Sickle cell disease (SCD) includes a group of hereditary disorders characterized by mutations on the gene that codes hemoglobin (Hb). Patients with SCD are vulnerable to vascular occlusion within bone tissue, which may result in complications such as medullary infarction in the diaphysis and osteonecrosis (ON), which affects the epiphysis. Both processes may result in substantial morbidity and pain for the patients. This study aims to identify factors associated with the development of ON in patients with SCD.

A nested case-control study of patients with SCD from six Brazilian blood centers, participating in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Brazil SCD Cohort was performed. A history of ON was abstracted from participants medical record using standardized definitions to define cases. Cases were matched to controls without ON in a 1:3 ratio matched by age, genotype and blood center using propensity score. A genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms (SNPs) associated with ON.

There were 307 ON cases in the 2793 cohort participants (prevalence 11%) who were compared to 921 controls without ON. The most common locations of ON were the proximal femur (91.2%) and proximal humerus (7.7%). Variables independently associated with ON in a multivariable model included patients with more severe sickle cell disease (SS, Sβ0, severe Sβ+ or SD genotypes, OR 1.81, 95% CI 1.11; 2.95 compared to less severe genotypes SC/SB+), higher values of hemoglobin (OR 1.25, 1.12; 1.39), hospitalization by pain crisis (OR 1.44, 1.06; 1.94), chronic transfusion treatment (OR 1.53, 1.10; 2.11), acute chest syndrome (OR 1.46, 1.06; 2.00), sepsis/bacteremia (OR 1.67, 1.03; 2.70) and osteomyelitis (OR 1.72, 1.05; 2.80). Increased indirect bilirubin and stroke were associated with a lower chance of developing ON (OR 0.81, 0.71; 0.93 for indirect bilirubin and OR 0.42, 0.24; 0.72 for stroke). The GWAS suggested an association of ON with the gene doublesex and mab-3 related transcription factor 2 (DMRT2) (p < 5 × 10−8).

SCD is the most common monogenic disorder in Brazil and is associated with multisystem complications. Orthopedic complications represent 31.0% of these manifestations, with ON being the most common non-infectious joint complication. Knowing the risk factors that precede ON may help to diagnose and treat it early in order to improve the quality of life of patients. The few studies carried out in the Brazilian population on the occurrence of ON in SCD patients had small sample sizes.

A higher chance of having ON was associated with patients with higher hemoglobin levels, more hospitalizations for pain crises and acute chest syndrome. Also the relationship of treatment with chronic transfusion, sepsis/bacteremia and osteomyelitis were associated with ON, which may indicate that the occurrence of this complication may be multifactorial or related to the severity of SCD. SNPs near DMRT2, a gene previously associated with skeletal disorders, rib malformation in a newborn and transition of endochondral bone formation, showed an altered risk for ON.