11ß-Hydroxysteroid Dehydrogenase Type 1 Activity Predicts the Effects of Glucocorticoids on Bone
Mark S. Cooper,
Aubrey Blumsohn,
Philippa E. Goddard,
William A. Bartlett,
Cedric H. Shackleton,
Richard Eastell,
Martin Hewison and
Paul M. Stewart
Division of Medical Sciences (M.S.C., M.H., P.M.S.), University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom; Bone Metabolism Group (A.B., R.E.), University of Sheffield, Sheffield S5 7AU, United Kingdom; Department of Clinical Biochemistry and Immunology (P.E.G., W.A.B.), Birmingham Heartlands and Solihull NHS Trust, Birmingham B9 5SS, United Kingdom; and Children’s Hospital Oakland Research Institute (C.H.S.), Oakland, California 94609
Address all correspondence and requests for reprints to: Prof. Paul M. Stewart, M.D., F.R.C.P., F.Med.Sci., Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom E-mail: p.m.stewart{at}bham.ac.uk.
Individual susceptibility to glucocorticoid-induced osteoporosisis difficult to predict clinically. We recently characterizedexpression of 11ß-hydroxysteroid dehydrogenase type1 (11ß-HSD1) in human osteoblasts. This enzyme generatesactive cortisol (or prednisolone) from inactive cortisone (orprednisone) and regulates glucocorticoid action in vitro. We,thus, hypothesized that osteoblastic 11ß-HSD1 mediatessusceptibility to glucocorticoid-induced osteoporosis. Twentyhealthy males ingested 5 mg prednisolone twice daily for 7 d,and relationships between changes in bone turnover markers andurinary measures of corticosteroid metabolism were examined.The bone formation markers osteocalcin and N-terminal propeptideof type I collagen decreased in all subjects (P < 0.001),but resorption markers were unchanged. The extent of fall information markers correlated with baseline 11ß-HSD1activity with high activity predicting the greatest fall [forosteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); forN-terminal propeptide of type I collagen d 4, r = -0.51 (P <0.05)]. There was no correlation with measures of glucocorticoidinactivation or total corticosteroid metabolite production.Urinary measures of 11ß-HSD1 activity predict theresponse of bone formation markers to glucocorticoids, and thisappears to reflect increased generation of active glucocorticoidswithin osteoblasts. Measures of 11ß-HSD1 activitymay predict individual susceptibility to glucocorticoid-inducedosteoporosis, and these data should facilitate the developmentof bone-sparing glucocorticoids.
This work was supported by the Peel Medical Research Trust andthe Medical Research Council, United Kingdom, and was conductedin a Wellcome Trust Clinical Research Facility.
Abbreviations: BMD, Bone mineral density; ßCTX, ß-cross-linkedC-telopeptide of type I collagen; CV, coefficient of variation;11ß-HSD, 11ß-hydroxysteroid dehydrogenaseenzyme; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenasetype 1; OC, osteocalcin; PINP, N-terminal propeptide of typeI collagen; (THF+alloTHF)/THE ratio, tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisoneratio; UFF/UFE ratio, urinary-free cortisol/cortisone ratio.
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