Pre-transplant vulnerability and clinically consequential osteonecrosis after liver transplantation

Osteonecrosis of the femoral head (ONFH) after liver transplantation (LT) frequently progresses to joint collapse and surgical intervention. Although corticosteroids have traditionally been implicated in its pathogenesis, their independent contribution under contemporary immunosuppressive protocols remains uncertain. We aimed to identify factors associated with clinically consequential ONFH, with particular attention to pre-transplant disease burden and systemic vulnerability. This retrospective cohort study included 1,836 adults who underwent first-time LT between 2000 and 2023. To minimize time-dependent bias, corticosteroid exposure was assessed as cumulative dose over a fixed 3-month post-transplant period and examined using risk-set percentile analysis and an adjusted Cox model. Additional candidate factors were screened using covariate-balancing approaches and evaluated in a full-cohort multivariable Cox model. ONFH developed in 64 patients (3.5%) at a mean of 5.86±4.58 years after LT, and 71.9% of affected patients subsequently underwent surgical intervention. Corticosteroid exposure was not significantly associated with ONFH after adjustment for baseline covariates (p=0.47), and findings were consistent across analyses accounting for time-dependent bias. In contrast, other diagnoses including primary biliary cholangitis or Wilson disease (HR 4.21; 95% CI, 1.19-14.91; p=0.03) and preoperative enteral nutrition requirement (HR 2.98; 95% CI 1.03-8.64; p=0.04) were associated with increased risk. Cumulative smoking exposure (p=0.08) and time-weighted average MELD score (p=0.07) demonstrated suggestive associations with ONFH risk. Clinically consequential ONFH after LT may be influenced more by pre-transplant vulnerability and nutritional frailty than by corticosteroid exposure alone. These findings support a vulnerability-based framework for post-transplant ONFH and may help identify recipients who could benefit from heightened clinical awareness and timely diagnostic evaluation when compatible symptoms develop.