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 on bone.


OBJECTIVE
To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.


METHODS
A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).


METHODS
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.
Løvås
Kristian
K
Institute of Medicine, University of Bergen, 5020 Bergen, Norway Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway. kristian.lovas@med.uib.no
Gjesdal
Clara G
CG
Christensen
Monika
M
Wolff
Anette B
AB
Almås
Bjørg
B
Svartberg
Johan
J
Fougner
Kristian J
KJ
Syversen
Unni
U
Bollerslev
Jens
J
Falch
Jan A
JA
Hunt
Penelope J
PJ
Chatterjee
V Krishna K
VK
Husebye
Eystein S
ES
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000224:Addison Disease / Q000188:drug therapy* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics / Q000502:physiology; D006113:United Kingdom; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D006854:Hydrocortisone