Avascular necrosis of the femoral head (ANFH) occurs when the blood supply to the femoral head is interrupted resulting in ischemia, death of the bone cells, and bone collapse.

Non-traumatic ANFH is a serious and common problem that can occur when patients are on glucocorticoid (GC) therapy; between 5-40% of patients treated with long-term glucocorticoid therapy will develop ANFH.

Although, the exact and complete mechanism of ANFH due to GC therapy is still under determination, a few mechanisms have been proposed.

1. Hypercoagulable Conditions 

It is thought that GCs can alter endothelial function by modulation of the Alpha-2-

Image credit: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507066/

Macroglobulin (A2M)* gene and also by exerting effects on thrombosis formation. It is believed that through A2M and thromobosis formation alterations, GCs cause ischemia which ultimately results in ANFH.

A2M: a protein that plays a role in thrombosis by influencing inflammation, cell shedding, inhibiting fibrinolysis, and hemostatic plug formation.

 

2. Angiogenesis Suppression

It is hypothesized that angiogenesis is interrupted in patients with ANFH, however, the complete mechanism is not well understood.

Studies have shown that there is a relationship between ANFH and expression of VEGF. VEGF plays a key role in stimulating angiogenesis, but is also important in bone formation and repair. It has also been shown that when bone tissue undergoes VEGF gene transfection, the processes of angiogenesis and bone repair in necrotic bone are stimulated. These studies suggest that there is a correlation between use of GCs and angiogenesis suppression, however it remains to be more completely elucidated.

 

3. Increased Adipogenesis 

Although, the link between increased adipogenesis and long-term use of GCs is not completely understood, studies have shown the presence of an association.

Kim et al. (2008) looked at the association between sterol regulatory element binding factor (SREBP-2) gene polymorphisms and the risk of ANFH in the Korean population. SREBPs play a role lipogenesis, cholesterol homeostasis, and adipocyte development. In 2009, a study by Lee et al. showed that a polymorphism in intron 7 of the SREBP-1 gene was associated with increased likelihood of ANFH. Although, the relationship is still unclear, these studies do suggest the possibility of alterations in adipogenesis by GC therapy.

 

4. Bone Remodelling Shifting to Bone Resorption 

Bone morphogenetic proteins (BMPs) are proteins that are important in maintaining bone density through remodelling and repair processes. BMPs act as signals, or differentiating factors, which help convert mesenchymal cells into cells involved in forming bone and cartilage. Studies have shown that transfecting bone marrow stem cells with the human BMP-2 gene can repair early-stage ANFH. The results of these studies suggest that in ANFH, bone remodelling and repair may be altered by the use of GCs.

Image credit: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507066/

 

REFERENCES

  1. Pouya, Farzaneh, and Mohammed Amin Kerachian. “Avascular Necrosis of the Femoral Head: Are Any Genes Involved?” The Archives of Bone and Joint Surgery 3.3 (2015): 149-55.
  2. Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, et al. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev. 2013;24(3):297–310.
  3. Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest. 2002;110(6):751–9.
  4. Samara S, Dailiana Z, Varitimidis S, Chassanidis C, Koromila T, Malizos KN, et al. Bone morphogenetic proteins (BMPs) expression in the femoral heads of patients with avascular necrosis. Mol Biol Rep. 2013;40(7):4465–72.
  5. Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012;41(2):183–90.
  6. Kim TH, Baek JI, Hong JM, Choi SJ, Lee HJ, Cho HJ, et al. Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population. BMC Med Genet. 2008;9:94.
  7. Lee HJ, Choi SJ, Hong JM, Lee WK, Baek JI, Kim SY, et al. Association of a polymorphism in the intron 7 of the SREBF1 gene with osteonecrosis of the femoral head in Koreans. Ann Hum Genet. 2009;73(1):34–41.
  8. Cao K, Huang W, An H, Jiang DM, Shu Y, Han ZM. Deproteinized bone with VEGF gene transfer to facilitate the repair of early avascular necrosis of femoral head of rabbit. Chin J Traumatol. 2009;12(5):269–74.

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