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

Context: Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production. raising concern about adverse effects oil 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 front 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 (959% 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=0.0.15), 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 15-25mg 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.