunction compared to entecavir in post-liver-transplant hepatitis B virus patients.
      ;
      • Liu JK
      • Vutien P
      • Huang DQ
      • Ishigami M
      • Landis CS
      • Nguyen MH
      REAL-B Liver Transplant Study Group. Renal outcomes with tenofovir alafenamide in liver transplant recipients.
      ;
      • López Centeno B
      • Collado Borrell R
      • Pérez Encinas M
      • Gutiérrez García ML
      • Sanmartin Fenollera P
      Comparison of the effectiveness and renal safety of tenofovir versus entecavir in patients with chronic hepatitis B.
      ;
      • Park J
      • Jung KS
      • Lee HW
      • Kim BK
      • Kim SU
      • Kim DY
      • Ahn SH
      • Han KH
      • Park JY.
      Effects of entecavir and tenofovir on renal function in patients with hepatitis B virus-related compensated and decompensated cirrhosis.
      ;
      • Tsai HJ
      • Chuang YW
      • Yang SS
      • Chang YZ
      • Chang HR
      • Lee TY.
      Evaluating the renal safety of tenofovir disoproxil fumarate in hepatitis B patients without chronic kidney disease.
      ;
      • Udompap P
      • Kim D
      • Ahmed A
      • Kim WR.
      Longitudinal trends in renal function in chronic hepatitis B patients receiving oral antiviral treatment.
      ;
      • Wei MT
      • Le AK
      • Chang MS
      • Hsu H
      • Nguyen P
      • Zhang JQ
      • Wong C
      • Wong C
      • Cheung R
      • Nguyen MH.
      Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B.
      ], and two cross-sectional studies [
      • Rodríguez-Nóvoa S
      • García-Samaniego J
      • Prieto M
      • Calleja JL
      • Pascasio JM
      • Delgado Blanco M
      • Crespo J
      • Buti M
      • Bonet Vidal ML
      • Arenas Ruiz Tapiador J
      • Fernández-Rodríguez C
      • Solá R
      • Fraga E
      • González Diéguez L
      • Núñez O
      • Praga M
      • Del Pino-Montes J
      • Romero-Gómez M
      • Morillas R
      • Diago M
      • Á Castro
      • Study Group MENTE
      Altered underlying renal tubular function in patients with chronic hepatitis B receiving Nucleos(t)ide analogs in a real-world setting: the MENTE study.
      ;
      • Tien C
      • Xu JJ
      • Chan LS
      • Chang M
      • Lim C
      • Lee S
      • Huh B
      • Shinada S
      • Bae HS
      • Fong TL.
      Long-term treatment with tenofovir in Asian-American chronic hepatitis B patients is associated with abnormal renal phosphate handling.
      ]) were considered eligible and were included in the meta-analysis.
      Figure 1:
      Figure 1Flow of patient selection for the study analysis.

      Study characteristics and quality of evidence

      Table 1 describes the characteristics of the 16 included studies. A total of 7251 participants who received TDF (n = 3184) or ETV (n = 4067) were included. The participants were predominantly male. Most enrolled patients were between the age of 40 to 65 years. The duration of drug treatment ranged from 6 to 72 months. Among 16 studies, 11 provided eGFR data, 10 reported data on serum creatinine level, eight provided data on serum phosphorus level, three provided data on serum calcium level, and four reported the incidence rates of osteopenia/osteoporosis. Two of these studies included patients who received a liver transplant (
      • Kim SJ
      • Rhu J
      • Lee SH
      • Kim JM
      • Choi GS
      • Kim K
      • Joh JW.
      Tenofovir does not induce renal dysfunction compared to entecavir in post-liver-transplant hepatitis B virus patients.
      ;
      • Liu JK
      • Vutien P
      • Huang DQ
      • Ishigami M
      • Landis CS
      • Nguyen MH
      REAL-B Liver Transplant Study Group. Renal outcomes with tenofovir alafenamide in liver transplant recipients.
      ), and two studies analyzed patients with decompensated cirrhosis (
      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      ;
      • Park J
      • Jung KS
      • Lee HW
      • Kim BK
      • Kim SU
      • Kim DY
      • Ahn SH
      • Han KH
      • Park JY.
      Effects of entecavir and tenofovir on renal function in patients with hepatitis B virus-related compensated and decompensated cirrhosis.
      ).
      Table 1Basic characteristics of included studies
      AuthorYearStudy designPopulationAge (mean±SD)Gender female/maleCirrhosisEstimated glomerular filtration rate <60History of transplantationDosage(mg)tenofovir disoproxil fumarate/ entecavirDuration (mo)Newcastle-Ottawa Scale of Nonrandomized Studies / National Institutes of Health Study Quality Assessment Tools score
      Riveiro-Barciela2017prospective61150±13167/444YesNANO245/0.5,1608
      Centeno2016retrospective6449.69±15.6016/48NAYesNANA127
      Chon2022retrospective303348.8±11.61097/1936YesNANO300/0.5728
      Huang2021retrospective25850.0±12.374/184NANANANA368
      Kahraman2022prospective5840.09±10.3722/36NANANANA≥128
      Kara2019retrospective10434.64±11.5634/70NONONONA248
      Kim2020retrospective16955.10±7.1535/134NANOYesNA369
      Koklu2015prospective85748.96±13.02292/565YesNONONA248
      Koksal2019Prospective7636.01±3.2940/36NANONONA248
      Liu2022retrospective29858.43±10.7478/220NAYesYesNA247
      Park2017retrospective23555.8±8.580/155YesNONANA248
      Tsai2021retrospective77148.77±3.07254/517YesNONONA609
      Udompap2018retrospective81549.23±14.52365/450YesYesNANA≥248
      Wei2019retrospective122446.1±13.94519/705NONANANA3849
      Rodríguez-Nóvoa2016cross-sectional28047.88±11.16114/166NANANONA24/8
      Tien2015cross-sectional14648±1168/78NANANONA≥18/7
      Values are presented as mean ± standard deviation or number; estimated glomerular filtration rate was expressed in ml/min/1.73 m2.
      NA: not available.
      Cohort studies were assessed using Newcastle-Ottawa scale for nonrandomized studies, and cross-sectional studies were assessed using National Institutes of Health Study Quality Assessment Tools. For details on the quality of the included studies, see Table 1. The number of studies included in each time group was less than 10; hence, no publication bias test was performed.

      Change in serum creatinine level and eGFR

      Figure 2(a-c) shows the comparison of levels of serum creatinine in patients with CHB who were treated with TDF or ETV for 12 months, 18-24 months, and >24 months. Compared with the baseline, there was no significant difference in the changes in serum creatinine levels between the TDF and the ETV group (at 12 months: I2 = 54%, random-effects models (REM), mean deviation (MD) [95% confidence interval (CI)] = 0.02 [-0.03, 0.07], P-value = 0.40; at 18-24 months: I2 = 81%, REM, MD [95% CI] = 0.04 [-0.05, 0.12], P-value = 0.37; >24 months: I2 = 98%, REM, MD [95% CI] = -0.30 [-1.04, 0.45], P-value = 0.43).
      Figure 2:
      Figure 2Forest plot for the change of serum creatinine: (a) 12 months, (b) 18-24 months, (c) >24 months. Forest plot for the change of estimated glomerular filtration rate: (d) 12 months, (e) 18-24 months, (f) >24 months. Forest plot for TDF ETV serum phosphorus comparison: (g) 12 months, (h) 18-24 months, (i) > 24 months. (j) Forest plot for TDF ETV serum calcium comparison. Abbreviations: ETV, entecavir; TDF, Tenofovir disoproxil fumarate.
      Figure 2(d-f) shows the comparison of eGFR between the two groups at 12 months, 18-24 months, and > 24 months. Compared with baseline, the changes in eGFR in the TDF group at 12 months and 18-24 months were reduced more significantly than those in the ETV group (at 12 months: I2 = 0%, fixed-effects models (FEM), SMD [95% CI] = -0.07 [-0.12,-0.01], P-value = 0.02; 18-24 months: I2 = 15%, FEM, SMD [95% CI] = -0.11 [-0.17, -0.05], P-value = 0.0002). There was no significant difference in changes in eGFR between the two groups when the treatment duration was over 24 months (I2 = 81%, REM, SMD [95% CI] = -0.03 [-0.22, 0.16], P-value = 0.77).

      Changes in serum phosphate and serum calcium

      Figure 2(g-i) shows the comparison of serum phosphorus levels in patients with CHB who took TDF or ETV for 12 months, 18-24 months, and >24 months. Changes in serum phosphorus levels at 12 months were significantly greater in the TDF group than in the ETV group compared with baseline, whereas no significant difference emerged between the two groups at 18-24 months and >24 months (at 12 months: I2 = 41%, FEM, MD [95% CI] = -0.12 [-0.22, -0.03], P-value = 0.01; at 18-24 months: I2 = 99%, REM, MD [95% CI] = -0.47 [-1.70, 0.75], P-value = 0.45; >24 months: I2 = 0%, FEM, MD [95% CI] = 0.02 [-0.14, 0.17], P-value = 0.83).
      Figure 2(j) compares serum calcium levels between the two groups. Compared with baseline, there was no significant difference in serum calcium level changes between the TDF group and the ETV group at ≥24 months (I2 = 73%, REM, MD [95% CI] = -0.02 [-0.18, 0.13], P-value = 0.77).

      Incidence of osteopenia/osteoporosis

      Figure 3 compares the incidence of osteopenia/osteoporosis between the two groups. Compared with baseline, there was no significant difference in the incidence of osteopenia/osteoporosis between them (I2 = 41%, FEM, RR [95% CI] = 1.16 [0.96, 1.40], P-value = 0.13).
      Figure 3:
      Figure 3Forest plot for TDF ETV osteopenia/osteoporosis. Abbreviations: ETV, entecavir; TDF, Tenofovir disoproxil fumarate.

      Subgroup analysis

      To assess the difference between TDF and ETV in renal bone injury in a specific population, we performed a subgroup analysis of studies that reported eGFR and serum creatinine levels at 12 and 24 months in patients with decompensated cirrhosis (
      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      ;
      • Park J
      • Jung KS
      • Lee HW
      • Kim BK
      • Kim SU
      • Kim DY
      • Ahn SH
      • Han KH
      • Park JY.
      Effects of entecavir and tenofovir on renal function in patients with hepatitis B virus-related compensated and decompensated cirrhosis.
      ) and patients undergoing liver transplantation (
      • Kim SJ
      • Rhu J
      • Lee SH
      • Kim JM
      • Choi GS
      • Kim K
      • Joh JW.
      Tenofovir does not induce renal dysfunction compared to entecavir in post-liver-transplant hepatitis B virus patients.
      ;
      • Liu JK
      • Vutien P
      • Huang DQ
      • Ishigami M
      • Landis CS
      • Nguyen MH
      REAL-B Liver Transplant Study Group. Renal outcomes with tenofovir alafenamide in liver transplant recipients.
      ).

      Patients with decompensated cirrhosis

      There was no significant difference in eGFR between the two groups at 12 and 24 months after treatment for decompensated cirrhosis (12 months: I2 = 47%, FEM, SMD [95% CI] = -0.02 [-0.43, 0.39], P-value = 0.92); 24 months: I2 = 0%, FEM, SMD [95% CI] = [0.47, 0.34] = 0.06, P-value = 0.77), as shown in Figure 4(a-b).
      Figure 4:
      Figure 4Forest plot for decompensated cirrhosis estimated glomerular filtration rate: (a) 12 months, (b) 24 months. Forest plot for decompensated cirrhosis creatinine: (c) 12 months, (d) 24 months. Abbreviations: ETV, entecavir; TDF, Tenofovir disoproxil fumarate.
      In patients with decompensated cirrhosis, serum creatinine levels decreased more significantly in the TDF group than in the ETV group at 24 months (I2 = 0%, FEM, MD [95% CI] = -0.10 [-0.19, -0.01], P-value = 0.03). There was no significant difference between the two groups at 12 months (I2 = 0%, FEM, MD [95% CI] = -0.04 [-0.17, 0.10], P-value = 0.60), as shown in Figure 4(c-d).

      Liver transplant

      In patients who had undergone liver transplants, no significant differences in the changes of eGFR were observed between the TDF and the ETV group at 12 months and 24 months (at 12 months: I2 = 0%, FEM, SMD [95% CI] = 0.04 [-0.20, 0.29], P-value = 0.72; at 24 months: I2 = 0%, FEM, SMD [95% CI] = 0.05 [-0.20, 0.30], P-value = 0.70), as shown in Figure 5(a-b).
      Figure 5:
      Figure 5Forest plot for liver transplantation estimated glomerular filtration rate: (a) 12 months, (b) 24 months. Forest plot for liver transplantation creatinine: (c) 12 months, (d) 24 months. Abbreviations: ETV, entecavir; TDF, Tenofovir disoproxil fumarate.
      Changes in serum creatinine levels also showed no significant differences between the two groups at 12 months and 24 months (12 months: I2 = 0%, FEM, MD [95% CI] = -0.14 [-0.38, 0.09], P-value = 0.24; at 24 months: I2 = 0%, FEM, MD [95% CI] = -0.14 [0.39, 0.11], P-value = 0.27), as shown in Figure 5(c-d).

      Sensitivity analysis

      We performed a sensitivity analysis to assess heterogeneity between the two groups regarding eGFR, serum creatinine, serum phosphorus, and serum calcium.

      Serum creatinine

      Two articles by
      • Riveiro-Barciela M
      • Tabernero D
      • Calleja JL
      • Lens S
      • Manzano ML
      • Rodríguez FG
      • Crespo J
      • Piqueras B
      • Pascasio JM
      • Comas C
      • Gutierrez ML
      • Aguirre A
      • Suárez E
      • García-Samaniego J
      • Rivero M
      • Acero D
      • Fernandez-Bermejo M
      • Moreno D
      • Sánchez-Pobre P
      • de Cuenca B
      • Moreno-Palomares JJ
      • Esteban R
      • Buti M
      Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma.
      and
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      were found to be the main sources of heterogeneity regarding the levels of serum creatinine (at 12 months). The results, excluding those by
      • Riveiro-Barciela M
      • Tabernero D
      • Calleja JL
      • Lens S
      • Manzano ML
      • Rodríguez FG
      • Crespo J
      • Piqueras B
      • Pascasio JM
      • Comas C
      • Gutierrez ML
      • Aguirre A
      • Suárez E
      • García-Samaniego J
      • Rivero M
      • Acero D
      • Fernandez-Bermejo M
      • Moreno D
      • Sánchez-Pobre P
      • de Cuenca B
      • Moreno-Palomares JJ
      • Esteban R
      • Buti M
      Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma.
      , showed that the changes in serum creatinine levels at 12 months in the TDF group were significantly higher than in the ETV group (I2=1%, FEM, MD [95% CI] = 0.05 [0.01, 0.09], P-value = 0.008). The heterogeneity may be because all the patients in this study were Caucasian. There was a larger proportion in the groups of patients with liver cirrhosis: 133 (31.4%) in the TDF group and 64 (34.2%) in the ETV group. The results after excluding the study by
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      showed no statistically significant differences in serum creatinine levels at 12 months between the two groups (I2 = 15%, FEM, MD [95% CI] = -0.01 [-0.04, 0.03], P-value = 0.72). The heterogeneity may be because the
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      study excluded patients with liver cirrhosis, eGFR <60 ml/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration), liver decompensation, organ transplantation, etc., whereas other studies included such patients more or less, as shown in Figure 6 (a-b).
      Figure 6:
      Figure 6Forest plot of serum creatinine (12 months) heterogeneity: (a) Results after excluding
      • Riveiro-Barciela M
      • Tabernero D
      • Calleja JL
      • Lens S
      • Manzano ML
      • Rodríguez FG
      • Crespo J
      • Piqueras B
      • Pascasio JM
      • Comas C
      • Gutierrez ML
      • Aguirre A
      • Suárez E
      • García-Samaniego J
      • Rivero M
      • Acero D
      • Fernandez-Bermejo M
      • Moreno D
      • Sánchez-Pobre P
      • de Cuenca B
      • Moreno-Palomares JJ
      • Esteban R
      • Buti M
      Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma.
      . (b) Results after excluding
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      . (c) Forest plot of serum creatinine (18-24 months) heterogeneity. (d) Forest plot of serum creatinine (>24 months) heterogeneity. (e) Forest plot of eGFR (> 24 months) heterogeneity. Forest plot of serum phosphorus, serum calcium heterogeneity: (f) Serum phosphorus (18-24 months) excluded
      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      , (g) Serum calcium excluded
      • Kahraman R
      • Şahin A
      • Öztürk O
      • Çalhan T
      • Sayar S
      • Kanat E
      • Doğanay L
      • Özdil K.
      Effects of long-term tenofovir and entecavir treatment on bone mineral density in patients with chronic hepatitis B.
      . Abbreviations: ETV, entecavir; TDF, Tenofovir disoproxil fumarate.
      Similarly, as for levels of serum creatinine at 18-24 months, no significant difference was observed between the TDF and the ETV group after excluding the study of
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      (I2 = 29%, FEM, MD [95% CI] = -0.01 [-0.04, 0.03], P-value = 0.74), as shown in Figure 6(c).
      The study by
      • Udompap P
      • Kim D
      • Ahmed A
      • Kim WR.
      Longitudinal trends in renal function in chronic hepatitis B patients receiving oral antiviral treatment.
      was found to be the primary source of heterogeneity with respect to creatinine level when the treatment duration was over 24 months because no significant difference was observed between the two groups after the study by
      • Udompap P
      • Kim D
      • Ahmed A
      • Kim WR.
      Longitudinal trends in renal function in chronic hepatitis B patients receiving oral antiviral treatment.
      was excluded (I2 = 0%, FEM, MD [95% CI] = 0.06 [-0.02, 0.14], P-value = 0.15). Considering its heterogeneity mainly from the baseline of enrolled patients in the study of
      • Udompap P
      • Kim D
      • Ahmed A
      • Kim WR.
      Longitudinal trends in renal function in chronic hepatitis B patients receiving oral antiviral treatment.
      , a larger proportion of patients had hepatocellular carcinoma: 78 (37.7%) in ETV (n = 207) and 64 (33.5%) in TDF (n = 191), and many patients experienced pre-existing renal insufficiency (eGFR <60 ml/min/1.73 m2), decompensated liver cirrhosis, hypertension, diabetes, etc., as shown in Figure 6(d).

      eGFR

      As for eGFR (>24 months), we found that
      • Chon YE
      • Park SY
      • Kim SU
      • Hong HP
      • Lee JS
      • Lee HW
      • Kim MN
      • Park JY
      • Kim DY
      • Ahn SH
      • Kim BK.
      Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: a multicenter study.
      was the primary source of heterogeneity because no significant difference emerged between the two groups after it was removed (I2 = 31%, FEM, SMD [95% CI] = 0.05[-0.06, 0.17], P-value = 0.15). Considering its source of heterogeneity, the baseline adverse conditions of patients in the ETV study group (n = 1793) were significantly higher than the TDF patient group (n = 1240), and particularly, the ETV group had lower eGFR than the TDF group (mean 96.0 vs 101.9 ml/min/1.73 m2, P-value <0.001) Figure 6(e).

      Serum phosphorus and serum calcium

      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      was found to be the primary source of heterogeneity in serum phosphorus (at 18-24 months). After excluding this study, there was no significant difference between the two groups (I2 = 22%, MD [95% CI] = -0.11 [-0.30, 0.08], P-value = 0.25), as shown in Figure 6(f).
      • Kahraman R
      • Şahin A
      • Öztürk O
      • Çalhan T
      • Sayar S
      • Kanat E
      • Doğanay L
      • Özdil K.
      Effects of long-term tenofovir and entecavir treatment on bone mineral density in patients with chronic hepatitis B.
      was found to be the main source of heterogeneity in serum calcium. After excluding this study, there was no significant difference between the two groups (I2 = 0%, MD [95% CI] = -0.10 [-0.20, -0.00], P-value = 0.05), as shown in Figure 6(g).

      Discussion

      In this meta-analysis, we concluded: (i) serum creatinine levels were not significantly different between the TDF and the ETV group at 12 months, 18-24 months, and >24 months of treatment (0.02 mg/dl: 95% CI [-0.03, 0.07], I2 = 54%; 0.04 mg/dl: 95% CI [-0.05, 0.12], I2 = 81%; -0.30 mg/dl: 95% CI [-1.04, 0.45], I2 = 98%), indicating that there is no significant difference in the effects of the two drugs on serum creatinine level in short-term and long-term use. According to the sensitivity analysis of included studies regarding levels of creatinine at 12 months of treatment, the serum creatinine level in the TDF group was 0.05 higher than that in the ETV group at 12 months, with a significant difference (I2 = 1%, MD [95% CI] = 0.05 [0.01, 0.09], P-value = 0.008). (ii) There was a significant SMD in serum eGFR levels between the two groups from 12 to 24 months (12 months: SMD [95%CI] = -0.07 [-0.12, -0.01]; 18-24 months: SMD [95%CI] = -0.11 [-0.17, -0.05]). The TDF group showed a greater decline in eGFR than the ETV group after 12-24 months of drug use. However, there was no significant difference regarding the long-term treatment (>24 months). (iii) There was no significant difference in the incidence of osteopenia/osteoporosis between the two groups. The follow-up time of the included studies was more than 12 months. (iv) The changes in serum phosphorus levels in patients who took TDF for 12 months were significantly lower than in those taking ETV (MD [95% CI] = -0.12 [-0.22, -0.03]), and there was no significant change in serum calcium levels. (v) After taking medication for 24 months, serum creatinine levels in patients with decompensated cirrhosis who took TDF were significantly lower than those taking ETV (I2 = 0%, MD [95% CI] = -0.10 [-0.19, -0.01]), but there was no significant difference at 12 months. There was no significant difference in renal function changes in patients who received a liver transplant.
      Both TDF and ETV are eliminated by renal excretion. Although the exact mechanism of nephrotoxicity is still unclear, some studies (
      • Jafari A
      • Khalili H
      • Dashti-Khavidaki S.
      Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention.
      ) pointed out that the drug may accumulate in the proximal tubule during renal excretion and cause nephrotoxicity by directly damaging the proximal tubule cells and mitochondria. Many studies have investigated the effects of TDF and ETV on renal function; however, this topic remains controversial.
      Studies by
      • Koklu S
      • Gulsen MT
      • Tuna Y
      • Koklu H
      • Yuksel O
      • Demir M
      • Guner R
      • Dogan Z
      • Kucukazman M
      • Poyrazoglu OK
      • Biyik M
      • Ozturk NA
      • Aydogan T
      • Coban S
      • Kocaman O
      • Sapmaz F
      • Gokturk SH
      • Karaca C
      • Demirezer A
      • Tanoglu A
      • Yildirim B
      • Altinbas A
      • Atak BM
      • Cosar AM
      Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B.
      showed that eGFR decreased in the TDF group at 24 months of follow-up. However, when excluding patients with any possible renal risk factors (aged 50 years, decompensated cirrhosis, hypertension, and diabetes), there was no significant difference between the groups at the end of the 24th month of treatment (P-value = 0.582).
      • Chon YE
      • Park SY
      • Kim SU
      • Hong HP
      • Lee JS
      • Lee HW
      • Kim MN
      • Park JY
      • Kim DY
      • Ahn SH
      • Kim BK.
      Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: a multicenter study.
      pointed out that in the ETV group, the eGFR of patients with hypertension or diabetes decreased significantly. In contrast, the eGFR of patients without such comorbidities did not change significantly. In the TDF group, eGFR decreased significantly with or without hypertension and diabetes, and the decline in eGFR was accelerated with these comorbidities.
      • Kara AV
      • Yıldırım Y
      • Ozcicek F
      • Aldemir MN
      • Arslan Y
      • Bayan K
      • Çelen MK.
      Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients.
      included patients with treatment-naïve CHB and pointed out that eGFR was reduced in patients with HBV who had taken TDF for 24 months, indicating that TDF was an independent predictor of changes in eGFR.
      However, some studies (
      • Park J
      • Jung KS
      • Lee HW
      • Kim BK
      • Kim SU
      • Kim DY
      • Ahn SH
      • Han KH
      • Park JY.
      Effects of entecavir and tenofovir on renal function in patients with hepatitis B virus-related compensated and decompensated cirrhosis.
      ;
      • Riveiro-Barciela M
      • Tabernero D
      • Calleja JL
      • Lens S
      • Manzano ML
      • Rodríguez FG
      • Crespo J
      • Piqueras B
      • Pascasio JM
      • Comas C
      • Gutierrez ML
      • Aguirre A
      • Suárez E
      • García-Samaniego J
      • Rivero M
      • Acero D
      • Fernandez-Bermejo M
      • Moreno D
      • Sánchez-Pobre P
      • de Cuenca B
      • Moreno-Palomares JJ
      • Esteban R
      • Buti M
      Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma.
      ) showed that patients receiving TDF and ETV treatment did not show significant differences in eGFR levels during the 24-month observation period. A newly published study by
      • Tsai HJ
      • Chuang YW
      • Yang SS
      • Chang YZ
      • Chang HR
      • Lee TY.
      Evaluating the renal safety of tenofovir disoproxil fumarate in hepatitis B patients without chronic kidney disease.
      showed that TDF and ETV had a similar mean decrease in eGFR at up to 60 months of follow-up (TDF: 10.1 ml/min/1.73 m2, [95% CI]: 7.4-12.7; ETV: 8.0 ml/min/1.73 m2, [95% CI]: 6.4-9.6), indicating that TDF is safe for patients with CHB without chronic renal insufficiency. However, it was found that in older adults aged ≥60 years who were receiving TDF treatment, the 5-year cumulative incidence of renal insufficiency was significantly higher (TDF: 34.4%, [95% CI]: 17.7-59.8; ETV: 15.5%, [95% CI]: 9.4-25.1). Another 60-month follow-up also showed that the renal function of patients taking TDF or ETV remained stable. However,
      • Chon YE
      • Park SY
      • Kim SU
      • Hong HP
      • Lee JS
      • Lee HW
      • Kim MN
      • Park JY
      • Kim DY
      • Ahn SH
      • Kim BK.
      Long-term renal safety between patients with chronic hepatitis B receiving tenofovir vs. entecavir therapy: a multicenter study.
      reported that the TDF group showed progressive renal insufficiency despite small changes in annual eGFR in up to 72 months of follow-up, compared with ETV.
      In our study, the TDF group showed a more significant reduction in eGFR at ≤24 months of follow-up than the ETV group, and there was no significant difference regarding a longer treatment duration. For patients with decompensated cirrhosis, levels of serum creatinine were significantly lower in patients treated with TDF than those treated with ETV, indicating that TDF had smaller impacts on renal function, whereas for patients who had undergone liver transplants, there was no significance in the serum creatinine level. Hypertension, diabetes mellitus, pre-existing renal insufficiency, and age were found in previous studies to be factors that affect the changes in renal function in TDF and ETV groups. In our study, although there was no significant difference regarding renal function in the two groups during a long-term treatment period, a slight decline in renal function was observed in the TDF group when the treatment continued for no more than 24 months. Thus, it may be recommended that individual risk factors should be identified early and antiviral drugs should be selected with caution for relatively short-term treatment.
      In addition to the effect on renal function, damage to the bone caused by TDF and ETV regarding long-term drug use has attracted increasing attention. Some studies have suggested that the potential effects of these two drugs on proximal renal tubular cells may lead to phosphate depletion and thus lead to bone mineral density reduction.
      • Huang PY
      • Chiu SYH
      • Chang KC
      • Tseng PL
      • Yen YH
      • Tsai MC
      • Wang JH
      • Kee KM
      • Chen CH
      • Hung CH
      • Chiu KW
      • Hu TH.
      A novel evidence of serial changes of bone mineral density in chronic hepatitis B patients treated with entecavir.
      showed that patients with CHB treated with TDF may have increased bone mineral density loss.
      • Saeedi R
      • Mojebi-Mogharar A
      • Sandhu SK
      • Dubland JA
      • Ford JA
      • Yousefi M
      • Pudek M
      • Holmes DT
      • Erb SR
      • Peter Kwan WP
      • Kendler DL
      • Yoshida EM
      Lamivudine, entecavir, or tenofovir treatment of hepatitis B infection: effects on calcium, phosphate, FGF23 and indicators of bone metabolism.
      revealed a slightly increased risk of abnormal bone metabolism in patients with HBV receiving TDF therapy, especially involving vitamin D insufficiency. However, there are some different results.
      • Tien C
      • Xu JJ
      • Chan LS
      • Chang M
      • Lim C
      • Lee S
      • Huh B
      • Shinada S
      • Bae HS
      • Fong TL.
      Long-term treatment with tenofovir in Asian-American chronic hepatitis B patients is associated with abnormal renal phosphate handling.
      suggested that patients with HBV treated with TDF did not have an increased risk of osteoporosis during a follow-up period of ≥18 months.
      • Wei MT
      • Le AK
      • Chang MS
      • Hsu H
      • Nguyen P
      • Zhang JQ
      • Wong C
      • Wong C
      • Cheung R
      • Nguyen MH.
      Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B.
      observed no significant increase in the incidence of osteopenia/osteoporosis in patients with CHB treated with TDF or ETV during a median follow-up period of approximately 4-5 years.
      • Dessordi R
      • Watanabe LM
      • Guimarães MP
      • Romão EA
      • de Lourdes Candolo
      • Martinelli A
      • de Carvalho Santana R
      • Navarro AM
      Bone loss in hepatitis B virus-infected patients can be associated with greater osteoclastic activity independently of the retroviral use.
      proposed that the presence of HBV infection leads to an increased risk of changes in bone health regardless of the use of TDF, ETV, or lamivudine.
      • Bunchorntavakul C
      • Taweewattanakitbavorn V
      • Atsawarungruangkit A.
      Bone mineral density and renal function in chronic hepatitis B patients receiving nucleotide versus nucleoside analogs: a pilot prospective study.
      found that in patients with CHB without cirrhosis, the changes in bone mineral density were not significantly different between treatment with nucleotide and nucleoside analogs. A newly published study (
      • Kahraman R
      • Şahin A
      • Öztürk O
      • Çalhan T
      • Sayar S
      • Kanat E
      • Doğanay L
      • Özdil K.
      Effects of long-term tenofovir and entecavir treatment on bone mineral density in patients with chronic hepatitis B.
      ) revealed that long-term treatment of patients with HBV with TDF resulted in a significant decrease in the bone mineral density of the hip and L3 lumbar spine.
      Our study found no significant difference in the incidence of osteopenia/osteoporosis between the use of TDF and ETV at a follow-up of at least 12 months, but this may require longer-term validation.
      Our study is different from existing studies because of the following: (i) we collected continuous variable data of renal function changes over a longer period, up to 72 months. (ii) Serum calcium and serum phosphorus were investigated, and the changes in renal function were more comprehensively understood. (iii) We increased the inclusion of newly published studies from 2018 to 2022 through qualified research quality assessment methods and updated the data comparing the effects of TDF and ETV on renal function. (iv) Subgroup analysis was performed on renal function changes in patients with decompensated cirrhosis and receiving liver transplants. (v) The effects of TDF and ETV on bone mineral density in HBV patients were systematically analyzed for the first time.
      Our study also had several limitations: (i) through sensitivity analysis, we found that one study had a significant weight and effect size, which affected the results’ stability. The results after excluding this study showed no significant difference between the two medication groups. (ii) The formula for eGFR calculation varies from study to study. Although we used SMD for the meta-analysis, the results need to be interpreted with caution. (iii) The sample size of patients with HBV with decompensated cirrhosis and undergoing liver transplantation is insufficient, and an analysis of larger sample size may be required. (iv) The number of included studies on the effects of TDF and ETV on bone mineral density in patients with HBV is small, and more continuous data on bone mineral density cannot be collected. Further head-to-head randomized controlled studies with large sample sizes may be needed.

      Conclusion

      In conclusion, in this study, we found that compared with patients who took ETV, those who took TDF had a more significant decrease in eGFR and serum phosphorus level at <24 months of follow-up, with no significant difference at a longer time. However, in patients with decompensated cirrhosis, TDF had a lesser effect on renal function than ETV. At least 12 months of follow-up, TDF, and ETV showed no significant difference in the incidence of osteopenia/osteoporosis, but this may be affected by the insufficient sample size and follow-up time, so further research with a large sample and long-term monitoring is required.

      Author contributions

      All authors have read and approved the final version of the manuscript.

      Funding

      This study was funded by the National Natural Science Foundation of China (No. 81673967) and Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (No. C12021A00803).

      Ethical approval

      Not applicable.

      Data availability statement

      The extracted data are available on request to the corresponding author.

      CRediT authorship contribution statement

      Xiaoxian Yang: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Haiyi Yan: Investigation, Supervision, Writing – original draft, Writing – review & editing. Xiuju Zhang: Project administration, Writing – original draft, Writing – review & editing. Xueying Qin: Software, Writing – original draft, Writing – review & editing. Peng Guo: Funding acquisition, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing.

      Declaration of Competing Interest

      The authors have no competing interests to declare.

      Acknowledgments

      The authors would like to thank the researchers and study participants for their contributions.

      Appendix. Supplementary materials

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