Does long-term use of tenofovir disoproxil fumarate affect fracture risk in patients with chronic hepatitis B?
Authors: Haitao Zhang, Jin Huang, Wenhao Zhu, Wenjun Feng, Yirong Zeng
Journal: Journal of Hepatology (2024)

Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis BJournal of HepatologyVol. 80Issue 4PreviewThe use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB). Full-Text PDF Tenofovir disoproxil fumarate (TDF), exemplifying the class of nucleotide analogs, stands as a forefront pharmaceutical in international therapeutic guidelines for the treatment of chronic hepatitis B[1Wong G.L. Seto W.K. Wong V.W. et al.Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B.Alimentary pharmacology & therapeutics. 2018; 47: 730-737Crossref PubMed Scopus (0) Google Scholar]. Previous clinical trials have indicated that TDF may elevate the risk of renal toxicity and loss of bone mineral density (BMD)[2Lampertico P. Chan H.L. Janssen H.L. et al.Review article: long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients.Alimentary pharmacology & therapeutics. 2016; 44: 16-34Crossref PubMed Scopus (0) Google Scholar]. Nevertheless, the impact of TDF on the clinical risk of fractures remains uncertain. Recently, we were intrigued to read the study titled "Long-term use of TDF increases fracture risk in elderly patients with chronic hepatitis B"[3Yip T.C. Lai J.C. Yam T.F. et al.Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B.Journal of hepatology. 2024; 80: 553-563Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Yip et al. utilized a comprehensive database encompassing 41,531 cases of chronic hepatitis B (CHB) across Hong Kong to employ propensity score matching (PSM) methodology in comparing the risk of fractures between patients treated with entecavir and TDF over 24 months. The findings from this real-world study confirm that in elderly patients with CHB, the risk of fractures increases following treatment with TDF for ≥24 months. We greatly appreciate the considerable effort invested by all the authors in exploring this intriguing topic. However, certain aspects of this study have raised our attention. We would like to pose some valuable questions to the researchers. Firstly, regarding the exclusion criteria, although the authors have established strict parameters for the inclusion and exclusion of participants, we believe that excluding merely patients with bone cancer and bone metastasis may not suffice. It is worth noting that malignant tumors exert a substantial impact on bone metabolism regardless of whether bone metastasis occurs. Compared to non-cancer control groups, cancer patients have a higher risk of fractures[4Gong I.Y. Chan K.K.W. Lipscombe L.L. et al.Fracture risk among patients with cancer compared to individuals without cancer: a population-based study.British journal of cancer. 2023; 129: 665-671Crossref Scopus (2) Google Scholar]. Therefore, we advocate for the exclusion of all patients with malignant tumors before baseline. Secondly, throughout follow-up, patients may have been prescribed calcium supplements, bisphosphonates, or estrogen—an important protective factor against the risk of fractures—known to counteract or even reverse the adverse impact of TDF or entecavir on BMD[5Gregson C.L. Armstrong D.J. Bowden J. et al.UK clinical guideline for the prevention and treatment of osteoporosis.Archives of osteoporosis. 2022; 17: 58Crossref PubMed Scopus (0) Google Scholar]. This consideration is paramount. Although the article included it as a covariate in the PSM, we recommend excluding patients taking the aforementioned anti-osteoporosis medications to mitigate potential interference from this factor. Naturally, the coverage of the final cohort and whether the final cohort can effectively represent the majority of the target patient population of interest are important factors in deciding inclusion and exclusion criteria. If the authors wish to focus their study on a population at higher risk of fractures due to anti-osteoporosis medication indications, then our suggestion would not apply. Thirdly, the baseline bone density levels of patients in both the TDF and ETV groups are unknown. However, BMD levels play a predominant role in the risk of fractures, which constitutes a crucial confounding factor. If there is a considerable difference in baseline BMD levels between the two groups of patients, it warrants further exploration into the conclusions of the study. In this kind of retrospective study based on large-scale real-world data on an electronic healthcare database, it may be unrealistic to request BMD for all patients in the propensity score matching analysis as the DEXA scan is not a routine test for patients with chronic hepatitis B. One may not expect retrospective real-world data to capture BMD for every patient. Nevertheless, if the authors could screen out a subset of patients who have undergone DEXA scans for a sensitivity analysis, it would enhance the robustness of the study's conclusions. Fourthly, despite the rigorous and comprehensive PSM of various covariates in this study, we recommend enhancing consideration for other potential confounding factors, including income, education level, nutritional intake, marital status, and physical activity[6Morin S.N. Feldman S. Funnell L. et al.Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update.CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2023; 195: E1333-e1348Crossref Scopus (10) Google Scholar]. This will further strengthen the reliability and stability of the study findings. Finally, the impact of different medication dosages on BMD and fracture risk may vary. Would it be feasible to subgroup the dosage of TDF and entecavir medications to clarify the range of dosages that are safe in terms of fracture risk? Additionally, if it is not feasible to meticulously document the medication dosages for each patient, it is also possible to assess the proportion of patients in the entire retrospective cohort who require dosage adjustments and their impact on the overall study findings. This approach would provide better guidance for clinical medication practices. In summary, the study conducted by Yip et al. offers a comprehensive insight into the association between TDF usage and fracture risk among CHB patients. Their significant advancements in this clinically relevant area notably enrich our understanding. We appreciate the opportunity to provide feedback on this study and eagerly anticipate the continued scholarly contributions of Yip et al. in the fields of CHB and bone metabolism research. We trust that our suggestions will further support their ongoing academic excellence. National Natural Science Foundation of China (82374484 and 82104882) and 2024 Gansu Talent Project. Prof. Yirong Zeng, MD Haitao Zhang, and MD Wenjun Feng: Design of the work and final approval of the manuscript for submission. MD Haitao Zhang, MD Jin Huang and Wenhao Zhu: Drafting and revision of the manuscript. The authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the Supplementary data to this article: Download .docx (.03 MB) Help with docx files Download .docx (.03 MB) Help with docx files Download .docx (.03 MB) Help with docx files Download .docx (.03 MB) Help with docx files Download .docx (.03 MB) Help with docx files