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

Abstract

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 (nZ187) and from UK and New Zealand (nZ105). 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 K0.28 (95% confidence intervals (CI) K0.42, K0.16); UK and New Zealand: K0.21 (95% CI K0.36, K0.06)). Lumbar spine Z-scores were reduced (Norway: K0.17 (K0.36, C0.01); UK and New Zealand: K0.57 (K0.78, K0.37)), and significantly lower in males compared with females (PZ0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CTOTT PZ0.015), 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 15-25mg 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.

Body composition and bone mineral density in women with Cushing's syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity

“…In our study, the Bcl1 polymorphism in the GC receptor gene was associated with reduced BMD in total body and femur neck, which is in line with a study of patients with active CS (17) and other studies demonstrating increased GC sensitivity in subjects carrying this genotype (33,34,35). A common polymorphism (rs1045642) in the ABCB1 gene was recently found to be associated with reduced bone mass in patients with Addison's disease (22). The gene encodes for a transport protein that is important for efflux of intracellular GC (36).…”

“…Five single-nucleotide polymorphisms (SNPs) in four genes were analysed; Bcl1 (rs41423247) and A3669G (rs6198) in the NR3C1 gene, I180V (rs5522) in the NR3C2 gene, rs11119328 in the HSD11B1 gene and rs1045642 in the ABCB1 gene. The selection of the candidate genes was based on their previously described effects on GC sensitivity (16,17,18,19,20,21,22). Due to the limited size of our cohort, we chose only SNPs with a minor allele frequency (MAF) O10% in the HapMap CEU Panel.…”

“…In patients with active CS, BclI is associated with reduced BMD (17) and A3669G, with a decreased risk of developing diabetes mellitus (18). In addition, polymorphisms in the genes coding for the mineralocorticoid receptor (NR3C2) (19), 11b-hydroxysteroid dehydrogenase type 1 (HSD11B1) (20,21) and ATP-binding cassette B1 (ABCB1) (22) may also be important for GC sensitivity. Recently, we have demonstrated that polymorphisms in the HSD11B1 and NR3C1 genes are associated with impaired cognitive function in patients with CS in remission (23).…”

Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients

“…The majority of available studies have been carried out in subjects with primary adrenal failure, with some studies finding a reduced bone mineral density (BMD) in men with increasing hydrocortisone (HC) equivalent doses (7,8) and a lower femoral neck BMD correlated with weight-adjusted GC dose (9), while others have found no difference in BMD compared with that of the control population (10,11), except in subjects on prednisolone, in whom a significant decrease in BMD was observed (12).…”

Skeletal fragility induced by overtreatment of adrenal insufficiency

“…So far the number of studies on fractures in patients on glucocorticoid and mineralocorticoid replacement therapy has been very limited [2,3,[6][7][8]. An article published in this issue of Endocrine by Camozzi et al adds some important data on glucocorticoid and mineralocorticoid replacement on bone health [9].…”