Estrogen Receptor (ER) Gene Polymorphism May Predict the Bone Mineral Density Response to Raloxifene in Postmenopausal Women on Chronic Hemodialysis

Abstract

The estrogen receptor (ER) gene has been considered as a candidate genetic marker for osteoporosis, and PvuII and XbaI polymorphisms of the ERalpha gene have been associated with low bone mineral density (BMD). We investigated whether ER polymorphism could predict the response of BMD in 28 postmenopausal women on hemodialysis with marked osteopenia or osteoporosis, randomized to receive raloxifene, a selective estrogen receptor modulator (SERM), or placebo for 1 year. BMD was assessed by dual X-ray absorptiometry and PvuII and XbaI restriction fragment-length polymorphism of the ER gene was determined using polymerase chain reaction. Baseline lumbar spine or femoral neck BMD parameters were not different between patients presenting either homozygous PP or xx when compared with heterozygous Pp or Xx genotypes. After 1 year, patients on raloxifene, presenting with PP or xx genotypes (but not those with Pp or Xx), showed a significantly higher mean lumbar spine BMD (0.942 +/- 0.18 vs. 0.925 +/- 0.17 g/cm2, p < .01) and lower serum pyridinoline (19.7 +/- 9.7 vs. 30.6 +/- 16.5 nmol/L, p < .02) when compared with baseline values. No changes were detected in the placebo-treated patients or in the femur neck sites. In conclusion, after 1 year on raloxifene, postmenopausal osteoporotic women on chronic hemodialysis, homozygous for the P or x (PP or xx) alleles of the ER, exhibited a better lumbar spine BMD response and decreased serum pyridinoline values when compared with heterozygous women (Pp or Xx), suggesting that ERalpha allelic variants may explain, at least in part, the different outcomes after treatment of osteoporosis with SERM.

Pharmacogenetics of osteoporosis

“…Very few data [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] are available to date on the pharmacogenetics of osteoporosis. Some major osteoporosis candidate genes, such as those encoding the vitamin D receptor (VDR), estrogen receptors alpha (ERa) and beta (ERb), and collagen I alpha 1 (COL1A1), have been investigated with regard to anti-resorptive drug (i.e., hormone replacement therapy, raloxifene, and bisphosphonates) responses.…”

A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density

“…It has been reported that the TA microsatellite, and several SNPs in intron 1 and other regions of the ER, modulate the skeletal response to hormone replacement therapy both in Asian and European women (30)(31)(32)(33). The AG SNP in intron 1 has also been reported to modulate the BMD response to raloxifene in women on chronic hemodialysis (34). As a matter of fact, the influence of the ER genotype on the body response to endogenous and exogenous estrogens appears to be widespread, involving tissues other than the skeleton (35)(36)(37)(38).…”

Genetics in Dialysis: Gene Polymorphism Association Studies in Dialysis: Bone and Mineral Metabolism

“…Further, the impact of ER-α gene Pvu II and Xba I polymorphisms on the response to raloxifene, a selective ER modulator, was studied in 28 postmenopausal women on hemodialysis. Although no significant differences were observed at baseline between patients with different genotypes, after 1 year of treatment, patients with the PP and xx genotype displayed higher lumbar spine bone mineral density (55,56).…”