Comparative risk of osteoporosis and fractures in chronic hepatitis B patients: Tenofovir disoproxil fumarate vs. entecavir in a Korean nationwide cohort.

Background & aims: The optimal antiviral agent for patients with chronic hepatitis B (CHB) at risk for osteoporosis remains debated. The aim of this study was to compare the incidence of osteoporosis and osteoporotic fractures between patients treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) using a nationwide cohort in South Korea.

Method: We analyzed 40,404 patients with CHB treated with either TDF (n = 23,779) or ETV (n = 16,625). The risk of osteoporosis and osteoporotic fractures was evaluated using Cox proportional hazards models, incidence rate ratios (IRRs), and Kaplan-Meier survival analysis. To adjust for baseline differences, inverse probability of treatment weighting was applied.

Result: Over a mean follow-up of 50.8 months, osteoporosis occurred in 1,712 TDF users and 1,094 ET V users. The incidence rate of osteoporosis was significantly higher in the TDF group (IRR 1.30, 95% CI 1.23-1.37; p <0.001). Multivariate Cox regression also confirmed increased osteoporosis risk with TDF (hazard ratio [HR] 1.328, 95% CI 1.258-1.401; p <0.001), while fracture incidence was not significantly different (HR 1.027, 95% CI 0.939-1.122, p = 0.569). In patients aged ≥60 years, the TDF group had a significantly higher risk of both osteoporosis (HR 1.347, 95% CI 1.224-1.484; p <0.001) and fractures (HR 1.213, 95% CI 1.051-1.403; p = 0.009), with divergence in Kaplan-Meier curves evident after 1 and 3 years of treatment, respectively.

Conclusion: Long-term use of TDF is associated with a significantly increased risk of osteoporosis and fractures, especially in patients aged ≥60 years. These findings support the need for proactive bone health surveillance in patients with CHB receiving long-term TDF therapy.

Impact and implications: Our study highlights the need for careful antiviral selection in patients with chronic hepatitis B aged ≥60 due to the increased risk of osteoporosis and fractures with long-term tenofovir disoproxil fumarate use. We recommend using entecavir or tenofovir alafenamide fumarate as the preferred therapies for patients at high risk of fractures. Early intervention is essential, as fracture incidence tends to rise after 2-3 years of tenofovir disoproxil fumarate therapy, making regular bone mineral density monitoring critical for these patients.