title: Estrogen receptor alpha gene polymorphisms are associated with changes in bone remodeling markers and treatment response to estrogen.
abstract: OBJECTIVE
  Association studies between estrogen receptor alpha (ERalpha) gene polymorphisms and bone mineral density (BMD) have yielded inconsistent results. In the present study we evaluated the influence of XbaI and PvuII ERalpha gene polymorphisms on BMD, biochemical markers, rates of bone loss and the response to estrogen/hormone therapy (ET/HT) in elderly postmenopausal women.
  
  
  METHODS
  At baseline, we measured the association between ERalpha genotypes and BMD and biochemical markers in 489 elderly women, mean age 71 +/- 3 years. In the longitudinal study, the changes in the same measures were determined in 96 women on placebo and in 79 women receiving the ET/HT for 3 years. The XbaI and PvuII ERalpha polymorphisms were determined by polymerase chain reaction (PCR). BMD measurements for spine, femoral neck and total body were performed by DEXA, and biochemical indices were measured by standard methods.
  
  
  RESULTS
  Neither the PvuII nor the XbaI ERalpha gene polymorphisms were associated with baseline BMD and biochemical indices. In the longitudinal study, there were trends for higher bone loss in the placebo group in the genotypes pp or xx compared to PP or XX genotypes, but the changes were not significant. However, the changes in the bone markers were significantly (p < 0.05) higher in genotype group pp compared to PP (serum osteocalcin, 4.9 +/- 7.0% versus -13.4 +/- 6.7%; urine NTx:Cr ratio, 32.3+/-10.3% versus -2.5 +/- 10.3%) or xx compared to XX (serum osteocalcin, 7.5 +/- 6.4% versus -15.6+/-7.3%; urine NTx:Cr ratio, 39.4 +/- 9.2% versus -8.84+/-10.7%). At the end of 3 years, the mean urine NTx:Cr ratio was 78.7 +/- 9.0 versus 44.6 +/- 4.9 in pp versus PP (p < 0.05) and 75.5 +/- 10.7 versus 48.7 +/- 5.4 in xx versus XX (p < 0.05) genotypes. The response in total body BMD to ET/HT treatment was significantly higher in women with the PP genotype compared to pp genotype (2.48 +/- 0.55% versus 0.66 +/- 0.46%). Similar trends were seen at other skeletal sites for both XX and PP compared to pp and xx genotypes.
  
  
  CONCLUSIONS
  Women with ERalpha, PP and XX genotypes have lower bone remodeling, lower rates of bone loss and benefit more from hormone therapy.
authors.affiliation: Bone Metabolism Unit, Creighton University, School of Medicine, 601 North 30th Street, Room 6718, Omaha, NE 68131, USA. thiyyari@creighton.edu
authors.forename: P B
authors.initials: PB
authors.lastname: Rapuri
authors.forename: J C
authors.initials: JC
authors.lastname: Gallagher
authors.forename: J A
authors.initials: JA
authors.lastname: Knezetic
authors.forename: V
authors.initials: V
authors.lastname: Haynatzka
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D002117:Calcitriol / Q000627:therapeutic use; D015930:Diet Records; D004311:Double-Blind Method; D047628:Estrogen Receptor alpha / Q000235:genetics*; D015914:Estrogen Replacement Therapy / Q000379:methods; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000235:genetics* / Q000652:urine; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000502:physiology
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D047628:Estrogen Receptor alpha; D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate; D002117:Calcitriol