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Human Reproduction, Vol. 19, No. 1, 59-64, January 2004
© 2004 European Society of Human Reproduction and Embryology

Effects of vitamin D and estrogen receptor gene polymorphisms on the changes in lumbar bone mineral density with multiple pregnancies in Japanese women

H. Matsushita, T. Kurabayashi1, M. Tomita and K. Tanaka

Department of Obstetrics and Gynecology, Niigata University School of Medicine, 1-757 Asahimachi-dori, Niigata 951-8510, Japan

1 To whom correspondence should be addressed. e-mail: takumi{at}med.niigata-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Our aims were to follow the longitudinal changes in lumbar spine bone mineral density (BMD) with multiple pregnancies, and to study whether polymorphisms in the vitamin D receptor (VDR) and estrogen receptor (ER) genes may influence the results. METHODS: We repeatedly measured the BMD of the lumbar spine (L2–L4) of 133 women who had undergone two successive pregnancies and 73 non-pregnant controls, and analysed the restriction fragment length polymorphisms using restriction endonucleases TaqI, ApaI and FokI for the VDR gene, and PvuII and XbaI for the ER gene. RESULTS: Cases and controls had no significant differences in the longitudinal BMD changes. The mean percentage change in lumbar BMD ({Delta}BMD%) of the women with the XX/Xx genotype was significantly lower than that of the women with the xx genotype after adjusting for age at each delivery, BMD of the first scan, and interval between the scans (0.2 ± 3.3 versus 2.0 ± 4.2%; P = 0.030, analysis of covariance). Multiple regression analyses to evaluate the contribution of the XbaI polymorphism of the ER gene on {Delta}BMD% showed that the percentage decrease in BMD was greater for women lacking the XbaI restriction site (adjusted R2 = 0.188, P < 0.0001). CONCLUSIONS: The present study suggests that the {Delta}BMD% was significantly influenced by the XbaI polymorphism of the ER gene.

Key words: bone mineral density/estrogen receptor/genetic polymorphism/pregnancy/vitamin D receptor


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Women with a lower peak bone mass in adulthood and a higher rate of bone loss in later life are at higher risk of developing osteoporosis (Hansen et al., 1991Go). Pregnancy, post-partum amenorrhoea (PPA) and lactation can all alter the hormonal and physiological status of women and influence the peak bone mass. Some prospective studies with baseline measurement have demonstrated that there is a decrease of ~3–4.5% in the lumbar bone mineral density (BMD) during pregnancy (Drinkwater and Chesnut, 1991Go; Ritchie et al., 1998Go; Holmberg-Marttila et al., 1999Go; Black et al., 2000Go; Naylor et al., 2000Go). Additionally, lumbar BMD is decreased by 3–6% during lactation and PPA (Kalkwarf and Specker, 1995Go; Laskey and Prentice, 1997Go; Polatti et al., 1999Go; Karlsson et al., 2001Go). However, these decreases are transient and show complete recovery on cessation of lactation and resumption of menstruation (Drinkwater and Chesnut, 1991Go; Cross et al., 1995Go; Kalkwarf and Specker, 1995Go; Sowers et al., 1995Go; López et al., 1996Go; Laskey and Prentice, 1997Go, 1999; Laskey et al., 1998Go; Ritchie et al., 1998Go; Polatti et al., 1999Go; Karlsson et al., 2001Go). However, if a woman becomes pregnant again before recovery has been completed, the successive pregnancy could be a risk factor for decreasing the peak bone mass. Studies of this kind are limited, and previous studies have failed to show that multiple pregnancies may curtail the lumbar peak bone mass (Sowers et al., 1995Go; Laskey and Prentice, 1997Go), even when the women were grand multiparous (Henderson et al., 2000Go; Karlsson et al., 2001Go). However, these studies did not have a sufficient number of subjects to demonstrate that the peak bone mass was similarly maintained in the subsequent pregnancy in all women, in all circumstances. Though it is likely that variation in the results arose due to the individual’s age, or aspects of their social, environmental, hormonal or nutritional background, these data have also been lacking. Recently, the importance of genetic interactions on bone metabolism has been noted, thus introducing another source of variation. Polymorphisms in the vitamin D receptor (VDR) (Morrison et al., 1994Go; Tokita et al., 1996Go; Sainz et al., 1997Go; Gennari et al., 1998Go; Kurabayashi et al., 1999Go; Palomba et al., 2003Go) and the estrogen receptor (ER) (Kobayashi et al., 1996Go; Mizunuma et al., 1997Go; Gennari et al., 1998Go; Salmén et al., 2000Go; Albagha et al., 2001Go; Ioannidis et al., 2002Go) genes have been reported to have associations with BMD.

In this study, we investigated women who underwent two successive pregnancies. We repeatedly measured their lumbar BMD after each delivery and compared its longitudinal change with that of non-pregnant control women. Our focus is whether all women with multiple pregnancies are safe from the loss of peak bone mass, and the aim of this study was to examine the associations of the VDR and ER gene polymorphisms on the bone changes of women with multiple pregnancies.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Subjects
The subjects were 133 healthy Japanese women aged 20–40 years (at the first delivery), who had undergone two successive deliveries at Niigata University Hospital. All deliveries (mean age: 30.2 ± 3.5 and 32.8 ± 3.7 years respectively) were at term, and without any obstetrical complications requiring prolonged bed rest during the pregnancy. During the study period, they did not perform inappropriate dietary restriction, and did not display eating disorders such as anorexia nervosa or hyperemesis gravidarum. Women who had had any miscarriages (n = 14), taken excessive caffeine (n = 4), or used oral contraceptives (n = 1) between each delivery had been excluded. Women had also been excluded if they had had any medical complications (n = 7) or taken drugs (n = 3) that would affect bone metabolism during or before pregnancy. Seventy-three non-pregnant and healthy women derived from our normative database, selected to have the same mean age (30.5 ± 2.9 years) and age ranges as the cases, were included as controls.

Height was measured at the first scan, and weights were measured at each scan of BMD. Their backgrounds between the two deliveries, including lactational information, were collected by questionnaire immediately after the next delivery. Between the deliveries, three women had formula-fed, and the others breast-fed their infants with or without formula feeding. Fourteen women became pregnant while they were still lactating.

Before enrolment in the study, written informed consent was obtained from the women, and the study was approved by the Niigata University Human Investigation Committee.

Measurement
Bone mineral content (BMC) and bone area (BA) of the lumbar spine (L2–L4) were repeatedly measured by dual-energy X-ray absorptiometry (DXA) (QDR-2000; Hologic, Inc., USA) within 7 days of each delivery (range: 1.1–5.3 years; mean: 2.5 ± 1.2 years), and BMD was calculated as the BMC divided by the BA (BMD1 and BMD2 respectively). The average coefficients of variation (CV) of phantom measurements for BMC, BA and BMD during the study period were 1.1, 0.7 and 0.6% respectively. In addition, the CV for BMD in-vivo precision between two measurements (mean interval: 2.6 ± 1.2 years) of the control women was 0.9%. There was no scanner drift during the study period.

Genomic DNA analysis
Peripheral blood samples were obtained from each woman, and genomic DNA was extracted from peripheral blood leukocytes. DNA analyses were carried out to identify restriction fragment length polymorphisms (RFLP) using restriction endonucleases as previously reported by Morrison et al. (1992, 1994) (TaqI and ApaI) and Gross et al. (1996Go) (FokI) for VDR gene, and Yaich et al. (1992Go) (PvuII) and Zuppan et al. (1989Go) (XbaI) for ER gene followed by PCR amplification. Genotypes detected by using the enzymes TaqI, ApaI, FokI, PvuII and XbaI were defined as T, A, F, P and X (indicating the absence of the respective restriction site) or t, a, f, p and x (indicating the presence of the restriction site).

Statistical analysis
All data were expressed as the mean ± SD, and all data management and statistical analyses were performed with StatView 5.0 (Abacus Concepts, USA).

The percentage change in BMD ({Delta}BMD%) was calculated by the formula: (BMD2 – BMD1)/BMD1*100. {Delta}BMD% was considered significant if >1.96{checkmark}2*CV (i.e. 2.5%) (Garnero et al., 1999Go; Holmberg-Marttila et al., 1999Go), so we interpreted {Delta}BMD% between –3% and +3% as no significant change.

Group characteristics were compared with analysis of variance (ANOVA), and {Delta}BMD% were with analysis of covariance (ANCOVA), with Fisher’s protected least significant difference (PLSD) test. Since the frequency of the genotype tt for VDR TaqI is rare in Japanese, the Tt and tt were analysed together versus TT (Tokita et al., 1996Go). In addition, TT is highly associated with aa for ApaI polymorphisms, so AA and Aa were compared together versus aa. The XX for ER XbaI was also analysed together with Xx versus xx due to its rarity in our population. The following covariates were considered for ANCOVA analysis: age at each delivery, interval between the scans, and BMD1, because our previous study showed that age was a significant determinant of the {Delta}BMD% (Matsushita et al., 2002Go). In addition, the interval between the scans was included because of its wide scan range, and BMD1 to avoid regression to the mean.

If a significant difference was found in {Delta}BMD%, multiple regression analysis was carried out to evaluate the contribution of the genotype. Genotypes were coded numerically as 0, 1 or 2 representing the absence of the restriction site in neither allele, one allele or both alleles respectively. Differences of P < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Mean {Delta}BMD% of all the 133 women was significantly higher than that of the control (1.4 ± 4.0 versus 0.1 ± 3.6%; P = 0.025, unpaired t-test). Women with {Delta}BMD% >3% accounted for 32.3% (43/133) in the cases and 20.5% (15/73) in the control group, which was not significantly different (P = 0.072). There was also no difference between the proportions of the women whose {Delta}BMD% were <–3% (14.3 versus 17.8%; P = 0.50). Even if women became pregnant while lactating, {Delta}BMD% of these women was not significantly different from that of the others (1.1 ± 4.2 versus 1.4 ± 4.0%; P = 0.77, unpaired t-test).

All of the genotype distributions were in accordance with Hardy–Weinberg equilibrium, and the PvuII and XbaI ER gene polymorphisms were in strong linkage disequilibrium in the cases as well as in the control group. The genotype frequencies and characteristics for the VDR (TaqI, ApaI and FokI) and the ER (PvuII and XbaI) gene polymorphisms of the women with multiple pregnancies are shown in Tables I and II respectively. It was not significant but there was a trend that {Delta}BMD% of the women with the AA/Aa genotype was higher than that of the women with the aa genotype, when adjusted for Age 2 and BMD1 (2.0 ± 3.5 versus 0.6 ± 4.5%; P = 0.056, ANCOVA) (Table I). {Delta}BMD% of the women with the XX/Xx genotype was lower than that of the women with the xx genotype after adjusting for Age 1, Age 2, BMD1 and interval between the scans (0.2 ± 3.3 versus 2.0 ± 4.2%; P = 0.030, ANCOVA) (Table II). In the control group, {Delta}BMD% of the women with the Xx genotype (n = 32; no XX genotype) was not significantly different from that of the women with the xx genotype (n = 41) (–0.4 ± 2.3 versus 0.4 ± 4.3%; P = 0.33, ANOVA). There were no differences in {Delta}BMD% for TaqI, FokI and PvuII, and {Delta}BMD% in all genotype groups were considered non-significant (within –3% to 3%) (Tables I and II).


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  		Table I. Genotype frequencies and characteristics according to the VDR gene polymorphism
 

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  		Table II. Genotype frequencies and characteristics according to the ER gene polymorphism
 
Multiple regression analyses were carried out to evaluate the contribution of the genotypes for XbaI of the ER gene polymorphisms, which demonstrated that {Delta}BMD% was negatively correlated with the number of X alleles, indicating that the percentage decrease in BMD was greater for the women whose ER gene alleles lacked the XbaI restriction site (adjusted R2 = 0.188, P < 0.0001) (Table III).


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  		Table III. Multiple regression models examining the influences of the XbaI polymorphisms of the estrogen receptor (ER) gene on the percentage change in bone mineral density ({Delta}BMD%)
 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
There are very limited data concerning the effect of multiple pregnancies on maternal bone health. Previous studies with small numbers of subjects (Sowers et al., 1995Go; Laskey and Prentice, 1997Go) have concluded that lumbar BMD did not decrease, even if the women were grand multiparous (Henderson et al., 2000Go; Karlsson et al., 2001Go). In this longitudinal study, we showed that the change in lumbar BMD of women with multiple pregnancies was significantly higher than that of age-matched non-pregnant women, and the proportions of the women with multiple pregnancies who had >3% changes were not significantly different from the control group, which enables us to suggest that multiple pregnancy might not be a risk factor for reducing the peak bone mass in adulthood.

Previously, we had reported that the percentage decrease in lumbar BMD of women with multiple pregnancies had been greater for women whose age at the latter delivery were higher, and that the length of lactation, body weight change, or the interval between the scans did not affect the percentage change in lumbar BMD (Matsushita et al., 2002Go). In the present study, we investigated the possible relationships between VDR and ER gene polymorphisms and changes in lumbar BMD, and found that lumbar {Delta}BMD% was significantly influenced by the XbaI polymorphism of the ER gene, and furthermore, the percentage decrease in lumbar BMD was greater for women whose ER gene alleles lacked the XbaI restriction site.

The functional roles and the effects of these genetic polymorphisms on bone metabolism remain controversial. Thus the mechanisms by which the bone changes may have an association with the ER gene polymorphism (XbaI), but not with the VDR gene polymorphisms, are unclear. During PPA and lactation, postpartum women are assumed to be in an equally hypoestrogenic status (Battin et al., 1985Go) similar to the peri-menopausal period, when a higher rate of bone loss is observed. Mizunuma et al. (1997Go) reported that Japanese late pre-menopausal women with the Xx and XX genotype had been likely to have a faster bone loss rate over 1 year than women with the xx genotype. However, the cross-sectional study of Han et al. (1999Go) failed to find an association between the XbaI polymorphism of the ER gene and bone turnover in peri-menopausal Korean women. On the other hand, a recent meta-analysis of the ER gene polymorphisms and BMD showed that XX homozygotes had significantly higher BMD compared with carriers of the x haplotypes (Ioannidis et al., 2002Go). In the present study, a similar trend of XX homozygotes (0.041 g/cm2 higher compared with Xx, and 0.057 g/cm2 compared with xx) was observed, although the difference was not significant. Though the mechanism remains unclear, speculation might be that our result was due to the differences in susceptibility to their estrogen status. As for VDR gene polymorphisms, there was a trend between ApaI polymorphisms and lumbar {Delta}BMD%, which did not reach statistical significance. Although the result might have been different according to their calcium and vitamin D status (Ferrari et al., 1998Go), we could not include this information in this study.

A limitation of this study is that it is impossible to know when the ER XbaI gene polymorphism may interfere to make a difference in the lumbar {Delta}BMD%. In the present study, {Delta}BMD% should ideally have been determined from the bone loss during lactation and PPA, the recovery after the cessation of breast-feeding and resumption of menstruation, and the substantial change during the successive pregnancy. The {Delta}BMD% for a comparison group should have been similarly measured at equivalent time-points.

Association studies between the bone change with pregnancy or its related events and genetic variations are extremely limited, and to the best of our knowledge, there are only two studies in the literature. Laskey et al. (1998Go) reported that the changes in BMC after 3 months of lactation were not related to the BsmI genotype of the VDR gene. Holmberg-Marttila et al. (2000Go) reported that they failed to find any association between bone mineral changes during PPA or 1 year after resumption of menstruation, and the BsmI polymorphisms of the VDR gene and PvuII polymorphisms of the ER gene. Though the incompleteness of our study might be partly compensated by these studies, genetic involvement in the bone changes with pregnancy and its related events should be resolved further. On the other hand, since it could be that future larger population studies or meta-analyses may fail to replicate genetic associations with the susceptibility to human diseases (Ioannidis et al., 2001Go; Lohmueller et al., 2003Go), our findings should also be interpreted with much caution.

In summary, our current study demonstrated that lumbar BMD of the women was not decreased with multiple pregnancies, suggesting that multiple pregnancies are not a risk for reducing peak bone mass of women. On the other hand, the {Delta}BMD% was significantly influenced by the XbaI polymorphism of the ER gene, and the percentage decrease was greater for the women with ER alleles lacking the XbaI restriction site. Further work is needed to clarify the factors which affect the changes in BMD with multiple pregnancies.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Albagha OME, McGuigan FEA, Reid DM and Ralston SH (2001) Estrogen receptor {alpha} gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 16,128–134.

Battin DA, Marrs RP, Fleiss PM and Mishell DR (1985) Effect of suckling on serum prolactin, luteinizing hormone, follicle-stimulating hormone, and estradiol during prolonged lactation. Obstet Gynecol 65,785–788.[Web of Science][Medline]

Black AJ, Topping J, Durham B, Farquharson RG and Fraser WD (2000) A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy. J Bone Miner Res 15,557–563.[CrossRef][Web of Science][Medline]

Cross NA, Hillman LS, Allen SH, Krause GF and Vieira NE (1995) Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 61,514–523.[Abstract/Free Full Text]

Drinkwater BL and Chesnut CH (1991) Bone density changes during pregnancy and lactation in active women: a longitudinal study. Bone Miner 14,153–160.[CrossRef][Web of Science][Medline]

Ferrari S, Rizzoli R, Slosman D and Bonjour JP (1998) Do dietary calcium and age explain the controversy surrounding the relationship between bone mineral density and vitamin D receptor gene polymorphisms? J Bone Miner Res 13,363–370.[CrossRef][Web of Science][Medline]

Garnero P, Darte C and Delmas PD (1999) A model to monitor the efficacy of alendronate treatment in women with osteoporosis using a biochemical marker of bone turnover. Bone 24,603–609.[Medline]

Gennari L, Becherini L, Masi L, Mansani R, Gonnelli S, Cepollaro C, Martini S, Montagnani A, Lentini G, Becorpi AM et al (1998) Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density. J Clin Endocrinol Metab, 83,939–944.[Abstract/Free Full Text]

Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R and Feldman D (1996) The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res 11,1850–1855.[Web of Science][Medline]

Han K, Choi J, Moon I, Yoon H, Han I, Min H, Kim Y and Choi Y (1999) Non-association of estrogen receptor genotypes with bone mineral density and bone turnover in Korean pre-, peri-, and postmenopausal women. Osteoporos Int 9,290–295.[CrossRef][Web of Science][Medline]

Hansen MA, Overgaard K, Riis BJ and Christiansen C (1991) Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. Br Med J 303,961–964.[Abstract/Free Full Text]

Henderson PH, Sowers M, Kutzko KE and Jannausch ML (2000) Bone mineral density in grand multiparous women with extended lactation. Am J Obstet Gynecol 182,1371–1377.[CrossRef][Web of Science][Medline]

Holmberg-Marttila D, Sievänen H and Tuimala R (1999) Changes in bone mineral density during pregnancy and postpartum: prospective data on five women. Osteoporos Int 10,41–46.[CrossRef][Web of Science][Medline]

Holmberg-Marttila D, Sievänen H, Järvinen TLN and Järvinen TAH (2000) Vitamin D and estrogen receptor polymorphisms and bone mineral changes in postpartum women. Calcif Tiss Int 66,184–189.[CrossRef][Web of Science][Medline]

Ioannidis JPA, Ntzani EE, Trikalino TA and Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29,306–309.[CrossRef][Web of Science][Medline]

Ioannidis JPA, Stavrou I, Trikalinos TA, Zois C, Brandi ML, Gennari L, Albagha O, Ralston SH and Tsatsoulis A (2002) Association of polymorphisms of the estrogen receptor {alpha} gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17,2048–2060.[CrossRef][Web of Science][Medline]

Kalkwarf HJ and Specker BL (1995) Bone mineral loss during lactation and recovery after weaning. Obstet Gynecol 86,26–32.[CrossRef][Web of Science][Medline]

Karlsson C, Obrant KJ and Karlsson M (2001) Pregnancy and lactation confer reversible bone loss in humans. Osteoporos Int 12,828–834.[CrossRef][Web of Science][Medline]

Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M and Orimo H (1996) Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res 11,306–311.[Web of Science][Medline]

Kurabayashi T, Tomita M, Matsushita H, Yahata T, Honda A, Takakuwa K and Tanaka K (1999) Association of vitamin D and estrogen receptor gene polymorphism with the effect of hormone replacement therapy on bone mineral density in Japanese women. Am J Obstet Gynecol 180,1115–1120.[CrossRef][Web of Science][Medline]

Laskey MA and Prentice A (1997) Effect of pregnancy on recovery of lactational bone loss. Lancet 349,1518–1519.[Web of Science][Medline]

Laskey MA and Prentice A (1999) Bone mineral changes during and after lactation. Obstet Gynecol 94,608–615.[CrossRef][Web of Science][Medline]

Laskey MA, Prentice A, Hanratty LA, Jarjou LMA, Dibba B, Beavan SR and Cole TJ (1998) Bone changes after 3 mo of lactation: influence of calcium intake, breast-milk output, and vitamin D-receptor genotype. Am J Clin Nutr 67,685–692.[Abstract]

Lohmueller KE, Pearce CL, Pike M, Lander ES and Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33,177–182.[CrossRef][Web of Science][Medline]

López JM, González G, Reyes V, Campino C and Díaz S (1996) Bone turnover and density in healthy women during breastfeeding and after weaning. Osteoporos Int 6,153–159.[Web of Science][Medline]

Matsushita H, Kurabayashi T, Tomita M, Honda A, Takakuwa K and Tanaka K (2002) The effect of multiple pregnancies on lumbar bone mineral density in Japanese women. Calcif Tiss Int 71,10–13.[CrossRef][Web of Science][Medline]

Mizunuma H, Hosoi T, Okano H, Soda M, Tokizawa T, Kagami I, Miyamoto S, Ibuki Y, Inoue S, Shiraki M et al (1997) Estrogen receptor gene polymorphism and bone mineral density at the lumbar spine of pre- and postmenopausal women. Bone 21,379–383.[Medline]

Morrison NA, Yeoman, R, Kelly, PJ and Eisman, JA (1992) Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA 89,6665–6669.[Abstract/Free Full Text]

Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN and Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367,284–287.[CrossRef][Medline]

Naylor KE, Iqbal P, Fledelius C, Fraser RB and Eastell R (2000) The effect of pregnancy on bone density and bone turnover. J Bone Miner Res 15,129–137.[CrossRef][Web of Science][Medline]

Palomba S, Numis FG, Mossetti G, Rendina D, Vuotto P, Russo T, Zullo F, Nappi C and Nunziata V (2003) Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes. Hum Reprod 18,192–198.[Abstract/Free Full Text]

Polatti F, Capuzzo E, Viazzo F, Colleoni R and Klersy C (1999) Bone mineral changes during and after lactation. Obstet Gynecol 94,52–56.[CrossRef][Web of Science][Medline]

Ritchie LD, Fung EB, Halloran BP, Turnlund JR, Van Loan MD, Cann CE and King JC (1998) A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. Am J Clin Nutr 67,693–701.[Abstract]

Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF and Gilsanz V (1997) Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 337,77–82.[Abstract/Free Full Text]

Salmén T, Heikkinen A, Mahonen A, Kröger H, Komulainen M, Saarikoski S, Honkanen R and Mäenpää PH (2000) Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy. J Bone Miner Res 15,315–321.[CrossRef][Web of Science][Medline]

Sowers M, Randolph J, Shapiro B and Jannausch M (1995) A prospective study of bone density and pregnancy after an extended period of lactation with bone loss. Obstet Gynecol 85,285–289.[CrossRef][Web of Science][Medline]

Tokita A, Matsumoto H, Morrison NA, Tawa T, Miura Y, Fukamauchi K, Mitsuhashi N, Irimoto M, Yamamori S, Miura M et al (1996) Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. J Bone Miner Res 11,1003–1009.[Web of Science][Medline]

Yaich L, Dupont WD, Cavener DR and Parl FF (1992) Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res 52,77–83.[Abstract/Free Full Text]

Zuppan PJ, Hall JM, Ponglikitmongkol M, Spielman R and King MC (1989) Polymorphisms at the estrogen receptor (ESR) locus and linkage relationships on chromosome 6q. Cytogenet Cell Genet 51,11.

Submitted on February 14, 2003; resubmitted on July 18, 2003; accepted on September 19, 2003.


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