Association of the vitamin D receptor genotype BB with low bone density in hyperthyroidism.

Bone mineral density (BMD) is modulated by genetic and environmental factors or certain diseases. In several conditions such as low calcium intake, an influence of vitamin D receptor (VDR) polymorphisms on BMD has been suggested. In the present study, we investigated the relationship of Bsm I and Fok I polymorphisms of the VDR gene and BMD in patients with hyperthyroidism, a disease that often results in low BMD. Bsm I and Fok I genotypes were determined in 76 postmenopausal hyperthyroid patients and 62 healthy postmenopausal women as controls. Patients and controls were matched for age, time since menopause, and lifestyle factors and were free of estrogen medication. BMD evaluation included axial dual X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (PQCT). Low BMD was defined as -2.5 STD below the young adult mean value. Biochemical parameters investigated were thyroid hormones, osteocalcin, and 25-(OH)-vitamin D3 as well as routine laboratory data. Low BMD was found in 61% of hyperthyroid patients and in only 23% of euthyroid controls. In the group of hyperthyroid patients with low bone density, the BB genotype (VDR Bsm I polymorphisms) was significantly more frequent (39%) than in controls (13%; p = 0.003) and hyperthyroid patients with normal BMD (6%; p = 0.013). The odds ratio (OR) for low BMD in patients with BB genotype was 5.7 (95% CI, 1.7-19.1; p < 0.005) as compared with the Bb and bb genotypes and 5.5 (95% CI, 2.3-13.2; p < 0.0001) for hyperthyroidism alone. The cumulative risk for low BMD in patients with hyperthyroidism and BB genotype was 31.4 (95% CI, 3.9-256; p < 0.0003). VDR Fok I genotypes showed no significant relationship with BMD or other general or bone-specific parameters. Thus, hyperthyroidism and the genetic background of a BB genotype may promote synergistically the development of low BMD in hyperthyroid patients. Screening for the BB genotype in these patients therefore could help to identify those with particularly high risk for the development of low BMD and allow early treatment.     

Association of vitamin d receptor genotypes with calcium excretion in nephrolithiatic subjects in northern India

Our objective was to investigate the association between the vitamin D receptor (VDR) allelic variants (Bsm I and Fok I) and nephrolithiasis in northern India. A total of 150 nephrolithiatic patients and 100 age and sex matched controls were enrolled for study. A 10 ml blood sample was obtained for biochemical analysis and DNA isolation. In addition, 24 h urine samples were obtained from each patient for the estimation of calcium and creatinine. PCR was performed for the Bsm I and Fok I VDR variants. The association between Bsm I and Fok I VDR polymorphism and nephrolithiasis was investigated after digestion with restriction enzymes (3 U). The product was analysed on 3% agarose gel for Bsm I and 15% polyacrylamide gel for Fok I allelic variants. We did not observe any significant differences in the prevalence of either the Bsm I or Fok I VDR genotypes between stone formers and controls. The B allele was found to be more prevalent in hypercalciuric patients compared to controls and nephrolithiatic subjects. The subjects with the bb genotype exhibited a higher calcium excretion than the BB genotype. Patients with the F allele were also found to excrete higher urinary calcium. VDR genotypes may be associated with increased calcium excretion in hypercalciuric nephrolithiatic subjects.     

Risk factors for osteoporosis after renal transplantation and effect of vitamin D receptor Bsm I polymorphism

Objective

Rapid loss of vertebral or hip mineral density after renal transplantation is a major complication which occurs within 6-12 months. The aim of this study was to evaluate risk factors contributing to bone disease in the early stage after renal transplantation and the effect of vitamin D receptor (VDR) gene polymorphisms.

Methods

We prospectively followed for up to 12 months 44 patients (29 men and 15 women) with end-stage renal disease who underwent kidney transplantation. All patients received prednisone with either cyclosporine (CsA)/mycophenolate mofetil (MMF) or tacrolimus (Tac)/MMF therapy. Spine, hip, and whole body bone mineral density (BMD) was measured at 12 months after transplantation. According to World Health Organization recommendations, our patients were categorized as normal, osteopenic, or osteoporotic BMD levels. VDR alleles were genotyped as BB, Bb, or bb by polymerase chain reactions based on polymorphism at the Bsm I restriction site.

Results

Forty-six percent of patients were normal, 43% osteopenic, and 11% osteoporotic. Significant risk factors for osteoporosis among renal transplant recipients were younger age and pretransplant high intact parathyroid hormone (iPTH) levels. (P values .045 and .027, respectively). According to polymorphic group categorization, posttransplant serum Ca was significantly higher in patients with BB or Bb genotype than in those with bb genotype (P = .012). Although there was no statistical significance regarding iPTH levels, it was higher among Bb+BB than the bb genotype group. Also, first-year BMD analysis after transplantation according to Bsm I polymorphism showed significant differences in femur BMD levels according to the dual classification of polymorphism (P < .05). The BMD levels in the bb group was higher than in the Bb+BB group.

Conclusions

Although high pretransplant iPTH levels and younger age enhanced posttransplant bone loss, functionally different alleles of the VDR gene may modulate bone turnover during the first year after renal transplantation.     

Vitamin D receptor genetic variants among patients with end-stage renal disease

Back ground and objectives: Vitamin D receptor (VDR) gene polymorphism is reported to be associated with end-stage renal disease (ESRD). We have investigated the potential role of VDR gene polymorphisms among ESRD. Design and methods: The influence of VDR gene polymorphism in 258 ESRD patients comprising of 226 (87.5%) male and 32 (12.5%) females was investigated in this study. We compared ESRD patients with 569 healthy controls. The distribution of male and female among controls was 485 (85.3%) males and 84 (14.7%) females. This polymorphism was studied by using polymerase chain reaction (PCR). The product was digested by using restriction enzymes Apa1, Taq1, Fok1, and Bsm1. Results: We observed a significant difference in the genotype frequencies of the Apa1-aa (p = 0.0001, OR = 2.1, 95% CI = 1.45–3.08), Fok1-ff (p = 0.001, OR = 3.44, 95% CI = 1.76–6.76), and Bsm1-BB (p = 0.0004, OR = 6.8, 95% CI = 2.2–21.58). At allelic level B allele of Bsm1 was significantly different among ESRD patients as compared to controls (p = 0.0001). The combined analysis revealed that ESRD patients with Fok1 and Bsm1 polymorphism were at increased risk of 4.33-fold. The haplotype analysis revealed individuals with a/t/F/b haplotype were at greater risk of 11.0-fold (95% CI = 1.38–87.69). The serum calcium levels were significantly higher (p = 0.001) in Bsm1 “BB” genotype. Interpretations and conclusions: Bsm1 and Fok1 gene polymorphism of VDR gene were associated with ESRD among north Indians.     

VDR Genotype and Response to Etidronate Therapy in Late Postmenopausal Women

Twenty-four late postmenopausal women with osteoporosis were studied. The patients were separated in three subgroups according to the BsmI polymorphism of the vitamin D receptor (VDR) gene: BB (n= 8), Bb (n = 10) and bb (n = 6). They did not differ in age (mean ages were 66.0 years, 65.9 years and 63.9 years, respectively), years after menopause (18.7 years, 18.1 years and 18.4 years) or body weight (64.9 kg, 65.3 kg and 63.8 kg), the variables known to be associated with bone mineral density (BMD). The results show that the response to antiresorptive bisphosphonate therapy in combination with calcium supplementation is modified by VDR genotype. The lumbar spine BMD increased significantly faster in the BB and Bb groups (7.3% and 7.0%, respectively) compared with the bb group (2.5%) during 1 year of cyclic etidronate therapy (400 mg/day) and calcium supplementation (1000 mg/day). The biochemical marker of bone resorption (urinary hydroxyproline excretion) as well as the bone formation marker (serum levels of osteocalcin) decreased during the treatment. With respect to VDR genotype, a significantly higher decrease in osteocalcin level was observed in bb as compared with BB subjects. We conclude that the VDR genotype is involved in an individual’s response to cyclic etidronate therapy with calcium supplementation. Received: 12 December 1998 / Accepted: 18 March 1999     

Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.     

The Contribution of Vitamin D Receptor Gene Polymorphisms in Osteoporosis and Familial Osteoporosis

It is well established that genetic factors play a major role in the pathogenesis of osteoporosis. Previous reports have suggested that vitamin D receptor (VDR) gene polymorphisms, particularly the BB, tt and AA genotypes, are associated with low bone mineral density (BMD). If these VDR genotypes are indeed an important determinant of BMD, then a population of related osteoporotic individuals (mother–daughter or sister–sister relationship) should have a high prevalence of the BB, tt or AA VDR genotypes. To test this hypothesis we determined the VDR genotypes in 26 osteoporotic persons (age 44.3 ± 12.7 years, mean ± SD) belonging to 12 families. Furthermore, for comparison with existing studies, we applied the VDR genotype analysis in a population of 53 unrelated healthy subjects (age 45.2 ± 9.8 years, mean ± SD) and 59 unrelated osteoporotic subjects (age 52.1 ± 9.0 years, mean ± SD). The menopausal status of the healthy and osteoporotic populations was pre-, peri- and mostly early postmenopausal. The proportions of the three genotypes, BB, tt and AA, within the 12 osteoporotic families were 15%, 12% and 27%, respectively, whereas the proportions of the other three homozygous genotypes (bb, TT, aa) were 50%, 50% and 23%. The distribution of the BB, tt and AA genotypes in the normal population was 21%, 21% and 36%, respectively (vs bb, TT, aa: 36%, 38%, 21%), whereas in the osteoporotic population it was 24%, 20% and 34% (vs bb, TT, aa: 27%, 34%, 14%). Our data indicate that there is not a statistically significant (p>0.05) difference in the VDR genotype frequencies within osteoporotic families as compared with the same genotypes in the population of unrelated normal or osteoporotic subjects. VDR genotype analysis showed no significant relation between VDR polymorphisms and BMD or Z-score values at the lumbar spine. This study demonstrates the lack of a heritability pattern between the BB, tt and AA genotypes and low BMD. Received: 29 October 1998 / Accepted: 19 April 1999     

Vitamin D Receptor Polymorphisms and Falls Among Older Adults Living in the Community: Results From the ilSIRENTE Study

Vitamin D receptor (VDR) genotypes were associated with cognitive status, depressive symptoms, strength, and sarcopenia, but, thus far, no study has assessed their relationship with falls. The objective of this study is to evaluate whether, in a population of older adults living in the community, VDR FokI and BsmI genotypes are associated with falls. To this aim, we used data from the baseline evaluation of the ilSIRENTE study, which enrolled older adults ≥80 yr of age living in the community in Italy. Falls occurring within 90 days of assessment were assessed by study personnel. The mean age of 259 study participants was 85.0 ± 4.5 (SD) yr; 172 (66.4%) were women. Overall, 33 (12.7%) participants reported one or more falls. The rate of falls was 19.5% in participants with the BB genotype, 11.1% in those with Bb genotype, and 5.9% in those with bb genotype (p for linear trend = 0.02). After adjusting for potential confounders, compared with participants with the BB genotype, those with the bb genotype had a significantly lower OR for falls 0.14 (95% CI, 0.03–0.66). Rate of falls did not differ significantly across FokI genotypes (FF: 14.4%, Ff: 11.9%, ff: 9.1%; p = 0.43). In conclusion, the VDR bb genotype of the BsmI gene is associated with a reduced rate of falls compared with the BB genotype, whereas no effect on falls was shown for FokI polymorphism. Further studies conducted in larger population are needed to confirm the association of BsmI genotype and falls and to understand reasons for these findings.     

Vitamin D receptor gene polymorphisms and bone mass indices in post-menarchal Indian adolescent girls

To study the association between vitamin D receptor (VDR) gene polymorphisms and bone mass indices in adolescent girls, a cross-sectional study was conducted in 120 post-menarchal girls aged 15–18 years in Pune city, India. Serum levels of ionised calcium, inorganic phosphorous, parathyroid hormone and 25-hydroxy vitamin-D were measured. Bone mineral content (BMC), bone area (BA) and bone mineral density (BMD) were measured at total body (TB), lumbar spine (LS) and left femoral neck (FN) using dual energy X-ray absorptiometry. Polymorphisms of the VDR gene at the Fok1 and Bsm1 loci were detected using SYBR Green quantitative polymerase chain reaction. The overall distribution of genotypes at the Bsm1 locus in this study was 33.3 % Bb, 29.2 % bb and 37.5 % BB while that for the Fok1 locus was 44.2 % Ff, 7.5 % ff and 48.3 % FF. There were no significant differences in the blood parameters when classified according to Bsm1 or Fok1 genotypes. Subjects with BB genotype have significantly higher mean TBBMC, TBBA, TBBMD and LSBMD than Bb and bb (p < 0.05) and showed a tendency for association with LSBMC and LSBA (p < 0.1). Subjects with Ff genotype showed a tendency for association with left FNBMC and FNBA (p < 0.1). Bsm1 genotype did not show an association with FN bone indices whereas Fok1 genotype did not show association with TB or LS bone indices. In conclusion, the present study demonstrates VDR gene polymorphism, defined by Bsm1 genotype, has an influence on total body and lumbar spine bone mass indices in post-menarchal Indian girls.     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998     

Genotypes and clinical aspects associated with bone mineral density in Argentine postmenopausal women

The aim of this study was to determine genotypes and clinical aspects associated with bone mineral density (BMD) in postmenopausal women from Córdoba, Argentina. Polymorphisms were assessed by RFLP-PCR technique using BsmI and FokI for vitamin D receptor gene (VDR) and XbaI and PvuII for estrogen receptor-alpha gene (ERalpha) as restrictases. Sixty-eight healthy, 54 osteopenic, and 64 osteoporotic postmenopausal women were recruited. Femoral neck and lumbar spine BMD were inversely correlated with age in the entire analyzed population. Height was lower in osteopenic and osteoporotic women as compared to healthy women (P < 0.05). Weight and body mass index (BMI) were the lowest in osteoporotic women (P < 0.01 versus healthy group). Serum procollagen type I Nterminal propeptide (PINP) was higher in osteoporotic women as compared to the other groups. Distribution of VDR and ERalpha genotypes was similar in the three groups. Genotype bb (VDR) was associated with low values of lumbar BMD in the healthy group (P < 0.05 versus genotype Bb), and with low values of femoral BMD (P < 0.05 versus genotype BB) in osteoporotic women. BB*Pp interaction was associated with the highest femoral neck BMD (P < 0.05), whereas the bb*xx interaction was associated with the lowest femoral neck BMD in the total population analyzed (P < 0.05). In conclusion, parameters such as age, height, weight, BMI, serum PINP, VDR genotypes, and interactions between VDR and ERalpha genotypes could be useful to predict a decrease in BMD in Argentine postmenopausal women.     

BsmI,TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and risk of fracture in Caucasians: A meta-analysis

ContextVitamin D receptor (VDR) gene polymorphisms have been strongly associated with bone mineral density in some studies. However, in a recent meta-analysis, no relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data.Objective and designOur meta-analysis studied whether a relationship exists between BsmI, TaqI, ApaI and FokI polymorphisms in the VDR gene and risk of fracture.Data sourcesRelevant studies were identified from the following electronic databases: MEDLINE, EMBASE and Current Contents before January 2010.Data synthesisThis meta-analysis included 17 studies with a total of 21 eligible comparisons, which included 2112 fracture cases and 4521 controls. All of these studies reported on Caucasians. The combined results based on all studies showed that fracture cases had a significantly lower frequency of bb genotype of BsmI [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.76, 0.98]. When stratifying by fracture type, we found that (1) hip fracture cases had a significantly lower frequency of bb genotype of BsmI (OR = 0.82, 95% CI = 0.70, 0.97); (2) hip fracture cases had a significantly lower frequency of Tt genotype of TaqI (OR = 0.65, 95% CI = 0.43, 0.97); (3) hip fracture cases had a significantly higher frequency of tt genotype of TaqI (OR = 1.74, 95% CI = 1.05, 2.91); (4) vertebral fracture cases had a significantly higher frequency of Aa genotype of ApaI (OR = 1.63, 95% CI = 1.03, 2.59). No significant difference was found in any genotype of FokI.ConclusionOur meta-analysis suggests that there is a modest but statistically significant association between the BsmI bb genotypes and fracture.     

The Importance of Previous Fracture Site on Osteoporosis Diagnosis and Incident Fractures in Women

Previous fracture increases the risk of subsequent fractures regardless of the site of the initial fracture. Fracture risk assessment tools have been developed to guide clinical management; however, no discrimination is made as to the site of the prior fracture. Our objective was to determine which sites of previous nontraumatic fractures are most strongly associated with a diagnosis of osteoporosis, defined by a bone mineral density (BMD) T‐score of ≤ ?2.5 at the femoral neck, and an incident major osteoporotic fracture. Using administrative health databases, we conducted a retrospective historical cohort study of 39,991women age 45 years and older who had BMD testing with dual‐energy X‐ray absorptiometry (DXA). Logistic regression and Cox proportional multivariate models were used to test the association of previous fracture site with risk of osteoporosis and incident fractures. Clinical fractures at the following sites were strongly and independently associated with higher risk of an osteoporotic femoral neck T‐score after adjustment for age: hip (odds ratio [OR], 3.58; 95% confidence interval [CI], 3.04–4.21), pelvis (OR, 2.23; 95% CI, 1.66–3.0), spine (OR, 2.16; 95% CI, 1.77–2.62), and humerus (OR, 1.74; 95% CI, 1.49–2.02). Cox proportional hazards models, with adjustment for age and femoral neck BMD, showed the greatest increase in risk for a major osteoporotic fracture for women who had sustained previous fractures of the spine (hazard ratio [HR], 2.08; 95% CI, 1.72–2.53), humerus (HR, 1.70; 95% CI, 1.44–2.01), patella (HR, 1.54; 95% CI, 1.10–2.18), and pelvis (HR, 1.45; 95% CI, 1.04–2.02). In summary, our results confirm that nontraumatic fractures in women are associated with osteoporosis at the femoral neck and that the site of previous fracture impacts on future osteoporotic fracture risk, independent of BMD. © 2014 American Society for Bone and Mineral Research.     

Variation in the Efficacy of Hormone Replacement Therapy in the Prevention of Hip Fracture

Use of postmenopausal hormone replacement therapy (HRT) has been associated with a reduced risk of osteoporotic fractures. However, it is uncertain whether this risk reduction is modified by other risk factors for hip fracture. In a population-based case–control study in Sweden, we investigated the association between HRT and hip fracture risk within categories of age, body measures and lifestyle factors in postmenopausal women, 50–81 years of age. Mailed questionnaires and telephone interviews were used to collect data. Of those eligible, 1328 incident cases with hip fracture (82.5%) and 3312 randomly selected controls (81.6%) answered the questionnaire. Ever use of HRT in women less than 75 years old was associated with an odds ratio (OR) of 0.66 (95% confidence interval: 95% CI 0.50–0.87) for hip fracture compared with OR 0.40 (95% CI 0.21–0.77) in women 75 years or older. We found a significant interaction between HRT and both weight and physical activity (p<0.05). The protective effect of HRT was particularly pronounced in lean women: compared with never HRT users, ever users weighing under 60 kg had an OR of 0.44 (95% CI 0.30–0.66) whereas women weighing more than 70 kg had an OR of 0.91 (95% CI 0.53-1.-56). Women with low recent leisure physical activity (less than 1 h/week) similarly benefited more from HRT for hip fracture prevention than women with a higher degree of recreational physical activity. The observed interactions with weight and physical activity suggest that HRT has the best protective effect against hip fracture among high-risk women. Received: 7 October 1997 / Revised: 21 January 1998     

Differences in Site-Specific Fracture Risk Among Older Women with Discordant Results for Osteoporosis at Hip and Spine: Study of Osteoporotic Fractures

To examine the fracture pattern in older women whose bone mineral density (BMD) T-score criteria for osteoporosis at hip and spine disagree, hip and spine BMD were measured in Study of Osteoporotic Fractures participants using dual energy X-ray absorptiometry (DXA). Hip osteoporosis was defined as T-score ≤−2.5 at femoral neck or total hip, and spine osteoporosis as T-score ≤−2.5 at lumbar spine. Incident clinical fractures were self-reported and centrally adjudicated. Incident radiographic spine fractures were defined morphometrically. Compared to women with osteoporosis at neither hip nor spine, those osteoporotic only at hip had a 3.0-fold age- and weight-adjusted increased risk for hip fracture (95% confidence interval [CI]: 2.4–3.6), and smaller increases in risk of nonhip nonspine (hazard ratios [HR] = 1.6), clinical spine (odds ratio [OR] = 2.2), and radiographic spine fractures (OR = 1.5). Women osteoporotic only at spine had a 2.8-fold increased odds of radiographic spine fracture (95% CI: 2.1–3.8), and smaller increases in risk of clinical spine (OR = 1.4), nonhip nonspine (HR = 1.6), and hip fractures (HR = 1.2). Discordant BMD results predict different fracture patterns. DXA fracture risk estimation in these patients should be site specific. Women osteoporotic only at spine would not have been identified from hip BMD measurement alone, and may have a sufficiently high fracture risk to warrant preventive treatment.     

广西壮、汉族绝经后妇女维生素D受体基因型与骨密度的关系

目的 探讨维生素D受体基因(VDR)型在广西壮、汉族绝经后妇女中的分布及其与骨密度(BMD)的关系。方法 在广西居住20年以上、无血缘关系的健康绝经后妇女198名,其中三代均为壮族的116名,均为壮族的82名。记录他们的年龄、绝经年龄,测量他们的身高、体重。用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法测定受试者的VDR基因型;用双能X线吸收法测定髋部、腰椎和前臂的骨密度。结果 壮、汉两组妇女VDR基因型和VDR等位基因频率分布均无显著性差异(P>0.05);198名妇女BB、Bb、bb基因型检出率分别为6.57％、66.16％和27.27％;B、b等位基因分别为39.65％和60.35％。BB基因型组第二腰椎(L2)BMD较bb基因型组低10.03％(P=0.047),第四腰椎(L4)BMD分别较bb、Bb基因型组低9.63％(P=0.043)和12.44％(P=0.005)。BB基因型组骨质疏松发生率最高(46.15％),Bb基因型组次之(19.86％),bb基因型组最低(14.81％),差异有显著性(P=0.04)。结论 VDR基因型与广西壮、汉族绝经后妇女BMD有关联,BB基因型可能可作为预测广西壮、汉族绝经后妇女骨质疏松危险性的遗传学标志之一。     

Risk factors for foot fracture among individuals aged 45 years and older

A case-control study undertaken among members of five Northern California Kaiser Permanente medical centers sought to identify risk factors for foot fractures among persons aged 45 years and older. Foot fracture cases (n=920) and frequency matched controls (n=2366) were interviewed between October 1996 and May 2001 using a standardized questionnaire. Foot fractures occurred most often while walking or climbing stairs. While 60% of foot fractures resulted from falls, 20% were attributed to other causes, such as hitting the foot or tripping on sidewalks and curbs. Having a self-reported history of physician-diagnosed diabetes [adjusted odds ratio (OR)=1.45, 95% confidence interval (CI)=1.10–1.91] or cataracts (OR=1.40, 95% CI=1.07–1.83), having a self-reported foot problem (OR=1.38, 95% CI=1.06–1.78 for two or more foot problem versus no foot problems), having difficulty walking in minimum light (OR=1.86, 95% CI=1.14–3.05) and having had a prior fracture (OR=1.20, 95% CI=1.05–1.37) were associated with increased risk. Putative protective factors for osteoporotic fractures, such as menopausal hormone therapy use, thiazide or water pill use, high calcium intake, and high body mass index were not associated with foot fracture risk. These findings suggest that risk factors for foot fractures among older people differ in part from risk factors for other fracture sites generally considered to be osteoporotic, such as the hip, vertebrae, and forearm.     

Association of the VDR translation start site polymorphism and fracture risk in older women.

We evaluated the association between the VDR translation start site polymorphism and osteoporotic phenotypes among 6698 older white women. Women with the C/C genotype had lower wrist BMD and an increased risk of wrist and all non-spine/low-trauma fractures. The high frequency of this variant confers a population attributable risk that is similar to several established risk factors for fracture. INTRODUCTION: The vitamin D receptor (VDR) is a nuclear receptor that regulates bone formation, bone resorption, and calcium homeostasis. A common C to T polymorphism in exon 2 of the VDR gene introduces a new translation start site and a protein that differs in length by three amino acids (T = 427aa, C = 424aa; rs10735810). MATERIALS AND METHODS: We conducted genetic association analyses of this polymorphism, BMD, and fracture outcomes in a prospective cohort of 6698 white American women >or=65 years of age. Incident fractures were confirmed by physician adjudication of radiology reports. There were 2532 incident nontraumatic/nonvertebral fractures during 13.6 yr of follow-up including 509 wrist and 703 hip fractures. RESULTS: Women with the C/C genotype had somewhat lower distal radius BMD compared with those with the T/T genotype (CC=0.358 g/cm(2), CT=0.361 g/cm(2), TT=0.369 g/cm(2), p=0.003). The C/C genotype was also associated with increased risk of non-spine, low traumatic fractures (HR: 1.18; 95% CI: 1.04, 1.33) and wrist fractures (HR: 1.33; 95% CI: 1.01, 1.75) compared with the T/T genotype in age-adjusted models. Further adjustments for distal radius BMD only slightly attenuated these associations. The VDR polymorphism was not associated with hip fracture. The population attributable risk (PAR) of the C/C genotype for incident fractures was 6.1%. The PAR for established risk factors for fracture were: low femoral neck BMD (PAR=16.3%), maternal history of fracture (PAR=5.1%), low body weight (PAR=5.3%), corticosteroid use (PAR=1.3%), and smoking (PAR=1.6%). Similar PAR results were observed for wrist fractures. CONCLUSIONS: The common and potentially functional VDR translation start site polymorphism confers a modestly increased relative risk of fracture among older white women. However, the high frequency of this variant confers a population attributable risk that is similar to or greater than several established risk factors for fracture.     

Polymorphism of the Vitamin D Receptor Gene and Corticosteroid-Related Osteoporosis

Corticosteroid therapy (CST) is associated with reduced intestinal calcium absorption, bone loss and increased fracture risk. As polymorphisms of the vitamin D receptor (VDR) gene may be associated with bone mineral density (BMD) and intestinal calcium absorption, we asked whether patients with a given VDR genotype receiving CST may be at increased or decreased risk for corticosteroid-related bone loss and osteoporosis. We measured areal BMD (g/cm²) by dual-energy X-ray absorptiometry in 193 women (50 premenopausal, 143 postmenopausal) and 70 men with rheumatoid arthritis (n= 44), obstructive airway diseases (n= 128) and other corticosteroid-treated diseases (n= 91). All patients received a cumulative dose greater than 1.8 g per year or a minimum of 5 mg daily of prednisolone or equivalent for at least 1 year. VDR alleles were typed by polymerase chain reaction assay based on the polymorphic BsmI and TaqI restriction sites. BMD in patients was expressed as a Z-score (mean ± SEM) derived from age- and gender-matched controls. BMD was reduced in patients at the lumbar spine (bb, −0.52 ± 0.12; Bb, −0.47 ± 0.11; BB, −0.65 ± 0.18 SD; p<0.01), femoral neck (bb, −0.46 ± 0.10; Bb, −0.34 ± 0.10; BB, −0.54 ± 0.14 SD; p<0.01), Ward’s triangle (bb, −0.44 ± 0.10; Bb, −0.31 ± 0.10; BB, −0.45 ± 0.13 SD; p<0.01), and trochanter (bb, −0.50 ± 0.10; Bb, −0.30 ± 0.10; BB, −0.44 ± 0.14 SD; p<0.01). However, there was no significant difference in the deficit in BMD in any of the genotypes, either before or after adjusting for age, sex, body mass index, disease type, age at onset of disease, disease duration, cumulative steroid dosage, smoking status and dietary calcium intake. Similarly, there were no detectable differences between the BsmI genotypes and the rate of bone loss in 79 patients with repeated BMD measurements at an interval of 4–48 months. The data suggest that the VDR genotypes may not be a means of identifying patients at greater risk of corticosteroid-related bone loss. Received: 23 December 1997 / Accepted: 26 May 1998     

Association between vitamin D receptor gene polymorphisms, falls, balance and muscle power: results from two independent studies (APOSS and OPUS)

Summary  

Fall prevention is a key strategy for reducing osteoporotic fractures. We investigated the association between vitamin D receptor (VDR) polymorphisms and reported falls in postmenopausal women. Bsm1 polymorphisms were associated with falls, balance and muscle power measurements. These results may explain some of the excess fracture risk associated with VDR in some studies.