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.

Pharmacogenomics of Osteoporosis

“…At present, the possibility of a modulation of raloxifene effects on bone, according to different ESRs genotypes, has been poorly investigated. A preliminary analysis in 28 postmenopausal osteoporotic women on chronic hemodialysis, homozygous subjects for the P or x alleles of the ESR1rs 2234694 polymorphism exhibited a better lumbar spine BMD response and decreased serum pyridinoline values (a marker of bone resorption) when compared with heterozygotes [92]. In a different study on postmenopausal women with osteoporosis, the change in hip BMD after 1 year of treatment with raloxifene appeared higher in women with PP or Pp genotypes than women with pp genotype [93].…”

Pharmacogenomics of Osteoporosis

“…On the other hand, in a very small study of women on hemodialysis, Heilberg reported an influence of ESR1 gene on drug response, with greater BMD increases in women with PP (or xx) genotype [Heilberg et al 2005]. Thus, this result goes in the same direction of HRT studies, showing greater responses in women with P alleles.…”

Pharmacogenomic Approaches to Osteoporosis: 2005 Update

“…Based on the results from the clinical trial on postmenopausal women with osteopenia or osteoporosis, Heilberg et al [2005] tentatively suggested that ESR1 allelic variants may explain, at least in part, the different outcomes after treatment of osteoporosis with SERMs. With respect to HRT therapy, a latest research demonstrated that PP and XX homozygotes of ESR1 PvuII and XbaI loci may be more advantageous than other genotypes in terms of BMD accrual [Rapuri et al 2006], while Salmen et al [2000] found women with P allele may benefit more from the protect effect of HRT on fracture risk than those with p allele.…”

“…Such genes include but are not limited to: vitamin D receptor (VDR) [Dawson-Hughes et al 1995;Brodowska, 2003;Palomba et al 2003a;Palomba et al 2003b;Palomba et al 2005], estrogen receptor alpha (ESR1) [Deng et al 1998;Brodowska, 2003;Heilberg et al 2005;Yim et al 2005], type I collagen 1 (COLIA1) [Qureshi et al 2002], Transforming growth factor 1 (TGF-1) [Yamada et al 2000], and GATA-3 binding protein G3B (RIZ1) [Grundberg et al 2004].…”