Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration

STUDY DESIGN: A study in genetic epidemiology of disc degeneration, based on lifetime exposure data, findings on magnetic resonance imaging, and genotyping of intragenic markers. OBJECTIVES: To pursue the potential correlation between common allelic variations in the vitamin D receptor locus and degeneration of the intervertebral disc. SUMMARY OF BACKGROUND DATA: Familial aggregation has been observed in intervertebral disc degeneration, but the relative significance of the genetic component and shared environmental influences is unknown. The identification of relevant candidate genes associated with disc degeneration would specify a genetic component and increase our understanding of the etiopathogenesis of disc degeneration. METHODS: From the population-based Finnish Twin cohort, 85 pairs of male monozygotic twins were selected based on exposure to suspected risk factors for disc degeneration. Interview data were gathered on relevant lifetime exposures, and thoracic and lumbar disc degeneration was determined through quantitative and qualitative assessments of signal intensity on magnetic resonance imaging, and qualitative assessments of disc bulging and disc height narrowing. Possible associations were examined between disc degeneration measures and two polymorphisms of the coding region of the vitamin D receptor locus. RESULTS: Two intragenic polymorphisms of the vitamin D receptor gene revealed an association with disc degeneration. Quantitatively assessed signal intensities of thoracic and lumbar (T6-S1) discs were 12.9% worse in men with the Taql tt genotype and 4.5% worse in men with the Tt genotype, compared with signal intensity in men with the TT genotype (age adjusted P = 0.003). A similar pattern was found between disc signal intensity and Fokl genotypes; men with the ff and Ff genotypes had mean signal intensities that were 9.3% and 4.3% lower, respectively, than those in men with FF genotypes (age-adjusted P = 0.006). The summary scores of qualitatively assessed signal intensity, bulging, and disc height were 4.0% and 6.9% worse in men with Ff and ff genotypes, respectively, when compared with those in men with the FF genotype (age-adjusted P = 0.029). CONCLUSION: Specific vitamin D receptor alleles were associated with intervertebral disc degeneration as measured by T2-weighted signal intensity, demonstrating for the first time, the existence of genetic susceptibility to this progressive, age-related degenerative process.     

Bone mineral density and bone markers in relation to vitamin D receptor gene polymorphisms in Chinese men and women

Whether vitamin D receptor gene (VDRG) polymorphism can be used as a predictor for bone turnover rate or bone mass remains controversial. Its role within various ethnic populations are also unsettled. We examined VDRG polymorphism using restrictive enzymes Bsm-I, Apa-I, and Taq-I in 155 men aged 22-88 and 113 premenopausal women aged 40-53. The bone mineral density (BMD) of the vertebrae (L2-4), proximal femur, and total body bone mineral content (tb-BMC) (women only), as well as urinary N-terminal crosslinked fragment of type I collagen (NTX), serum osteocalcin, bone isozyme of alkaline phosphatase, and caboxyterminal propeptide of type I procollagen levels were measured. Chinese men and women exhibited a low prevalence for B (absence of Bsm-I restriction site) phenotypes than white and Japanese. Within the tested samples there were 0.4% BB homozygotes, 6.7% Bb heterozygotes, and 93% bb homozygotes. The distributions of Apa-I polymorphism (9.0% AA, 42.5% Aa, and 48.5% aa) also differed from those reported for the white populations. Most of the Chinese men and women were TT homozygous (96.6%). A comparison of actual values and values adjusted for age and weight of tb-BMC and BMD at the lumbar spine, Trochanter, Ward's triangle, and femoral neck showed no significant difference among three subgroups in each of the three sets of polymorphism. Furthermore, the actual values and adjusted values (adjusted for age) of the four bone markers, respectively, showed no significant differences. We conclude that given the very low prevalence of the suspected high risk genotypes (B, A, and t), and the lack of difference among the polymorphic subgroups, VDRG polymorphism may not be an important determinant of the bone turnover rate and bone mass of Chinese men and women.     

Association between intestinal vitamin D receptor, calcium absorption, and serum 1,25 dihydroxyvitamin D in normal young and elderly women

This paper systematically reviews the results from epidemiologic studies investigating the hypothesis that breast cancer risk in postmenopausal women increases with increasing concentrations of estradiol in blood and with increasing urinary estrogen excretion rates. Data from 29 epidemiologic studies of endogenous hormones and postmenopausal breast cancer were used. The ratio of the average estrogen concentration in the women with breast cancer to that in the women without breast cancer (and its 95 percent confidence interval [CI]) was calculated for each study, and the results were summarized by calculating weighted averages of the log ratios. In six prospective studies of serum estradiol concentration, 329 women who subsequently developed breast cancer had, overall, a 15 percent (CI = 6-24 percent, P = 0.0003) higher mean concentration of estradiol in their blood than the 1,105 women who remained free of cancer. The results of these prospective studies did not differ significantly from each other (chi2 for heterogeneity = 8.7; degrees of freedom = 5; P > 0.1). Similar differences in mean estrogen levels were seen in the case-control studies which reported either estradiol concentrations in the blood or urinary estrogen excretion. However, the case-control studies showed significant heterogeneity among their results. The data from the prospective studies strongly suggest that breast cancer risk in postmenopausal women is associated with relatively high concentrations of endogenous estradiol.     

Interrater and intrarater reliability in the measurement of kyphosis in postmenopausal women with osteoporosis

STUDY DESIGN: A reliability study was performed using repeated random measurements involving three observers, 26 subjects and three instruments. OBJECTIVES: To determine the most reliable, cost-effective, noninvasive, and clinically feasible method of measuring spinal kyphosis. SUMMARY OF BACKGROUND DATA: The most clinically useful, noninvasive and reliable method of measuring postural deformity in spinal osteoporosis (kyphosis) remains unqualified. Despite traditional use of costly, invasive roentgenographs for the evaluation of spinal kyphosis, the reliability of this method remains questionable. METHODS: Twenty-six postmenopausal women with known bone mineral density and a diagnosis of osteoporosis were recruited from the Osteoporosis Program at Women's College Hospital, Toronto, Canada. Non-invasive measurements of thoracic kyphosis were obtained by three trained examiners using the DeBrunner's kyphometer and the flexicurve ruler. The intrarater and interrater reliability of and between each method was compared, using roentgenographic films obtained in the sagittal plane. Spinal posture was classified according to the method of Itoi (1990). Statistical computations were performed using SAS statistical software. RESULTS: Consistent measurements were obtained with the DeBrunner's kyphometer and the flexicurve ruler by each observer, according to the results of critical two-way analysis of variance (Intraclass Correlation Coefficient 2, 1). Measurements in two subgroups, healthy backs (n = 11) and rounded backs (n = 13), showed consistent use of each noninvasive instrument with some examiner preference for specific tools. There was marginally better intrarater and interrater reliability using the DeBrunner's kyphometer compared with that obtained with the flexicurve ruler. Two-way analysis of variance (Intraclass Correlation Coefficient 2, 1) of collapsed data showed no significant difference in the reliability of the kyphometer, flexicurve ruler, or roentgenographs in the measurement of thoracic kyphosis. CONCLUSIONS: The flexicurve ruler and DeBrunner's kyphometer had the closest agreement in the measurement of spinal kyphosis. The kyphometer demonstrated the least variation in intrarater and interrater reliability when compared with the flexicurve ruler and roentgenographs. The flexicurve ruler permits qualitative assessment of posture, however, and is the most cost-effective instrument. The results of this study challenge the traditional belief that roentgenographic analysis is the best method for evaluating spinal kyphosis. The DeBrunner's kyphometer and flexible ruler may represent viable, cost-effective and noninvasive alternatives to roentgenographic evaluation of spinal kyphosis.     

Low serum vitamin D metabolites in women with rheumatoid arthritis

The aim of the study was to examine the opinions of psychiatric patients regarding the aims of their care and to compare these to the aims recorded by the nursing staff on the treatment plan forms. Attention was also paid to the reasons quoted by the patients for the given helping methods and their opinions on factors which promote or hamper treatment. The basic group consisted of patients who had been treated at the Department of Psychiatry in the University Hospital District of Northern Ostrobothnia for at least two weeks. The group was divided into two parts: 1) patients treated in a close ward and 2) those in an open ward. Thirty-one patients of each kind were selected by random sampling and interviewed using five open questions which concerned the aims of the treatment, their grounds for participating in the treatment concerned and factors promoting or hampering treatment. The notes on the aims of the treatment made by the nursing staff were gathered from the treatment plan forms for the patients in question. The data were analyzed by content analysis. The primary finding was that there are still discrepancies between the aims recorded in the course of treatment and patient's own opinions. The results indicate that the patients regarded social interaction as the primary reason for seeking treatment, followed by therapeutic interaction and normative factors in the ward. Factors considered to promote helping were therapeutic interaction, medical treatment, self realization and social interaction, whereas the detrimental factors were related to the patients themselves, their individual needs, the environment, the therapeutic community or the medication provided.     

Vitamin D receptor gene polymorphism is associated with urinary calcium excretion but not with bone mineral density in postmenopausal women

Polymorphism of vitamin D receptor (VDR) gene has been found to be associated with serum osteocalcin (OC) levels and bone mineral density (BMD) in Caucasian identical twins and unrelated postmenopausal women. Being ethnically different and living in a geographic area with adequate vitamin D status due to abundant sunshine exposure, it is unclear whether VDR gene polymorphism will affect bone mass in Thai population. In the present study, we investigated the association between VDR gene polymorphism and bone metabolism in Thai postmenopausal women. Subjects consisted of 84 postmenopausal women. Bsm I, Taq I and Apa I polymorphisms of VDR gene were determined by PCR-RFLP. B, T and A represent the absence of the corresponding restriction sites while b, t and a indicate the presence of the restriction sites. Data were expressed as mean +/- SE. Sixty-six subjects (78.6%) had bb genotype while 18 (21.4%) had Bb genotype. None of the subjects was found to have BB genotype. Taq I restriction site was in linkage disequilibrium to the Bsm I site. For Apa I polymorphism, 33 (39.3%), 42 (50.0%) and 9 (10.7%) of the subjects had aa, Aa and AA genotypes, respectively. There was no significant difference in serum intact OC levels and BMD at various skeletal sites among subjects with different genotypes. Despite the lack of difference in BMD and intact OC levels, subjects with bb genotype had higher 24-hour urinary calcium excretion than those with Bb genotype (bb, 6.1 +/- 0.3 mmol/day; Bb, 4.4 +/- 0.6 mmol/day; p < 0.05). The effect of Bsm I VDR genotype was still significant (p < 0.05) after dietary calcium intake was controlled using analysis of covariance. Despite the difference in urinary calcium levels, there was no significant difference in fractional excretion of calcium among subjects with different Bsm I-related genotypes, suggesting that the effect of the VDR gene polymorphism on urinary calcium excretion is more likely due to the effect on intestinal calcium absorption rather than renal tubular calcium reabsorption. We conclude that VDR genotype distributions in Thai postmenopausal women are different from those reported in Caucasians. VDR gene polymorphism does not appear to be associated with BMD or bone turnover in Thai postmenopausal women. However, Bsm I VDR polymorphism may have physiologic role in calcium homeostatasis by modulating intestinal calcium absorption.     

Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women

To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986. Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.     

Association of bone mineral density with vitamin D receptor gene polymorphism--changes in radial bone mineral density with long-term follow-up: longitudinal study

Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to vitamin D receptor (VDR) gene polymorphism. However, discordant studies have been published and it is still not clear whether VDR genotypes influence bone mass accretion and/or postmenopausal bone loss. To assess allelic influence of the VDR gene on BMD, we determined changes in 1/6-radial-BMD by several repeat measurements in the same subjects for about ten years and analyzed VDR polymorphism of BsmI restriction enzyme in 53 normal healthy Japanese women (age: 50.3 +/- 4.7 years, mean +/- SD). Twenty-seven (age: 53.2 +/- 4.7 years) of the subjects were post-menopausal (POST group). Among these 53 subjects, the distribution of bb, Bb and BB genotypes was 64.2%, 34% and 1.9%, respectively. The genotype frequencies in this study were very similar to those in previous reports concerning other Japanese women. There was no difference between the b group (women with bb genotype) and B group (women with BB or Bb genotype) in age, body weight, height, body mass index (BMI), years since menopause, serum osteocalcin and serum alkaline phosphatase values. In the POST group, BMD of the B group at menopause was lower than that of the b group (p < 0.05). About ten years after menopause, BMD did not differ significantly between these groups because the decrease in BMD in the b group was larger than that in the B group. Regarding changes in BMD in the POST group for four years after menopause, BMD of the b group was significantly decreased compared with the B group (p < 0.01). Our findings suggest that the differences in BMD by VDR genotype were larger among pre- and pri-menopausal women and seemed to decrease with years after menopause. It is suggested that there are other factors influencing BMD and postmenopausal bone loss in elderly women.     

Genotype distribution of estrogen receptor polymorphisms in men and postmenopausal women from healthy and coronary populations and its relation to serum lipid levels

The cardiovascular protective effects of estrogen are known to be mediated by its beneficial effects on lipid metabolism and its direct actions on the vessel wall. The latter can be mediated by a specific receptor for estrogen present on smooth muscle cells and endothelial cells. The gene for the receptor (the classic estrogen receptor [ER]) has three known polymorphisms, Pvu II, Xba I, and B-variant polymorphisms, which are reportedly associated with receptor expression and altered receptor function and with some disorders including breast cancer, hypertension, and spontaneous abortion. However, the significance of genetic variations of the ER in vascular diseases has not been reported. We have examined the association between coronary artery disease (CAD) and the three polymorphisms in ER. Genotypes (P1/P2, X1/X2, and B-wild type/B-variant type) were determined in 87 men and postmenopausal women with myocardial infarction or angina pectoris whose lesions were confirmed by coronary angiography, as well as from 94 control individuals from the general population with no coronary heart disease and normal resting ECG. For B-variant polymorphism, all individuals examined had B-wild type, which contrasts with the reported allele frequency for B-variant type (0.1) in the white population. Genotype distributions and allele frequencies of Pvu II or Xba I polymorphisms were not significantly different between control subjects and patients (P > .05 for Pvu II or Xba I genotypes; P > .05 for Pvu II or Xba I allele frequencies). When the allele frequencies were analyzed separately by sex, there was still no statistically significant difference for both polymorphisms (P > .05 for men; P > .05 for women). No association was found between the polymorphisms and the angiographic severity of CAD. Total cholesterol, triglyceride, or HDL-cholesterol levels were not significantly different among ER genotypes. These findings suggest that the three polymorphisms in ER are not associated with the prevalence and severity of CAD and that the polymorphisms are unrelated to the serum lipid levels in control subjects and patients.     

Evaluation and treatment of postmenopausal osteoporosis

OBJECTIVES: To review the recent literature and develop a logical strategy with which to approach the diagnosis and treatment of osteoporosis, based on clinical evidence and accepted practices. METHODS: Published reports from 1983 through 1997 obtained by MEDLINE search were reviewed and analyzed by both authors. RESULTS: Osteoporosis is a widespread medical condition readily identifiable by current diagnostic modalities, including quantitative computed tomography, single and dual x-ray absorbtiometry, radio-absorbtiometry, and ultrasound. Properly implemented prevention and treatment strategies, such as calcium and vitamin D supplementation, exercises, hormone replacement therapy, alendronate, and calcitonin, may reduce the future fracture risk in many individuals. An algorithm is provided based on currently available clinical evidence for the evaluation and treatment of osteoporosis. CONCLUSIONS: Expanded use of currently available and emerging diagnostic and therapeutic modalities should lead to decreased fracture rates and a resultant increase in quality of life for patients with osteoporosis.     

Prevention and treatment of postmenopausal osteoporosis

The purpose of the review is to outline the interventions, both pharmacological and non-pharmacological, available to prevent postmenopausal osteoporosis (PMO) and treat the established disease. Current suggested guidelines for the most cost-effective treatment and prophylactic strategies are included following a consideration of the available options. As life expectancy has increased so has the incidence of PMO which has major quality of life implications for the sufferers and economic implications for the authorities responsible for their treatment. PMO represents a significant public health problem and although more effective treatments are becoming available prevention of the disease by taking account of existing risk factors is preferable. Indeed, a population approach to prevention may be more cost effective than screening for the disease. Attention to dietary calcium intake and exercise regimes have been shown to be effective prophylactic measures premenopausally, while the treatment of choice is hormone replacement therapy (HRT). HRT treats other postmenopausal symptoms in addition to PMO and is available in many presentations, containing different hormones, at different doses intended for different routes of administration. The optimum treatment duration is controversial and may contribute to some of the risks associated with HRT such as endometrial and breast carcinoma and venous thromboembolism (VTE). Newer effective treatments include the bisphosphonates and novel formulations of calcitonin, but older approaches such as vitamin D, anabolic steroids and fluoride are still utilised in some circumstances. However, most promise has been shown by synthetic hormonal modulators currently being trialled.     

Polymorphisms of the calcitonin receptor gene are associated with bone mineral density in postmenopausal Italian women

Recognition of a major genetic component in bone mass determination represented the basis for studies aiming to the identification of underlying major and minor genes. Bone mineral density (BMD) represents the continuous trait to be quantified in order to evaluate segregation of candidate genes with risk of osteoporosis. Polymorphisms at the vitamin D receptor (VDR), estrogen receptor, (ER), collagen type I, and interleukin 6 (IL6) gene loci have been correlated to BMD. However, in a polygenic disorder, such as osteoporosis, the number of genes expected to influence BMD is very large. In the present study we examined the presence of restriction fragment length polymorphisms (RFLPs) for the calcitonin receptor (CTR) gene in postmenopausal women. We identified a polymorphic (Tt) site at the CTR gene locus using the Taq I restriction fragment enzyme. Three genotypes were observed, whose Tt was the most frequent in our population (49.7%). In addition, Ancova analysis and Tukey's test showed that women with tt genotype had significantly lower lumbar BMD in comparison with Tt genotype (Tukey's test: p = 0.005). In conclusion, evidence of RFLPs at the CTR gene locus in Caucasian postmenopausal women of Italian origin made it possible to identify the involvement of another gene, the CTR gene, in the determination of bone mass.