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Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone
Kristian Løvås1, Clara G Gjesdal, Monika Christensen
1Institute of Medicine, University of Bergen, 5020 Bergen, Norway Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway. kristian.lovas@med.uib.no
Unlabelled:
Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.
Objective:
To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.
Design, Setting And Participants:
A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).
Main Outcome Measures:
Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity.
Results:
Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine.
Conclusions:
BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.
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