11beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone.
Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. We recently characterized expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in human osteoblasts. This enzyme generates active cortisol (or prednisolone) from inactive cortisone (or prednisone) and regulates glucocorticoid action in vitro. We, thus, hypothesized that osteoblastic 11beta-HSD1 mediates susceptibility to glucocorticoid-induced osteoporosis. Twenty healthy males ingested 5 mg prednisolone twice daily for 7 d, and relationships between changes in bone turnover markers and urinary measures of corticosteroid metabolism were examined. The bone formation markers osteocalcin and N-terminal propeptide of type I collagen decreased in all subjects (P < 0.001), but resorption markers were unchanged. The extent of fall in formation markers correlated with baseline 11beta-HSD1 activity with high activity predicting the greatest fall [for osteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); for N-terminal propeptide of type I collagen d 4, r = -0.51 (P < 0.05)]. There was no correlation with measures of glucocorticoid inactivation or total corticosteroid metabolite production. Urinary measures of 11beta-HSD1 activity predict the response of bone formation markers to glucocorticoids, and this appears to reflect increased generation of active glucocorticoids within osteoblasts. Measures of 11beta-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.
Cooper
Mark S
MS
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom.
Blumsohn
Aubrey
A
Goddard
Philippa E
PE
Bartlett
William A
WA
Shackleton
Cedric H
CH
Eastell
Richard
R
Hewison
Martin
M
Stewart
Paul M
PM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000328:Adult; D015415:Biomarkers; D015519:Bone Density; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D008297:Male; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011239:Prednisolone / Q000097:blood; D013256:Steroids / Q000097:blood / Q000652:urine
D015415:Biomarkers; D005938:Glucocorticoids; D013256:Steroids; D011239:Prednisolone; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human