The relationship among breakfast time, morningness-eveningness preference and body mass index in Type 2 diabetes.

AIMS: Obesity is prevalent and related to poor outcomes in Type 2 diabetes. Evening preference and late meal times have been shown to be associated with obesity, but data are lacking in people with Type 2 diabetes. This study examined the relationship among meal timing, morningness-eveningness preference and BMI in Type 2 diabetes, using a mediation analysis. METHODS: Some 210 non-shift workers with Type 2 diabetes participated in the study. Morningness-eveningness preference was assessed using a standard questionnaire, the Composite Scale of Morningness (CSM). Meal timing and daily calorie intake were obtained from 1-day food recall. A mediation analysis adjusting for relevant covariables was performed to explore whether morningness-eveningness had a direct effect on BMI, or whether the effect was mediated through the intermediate variable of meal timing. RESULTS: Mean BMI was 28.4 ± 4.8 kg/m2 . A higher BMI was associated with greater evening preference (P = 0.019), and non-significantly associated with late breakfast time (P = 0.053). BMI was not associated with other mealtimes or calorie intake. In addition, evening preference was associated with late breakfast time (P < 0.001). Mediation analysis revealed that breakfast time mediated the association between morningness-eveningness and BMI, i.e. morning preference (CSM ≥ 45) was associated with earlier breakfast time, and lower BMI by 0.37 kg/m2 [coefficient = -0.365, 95% confidence intervals (CI): -0.877, -0.066), whereas the direct relationship between BMI and morningness-eveningness was non-significant. CONCLUSIONS: Late breakfast time mediated the relationship between morningness-eveningness preference and BMI. These results suggest that circadian preference and meal timing are novel and possibly modifiable risk factors for obesity in Type 2 diabetes.

Thai Osteoporosis Foundation (TOPF) position statements on management of osteoporosis.

The adjusted incidence rate of hip fracture in Thailand has increased more than 31% from 1997 to 2006. Mortality and morbidity after hip fracture are also high. One year mortality after a hip fracture has increased from 18% in 1999 to 21% in 2007. The Thai Osteoporosis Foundation (TOPF) developed the first Clinical Practice Guideline (CPG) in 2002 and keeps updating the CPG since then. This latest version of the CPG is our attempt to provide comprehensive positional statement on the diagnosis, prevention and treatment of osteoporosis in Thailand. The study group who revised this position statement contains experts from the TOPF, Four Royal Colleges of Thailand, includes the Orthopaedic Surgeons, Gynecologists and Obstetricians, Physiatrists, Radiologists and 2 Associations of Endocrinologists and Rheumatologists which have involved in the management of patients with osteoporosis.

Serum C3 epimer of 25-hydroxyvitamin D and its determinants in adults: a national health examination survey in Thais.

UNLABELLED: A high percentage have detectable C3 epimer of 25-hydroxyvitamin D3 (3-epi-25(OH)D3) in the population of Thai National Health Examination Survey IV. INTRODUCTION: C3 epimers of vitamin D have recently been shown to contribute significantly to 25-hydroxyvitamin D (25(OH)D) levels in an infant population. However, the findings in the general adult population are unclear. Therefore, the purpose of the present study is to determine the percentage of the C3 epimer of 25(OH)D (3-epi-25(OH)D) and its determinants in an adult population. METHODS: A subsample of 1148 sera randomly selected from the Thai National Health Examination Survey IV (2009) samples were measured for serum 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D2, and 3-epi-25(OH)D3 by LC-MS/MS method. The relative 3-epimer contribution (%) was used to express the amount of 3-epimer-25(OH)D3 as a percentage of total 25(OH)D3 (the sum of 25(OH)D3, and 3-epi-25(OH)D3). RESULTS: A high proportion of subjects had detectable 3-epi-25(OH)D3 that was <10 % of the total 25(OH)D levels. Since the level of total 25(OH)D2 is low, only a minority of subjects had detectable 3-epi-25(OH)D2. Multivariate analysis suggested that age, male gender, and rural residence were independently related to the 3-epi-25(OH)D3/total 25(OH)D3 ratio. CONCLUSIONS: A high percentage of Thai adults had detectable 3-epi-25(OH)D3 that was <10 % of the total 25(OH)D levels. Age, gender, and living in a rural area were associated with the relative amount of 3-epi-25(OH)D3 to total 25(OH)D3.

Causal relationship between the AHSG gene and BMD through fetuin-A and BMI: multiple mediation analysis.

UNLABELLED: Using mediation analysis, a causal relationship between the AHSG gene and bone mineral density (BMD) through fetuin-A and body mass index (BMI) mediators was suggested. INTRODUCTION: Fetuin-A, a multifunctional protein of hepatic origin, is associated with bone mineral density. It is unclear if this association is causal. This study aimed at clarification of this issue. METHODS: A cross-sectional study was conducted among 1,741 healthy workers from the Electricity Generating Authority of Thailand (EGAT) cohort. The alpha-2-Heremans-Schmid glycoprotein (AHSG) rs2248690 gene was genotyped. Three mediation models were constructed using seemingly unrelated regression analysis. First, the ln[fetuin-A] group was regressed on the AHSG gene. Second, the BMI group was regressed on the AHSG gene and the ln[fetuin-A] group. Finally, the BMD model was constructed by fitting BMD on two mediators (ln[fetuin-A] and BMI) and the independent AHSG variable. All three analyses were adjusted for confounders. RESULTS: The prevalence of the minor T allele for the AHSG locus was 15.2%. The AHSG locus was highly related to serum fetuin-A levels (P < 0.001). Multiple mediation analyses showed that AHSG was significantly associated with BMD through the ln[fetuin-A] and BMI pathway, with beta coefficients of 0.0060 (95% CI 0.0038, 0.0083) and 0.0030 (95% CI 0.0020, 0.0045) at the total hip and lumbar spine, respectively. About 27.3 and 26.0% of total genetic effects on hip and spine BMD, respectively, were explained by the mediation effects of fetuin-A and BMI. CONCLUSIONS: Our study suggested evidence of a causal relationship between the AHSG gene and BMD through fetuin-A and BMI mediators.

Malic enzyme gene polymorphism is associated with responsiveness in circulating parathyroid hormone after long-term calcium supplementation.

OBJECTIVE: To identify genetic variations associated with parathyroid hormone (PTH) suppression after long-term calcium supplementation. DESIGN AND PARTICIPANTS: For high throughput SNP screening, subjects consisted of 171 postmenopausal women without osteoporosis at the lumbar spine. A separate group of 19 premenpausal women were recruited for calcium absorption study. Postmenopausal women in the screening group were given 500 mg/day calcium supplementation. SETTING: Bangkok, Thailand. MEASUREMENTS: Parathyroid hormone (PTH) and bone mineral density (BMD) were measured at baseline and 2 years after calcium supplementation. High throughput single-nucleotide polymorphism (SNP) screening was performed by comparing estimated allele frequencies derived from hybridization signal intensities of pooled DNA samples on Affymetrix's 10K SNP genotyping microarrays based responsiveness in PTH after calcium supplementation. Genotyping of SNP rs1112482 in malic enzyme gene (ME1) gene, a SNP among those with highest odds ratio of being related to PTH suppression after calcium, was performed in all postmenopausal subjects in the screening group and premenopausal women in the calcium absorption study group in which fractional calcium absorption was assessed by stable isotope dilution. Data were expressed as mean +/- SEM. RESULTS: PTH significantly decreased after 2 years of calcium supplementation (4.7 ± 1.9 vs. 4.4 ± 1.6 pmol/L, P < 0.01). There was a significant increase in lumbar spine BMD (1.03 ± 0.01 vs. 1.01 ± 0.01 g/cm2, P < 0.001) but not femoral neck BMD. In 108 subjects whose PTH levels decreased after calcium, the suppression of PTH was higher in those with at least one C allele in rs1112482 of ME1 gene (-26.3 ± 2.1 vs. -16.9 ± 1.4%, P < 0.001). Fractional calcium absorption also tends to the higher in subjects in the calcium absorption study group with at least one C allele (n = 6) compared to those without the C allele (n = 13) (58.0 ± 4.9 vs. 49.3 ± 2.8%, P = 0.054). CONCLUSION: Cytosolic malic enzyme 1 gene polymorphism is associated with the degree of suppression of parathyroid hormone after long-term calcium supplementation. The effect is probably mediated through an increase in intestinal calcium absorption.

The relationship of fetuin-A and lactoferrin with bone mass in elderly women.

SUMMARY: The relationships of fetuin-A and lactoferrin to bone-related phenotypes were investigated in elderly women. Fetuin-A was associated not only with bone mineral density (BMD) but also with bone resorption marker suggesting an influence of fetuin-A on osteoclasts. INTRODUCTION: The aim of this study is to investigate the relationship of bone-related phenotypes in elderly women with circulating fetuin-A and lactoferrin. METHODS: Eighty-two elderly women were studied. Serum fetuin-A, lactoferrin, C-terminal telopeptide of type I collagen (CTx), total procollagen type 1 amino-terminal propeptide, and plasma intact parathyroid hormone (PTH) were analyzed. BMD of the lumbar spine at L2-4 and at the femoral neck was measured. RESULTS: Serum fetuin-A was significantly associated with L2-4 BMD (r = 0.23, P < 0.05). After controlling for age and body weight, the association remained statistically significant. There was a significant association between serum fetuin-A and serum CTx (r = -0.37, P < 0.001). The association between fetuin-A and L2-4 BMD no longer existed after controlling for serum CTx. There were positive associations of circulating lactoferrin with plasma PTH (r = 0.24, P < 0.05) and serum CTx (r = 0.26, P < 0.05). No association between serum lactoferrin and BMD at the lumbar spine or femoral neck was detected. CONCLUSIONS: Circulating fetuin-A is related to bone mass and bone resorption markers in elderly women. Lactoferrin, in contrast, is associated only with bone resorption markers.

Association of genetic variations near P2 promoter of the hepatocyte nuclear factor-4alpha gene and insulin secretion index in Thais.

This study was aimed to assess the association of the two single nucleotide polymorphisms (SNPs) near P2 promoter (rs1884614 and rs2144908) of hepatocyte nuclear factor-4alpha (HNF4A) with insulin secretion index and type 2 diabetes in Thais. Participants were categorized into three groups; unrelated type 2 diabetes (N = 219), prediabetes subjects (N = 228), and normal glucose tolerant controls (N = 203). Homeostasis model assessment was calculated for individual insulin secretion and insulin sensitivity index. Genotyping of both SNPs was done by allele-specific PCR technique. Difference of SNP allele frequencies between groups were computed using the chi (2)-statistic. Multivariate regression analysis was performed to determine the effect of SNPs on insulin secretion index. The clinical features of all groups were similar. We demonstrated genotype TT at rs1884614, BMI, and waist circumference were significantly associated with insulin secretion index (P = 0.023) but not with diabetes phenotype.

A comparison of teriparatide and calcitonin therapy in postmenopausal Asian women with osteoporosis: a 6-month study.

OBJECTIVE: The number of hip fractures is expected to double in the next 20 years, with current estimates that Asia will account for 37% of these cases. As bone mineral density (BMD) may be used as a measure of fracture risk, we sought to compare the effects of teriparatide with salmon calcitonin treatment on changes in BMD, biochemical bone markers, and safety in postmenopausal Asian women with osteoporosis. METHODOLOGY: A total of 104 patients (n = 47 teriparatide [20 g/day subcutaneously] and n = 57 calcitonin [100 IU/day subcutaneously]) were enrolled in Hong Kong, Singapore, Philippines, Malaysia, and Thailand. Calcium (> or = 500 mg/day) and vitamin D (200-400 IU/day) supplements were taken throughout the 6-month controlled, randomized study. RESULTS: Teriparatide was associated with a 5.03 +/- 4.77% increase in lumbar spine BMD (p < 0.0001, mean +/- SD change from baseline), whereas changes in lumbar spine BMD for patients on calcitonin were not statistically significant (mean change of 0.36 +/- 4.12%, p = 0.16). Comparison of the two groups indicated that teriparatide treatment improved lumbar spine BMD statistically significantly more than calcitonin (p < 0.0001). No statistically significant changes were observed for total hip or femoral neck BMD. Serum bone-specific alkaline phosphatase (BSAP) increased by 55.9% (median change from baseline, p < 0.0001) in the teriparatide group, and remained stable with calcitonin (5.0% change, p = 0.24); osteocalcin increased by 156.15% (median change from baseline, p < 0.0001) with teriparatide, and decreased with calcitonin (-15.25%, p = 0.03). Similar rates of adverse events were observed, with nausea and dizziness the most commonly reported for both groups (teriparatide versus calcitonin, 13.0% versus 23.2% p = 0.21, 10.9% versus 21.4% p = 0.19, respectively). There were no clinically relevant changes observed in laboratory parameters. CONCLUSIONS: Both treatments were similarly tolerated, however teriparatide was associated with greater increases in lumbar spine BMD and bone formation markers, demonstrating the unique mechanism of action and safety of this treatment for osteoporosis in these Asian women.

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-alpha (ERalpha) 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 (3'UTR) of the ERalpha 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 ERalpha 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.

Differential associations of residual estradiol levels with bone mineral density and serum lipids in postmenopausal women with osteoporosis.

OBJECTIVES: To examine the associations of residual endogenous estradiol (E2) to bone mineral density (BMD) and lipid concentrations in elderly women. METHODS: Subjects consisted of 59 elderly postmenopausal women with vertebral or femoral osteoporosis. BMD was measured at L2-4 and femoral neck by dual-energy X-ray absorptiometry (DEXA). Residual E2 concentrations were assessed by a sensitive radioimmunoassay. Data were expressed as mean +/- S.E.M. RESULTS: The age of the subjects was 65.2 +/- 0.8 years with 18.9 +/- 1.0 years postmenopausal. The mean residual E2 concentration was 6.0 +/- 0.5 pg/ml. There was a correlation between E2 levels and BMD at L2-4 (r = 0.32, P < 0.01) while no association was found at the femoral neck. The association between E2 and L2-4 BMD persisted after adjusting for years since menopause and body weight (r = 0.33, P < 0.05). With regard to serum lipid concentrations, no association of serum total cholesterol, LDL-cholesterol, HDL-cholesterol or triglyceride concentrations with residual E2 was found. CONCLUSIONS: Our findings confirm the role of residual endogenous E2 in the determination of bone mass in postmenopausal women with osteoporosis. The effect of residual E2 appears to be skeletal specific and possess no association with serum lipid concentrations.

Effect of estrogen replacement on insulin sensitivity, serum lipid and bone resorption marker in hypogonadal males.

Recent reports of osteoporosis in congenital estrogen deficiency in humans from estrogen resistance or aromatase deficiency have called attention to the importance of estrogen in males. It is the purpose of the present study to evaluate the effects of low- dose estrogen on glucose, lipid and bone metabolism in males with hypogonadism. Nine Thai males with primary or secondary hypogonadism were included in the study. Testosterone was discontinued at least 8 weeks before the study. The subjects received 0.3 mg of conjugated equine estrogen (CEE) daily for 4 weeks. Serum C-terminal telopeptide of type 1 collagen (CTX), total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglyceride (TG) and parameters related to insulin sensitivity were measured at baseline and 4 weeks after treatment. Insulin sensitivity was assessed by frequent intravenous glucose tolerance test. The mean age of subjects was 35.77 years (22-70 years). Insulin sensitivity index (SI) did not change significantly after the administration of CEE (P=0.09). Likewise, no change in acute insulin response (AIR(glucose)) was detected. However, glucose effectiveness (SG) significantly decreased after CEE (P<0.05). No significant change in serum TC, LDL-C, HDL-C or TG was detected. In regard to bone turnover, serum CTX significantly decreased after CEE administration (P<0.05). We concluded that low-dose estrogen administration in hypogonadal males for 4 weeks causes a decrease in bone turnover and an increase in glucose effectiveness. No effect on serum lipid concentrations or insulin sensitivity and secretion was detected.

Differences in bone mineral density and lifestyle factors of postmenopausal women living in Bangkok and other provinces.

UNLABELLED: Decreased bone mineral density (BMD) with age is an increasing health problem, especially for postmenopausal women. Multiple factors have been reported to affect BMD including both genetic and environmental factors such as calcium intake and physical activity. For Thailand, people residing in different regions may differ in BMD due to these factors. However, there is a paucity of data concerning this issue. The objectives of this study were to identify the lifestyle factors which may influence BMD and to investigate the association between BMD and these factors in postmenopausal women who have been living in Bangkok and other provinces in Thailand. Subjects consisted of 466 postmenopausal women aged 46-90 years including 236 Bangkokians (116 early postmenopausals and 120 late postmenopausals) and 230 non-Bangkokians (134 early postmenopausals and 96 late postmenopausals). All were healthy and ambulatory. BMD was measured by dual energy X-ray absorptiometry (DEXA, Expert XL). Calcium intake was assessed by food-frequency questionnaire. Data were expressed by mean + /- SEM. There were 22 per cent (n=52), 5.9 per cent (n=14), and 4.2 per cent (n=10) of postmenopausal Bangkokians while 13.9 per cent (n=32), 4.3 per cent (n=10), and 2.2 per cent (n=5) of postmenopausal non-Bangkokians who had low BMD at spine, femoral neck, and at both sites, respectively. Spine BMD (SPBMD) and femoral neck BMD (FNBMD) increased significantly across the quartiles of calcium intake in both groups of subjects (P<0.05) and a significant difference was found between the lowest and the highest quartiles of calcium intake (P<0.05). Moreover, BMD at both regions was shown to be correlated with calcium intake, exercise and sunlight exposure in these subjects (P<0.001). Further analysis revealed higher BMD at spine (0.992 + 0.02 vs 0.945 +/- 0.02 g/cm2, P<0.05) and at femur (0.780 +/- 0.01 vs 0.740 +/- 0.01 g/cm2, P<0.05), calcium intake (348.9 +/- 12.7 vs 316.3 +/- 8.0 mg/day, P<0.05), exercise (2.8 +/- 0.1 vs 2.4 +/- 0.1 h/wk, P<0.001) and sunlight exposure (2.9 +/- 0.06 vs 1.9 +/- 0.04 h/day, P<0.001) were found in late postmenopausal women in other provinces than their counterparts in Bangkok. Nevertheless, no significant difference of BMD at both sites, calcium intake and exercise was found in the early postmenopausal groups of these two areas. CONCLUSIONS: There were significant differences in BMD and lifestyle factors between late postmenopausal women in Bangkok and other provinces. Environmental factors especially calcium intake, exercise and sunlight exposure, may influence BMD in late postmenopausal Thai women.

A simple prediction rule and a neural network model to predict pancreatic beta-cell reserve in young adults with diabetes mellitus.

In the present study we developed and assessed the performance of a simple prediction rule and a neural network model to predict beta-cell reserve in young adults with diabetes. Eighty three young adults with diabetes were included in the study. All were less than 40 years old and without apparent secondary causes of diabetes. The subjects were randomly allocated to 2 groups; group 1 (n = 59) for developing a prediction rule and training a neural network, group 2 (n = 24) for validation purpose. The prediction rule was developed by using stepwise logistic regression. Using stepwise logistic regression and modification of the derived equation, the patient would be insulin deficient if 3(waist circumference in cm) + 4(age at diagnosis) < 340 in the absence of previous diabetic ketoacidosis (DKA) or < 400 in the presence of previous DKA. When tested in the validation set, the prediction rule had positive and negative predictive values of 86.7 per cent and 77.8 per cent respectively with 83.3 per cent accuracy while the ANN model had a positive predictive value of 88.2 per cent and a negative predictive value of 100 per cent with 91.7 per cent accuracy. When testing the performance of the prediction rule and the ANN model compared to the assessment of 23 internists in a subgroup of 9 diabetics whose age at onset was less than 30 years and without a history of DKA, the ANN had the highest ability to predict beta-cell reserve (accuracy = 88.9), followed by the prediction rule (accuracy = 77.8%) and assessments by internists (accuracy = 60.9%). We concluded that beta-cell reserve in young adults with diabetes mellitus could be predicted by a simple prediction rule or a neural network model. The prediction rule and the neural network model can be helpful clinically in patients with mixed clinical features of type 1 and type 2 diabetes.

Biochemical markers of bone turnover and response of bone mineral density to intervention in early postmenopausal women: an experience in a clinical laboratory.

BACKGROUND: Markers of bone formation and resorption may be useful as early indicators of response to therapy. Our aim in this study was to investigate the use of bone markers for monitoring of intervention for bone loss in early postmenopausal women and to assess the relationships between these markers and changes in bone mineral density (BMD). METHODS: Subjects were randomly assigned to the following groups: a control group; a group receiving calcium alone; groups receiving calcium plus low or conventional doses of conjugated equine estrogen; and groups receiving calcium plus low or conventional doses of calcitriol. At baseline and at 1 and 3 months after intervention, we measured serum intact osteocalcin, serum N-terminal midfragment osteocalcin, serum C-terminal telopeptide of type I collagen (CTx), urinary deoxypyridinoline cross-links, and urinary CTX: The BMD of the lumbar spine and the femoral neck was measured at baseline and after 1 and 2 years of intervention. RESULTS: No marker changed significantly in the control group except urinary CTx, which increased at 3 months. Serum CTx decreased in all regimens at 1 or 3 months of intervention. In addition, the changes of all markers at 3 months were inversely associated with the change in the BMD of the lumbar spine at 1 or 2 years (r = -0.144 to -0.314), whereas only the changes of bone resorption markers at 3 months were inversely correlated with the changes in femoral BMD at 1 or 2 years (r = -0.143 to -0.366). CONCLUSIONS: Biochemical markers of bone turnover appear to be of use in assessing early response to therapy. Bone resorption markers, especially serum CTx, are better indicators than bone formation markers for estimating the response to intervention in early postmenopausal women. However, the early changes in bone markers were weakly related to the later changes in BMD.

Bone mineral density and histology in distal renal tubular acidosis.

BACKGROUND: Chronic metabolic acidosis in distal renal tubular acidosis (RTA) has been implicated in the pathogenesis of enhanced bone resorption and osteopenia, resulting in a loss of bone mineral content. However, histomorphometric and bone densitometric studies of patients who suffered from long-standing distal RTA have rarely been done. METHODS: A cross-sectional study to determine the alterations of bone mineral density (BMD) and histology was done in 14 nonazotemic RTA patients (11 females and 3 males) who had never received alkaline therapy before enrolling into this study. The mean age was 32.7 +/- 11.9 years. BMD measurements and transiliac bone biopsy were done in all patients. Blood chemistries, intact parathyroid hormone level, and a 24-hour urine collection for the determination of urinary calcium, phosphate, sodium, and potassium were obtained from the RTA patients at the time of bone biopsy. Data from 28 age-, sex-, and body mass index-matched, normal controls who were residents in the same area were also obtained. RESULTS: Urinary excretion of calcium was 2.05 +/- 1.59 mmol/day. No patient had hypercalciuria. The serum intact parathyroid hormone level was 15.92 +/- 8.48 pg/mL. RTA patients had lower BMD in most areas when compared with normal controls. There were two patients who suffered from a pathologic fracture at the femur. Bone histomorphometry from RTA patients shows a significantly decreased bone formation rate (0.02 +/- 0.02 vs. 0.07 +/- 0.045 microm(3)/microm(2)/day, P < 0.05), not significantly decreased osteoblastic surface (0.78 +/- 1.03% vs. 2.6 +/- 1.1%) and osteoclastic surface (0.05 +/- 0.03 vs. 0.13 +/- 0.23%), but significantly increased osteoid surface (31.47 +/- 24.52 vs. 5.79 +/- 4.39%, P < 0.05) and osteoid volume (2.95 +/- 3.09 vs. 0.92 +/- 1.05%, P < 0.05) when compared with those of normal controls. There was no difference in osteoid thickness (10.65 +/- 6.10 vs. 8.69 +/- 2.14 microm). Only one distal RTA patient who had a marked increase in osteoid thickness justified the diagnosis of osteomalacia. CONCLUSIONS: This study demonstrates that low bone mass is common in distal RTA patients. Chronic metabolic acidosis results in suppression of bone formation and resorption, which in turn may contribute to the development of low bone mass in distal RTA patients. Although minor elevations in osteoid surface and osteoid volume are found among distal RTA patients, overt osteomalacia is not the predominant bone lesion.

Association of a G2014A transition in exon 8 of the estrogen receptor-alpha 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-alpha (ERalpha) 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 ERalpha is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3'-untranslated region of the ERalpha gene which may participate in the regulation of ERalpha gene expression remains to be determined.

Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women.

Polymorphic genetic markers of estrogen-receptor-alpha (ERalpha) gene studied so far in osteoporosis reside in non-coding region with uncertain functional significance. The purpose of the present study was to search for nucleotides changes in the exon 1 and 5' regulatory region of ERalpha gene, to study the nature of their linkages to the previously reported Pvull polymorphism in intron 1 and their functional significance in postmenopausal osteoporosis. Direct sequencing of exon 1 and promotor region of ERalpha gene revealed a synonymous nucleotide substitution from T to C at position 262, 29 nucleotides downstream from the putative start codon. No nucleotide change was found in the promotor region. Linkage disequilibrium between the T262C polymorphism and the Pvull polymorphism in intron 1 of ERalpha gene was demonstrated in 129 post-menopausal women (p<0.001). After treating 96 post-menopausal with 0.3 mg or 0.625 mg conjugated equine estrogen (CEE) for 2 yr, vertebral bone mineral density (BMD) increased regardless of the T262C genotype. However, with regard to femoral neck BMD, only those subjects that were homozygous for the T262C polymorphism had an increase in femoral BMD (+5.9+/-1.4%, mean+/-SE; p<0.0001). Using analysis of covariance to assess the effects of the T262C polymorphism, the intronic Pvull polymorphism, doses of CEE and the corresponding baseline BMD on the changes in vertebral or femoral BMD after treatments, it was found that the change in vertebral BMD was related only to the baseline BMD (p<0.05). The change in femoral BMD was independently related to the T262C polymorphism (p<0.01) and the baseline femoral BMD (p<0.01). No effect of the Pvull polymorphism or the doses of CEE on femoral BMD was demonstrated. We concluded that the previously described intronic Pvull polymorphism of ERalpha gene is in linkage disequilibrium with a T262C polymorphism in exon 1. This T262C polymorphism appears to be more directly related to the skeletal response after long-term treatment with estrogen.

Risk of calcium oxalate nephrolithiasis after calcium or combined calcium and calcitriol supplementation in postmenopausal women.

Although calcium supplementation can cause hypercalciuria, the risk of nephrolithiasis has been shown to decrease rather than increase among subjects who had a higher calcium intake. Hypercalciuria is also a well-established side effect of calcitriol administration. However, the risk of nephrolithiasis is not well defined. The present study was undertaken to prospectively determine the effect of calcium with or without calcitriol on physicochemical risk factors associated with calcium oxalate nephrolithiasis in Thai postmenopausal women with osteoporosis. Subjects consisted of 53 Thai women more than 10 years postmenopausal who were randomly allocated to receive 750 mg of calcium carbonate supplement alone (n = 28) or 750 mg of calcium carbonate plus 0.5 microg calcitriol (n = 25) daily. Mean +/- SEM for age was 65.3+/-1.1 years, body weight 53.5+/-1.3 kg. Urine samples for biochemical assays were collected at baseline and 3 months after treatment. Supersaturation for calcium oxalate stone formation was assessed from the 24 h urine constituents by the Tiselius's index, AP(CaOx). Three months of calcium supplement alone resulted in a modest, but not significant, increase in urinary calcium (baseline, 2.90+/-0.43 mmol/day; after treatment 3.58+/-0.54 mmol/day) with no change in urinary oxalate, citrate or magnesium. In contrast, calcium together with calcitriol caused a significant increase in urinary calcium (baseline, 2.87+/-0.41 mmol/day; after treatment, 4.08+/-0.57 mmol/day; p < 0.05). No significant change in other urine constituents after treatment with calcium and calcitriol was detected. Therefore, AP(CaOx) did not significantly increase either after calcium alone (baseline, 1.17+/-0.39; after treatment, 1.36+/-0.28) or after calcium plus calcitriol (baseline, 1.09+/-0.17; after treatment, 1.09+/-0.19). However, after treatments, 12 subjects (23%)--6 receiving calcium supplement alone and 6 receiving calcium plus calcitriol supplement--had high AP(CaOx) values (greater than the upper limit of 95% Cl for AP(CaOx) derived from non-stone-forming Thai women). The post-treatment/baseline ratio was 3.21+/-0.74 for urinary calcium, 1.01+/-0.19 for urinary oxalate, and 2.23+/-0.42 (median 1.15) for AP(CaOx). The post-treatment/baseline ratio of calcium, but not for urinary oxalate, had a significant correlation with the post-treatment/baseline ratio of AP(CaOx). Our findings suggest that the alteration in the risk of calcium oxalate nephrolithiasis based on urinary composition is related to the alteration in urinary calcium. The risk of calcium oxalate nephrolithiasis does not increase significantly after calcium or combined calcium and calcitriol supplement in the majority of postmenopausal women with osteoporosis.

Correlation between serum insulin and features of metabolic syndrome in Thais.

Several clinical and metabolic abnormalities, i.e. central obesity, hypertension, impaired glucose tolerance or diabetes and dyslipidemia often cluster together and are commonly found in patients with atherosclerotic cardiovascular disease. Hyperinsulinemia and insulin resistance are often evident in subjects with these metabolic abnormalities, so called insulin resistance or metabolic syndrome. In the present study, we looked into the correlations between serum insulin or index of insulin sensitivity and various clinical and metabolic abnormalities. Subjects consisted of 103 males and 118 females. Oral glucose tolerance test was performed on all subjects. Homeostasis model assessment of insulin sensitivity (HOMA-S) was used to determine insulin sensitivity. In males, HOMA-S was found to be significantly correlated with BMI, plasma glucose, insulin, triglycerides and waist circumference. Male subjects in the highest quartile of HOMA-S also had significantly higher systolic blood pressure compared to those in the lowest quartile. In females, HOMA-S was significantly correlated with BMI, blood pressure, plasma glucose, insulin, triglycerides, HDL-cholesterol, waist circumferences and waist-hip ratio. However, after adjustment for BMI, correlation between HOMA-S and blood pressure in women was no longer statistically significant. We, therefore, concluded that correlations between serum insulin or index of insulin sensitivity with certain metabolic abnormalities also existed in Thai subjects. Some of these correlations seem to be at least in part dependent on obesity.