Association of estrogen receptor α gene microsatellite polymorphism with annual changes in bone mineral density in Korean women with hormone replacement therapy

Variation in drug response to hormone replacement therapy (HRT) may reflect genetic heterogeneity in the estrogen-related genes, possibly including estrogen receptor alpha (ERα) gene. However, only a few association studies of the drug response to HRT have been reported, focusing mainly on the intronic polymorphisms of the ERα gene. We therefore examined 284 postmenopausal women (mean age, 52.2 ± 5.0 years) for the microsatellite thymine–adenine (TA) repeat polymorphism in the promoter of the ERα gene and its relationship to drug response by measuring changes in bone mineral density (BMD) after 1 year of HRT. In our study population, the most common number of TA repeats was 14, with a range of values between 11 and 27. At baseline, the number of TA repeats was neither associated with measured lumbar spine or femoral neck BMD nor with bone markers. When we categorized the subjects by the TA repeat numbers into an L group (n = 142), with a low mean number of repeats (TA < 16), and an H group (n = 142), with a high mean number of repeats (TA ≥ 16), no significant genotypic differences were noted in spinal or femoral neck BMD or in bone markers. However, the drug response on lumbar spine BMD after 1 year of HRT correlated with the mean number of TA repeats (r = −0.131, P = 0.035) after adjustment for confounding factors such as body mass index and years since menopause. This correlation was also seen with the number of TA repeats on the shorter allele (r = −0.159, P = 0.012), which was defined as the allele with the lower number of TA repeats. However, this genotypic association was not found in the femoral neck BMD (r = 0.053, P = 0.396). When we defined the nonresponder group as women who had lost BMD even with HRT, 15.9% of the subjects were included, and this group was significantly younger and had higher initial BMD than the responder group. After further adjustment for age and initial BMD, the number of TA repeats on the shorter allele remained significantly associated with drug responsiveness (P = 0.005). These data indicate significant effects of the ERα TA repeat polymorphism on the estrogen responsiveness of lumbar spine BMD after 1 year of HRT in Korean women.     

Association of estrogen receptor-α gene polymorphisms with bone mineral density in postmenopausal Korean women

We examined the potential associations between PvuII and XbaI polymorphisms in the first intron of the estrogen receptor alpha (ER-) gene and bone mineral density (BMD) in a population-based study of 174 postmenopausal Korean women. BMD was measured at the lumbar spine (L₂–L₄), right femoral neck, right trochanter, and right Wards triangle. ER- gene polymorphisms were detected by PvuII and XbaI restriction endonuclease digestion of polymerase chain reaction products. Differences in BMD values between the ER- genotypes were analyzed in a general linear model, with adjustments for age, height, weight, and smoking status. The following genotype frequencies were noted: PP, 14.9%; Pp, 46.0%; pp, 39.1%; XX, 3.5%; Xx, 29.3%; and xx, 67.2%. Both the femoral neck and Wards triangle BMD values in women with the Pp genotype were significantly (P < 0.05) higher than those in women with the pp genotype. No significant effect of the XbaI genotype on BMD was found at any site. Carriers of the pX haplotype were more likely to have lower BMD values at the trochanter than noncarriers, after adjustment for potentially confounding factors. Women with the pp genotype had more previous hip or spine fractures than those with other genotypes (P = 0.05). These results suggest that the PvuII polymorphism and the ER- haplotype may be associated with the BMD at several femur sites in postmenopausal Korean women.     

Association of dietary consumption and serum levels of vitamin A and β-carotene with bone mineral density in Chinese adults

BackgroundFormer studies suggested an adverse effect of hypervitaminosis A on bone health, while the effects of retinol and its precursor (β-carotene) remain uncertain in populations consuming vitamin A (VA) mainly from plant sources.ObjectiveWe investigated the association of serum, dietary retinol, and β-carotene with bone mineral density (BMD) in Chinese adults.MethodsWe recruited 2101 women and 1053 men (aged 40–75 years) in Guangzhou, China. Dietary intake was assessed through face-to-face interviews with food-frequency questionnaires at baseline and 3 years later. Serum levels of retinol and β-carotene were determined by HPLC using a baseline specimen, and the BMD for the whole body (WB), lumbar spine (LS), total hip (TH), and femur neck (FN) were measured using dual energy X-ray absorptiometry at follow-up.ResultsIn general, greater levels of serum retinol, β-carotene, and the β-carotene-to-retinol ratio were associated with a higher BMD after adjustment for potential covariates in the total sample. BMD values in the top (vs. bottom) quartile were increased by 2.06% (TH) for retinol; 2.87% (WB), 2.51% (LS), 3.10% (FN) for β-carotene; 2.21% (WB) and 2.05% (FN) for the β-carotene-to-retinol ratio in the total sample (all p < 0.05). A significant positive association with BMD was observed for dietary intake of β-carotene and total VA in retinol equivalents at the hip sites in the total sample.ConclusionHigher circulating and dietary levels of VA and β-carotene and higher serum β-carotene-to-retinol ratios were positively associated with BMD in Chinese adults consuming relatively low levels of VA, mainly from plant foods.     

Collagen type Iα1 gene polymorphism may be associated with the rate of bone mineral density decrease in female hemodialyzed patients

Background. Polymorphism of the collagen type Iα1 gene (COLIA1) has been shown to be involved in bone density in the general population. However, the significance of this polymorphism has not been examined in patients with chronic renal failure. Methods. We first determined the COLIA1 Bal I restriction fragment length polymorphism (RFLP) at the Sp 1 binding site, and, next, we measured biochemical bone markers and the bone mineral density (BMD) of the lumbar spine (L2–L4) and radius (distal one-third) in 181 hemodialyzed patients. Results. Distributions of the Bal I RFLP were: SS, 62%; Ss, 32%; and ss, 6%. The Z scores for the BMD and for the serum levels of Ca, P, alkaline phosphatase, intact-parathyroid hormone (PTH), osteocalcin, and tartrate-resistant acid phosphatase were not significantly different among the three genotype groups. The slope of the regression line in the age-BMD relationship, a measure of the rate of BMD decrease, was similar among the three genotypes in men, but was significantly (P < 0.05) larger in the ss group than in the SS and Ss groups in women. Conclusions. The COLIA1 polymorphism may be associated with the bone loss seen in female patients on hemodialysis. Received: January 19, 2001 / Accepted: July 28, 2001     

Low bone mineral density in the femoral neck of medieval women: a result of multiparity?

An archaeological investigation of a medieval cemetery gave us the opportunity to investigate 49 Danish skeletons dating from 1000 to 1250 A.D. and to compare them with 298 contemporary Danes (aged 19-79 years) and assess the millennial trend in bone mineral density (BMD) in populations considered genetically closely related. BMD and bone mineral apparent density (BMAD) of the femoral neck were measured by dual-energy X-ray absorptiometry (DEXA) and transformed into z scores. BMD(zscore) was significantly lower in medieval women (-0.54 +/- 0.25, p = 0.04), whereas BMD(zscore) in medieval men was significantly higher (0.55 +/- 0.22, p = 0.02). In medieval women, BMD(zscore) tended to increase with age (r = 0.42, p = 0.07), whereas no change was seen in men (r = 0.19, not significant [n.s.]). Also, BMAD(zscore) was significantly elevated in medieval men (1.00 +/- 0.28, p < 0.01), but in medieval women no difference was found (-0.28 +/- 0.21, n.s.). However, the correlation between BMAD(zscore) and age was significant in the medieval women where it increased with advancing age (r = 0.49, p = 0.03). In conclusion, medieval women had lower BMD when compared with contemporary women, but this relationship was reversed in women who survived to older ages. In contrast, medieval men had significantly higher BMD as compared with contemporary men at all ages. The observed lower BMD in medieval women can be explained by the well-known selective mortality among the younger women. A high birth rate and prolonged periods of lactation are the main reasons for the observed increased mortality, and therefore can also very likely explain the associated low BMD. The increase in the incidence of osteoporosis in modern elderly women could possibly, or partially, be explained by the survival of women who would have died prematurely had they lived in earlier centuries.     

A specific haplotype in the 3′ end of estrogen-receptor alpha gene is associated with low bone mineral density in premenopausal women and increased risk of postmenopausal osteoporosis

It is well established that the development of postmenopausal osteoporosis is under genetic influence. We have recently identified a synonymous single nucleotide polymorphism (SNP) in exon 8 of estrogen receptor- (ER) gene in the vicinity of the stop codon (G2014A) that is associated with an increased risk of postmenopausal osteoporosis. In the present study, we attempted to locate SNPs in the 3-unstranslated region (3UTR) of the ER gene that are in linkage disequilibrium with the exon 8 SNP and assessed their utilization in the risk assessment of postmenopausal osteoporosis in 352 Thai postmenopausal women. The association with bone mineral density (BMD) in premenopausal women was also investigated in 202 premenopausal women. A C to A SNP 1,748 nucleotides distal to the end of the stop codon (C3768A) was identified. The C3768A SNP was not overrepresented in subjects with osteoporosis. However, the presence of the A-C haplotype allele based on the A2014 and C3768 alleles was significantly related to the risk of osteoporosis independently of age, body weight, the G2014A and C3768A SNPs (odds ratio 2.36, 95% CI 1.42–3.91). Moreover, the presence of the A-C haplotype allele was associated with lower femoral neck BMD in premenopausal women ( P =0.05). We concluded that a specific haplotype in the 3 end of the ER gene is associated with lower BMD in premenopausal women and is associated with a higher risk of osteoporosis in postmenopausal women. It is likely that the haplotype allele exerts its influence on bone as early as during young adulthood to increase the risk of osteoporosis later in life.     

Does using lower limit of normal values enhance the ability of a single bone mineral density measure to predict fractures?

Summary  

Using a single bone mineral density (BMD) measure, we demonstrated that the lower limit of normal (LLN) method is more consistent in predicting osteoporosis fractures than the T-score in white menopausal women from the Study of Osteoporosis Fracture (SOF).     

Changes in bone mineral density (BMD) around the cemented Exeter stem: A prospective study in 18 women with 5 years follow‐up

Background and purpose?THA changes the pattern of strain distribution in the proximal femur. We quantified the changes in BMD for 5 years after insertion of the cemented Exeter stem in women.

Methods?18 women aged 55–79 years, undergoing unilateral THA with the cemented Exeter stem, were included in the study. The BMD was measured in 7 femoral regions of interest according to Gruen, and the contralateral hip and spine using dual‐energy X‐ray absorptiometry postoperatively, at 18 and at 60 months of follow‐up. Results were tested using Wilcoxon matched‐pairs signed‐rank test.

Results?During the first 18 months, a significant decrease in BMD was seen in zones 2, 3, 6, and 7. No significant changes were seen in zones 4 and 5, in the contralateral hip, or at the spine. In zone 1, there was a small but significant rise in BMD. From 18 to 60 months, we observed a statistically significant rise in BMD in all zones except 4 and 7. Despite this, the total periprosthetic BMD decreased during the follow‐up relative to the immediate postoperative situation. There was no significant reduction in BMD in the contralateral hip. In the spine, we observed a significant rise in BMD.

Interpretation?18 months after THA, BMD had decreased in Gruen zones 2, 3, 6, and 7. The bone loss was similar to that seen after other implants and appears to be related to the changes in stress pattern within the proximal femur. At 5 years, BMD had increased again in these zones. It remained lower than baseline, however.     

Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density — Is there a role for mechanosensing?

Matrix strains due to external loading are different in bones of different pathologies with different bone mineral density (BMD), and are likely sensed by the osteocytes, the putative bone mechanosensors. The mechanosensitivity of osteocytes appears to be strongly influenced by their morphology. In this study, we explored the possibility that osteocyte morphology might play a role in various bone pathologies with different BMD.Confocal laser scanning microscopy and nano-CT were used to quantitatively determine 3D morphology and alignment of osteocytes and osteocyte lacunae in human proximal tibial bone with relatively low (osteopenic), medium (osteoarthritic), and high (osteopetrotic) BMD.Osteopenic osteocytes were relatively large and round (lengths 8.9:15.6:13.4 μm), osteopetrotic osteocytes were small and discoid shaped (lengths 5.5:11.1:10.8 μm), and osteoarthritic osteocytes were large and elongated (lengths 8.4:17.3:12.2 μm). Osteopenic osteocyte lacunae showed 3.5 fold larger volume and 2.2 fold larger surface area than osteoarthritic lacunae, whereas osteopetrotic lacunae were 1.9 fold larger and showed 1.5 fold larger surface area than osteoarthritic lacunae. Osteopetrotic osteocyte lacunae had lower alignment than osteopenic and osteoarthritic lacunae as indicated by their lower degree of anisotropy.The differences in 3D morphology of osteocytes and their lacunae in long bones of different pathologies with different BMD might reflect an adaptation to matrix strain due to different external loading conditions. Moreover, since direct mechanosensing of matrix strain likely occurs by the cell bodies, the differences in osteocyte morphology and their lacunae might indicate differences in osteocyte mechanosensitivity. The exact relationship between osteocyte morphology and bone architecture, however, is complex and deserves further study.     

Association between ER-α polymorphisms and bone mineral density in patients with Turner syndrome subjected to estroprogestagen treatment—a pilot study

Reduced bone mineral density (BMD) is present in many women with Turner syndrome (TS), and hypo-estrogenism is known to play a vital role in bone mineralization disturbances. It has been suggested that genetic factors play an important role in the regulation of BMD. The aim of this study was to analyze the association between Pvu II and XbaI ER-α polymorphisms and BMD in TS patients subjected to estroprogestagen (EP) treatment. Thirty-two TS patients aged 17–38 (mean age 22.7 ± 8.2) along with 82 healthy controls were the subjects for this study. Baseline values of hormonal parameters, BMD and bone density markers were measured in the subjects. Subsequently, TS patients underwent 4 years of EP therapy. The results of laboratory parameters and BMD were analyzed in regard to PvuII and XbaI polymorphic variants of the ER-α gene. The increase in BMD of TS subjects was the highest in the 1st (7.5%, p = 0.013) and 2nd (6.6%, p = 0.008) years of treatment. Four years of EP therapy was reflected by a significant increase in BMD z-scores in patients with xx and Xx genotypes of the XbaI gene and in those with with the pp and Pp genotypes of PvuII. In patients with haplotypes other than XXPP, BMD z-scores were significantly higher compared to their baseline after 2 (p = 0.002), 3 (p < 0.001) and 4 (p < 0.001) years of treatment. In conclusion, genotypes xx and pp were shown to be prognostic markers of a good response to EP treatment, whereas the XXPP haplotype carriers were revealed to have the risk factors for insufficient responsiveness against EP treatment in BMD control.     

Association of single nucleotide polymorphism of vitamin D receptor gene start codon and the suscepbility to prostate cancer in Han nationality in Hubei, China

Aim: To investigate the single nucleotide polymorphism of vitamin D receptor (VDR) gene start codon in the Han nationality in Hubei and its relationship to the susceptibility to prostate cancel (PCa). Methods: The VDR genotypes were determined by poly-merase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 80 patients with PCa and 96 normal male controls from the Han nationality in Hubei, using endonuclease Fok. Direct sequencing was done in part of the PCR products. Results: The frequency distribution of Fok I alleles in this cohort all followed the Hardy-Weinberg equilibrium. The distribution of genotypes and alleles had no significant difference between PCa patients and the controls (P>0.05). Conclusion: There was no significant relationship between Fok I polymorphism of VDR gene start codon and PCa in the Han nationality in Hubei.     

Association of urokinase gene 3′-UTR T/C polymorphism with calcium oxalate urolithiasis in children

INTRODUCTION AND OBJECTIVES: Urokinase is synthesized by various cells such as kidney, pneumocytes, and phagocytes. It cleaves plasminogen to plasmin and hence stimulates fibrinolysis. Urokinase breaks down the matrix protein within the stone and thus prevents stone formation and growth. Urokinase concentrations are lower and urokinase gene 3'-UTR T/C polymorphism is higher in patients with recurrent stones. Our aim was to investigate the role of urokinase gene 3'-UTR T/C polymorphism in childhood recurrent stone disease. MATERIAL AND METHODS: A control group of 40 healthy children having no history of stone formation (group 1) (mean age 10.5 +/- 4.2 years), 40 children (mean age 10.5 +/- 4.33 years) who had calcium oxalate stones for the first time (group 2), and 40 patients (mean age 11.2 +/- 3.8 years) with recurrent calcium oxalate stone disease (group 3) were included in the study. The groups were compared with respect to age, gender and urokinase gene 3'-UTR T/C polymorphism. Polymerase chain reaction-based restriction analysis was used to identify C/T polymorphism of the urokinase gene. RESULTS: No significant difference was observed between the three groups with respect to age and gender, while urokinase gene 3'-UTR T/C gene polymorphism was observed in four patients (10%) from group 3. In groups 1 and 2 there was no patient with T/C polymorphism. CONCLUSIONS: Urokinase 3'-UTR T/C gene polymorphism seems to appear more commonly in children with recurrent calcium oxalate stone disease than in healthy children and in those with stones for the first time. These results suggest that the urokinase gene might play a role in childhood recurrent calcium oxalate stone disease.     

Low bone mineral density for age/osteoporosis in triple A syndrome—an overlooked symptom of unexplained etiology

Summary

Triple A syndrome (alacrima, achalasia, adrenal failure, progressive neurodegenerative disease) is caused by mutations in the AAAS gene which encodes the protein alacrima achalasia adrenal insufficiency neurologic disorder (ALADIN). Our investigation suggests that low bone mineral density (BMD) for age/osteoporosis could be a common but overlooked symptom of unexplained etiology in this rare multisystemic disease.

Introduction

The purpose of this study is to evaluate incidence and etiology of BMD for age/osteoporosis, a possibly overlooked symptom in triple A syndrome.

Methods

Dual-energy X-ray absorptiometry (DXA) of the femoral neck, total hip, lumbar spine, and radius, bone turnover markers, minerals, total alkaline phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), 1,25-dihydroxy vitamin D (1,25-OH2D), intact parathyroid hormone (PTH), and adrenal androgens (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) were measured in five male and four female patients.

Results

At time of diagnosis, low BMD for age was suspected on X-ray in seven of nine patients aged 2–11 years (not performed in two patients); normal levels of minerals and ALP were found in nine patients and low levels of adrenal androgens in eight patients (not measured in one patient). Reevaluation 5–35 years after introduction of 12 mg/m²/day hydrocortisone showed low BMD for age in two children, osteopenia in one, and osteoporosis in six adults. Normal levels of minerals, ALP, PTH, 1,25-OH2D, procollagen type 1, crosslaps, and osteocalcin were found in all patients. Low levels of adrenal androgens were found in all and 25OHD deficiency in six patients. Body mass index was <25 % for age and sex in eight of nine patients.

Conclusion

Low BMD for age/osteoporosis in our patients probably is not a result of glucocorticoid therapy but could be the consequence of low level of adrenal androgens, neurological impairment causing physical inactivity, inadequate sun exposure, and protein malnutrition secondary to achalasia. Considering ubiquitous ALADIN expression, low BMD/osteoporosis may be a primary phenotypic feature of the disease. Besides optimizing glucocorticoid dose, physical activity, adequate sun exposure, appropriate nutrition, and vitamin D supplementation, therapy with DHEA should be considered.

     

Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-α Gene with Postmenopausal Osteoporosis

We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-α (ERα) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups – with vertebral or femoral osteoporosis (n= 106) or without osteoporosis (n= 122) – according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49–4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89–0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08–1.19). In a multiple linear regression model, L2–L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERα is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3′-untranslated region of the ERα gene which may participate in the regulation of ERα gene expression remains to be determined. Received: 17 October 2000 / Accepted: 11 June 2001     

Association of bone mineral density and diabetic retinopathy in diabetic subjects: the 2008–2011 Korea National Health and Nutrition Examination Survey

Summary

Because diabetic retinopathy increases fracture risk, we studied the association between bone mineral density (BMD) and diabetic retinopathy in a nationally representative sample. A significant association between the presence of diabetic retinopathy and low BMD was observed. Therefore, diabetic retinopathy might be considered as a marker of low BMD.

Introduction

Several diabetic complications, including nephropathy, retinopathy, and peripheral neuropathy, are associated with a higher fracture risk in diabetic subjects. However, in contrast to diabetic nephropathy and peripheral neuropathy, which are associated with low bone mineral density (BMD), little is known about the association between BMD and diabetic retinopathy. The aim of the present study was to determine whether the prevalence of diabetic retinopathy is associated with BMD.

Methods

This cross-sectional study included a nationally representative sample consisting of 4357 men aged 50 years and older and 4392 postmenopausal women who participated in the Korea National Health and Nutritional Examination Survey (KNHANES) from 2008 to 2011 and underwent BMD measurement by dual-energy X-ray absorptiometry (DXA) and diabetic retinopathy assessments using seven standard gradable photographs.

Results

The diabetic women with retinopathy had lower mean BMD at all measured sites than those without retinopathy, although the BMD difference between the two groups was small (3–5 %). In addition, the diabetic women with retinopathy were 2.27 times more likely to have osteoporosis following adjustments for all clinically relevant covariates. However, the prevalence of diabetes mellitus (DM) or diabetic retinopathy was not associated with the prevalence of osteoporosis in men.

Conclusions

This study has shown that the presence of diabetic retinopathy is significantly associated with a reduced BMD and increased prevalence of osteoporosis in diabetic women.

     

The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass—a randomized controlled 1-year trial

Summary  

Vitamin D is widely used in osteoporosis treatment, although the optimal dose is not known. This 1-year clinical study among 297 women aged 50–80 years old showed that a vitamin D₃ dose of 6,500 IU/day was not better than the standard dose of 800 IU/day in improving bone mineral density (BMD) in the hip and spine.     

Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women—the six-month effect of risedronate and teriparatide

Summary  

Sclerostin is expressed by osteocytes and inhibits bone formation by osteoblasts. In this study, serum sclerostin was positively correlated with either lumbar spinal bone mineral density or T-score. Furthermore, serum sclerostin was increased after 6 months treatment with risedronate, whereas remained unchanged after 6 months teriparatide treatment.