Steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy

Aim: We investigated the effect of massive doses of corticosteroid therapy on bone metabolism using specific biochemical markers of bone metabolism, and the prevalence of osteonecrosis in severe acute respiratory syndrome (SARS) patients at a university teaching hospital in Hong Kong. Methods: Seventy-one patients with a clinical diagnosis of SARS were studied according to the modified World Health Organization case definition of SARS who were involved in the SARS epidemic between 10 March and 20 June 2003. The clinical diagnosis was confirmed by serological test and/or molecular analysis. Biochemical markers of bone metabolism were analysed retrospectively using serial clotted blood samples collected from each patient during the course of hospital admission to discharge and subsequent follow-up at out-patient clinic using the arbitrary time periods: (i) Day < 10; (ii) Day 28-44; (iii) Day 51-84; and (iv) Day > 90 after the onset of fever. Magnetic resonance imaging of the knee and hip joints were performed post-admission to evaluate the prevalence of osteonecrosis amongst these SARS patients. Various risk factors for the development of osteonecrosis were assessed using receiver operating characteristics curve comparison with appropriate test statistics and Spearman's coefficients of rank correlation with biochemical bone markers. Results: Biochemical markers of bone metabolism showed significant bone resorption as evidenced by a marked increase in serum C-terminal telopeptide concentration (CTx) from Day 28-44 after the onset of fever. With tapering down of corticosteroid dosage, CTx started to return to previous baseline level from Day 51 onwards, while other bone formation markers, serum osteocalcin and bone-specific alkaline phosphatase concentrations (OC and BALP, respectively), started to increase. The latter effect was even more marked after Day > 90. Seven patients developed radiological evidence of osteonecrosis. The prevalence of osteonecrosis in this cohort was 9.9%. A total corticosteroid dosage of > 1900mg hydrocortisone, > 2000mg methylprednisolone, > 13 340mg hydrocortisone-equivalent corticosteroid therapy, and > 18 days on corticosteroid therapy were found to be significant risk factors for the subsequent development of osteonecrosis. There were also significant positive correlations amongst various biochemical bone markers in this patient cohort. Conclusions: Both bone resorption and formation markers were unable to predict the subsequent development of osteonecrosis. The use of high dose of hydrocortisone or methylprednisolone for an extended duration was shown to be a significant risk factor for osteonecrosis. Its prevalence in this cohort is comparable to those reported in the literature for SARS patients with high-dose corticosteroid therapy. The Day 28-44 increase in the serum CTx coincided with the timing of corticosteroid use. The Day > 51 increase in serum OC and BALP coincided with the timing of corticosteroid withdrawal.