The role of local corticosteroid generation in inflammation-associated bone loss
MS Cooper1, A Filer2, J Moore1, P Emery3, CD Buckley2, M Hewison1 & PM Stewart1
Generalised and periarticular osteoporosis are common features of inflammatory arthritides. These effects appear due to high levels of pro-inflammatory cytokines. 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an intracellular enzyme that generates active cortisol from inactive cortisone and is an important determinant of the effects of glucocorticoids on osteoblasts. In vitro, osteoblastic 11b-HSD1 expression is induced by pro-inflammatory cytokines. We thus hypothesised that inflammation-associated bone loss may reflect a localised form of corticosteroid-induced osteoporosis. Corticosteroid metabolism was examined in patients presenting with early rheumatoid arthritis (RA) (age 59+/-13 (mean+/-SD), n=31) or mechanical, non-inflammatory, joint conditions (n=9). Subjects had not received glucocorticoids or bone active medications. Serum markers of inflammation and clinical measures of disease severity were measured. Corticosteroid metabolite profiles were determined by gas chromatography/mass spectrometry on urine samples giving measures of total corticosteroid metabolite excretion, 11b-HSD1 activity (THF+alloTHF/THE ratio), 11b-HSD2 (urinary free cortisol/cortisone (UFF/UFE)) and 5alpha-reductase activity (THF/THE).
The THF+alloTHF/THE ratio (indicating 11b-HSD1 activity) was significantly increased in patients with RA compared with controls (1.54+/-0.08 (mean+/-SE) vs 1.20+/-0.11; p<0.05). There was no difference in total corticosteroid metabolite production, 11b-HSD2 or 5alpha-reductase activity. Amongst patients with RA, significant correlations between inflammatory markers and 11b-HSD1 activity were found with high inflammatory markers predicting increased 11b-HSD1 activity (r=0.40 for ESR, r=0.39 for CRP, both p<0.05). In contrast, there was no correlation of inflammatory markers with corticosteroid metabolite excretion or 5alpha-reductase activity. Cortisol/cortisone ratios in synovial fluid samples obtained from 5 subjects with RA were substantially elevated (4.5+/-1.4) suggesting local glucocorticoid generation.
11b-HSD1 activity is elevated in patients with early untreated RA and increases with disease activity. This activity appears to reflect local generation of active corticosteroids from circulating inactive precursors. Increased 11b-HSD1 activity and thus chronic local corticosteroid excess may account for the periarticular and generalised osteoporosis seen in RA.