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

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.