Glucocorticoid receptor polymorphisms and bone mineral density in patients receiving conventional glucocorticoid replacement.

INTRODUCTION

Addison's disease (AD) requires lifelong glucocorticoid (GC) replacement; however, long-term GC excess may lead to adverse effects, including osteoporosis. Former studies of bone mineral density (BMD) in AD revealed discrepant results, possibly due to variable individual sensitivity of the glucocorticoid receptor gene (NR3C1) variants. This study was designed to evaluate whether the NR3C1 polymorphisms rs6195, rs41423247, and rs6189/rs6190 might influence BMD in AD patients receiving standard steroid replacement.

MATERIAL AND

METHODS

Molecular analyses of three NR3C1 polymorphisms were performed in 178 AD patients (46 males, 132 females) treated for 15.4 ± 10.9 years, using the PCR-RFLP method and real-time polymerase chain reaction (PCR). Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). Additionally, retrospective bone scans were available for 89 individuals.

RESULTS

All subjects were receiving hydrocortisone (mean dose 24.4 ± 5.6 mg/day). Postmenopausal women displayed significantly lower BMD Z-scores than premenopausal females and males (p = 0.0162 for LS, p = 0.0201 for FN). Osteopenia was found in LS and FN in 32.6% and 37.3% patients, respectively, while osteoporosis was prevalent in postmenopausal women (23.2% in LS, 13.9% in FN). Carriers of rs6195 presented lower Z-scores in LS (p = 0.022), but not in FN (p = 0.072). Nonetheless, Z-score changes in either location were not affected by rs6195 (p > 0.05). In multiple linear regression only gender (p = 0.026), age (p < 0.001), and body mass (p = 0.011) correlated with BMD at LS, whereas disease duration, rs6195, and GC dose lost significance.

CONCLUSION

our study did not confirm a significant association of NR3C1 polymorphisms with BMD in AD patients receiving long-term GC replacement. Currently recommended GC substitution doses seem less harmful to bone, but prospective analyses in larger cohorts of patients are warranted.