Carmen Valero

Metabolic syndrome and bone metabolism: the Camargo Cohort Study

Objectives: The aims of this study were to compare in participants with and without metabolic syndrome (1) bone mineral density (BMD), (2) prevalent vertebral and nonvertebral fractures, and (3) calciotropic hormones and bone turnover markers and to examine the association of each component of metabolic syndrome with bone parameters. Methods: A cross-sectional study (495 men and 1,013 women) from the Camargo Cohort Study was conducted. A multivariable regression approach was used to analyze the relationship between the components of metabolic syndrome and bone parameters. Results: Women with metabolic syndrome had higher age-adjusted BMD at all localizations (P < 0.0001) than did women without metabolic syndrome. Adjusting for body mass index canceled out this difference at the spine and femoral neck, although borderline significance persisted at the total hip. Moreover, in regression analyses, waist circumference (P < 0.0001) and hypertension (P between 0.002 and <0.0001) highly correlated with BMD at the three sites. However, no significant differences in BMD were found in men between those with and without metabolic syndrome. No differences in the prevalence of vertebral or nonvertebral fractures between participants with metabolic syndrome and controls were found for either sex. 25-Hydroxyvitamin D was significantly lower (P < 0.0001) and parathyroid hormone was significantly higher (P < 0.0001) in women with metabolic syndrome than in women without metabolic syndrome, whereas no differences were seen in men. Propeptide of type I collagen and C-terminal telopeptide of type I collagen were significantly lower in participants with metabolic syndrome than in controls in either sex. Conclusions: Women with metabolic syndrome show higher BMD than controls do, mainly driven by their higher body weight. Bone remodeling in these women is lower. Despite the greater bone mass and lower bone turnover, fracture prevalence is not reduced, suggesting worse bone quality and/or higher tendency to fall. No differences in BMD or fractures were seen in men, suggesting that the impact of metabolic syndrome on bone is sex dependent.

Expression of Opioid Receptors in Osteoblast-Like MG-63 Cells, and Effects of Different Opioid Agonists on Alkaline Phosphatase and Osteocalcin Secretion by These Cells

We have previously shown that several stressful situations associated with tissue injury determine a decrease in serum osteocalcin concentration. Since reduced osteocalcin production is a marker of decreased osteoblastic activity, this finding could be related to the pathogenesis of osteoporosis secondary to some diseases. Endogenous opioids are involved in stress response. Proenkephalin-derived peptides have been shown to inhibit alkaline phosphatase activity, another marker of bone formation, in the murine cell line ROS-17/2.8. On the other hand, serum osteocalcin has been reported as being low in heroin abusers. We have therefore thought it of interest to study the presence of opioid receptors in the human osteoblast-like cell line MG-63, and to evaluate the effects of different opioid agonists on the secretion of alkaline phosphatase and osteocalcin by these cells. The presence of opioid receptors was studied by means of RT-PCR and immunohistochemistry. RT-PCR studies suggested the presence of specific mRNA for the three types of receptors, and immunohistochemistry clearly showed their occurrence. Osteocalcin synthesis was significantly inhibited by high concentrations of the mu agonists morphine and (D-Ala2,N-MePhe4,Gly5-ol)-enkephalin although no changes were seen with the delta agonist (D-Ala2,D-leu5)-enkephalin. Morphine-induced osteocalcin inhibition was abolished when osteoblastic cells were incubated simultaneously with naloxone, whereas it was potentiated when cells were preincubated with naloxone. None of the opioid agonists modified the secretion of alkaline phosphatase. In conclusion, human osteoblast-like cells MG-63 express the three types of opioid receptors. Endogenous opioids may be involved in the reduction of osteocalcin observed in stressful situations associated with tissue injury.

Bone mass in young adults with Down syndrome

BACKGROUND Down syndrome (DS) is a frequent cause of intellectual disability. With the increasing life expectancy of these patients, concerns have been raised about the risk of osteoporosis. In fact, several investigators have reported a reduced bone mass in DS. However, the results may be confounded by comorbid diseases, and differences in lifestyle habits and body size. Therefore, we planned to determine anthropometric and lifestyle factors influencing bone mineral density (BMD) in young adults with DS. METHODS Thirty-nine patients with DS (mean age 26 years) and 78 controls were studied. Areal BMD was measured by dual x-ray densitometry (DXA); volumetric BMD at the lumbar spine and femoral neck was estimated with published formulae. RESULTS DS patients had lower areal BMD than controls at all regions (spine, hip and total body). Height and projected bone area were also lower. There were no differences between both groups regarding estimated volumetric BMD at the femoral neck. However, spine volumetric BMD was also lower in DS than controls. In multivariate analysis, DS, male sex, little physical activity and low sunlight exposure were associated with lower spine volumetric BMD; on the other hand, fat mass and sunlight exposure were associated with femoral neck volumetric BMD. CONCLUSION This study shows that patients with DS had a reduced areal BMD, but it is in part a consequence of the reduced body size, particularly at the femoral neck. Physical activity and sunlight exposure are associated to volumetric BMD and should be stimulated in order to maintain an adequate bone mass in these patients.

The clinical spectrum of retroperitoneal hematoma in anticoagulated patients.

Bleeding into the retroperitoneal space is a serious complication of anticoagulation. The incidence may be on the rise due to the increasing number of patients prescribed anticoagulants for atrial fibrillation and other disorders. The clinical manifestations vary from leg paresis to abdominal pain or a catastrophic shock. Thus, an adequate index of suspicion is needed to reverse anticoagulation rapidly and initiate other therapeutic measures. We reviewed the cases diagnosed at our institution and reported in the literature to delineate the clinical manifestations and course of this process.

Bone turnover markers in Spanish postmenopausal women The Camargo cohort study

BACKGROUND This cross-sectional study was performed to determine the reference ranges for two bone turnover markers--aminoterminal propeptide of type I collagen (P1NP) and C-terminal telopeptide of type I collagen (beta-CrossLaps, beta-CTX)--in normal postmenopausal Spanish women as determined in serum by automated methods. METHODS A community-based population of 1080 healthy postmenopausal women was evaluated. Data regarding risk factors for osteoporosis and fractures were collected by means of a structured questionnaire. Fasting serum levels of P1NP, beta-CTX, 25-Hydroxivitamin D (25OHD), and intact parathyroid hormone (iPTH) were measured on the Elecsys 2010 automated analyzer (Roche). BMD at lumbar spine, femoral neck and total hip was determined by DXA. RESULTS The mean age of subjects was 63+/-9. Logarithmic transformation of both markers was performed to allow for normal distributions. Mid-95% ranges for P1NP and beta-CTX were 19-100 ng/ml and 0.112-1.018 ng/ml, respectively. Mean values of P1NP (47.7+/-19.9 ng/ml) were similar to those previously determined by the manufacturer of the assays, whereas beta-CTX mean values (0.387+/-0.197 ng/ml) were lower. Both markers were higher among osteoporotic women. CONCLUSIONS Values obtained from this well-characterized population study provide reference ranges for serum automated P1NP and beta-CTX in normal Spanish postmenopausal women.

Association of the Aromatase Gene Alleles With BMD:Epidemiological and Functional Evidence†‡

BMD has a strong heritable component. Estrogen activity depends on the aromatization of androgenic precursors in nongonadal tissues both in postmenopausal women and men. Therefore, aromatase is an appealing candidate gene to explain, in part, the genetic component of BMD. In fact, an association between aromatase polymorphisms and BMD has been previously reported in some relatively small groups. In this study, we explored the relationship between several SNPs in the aromatase region and hip BMD in 1163 postmenopausal women. We found significant differences across genotypes, particularly in older women. The BMD differences between homozygous women with opposing genotypes were 4.2% in the whole group and 7.3% in women >67 yr of age. Body weight was significantly associated with BMD also, but there was no evidence for a statistically significant interaction between body weight and aromatase polymorphisms. Electrophoretic mobility shift assays suggested the binding of the CEBPβ transcription factor to the C/G rs1062033 locus, located ∼12 kb upstream of the translation start site. Experiments of transient transfection of osteoblastic cells with luciferase reporters showed differences in the transcriptional activity of alleles C and G at this locus, with different responses to the co‐transfection of a CEBPβ expression vector. Furthermore, evidence for differential allelic expression was found in bone tissue samples. In conclusion, polymorphisms in a 12‐kb region of the aromatase gene are associated with BMD in postmenopausal women, particularly during the late postmenopausal period. In vitro functional studies point to rs1062033 as a true regulatory polymorphism.

MTHFR Polymorphism and Bone Mineral Density: Meta-Analysis of Published Studies

The C677T (rs1801133) polymorphism of methylenetetrahydrofolate reductase (MTHFR) has been associated with bone status in some studies, but the results have been mixed. In order to have a better understanding of this issue, we performed a meta-analysis of studies about the association of the C677T polymorphism and bone mineral density (BMD). Eight studies analyzed the relationship with spine BMD. When their results were combined, individuals with TT genotype showed a small but significantly reduced BMD compared to those with TC and CC genotypes. The weighted mean difference (WMD) was 18.0 mg/cm2 (P = 0.001, 95% confidence interval [CI] 7.1–28.9), without statistical evidence for between-study heterogeneity (P = 0.28, I2 = 17%). Six studies analyzed femoral neck BMD. A test for heterogeneity was significant (P = 0.03, I2 = 56%). Individuals with TT alleles tended to have somewhat lower BMD, but the difference was not statistically significant. In random effects model, the WMD between the TT and TC/CC genotypes was 6.4 mg/cm2 (95% CI –7.8 to 21.2, P = 0.36). Total hip BMD was measured in four studies. They showed a significantly lower BMD in subjects with TT alleles: WMD 19.7 (95% CI 5.3-34.1) mg/cm2, P = 0.007, in comparison with TC/CC subjects. When we considered only studies on women, the WMD in BMD between TT and TC/CC genotypes was significant at the spine (22.1 mg/cm2, 95% CI 8.6-35.6; P = 0.001) and the femoral neck (15.5 mg/cm2, 95% CI 4.3-26.7; P = 0.007). There was no evidence for heterogeneity. The small number of studies did not allow a meaningful sex-stratified analysis of total hip BMD or a separate analysis of male data. In conclusion, the C677T polymorphism of the MTHFR gene is associated with small differences in BMD, at least in women.

Bone turnover markers and bone mineral density in hypertensive postmenopausal women on treatment

OBJECTIVE To evaluate bone mineral density (BMD) and bone metabolism in hypertensive postmenopausal women, and to differentiate the effect of thiazides from that of other antihypertensive agents. SUBJECTS AND METHODS A community-based population of 636 postmenopausal women, 293 with hypertension (160 receiving thiazides, and 133 receiving other antihypertensive treatments), and 343 control women, were evaluated. Serum levels of aminoterminal propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (beta-CTX), 25-hydroxivitamin D, and intact parathyroid hormone were measured by electrochemiluminiscence. BMD was determined by DXA, and heel quantitative ultrasound measurements (QUS) with a gel-coupled device. RESULTS BMD expressed as Z-score was higher in both groups of hypertensive women at all locations. Expressed as g/cm(2), it was also higher in patients on thiazides at femoral neck and lumbar spine. Only in the latter site, differences remained significant after adjusting for potential confounding variables, including BMI. Bone turnover markers were lower in both groups of hypertensive women, although the difference was greater in those on thiazides. After adjusting for potential confounders, differences remained significant only in the thiazide group. CONCLUSIONS Our results add evidence to the idea that thiazides are beneficial to prevent bone loss.

Time course of bone loss in patients with anorexia nervosa

OBJECTIVE To evaluate the time course of bone mineral density (BMD) in women with anorexia nervosa (AN) during 2-year follow-up. METHOD We prospectively studied 51 female with AN aged 18-38 years, and 40 age-matched healthy women (19-34 years). BMD was measured in lumbar spine (LS), femoral neck (FN), and total hip (TH) by DXA. RESULTS At baseline, weight, body mass index, and lumbar and hip BMD were significantly (p < .001) lower in AN patients than in controls. Patients who gain weight showed a significant increase in BMD at FN (+1.6%; p < .05), and TH (+4.4%; p < .05) and lower nonsignificant changes in LS (+1.3%). Weight at entry, and percent change of weight were significant determinants (p < .05) of the variability in percent change of BMD at FN and TH, whereas weight at entry was the main determinant of bone modifications at lumbar spine. DISCUSSION Our data emphasize the influence of weight gain in recovery of bone mass in AN patients, especially at the hip.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2,666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at P<5x10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6 x 10-8. However, the association was not significant across 5,720 cases and 21,791 controls from 14 studies. Fixed-effects meta analyses summary estimate was 1.06 (95% CI: 0.98-1.14; P=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p= 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (P=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions are needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.