{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:03:13Z","timestamp":1781002993145,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objective: Long-term tenofovir disoproxil fumarate (TDF) therapy is associated with progressive bone mineral density loss in patients with chronic hepatitis B (CHB), yet existing fracture risk algorithms, such as FRAX, were not designed for this population. We aimed to develop and internally validate a clinical nomogram for identifying TDF-associated osteoporosis using penalized regression on demographic, virological, and biochemical predictors. Methods: In this single-center retrospective cohort study, 237 adult CHB patients receiving TDF for at least 12 months underwent dual-energy X-ray absorptiometry (DXA). Osteoporosis was defined as a T-score of \u22122.5 or lower at the lumbar spine or femoral neck. Thirteen candidate predictors were evaluated using LASSO regression with 10-fold cross-validation; selected variables were entered into an unpenalized multivariable logistic regression model; internal validation employed bootstrap resampling with 200 replications to derive optimism-corrected estimates of discrimination and calibration. The clinical utility was assessed using decision curve analysis (DCA). Results: Osteoporosis prevalence was 15.2% (n = 36). LASSO selected three predictors: prior fragility fracture (OR 11.45, 95% CI 4.82\u201327.15), the Charlson Comorbidity Index (OR 1.45 per unit, 95% CI 1.15\u20131.85), and alkaline phosphatase. The model demonstrated strong discrimination (apparent C-index 0.860; optimism-corrected 0.845) with excellent calibration (slope 0.94, intercept 0.02; Brier score 0.095). At a 0.15 probability threshold, sensitivity was 86.0%, specificity 78.0%, and negative predictive value 97.0%. DCA confirmed superior net clinical benefit over default strategies across the 0.10\u20130.30 threshold range; a pre-specified sensitivity analysis excluding fracture history retained meaningful discrimination (corrected C-index 0.791). Conclusions: This nomogram offers a clinically actionable, disease-specific tool for stratifying osteoporosis risk in TDF-treated CHB patients, particularly well suited for safely deferring DXA imaging in low-risk individuals. External validation in multicenter and ethnically diverse cohorts is required before widespread implementation.<\/jats:p>","DOI":"10.3390\/jcm15124442","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:46:54Z","timestamp":1780998414000},"page":"4442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Nomogram for Predicting Tenofovir-Associated Osteoporosis in Chronic Hepatitis B"],"prefix":"10.3390","volume":"15","author":[{"given":"Elif Can","family":"Semet","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Band\u0131rma Training and Research Hospital, Bal\u0131kesir 10200, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2210-820X","authenticated-orcid":false,"given":"Cihan","family":"Semet","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Band\u0131rma Onyedi Eyl\u00fcl University, Bal\u0131kesir 10250, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection","volume":"67","author":"Lampertico","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1056\/NEJMoa0802878","article-title":"Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B","volume":"359","author":"Marcellin","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.5152\/tjg.2020.18024","article-title":"Effects of Long-Term Tenofovir and Entecavir Treatment on Bone Mineral Density in Patients with Chronic Hepatitis B","volume":"33","author":"Kahraman","year":"2022","journal-title":"Turk. J. Gastroenterol."},{"key":"ref_4","first-page":"354908","article-title":"Tenofovir Nephrotoxicity: 2011 Update","volume":"2011","author":"Ferrer","year":"2011","journal-title":"AIDS Res. Treat."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chen, L., Tang, J., Zhang, L., Zheng, L., Wang, F., Guo, F., Han, Y., Song, X., Lv, W., and Cao, W. (2025). Bone Loss in Young Adults with HIV Following Antiretroviral Therapy Containing Tenofovir Disoproxil Fumarate Regimen Using Machine Learning. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1516013"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hou, K., Li, T., Zhang, S., He, J., Wan, T., Gao, Y., Xiong, L., Fu, S., Zhang, N., and Zhao, G. (2026). Multivariable analysis of bone mass reduction risk prediction and anxiety status in male HIV\/AIDS patients. Front. Reprod. Health, 7.","DOI":"10.3389\/frph.2025.1703420"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1097\/QAD.0b013e32801022eb","article-title":"Antiretroviral Therapy and the Prevalence of Osteopenia and Osteoporosis: A Meta-Analytic Review","volume":"20","author":"Brown","year":"2006","journal-title":"AIDS"},{"key":"ref_8","first-page":"1045","article-title":"Prospective Assessment of Renal Function and Bone Mineral Density in Japanese Patients with Chronic Hepatitis B Treated with Tenofovir Disoproxil Fumarate","volume":"30","author":"Ogawa","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00198-007-0543-5","article-title":"FRAX\u2122 and the Assessment of Fracture Probability in Men and Women from the UK","volume":"19","author":"Kanis","year":"2008","journal-title":"Osteoporos. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.7326\/M14-0697","article-title":"Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD): The TRIPOD Statement","volume":"162","author":"Collins","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_11","unstructured":"World Health Organization (1994). Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis: Report of a WHO Study Group, World Health Organization. WHO Technical Report Series."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","article-title":"A New Method of Classifying Prognostic Comorbidity in Longitudinal Studies: Development and Validation","volume":"40","author":"Charlson","year":"1987","journal-title":"J. Chronic Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a Simple Noninvasive Index to Predict Significant Fibrosis in Patients with HIV\/HCV Coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1053\/jhep.2003.50346","article-title":"A Simple Noninvasive Index Can Predict Both Significant Fibrosis and Cirrhosis in Patients with Chronic Hepatitis C","volume":"38","author":"Wai","year":"2003","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6212","DOI":"10.1158\/1078-0432.CCR-14-0442","article-title":"Systemic Immune-Inflammation Index Predicts Prognosis of Patients after Curative Resection for Hepatocellular Carcinoma","volume":"20","author":"Hu","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"m441","DOI":"10.1136\/bmj.m441","article-title":"Calculating the Sample Size Required for Developing a Clinical Prediction Model","volume":"368","author":"Riley","year":"2020","journal-title":"BMJ"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression Shrinkage and Selection via the Lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hastie, T., Tibshirani, R., and Friedman, J. (2009). The Elements of Statistical Learning: Data Mining, Inference, and Prediction, Springer. [2nd ed.]. Springer Series in Statistics.","DOI":"10.1007\/978-0-387-84858-7"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Van Calster, B., McLernon, D.J., van Smeden, M., Wynants, L., Steyerberg, E.W., and on behalf of Topic Group \u201cEvaluating Diagnostic Tests and Prediction Models\u201d of the STRATOS Initiative (2019). Calibration: The Achilles Heel of Predictive Analytics. BMC Med., 17.","DOI":"10.1186\/s12916-019-1466-7"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.jclinepi.2015.04.005","article-title":"Prediction Models Need Appropriate Internal, Internal\u2013External, and External Validation","volume":"69","author":"Steyerberg","year":"2016","journal-title":"J. Clin. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/0272989X06295361","article-title":"Decision Curve Analysis: A Novel Method for Evaluating Prediction Models","volume":"26","author":"Vickers","year":"2006","journal-title":"Med. Decis. Mak."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1002\/sim.8538","article-title":"Optimized Variable Selection via Repeated Data Splitting","volume":"39","author":"Capanu","year":"2020","journal-title":"Stat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1007\/s40618-021-01503-w","article-title":"New Insights into Vitamin D Regulation: Is There a Role for Alkaline Phosphatase?","volume":"44","author":"Bellastella","year":"2021","journal-title":"J. Endocrinol. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1080\/13102818.2007.10817444","article-title":"Causes of High Bone Alkaline Phosphatase","volume":"21","year":"2007","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_26","first-page":"305","article-title":"Osteocalcin and Bone Alkaline Phosphatase in the Serum of Women with Liver Disease","volume":"21","author":"Steinberg","year":"1991","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.abb.2010.05.030","article-title":"Liver and Bone","volume":"503","year":"2010","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.transproceed.2010.03.096","article-title":"Bone Disorders in Patients with Chronic Liver Disease Awaiting Liver Transplantation","volume":"42","author":"Loria","year":"2010","journal-title":"Transplant. Proc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/ki.2013.547","article-title":"The Three-Year Incidence of Fracture in Chronic Kidney Disease","volume":"86","author":"Naylor","year":"2014","journal-title":"Kidney Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"i1","DOI":"10.1136\/gut.50.suppl_1.i1","article-title":"Guidelines on the Management of Osteoporosis Associated with Chronic Liver Disease","volume":"50","author":"Collier","year":"2002","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1086\/656412","article-title":"Bone Disease in HIV Infection: A Practical Review and Recommendations for HIV Care Providers","volume":"51","author":"McComsey","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrd3669","article-title":"Inflammatory Bone Loss: Pathogenesis and Therapeutic Intervention","volume":"11","author":"Redlich","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2276","DOI":"10.1097\/MD.0000000000002276","article-title":"Hepatitis B Virus Infection and the Risk of Osteoporosis: A Nationwide Retrospective Cohort Study","volume":"94","author":"Lai","year":"2015","journal-title":"Medicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101489","DOI":"10.1016\/j.jhepr.2025.101489","article-title":"Comparative Risk of Osteoporosis and Fractures in Chronic Hepatitis B Patients: Tenofovir Disoproxil Fumarate vs. Entecavir in a Korean Nationwide Cohort","volume":"7","author":"Shin","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_35","first-page":"856","article-title":"Association between Hepatitis B Virus Replication and Bone Mineral Density in Patients with Chronic Hepatitis B","volume":"26","author":"Kim","year":"2019","journal-title":"J. Viral Hepat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9427","DOI":"10.3748\/wjg.v20.i28.9427","article-title":"Osteoporosis and Fractures in Liver Disease: Relevance, Pathogenesis and Therapeutic Implications","volume":"20","author":"Nakchbandi","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S2468-1253(16)30024-3","article-title":"Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate for the Treatment of HBeAg-Positive Chronic Hepatitis B Virus Infection: A Randomised, Double-Blind, Phase 3, Non-Inferiority Trial","volume":"1","author":"Chan","year":"2016","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.jhep.2017.11.039","article-title":"96 Weeks Treatment of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate for Hepatitis B Virus Infection","volume":"68","author":"Agarwal","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/sim.2929","article-title":"Evaluating the Added Predictive Ability of a New Marker: From Area under the ROC Curve to Reclassification and Beyond","volume":"27","author":"Pencina","year":"2008","journal-title":"Stat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4172\/1758-4272.1000156","article-title":"Case Finding for the Primary Prevention of Fragility Fractures with FRAX (without BMD) in Those over 70 Years: Reducing the Reliance on BMD as the Primary Tool","volume":"13","author":"Inderjeeth","year":"2018","journal-title":"Int. J. Clin. Rheumatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3329\/bjm.v34i20.66141","article-title":"Osteoporosis: Recent Advances","volume":"34","author":"Shahin","year":"2023","journal-title":"Bangladesh J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/heartjnl-2011-301247","article-title":"Risk Prediction Models: II. External Validation, Model Updating, and Impact Assessment","volume":"98","author":"Moons","year":"2012","journal-title":"Heart"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Collins, G.S., de Groot, J.A., Dutton, S., Omar, O., Shanyinde, M., Tajar, A., Voysey, M., Wharton, R., Yu, L.-M., and Moons, K.G.M. (2014). External Validation of Multivariable Prediction Models: A Systematic Review of Methodological Conduct and Reporting. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-40"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4442\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T10:49:58Z","timestamp":1781002198000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcm15124442"],"URL":"https:\/\/doi.org\/10.3390\/jcm15124442","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]}}}