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)
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
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, 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
- Powell C, Chang C, Naguwa S, et al.
Steroid induced osteonecrosis: an analysis of steroid dosing risk. Autoimmunity
- Seamon J, Keller T, Saleh J, Cui Q. The
pathogenesis of nontraumatic osteonecrosis. Arthritis 2012;2012:601763.
- Assouline-Dayan Y, Chang C, Greenspan A,
et al. Pathogenesis and natural history of osteonecrosis. Sem Arth Rheum
- Weinstein RS. Glucocorticoid-induced
osteonecrosis. Endocrine April 2012;41(2):183-90.
- 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.
- 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.
- Drescher W, Schlieper G, Floege J.
Steroid-related osteonecrosis-an update. Nephrol Dial Transplant
- Mankin HJ. Nontraumatic necrosis of bone
(osteonecrosis). N Engl J Med 1992;326(22):1473-79.
- Shoback D, Sellmeyer D. Greenspan's basic
and clinical endocrinology. 9th ed. New York: McGraw-Hill;2011. Chapter 8.
Metabolic bone disease. 2011.
- 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.
- 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.