Shin Yoon E, Kim Jae Young, Kim Hyuk, Yoo Jeong Ju, Kim Sang Gyune, Kim Young Seok
Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Republic of Korea.
Department of Internal Medicine, Soonchunhyang University School of Medicine, Republic of Korea.
JHEP Rep. 2025 Jun 21;7(9):101489. doi: 10.1016/j.jhepr.2025.101489. eCollection 2025 Sep.
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.
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.
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; 0.001). Multivariate Cox regression also confirmed increased osteoporosis risk with TDF (hazard ratio [HR] 1.328, 95% CI 1.258-1.401; 0.001), while fracture incidence was not significantly different (HR 1.027, 95% CI 0.939-1.122, = 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; 0.001) and fractures (HR 1.213, 95% CI 1.051-1.403; = 0.009), with divergence in Kaplan-Meier curves evident after 1 and 3 years of treatment, respectively.
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.
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.
对于有骨质疏松风险的慢性乙型肝炎（CHB）患者，最佳抗病毒药物仍存在争议。本研究的目的是利用韩国的全国性队列，比较接受替诺福韦酯（TDF）和恩替卡韦（ETV）治疗的患者中骨质疏松和骨质疏松性骨折的发生率。
我们分析了40404例接受TDF（n = 23779）或ETV（n = 16625）治疗的CHB患者。使用Cox比例风险模型、发病率比（IRR）和Kaplan-Meier生存分析评估骨质疏松和骨质疏松性骨折的风险。为了调整基线差异，应用了治疗权重的逆概率。
在平均50.8个月的随访中，1712例TDF使用者和1094例ETV使用者发生了骨质疏松。TDF组骨质疏松的发生率显著更高（IRR 1.30，95%CI 1.23 - 1.37；P < 0.001）。多变量Cox回归也证实TDF会增加骨质疏松风险（风险比[HR] 1.328，95%CI 1.258 - 1.401；P < 0.001），而骨折发生率无显著差异（HR 1.027，95%CI 0.939 - 1.122，P = 0.569）。在年龄≥60岁的患者中，TDF组骨质疏松（HR 1.347，95%CI 1.224 - 1.484；P < 0.001）和骨折（HR 1.213，95%CI 1.051 - 1.403；P = 0.009）的风险均显著更高，在治疗1年和3年后，Kaplan-Meier曲线分别出现明显差异。
长期使用TDF与骨质疏松和骨折风险显著增加相关，尤其是在年龄≥60岁的患者中。这些发现支持对接受长期TDF治疗的CHB患者进行积极的骨骼健康监测。
我们的研究强调，由于长期使用替诺福韦酯会增加骨质疏松和骨折风险，对于年龄≥60岁的慢性乙型肝炎患者，需要谨慎选择抗病毒药物。我们建议将恩替卡韦或富马酸替诺福韦艾拉酚胺作为骨折高风险患者的首选治疗药物。早期干预至关重要，因为替诺福韦酯治疗2 - 3年后骨折发生率往往会上升，因此对这些患者进行定期骨密度监测至关重要。
