Researchers identified associations between the bone morphogenetic protein 6 (BMP6), Klotho (KL), and annexin A2 (ANXA2) polymorphisms and avascular necrosis (AVN) in patients with sickle cell disease (SCD), as published in Revista Paulista de Pediatria.

The review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and covered 12 studies between 1998 and 2016 that evaluated 2362 patients.

“Understanding that bone involvement is an important factor in the worsening of individuals with SCD, identifying specific potential biomarkers can improve the prognostic mechanisms in the course of treatment,” the authors wrote.

“Based on the articles included in this review, the researched data associated AVN in SCD with polymorphisms in the BMP6, KL and ANXA2 genes, which are involved in bone metabolism.”

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AVN is a consequence of the vaso-occlusive crises experienced by patients with SCD. The research team identified polymorphisms that are involved in bone function in various ways. BMP6 is involved in bone formation via the growth and differentiation of chondrocytes and osteoblasts.

The KL gene regulates vitamin D levels by controlling ion channels and endocrine pathways and also induces the production of nitric oxide. ANXA2 regulates processes involved in homeostasis and contributes to bone mineralization.

The research team noted that only one of the studies reviewed identified a possible association between the MTHFR enzyme and osteonecrosis in patients with SCD. Given that various studies have investigated this issue with conflicting results, the authors were unable to reach a conclusion regarding this enzyme. However, the clear identification of BMP6, Klotho, and ANXA2 as biomarkers of AVN will help differentiate those patients at high risk for osteonecrosis and aid clinicians in determining prognosis and treatment.


Leandro MP, Almeida ND, Hocevar LS, de Sá CKC, de Souza AJ, Matos MA. Polymorphisms and avascular necrosis in patients with sickle cell disease – a systematic review. Rev Paul Pediatr. 2022;40:e2021013. doi:10.1590/1984-0462/2022/40/2021013IN