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The Impact of Estradiol on Bone Mineral Density Is Modulated by the Specific Estrogen Receptor- Cofactor Retinoblastoma-Interacting Zinc Finger Protein-1 Insertion/Deletion Polymorphism

Departments of Medical Sciences (E.G., A.K., O.L., H.B.) and Surgical Sciences (H.M.), Uppsala University Hospital, 75185 Uppsala, Sweden; Department of Orthopaedics (K.A., P.G., A.H.), Malmö University Hospital, 20502 Malmö, Sweden; Center for Bone Research at the Sahlgrenska Academy (D.M., C.O.), Department of Internal Medicine, Göteborg University, 41345 Gothenburg, Sweden; and Bone and Mineral Research Unit (E.O.), Oregon Health and Science University, Portland, Oregon 97239

Address all correspondence and requests for reprints to: Elin Grundberg, Department of Medical Sciences, Uppsala University Hospital, Ing 70, 3 tr, 75185 Uppsala, Sweden. E-mail: elin.grundberg{at}medsci.uu.se.

Context: Estrogens regulate bone mass by binding to the estrogen receptor (ER)- as well as ER-ß. The specific ER cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ER 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.

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

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

Participants: In total, 4058 men and women, aged 69–81 yr, were randomly selected from population registries.

Main Outcome Measures: 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 ER 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.