The impact of estradiol on bone mineral density is modulated by the specific estrogen receptor-alpha cofactor retinoblastoma-interacting zinc finger protein-1 insertion/deletion polymorphism.
BACKGROUND
Estrogens regulate bone mass by binding to the estrogen receptor (ER)-alpha as well as ER-beta. The specific ERalpha cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ERalpha function in the presence of estrogen.


OBJECTIVE
The objective of the study was to determine whether a RIZ P704 insertion (+)/deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects.


METHODS
This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively.


METHODS
The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital.


METHODS
In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries.


METHODS
BMD (grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body.


RESULTS
The RIZ P704(+/+) genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704(+/+) group than the P704(-/-) group (r = 0.19 vs. r = 0.08, P < 0.05).


CONCLUSIONS
These large-scale studies of elderly men and women indicate that the ERalpha cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.
Grundberg
Elin
E
Department of Medical Sciences, Uppsala University Hospital, Ing 70, 3 tr, Uppsala, Sweden. elin.grundberg@medsci.uu.se
Akesson
Kristina
K
Kindmark
Andreas
A
Gerdhem
Paul
P
Holmberg
Anna
A
Mellström
Dan
D
Ljunggren
Osten
O
Orwoll
Eric
E
Mallmin
Hans
H
Ohlsson
Claes
C
Brändström
Helena
H
D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D001851:Bone Diseases, Metabolic / Q000453:epidemiology / Q000235:genetics*; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004958:Estradiol / Q000097:blood*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000473:pathology; D017353:Gene Deletion; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012042:Registries / Q000706:statistics & numerical data; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D004958:Estradiol; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human