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Risk Factors and Mechanism for Steroid Induced Avascular Necrosis of the Femoral Head

Summary:

  • Acute vascular necrosis (AVN) is a complication of steroid therapy occurring in up to 40% of patients and accounts for a large percentage of total hip arthroplasties performed at a relatively young age.
  • Many patients who present with AVN have conditions that increase their baseline risk, including systemic lupus erythematous and renal transplant, making it difficult to determine the exact impact of steroid therapy in the disease pathophysiology.
  • AVN is associated with high-dose oral or intravenous therapy exceeding 20 mg of prednisone per day for extended periods of time.  There is also a cumulative dose risk that has not yet been clearly defined.
  • Evidence suggests a multifactorial process that results from an imbalance in bone resorption and repair, compromise of vasculature, and both direct and indirect bone cell apoptosis.

Author: Desiree Kosmisky, PharmD
Editor-in-Chief:
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors:
Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed:
August 2015

Explanation

  • Avascular necrosis (AVN) of the femoral head, also referred to as osteonecrosis or aseptic necrosis, is a well-recognized and often devastating complication related to glucocorticoid administration.(1) Avascular necrosis occurs in 3 to 40% of patients receiving corticosteroid treatment and occurs most frequently in the femoral head, which is hypothesized to be a result of the limited blood supply to this area.(1-7)  This adverse effect is caused by death of bone tissue in the femoral head, which often leads to pain, impaired mobility, fractures, and in 80% of untreated cases, collapse of the femoral head leading to necessitation of total hip arthroplasty.(2)  Currently, 10,000 to 20,000 cases occur per year in the United States, and steroid-related AVN accounts for 10% of the total hip arthroplasties performed each year. The average age at presentation is 33 years old, with a male to female ratio of 7:3.(1,4,5)

    Risk Factors:

    Avascular necrosis is most frequently associated with high doses of oral and intravenous steroids and prolonged duration of therapy; although, cases have been observed with short-term courses of high-dose steroids, single doses of intra-articular or intravenous injections, and administration of topical or inhaled corticosteroids.(1,4-6) A meta-analysis of 22 studies conducted in 1987 by Felson and Anderson suggested a 4.6-fold increase in the incidence of AVN with each 10 mg/day increase in prednisone therapy in the first 6 months of corticosteroid therapy.1,5  Most studies have found an increased risk of AVN in patients receiving greater than 20 mg of prednisone per day.(1,2,6)  Cumulative dose limits have not been established.

    Mechanism of Steroid-Induced AVN:

    Osteoblasts, responsible for bone formation, are the precursors of osteocytes, which are known to be mature bone cells.(8)  Osteoblasts stimulate the formation and activation of osteoclasts, which are responsible for resorption of osteocytes.  Homeostasis within the bone represents a balance between the activity of osteoclasts and osteoblasts.  In repair of necrotic bone, blood supply must first extend to the damaged bone through angiogenesis, which is then followed by resorption of the compromised bone and formation of new bone.(3-5) 

    As such the mechanisms of steroid-induced AVN can be classified into 3 broad categories which exist in a complex interplay: an imbalance of bone resorption and repair, impairment of vasculature within the bone, and apoptosis.(3-5,10,11)

    The Details For Those Interested:

    • Imbalance of Bone Resorption and Rebuilding:
      • Differentiation of bone marrow cells becomes skewed towards adipogenesis rather than osteogenesis in the presence of steroid therapy.(3-5,11)  This is due to an upregulation of the transcription factor peroxisome proliferator activated receptor-γ (PPAR-γ), which promotes adipogenesis, and down regulation of Runx2/core-binding factor a1 (Cbfa1), which regulates osteoblast differentiation and maturation.(4,11)  This mechanism directly reduces the number of bone precursor cells, which ultimately leads to a decrease in bone remodeling.  Existing adipocytes have also been noted to hypertrophy.(3-5,11)  Adipogenesis and adipocyte hypertrophy have been implicated in vascular impairment and apoptosis as discussed below.  Bone homeostasis is further disrupted by increasing Dickkopf-1 concentrations, which agonize the activity of osteoclasts and antagonize the activity of osteoblasts.(11)
      • Risk factors for AVN include conditions associated with hypercoagulability, alcoholism, systemic lupus erythematous, acute lymphoplasmocytic leukemia, and organ transplantation. These conditions place the patient at increased risk for AVN prior to the initiation of steroids.(1-3, 6) 
    • Vascular Impairment:
      • Epiphyseal arteries that branch from the medial circumflex artery provide limited blood flow to the femoral head and are subject to compromise by a variety of factors.(3)  Vascular endothelial growth factor, responsible for angiogenesis and bone repair, is decreased by up to 45% in the presence of steroids.(3,5)  Vascular impairment has also been noted due to fat emboli and direct compression of arteries due to increased intraosseal pressure from adipogenesis and adipocyte hypertrophy.  Thrombi may also cause occlusion of the vasculature due to increased thrombin production and decreased fibrinolytic activity.  Finally, hypertension, a well-known effect of steroid therapy, may lead to epiphyseal artery constriction and damage, ultimately reducing or eliminating blood supply to the femoral head.(3,5)  Several factors have been implicated in vasoconstriction and hypertension, including decreased production of the vasodilators prostaglandin and nitric oxide as well as increased production of and response to the vasoconstrictors angiotensin II and endothelia.
    • Apoptosis:
      • Apoptosis, or programmed cell death, of osteoblasts and osteocytes is mediated both directly through steroid interactions with the glucocorticoid receptor and indirectly through vascular compromise leading to ischemia and cell compression due to adipogenesis and increased intraosseal pressure.(3-5,10,11)  Death of mature bone cells and their progenitors further drives the imbalance of bone remodeling.


    References:

    1. Powell C, Chang C, Naguwa S, et al. Steroid induced osteonecrosis: an analysis of steroid dosing risk. Autoimmunity Rev 2010;9:721-43.
    2. Seamon J, Keller T, Saleh J, Cui Q. The pathogenesis of nontraumatic osteonecrosis. Arthritis  2012;2012:601763.
    3. Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Sem Arth Rheum 2002;32(2):94-124.
    4. Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine April 2012;41(2):183-90.
    5. Kerachian MA, Séguin C, Harvey EJ. Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem and Mol Bio 2009;114:121-28.
    6. Aaron RK, Voisinet A, Racine J, et al. Corticosteroid-associated avascular necrosis: dose relationships and early diagnosis. Ann NY Acad Sci 2011;1240;38-46.
    7. Drescher W, Schlieper G, Floege J. Steroid-related osteonecrosis-an update. Nephrol Dial Transplant 2011;26:2728-2731.
    8. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med 1992;326(22):1473-79.
    9. Shoback D, Sellmeyer D. Greenspan's basic and clinical endocrinology. 9th ed. New York: McGraw-Hill;2011. Chapter 8. Metabolic bone disease. 2011.
    10. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 2000;85(8):2907-2912.
    11. Tan G, Kang P, Pei F. Glucocorticoids affect the metabolism of bone marrow stromal cells and lead to osteonecrosis of the femoral head: a review. Chin Med J 2012;125(1):134-139.

MESH Terms & Keywords

  • Steroid Induced Avascular Necrosis, Avascular Necrosis Hip, Glucocorticoid Induced Avascular Necrosis, Prednisone, Dexamethasone, Methylprednisolone