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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 osteoporosis is difficult to predict clinically. We recently characterized expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-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 11ß-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 11ß-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 11ß-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.
This work was supported by the Peel Medical Research Trust and the Medical Research Council, United Kingdom, and was conducted in a Wellcome Trust Clinical Research Facility.
Abbreviations: BMD, Bone mineral density; ßCTX, ß-cross-linked C-telopeptide of type I collagen; CV, coefficient of variation; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase enzyme; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; OC, osteocalcin; PINP, N-terminal propeptide of type I collagen; (THF+alloTHF)/THE ratio, tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ratio; UFF/UFE ratio, urinary-free cortisol/cortisone ratio.
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