Statin Prevents Steroid-induced Osteonecrosis of the Femoral Head

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  • WANG Gwo-Jaw
    Department of Orthopedics Surgery, University of Virginia Department of Orthopedics Surgery, National Cheng-Kung University
  • CHEN Chung-Hwan
    Departments of Orthopaedics and Orthopaedic Research Center, Kaohsiung Medical University

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Nontraumatic osteonecrosis (ON) is related to alcohol consumption and glucocorticoid treatment and is of unknown pathogenesis. Numerous risk factors associated with nontraumatic ON include corticosteroid treatment, alcoholism, smoking, hyperlipidemia, and hyperviscosity. Steroids cause increased fat cell size and volume, and this might be one of the mechanisms of osteonecrosis. On exposure to dexamethasone, cloned murine D 1 pluripotent bone marrow cells accumulated lipid vesicles that were small initially but increased in size with time. The number of adipocytic cells in culture was correlated with the concentration of dexamethasone and with the time of treatment. Treatment of D1 cells with lovastatin, which was added to culture dishes before or at the same time as dexamethasone, decreased the appearance of fat cells. The adipogenic mRNA expression of 422 (aP2) was increased by dexamethasone and decreased by lovastatin. Chickens develop adipogenesis and osteonecrosis when given steroids, but these phenomena are reversed by treatment with lovastatin. We obtained bone marrow stromal cells (BMSCs) from 10 patients with ethanol-induced osteonecrosis, 10 patients with glucocorticoid-induced osteonecrosis, and 12 patients without osteonecrosis as control subjects; third-passage cells were checked for osteogenic and adipogenic gene expression and differentiation ability. BMSCs from patients with glucocorticoid-induced osteonecrosis exhibited low osteogenic gene expression and low osteogenic differentiation, whereas BMSCs from patients with ethanol-induced osteonecrosis possessed high adipogenic gene expression and high adipogenic differentiation. Dysfunction of BMSCs may be one of the causes of osteonecrosis, with ethanol-induced osteonecrosis and glucocorticoid-induced osteonecrosis having different types of dysfunction. Glucocorticoids may possess a more suppressive effect on osteogenesis than ethanol, whereas ethanol may possess a more potent adipogenic effect than glucocorticoids on BMSCs. These results of human cell studies are compatible with previous studies reporting that glucocorticoids suppress BMP gene expression in rodent marrow progenitor cells, whereas lovastatin can reverse the suppressive effects of dexamethasone on BMP-2 gene expression. Our study confirms that higher susceptibility to the suppression of osteogenic gene expression by glucocorticoid exists in the marrow stroma cells of patients with ON. This finding may explain why some patients develop ON after glucocorticoid treatment, whereas others do not.

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