Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone

Abstract

ContextPatients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.ObjectiveTo determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.Design, setting and participantsA cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).Main outcome measuresBone mineral density (BMD) was measured; theZ-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.ResultsFemoral neck BMDZ-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 spineZ-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 commonP-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TTP=0.015), with a similar trend at the hip and spine.ConclusionsBMD 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 transporterP-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.