A validated disease severity scoring system predicts risk of fractures in treated adults with type 1 Gaucher disease

Abstract

Aim: Gaucher disease type 1 (GD1) is a lysosomal storage disorder associated with heterogeneous systemic and skeletal manifestations. Fragility fractures remain an important source of morbidity, even after initiation of enzyme replacement therapy (ERT). Validated tools to predict fracture risk in treated patients are limited.

Methods: We retrospectively analyzed 133 adult patients with GD1who were enrolled in a previously published Disease Severity Scoring System (DS3) validation study (NCT01136304). 132 ERT-treated patients were included in fracture-free survival analyses from which the one miglustat-treated patient was excluded. Baseline DS3 scores and Gaucher Risk Assessment for Fracture (GRAF) scores were calculated at treatment initiation. Fracture-free survival was assessed using Kaplan-Meier analysis, and predictive performance was evaluated using receiver operating characteristic (ROC) analysis, including combined DS3+GRAF models and Cox proportional hazards regression with age included as a continuous variable.

Results: Thirty-three patients (24.8%) experienced at least one fragility fracture during follow-up. Patients with fractures were older at treatment initiation, had longer delays between diagnosis and treatment, higher baseline DS3 and GRAF scores, and were more likely to have undergone splenectomy. For GRAF tertiles, the overall uncorrected log-rank test was significant, but Holm-corrected pairwise comparisons were not. ROC analysis showed that both the baseline DS3 score and the GRAF score moderately predicted fracture risk [area under the curve (AUC) ~0.76, 0.66 respectively]. The combined model modestly enhanced predictive performance, particularly in adults treated before age 50. The age-adjusted DS3 Cox model demonstrated a C-index of 0.80, compared with 0.78 for the age-adjusted GRAF model. Inclusion of both scores together resulted in only minimal improvement in discrimination (C-index 0.80), suggesting limited incremental predictive value of combining the two measures.

Conclusions: Pre-treatment baseline DS3 is a modestly stronger predictor of fracture risk in patients on ERT than GRAF score (Kaplan-Meier), GD1 severity itself contributes to skeletal fragility beyond the effect of aging alone (COX), and inclusion of both scores together resulted in only minimal improvement in discrimination (ROC, C-index comparison).

In clinical practice, DS3 may be preferred for baseline risk stratification, while GRAF may retain value in settings where full DS3 assessment is not feasible. Because many other fracture risk variables are not included either in DS3 or GRAF, both should be interpreted as complementary rather than stand-alone predictive tools. Reliance on dual-energy X-ray absorptiometry (DXA)-derived bone mineral density alone as a surrogate for fracture risk warrants reassessment.

Keywords

Gaucher disease / DS3 / severity score / GRAF score / enzyme replacement therapy / Gaucher bone disease / fragility fracture / fracture-free survival

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