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

• Published in: European journal of endocrinology Vol. 160; no. 6; pp. 993 - 1002
• Main Authors: Løvås, Kristian, Gjesdal, Clara G, Christensen, Monika, Wolff, Anette B, Almås, Bjørg, Svartberg, Johan, Fougner, Kristian J, Syversen, Unni, Bollerslev, Jens, Falch, Jan A, Hunt, Penelope J, Chatterjee, V Krishna K, Husebye, Eystein S
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.06.2009
• Subjects: Addison Disease - drug therapy; Addison Disease - genetics; Adolescent; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Aged; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Bone and Bones - metabolism; Bone Density; Clinical Study; Cohort Studies; Cross-Sectional Studies; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Glucocorticoids - therapeutic use; Hormone Replacement Therapy - methods; Humans; Hydrocortisone - therapeutic use; Male; Medical sciences; Middle Aged; New Zealand; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pharmacogenetics; Polymorphism, Genetic - genetics; Polymorphism, Genetic - physiology; United Kingdom; Vertebrates: endocrinology; Young Adult; Endocrinopathy; Osteoarticular system; Pharmacogenetics; Replacement therapy; Adrenal insufficiency; Addison disease; Hypocorticism; Adrenal cortex diseases; Adrenal gland diseases; Genetics; Bone; Endocrinology
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-08-0880

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; 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.ResultsFemoral 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.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 transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.