BACKGROUND: A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT) , and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies. OBJECTIVE: Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center. METHODS: Longitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment. RESULTS: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001). CONCLUSIONS: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT, developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization. Funding: LSD Training Fellowship from Sanofi to MB.

PKM receives a research grant from Sanofi and has received travel support from Sanofi. LG and KK are employees of Sanofi and may hold stocks.

PKM receives a research grant from Sanofi and has received travel support from Sanofi. LG and KK are employees of Sanofi and may hold stocks. MB is supported by Lysosomal Disease Fellowship from Sanofi.

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Our observational study is approved by Yale's Human Investigation Committee HIC#0209021074 HIC#1005006783

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All data used for this study have been collected from patients' electronic medical records (EMR) and due to patient privacy and Health Insurance Portability and Accountability Act (HIPPA) we are not allowed to share patients' data. The main barrier for us is that for example patient identity would be identifiable based on the constellation of a specific Gaucher genotyping, age, gender, type of treatment, etc. therefore, we are only able to provide patients' data after Yale's IRB approval and re-consenting the patients. For interested researchers and academic physician investigators we can provide Excel sheet of our dataset with numbers used to plot the graphs and charts in our manuscript upon request. They can directly reach out to the corresponding author Dr. Pramod Mistry.