Assessment of Wnt pathway selected gene expression levels in peripheral blood mononuclear cells (PBMCs) of postmenopausal patients with low bone mass.

The purpose of the study was to assess the expression of selected genes of the Wnt pathway: APC, AXIN1, CTNNB1, DKK1, GSK3ß, KREMEN1, SFRP1, and WNT1 in peripheral blood mononuclear cells (PBMC) of patients, selected in consideration of their bone mineral density (BMD), and the occurrence of low-energy fractures. The study involved 45 postmenopausal women, divided into four groups, according to BMD and fracture history. Measurements of laboratory parameters and RNA expression in PBMC cells were carried out in material, collected once at the inclusion visit. The densitometric examination was performed on all participants. In the analysis of the relative expression levels (RELs) of the studied genes in the entire population, we observed an overexpression for SFRP1 in 100% of samples and WNT1. In addition, the REL of DKK1, APC, and GSK3ß genes were slightly elevated versus the calibrator. In contrast, CTNNB1 and AXIN1 presented with a slightly decreased RELs. Analysis did not show any significant differences among the groups in the relative gene expression levels (p < 0.05) of particular genes. However, we have observed quite numerous interesting correlations between the expression of the studied genes and BMD, the presence of fractures, and laboratory parameters, both in the whole studied population as well as in selected groups. In conclusion, the high level of CTNNB1 expression maintains normal BMD and/or protects against fractures. It also appears that the changes in expression levels of the Wnt pathway genes in PBMCs reflect the expected changes in bone tissue.

Assessment of safety and efficacy of pine bark extract in normal and ovariectomized mice.

We evaluated the influence of pine bark extract (PBE) on organs, the cytochrome-P450 (CYP) activities in liver and estrogenic effects in normal and ovariectomized (OVX) female mice. The PBE did not affect organ weights and liver-function indexes (activities of alkaline phosphatase, aspartate amino transferase, and alanine amino transferase) at doses; 0.04%, 0.4%, and 2.0% PBE in the diet, in normal and OVX female mice. In the OVX mice, CYP1A1 activity was significantly higher in the 0.4% and 2.0% PBE groups than in the OVX control group, and in the 0.4% and 2.0% PBE groups were significantly higher than in the 0.04% PBE group. CYP1A2 and 3A4 activities were significantly higher in the 2.0% PBE group than in all other groups. The PBE did not affect uterine weight and femoral bone mineral density at all PBE doses. These results showed that the dose of PBE at the recommended human intake, had no toxic and estrogenic effects in normal female and OVX mice, however, it may need attention to use the excess intake of PBE with some drugs in postmenopausal women.

Patient-Level Modeling Approach Using Discrete-Event Simulation: A Cost-Effectiveness Study of Current Treatment Guidelines for Women with Postmenopausal Osteoporosis.

Decision tree and Markov models have been the most commonly used modeling methods in health economic evaluations. Both methods are known for their limitations. Discrete-event simulation (DES), an event-driven model in continuous time at the patient level, is a relatively new method in health economic evaluations that addresses some limitations of the common modeling techniques. Specifically, with the advent of personalized medicine, conventional methods for value assessment that are based on population-level measures might not be appropriate. The best treatment would depend on patient characteristics and clinical profiles. Value assessment of health interventions can vary substantially and may lead to different health decision making due to patient heterogeneity. As such, modeling at the patient level is an appropriate approach for value assessment of health interventions. The DES model has several advantages, such as flexibility, ability to reflect patient heterogeneity, increased precision, and better characterization of modeling uncertainty, that may be preferred to decision tree and Markov models. In addition, with increasing health care spending and drug prices, it is important to quantify value of available treatment options for women with postmenopausal osteoporosis (PMO). The purpose of this Viewpoints article was to describe and demonstrate an application of a DES model to evaluate the cost-effectiveness of the current treatment guidelines for women with PMO. In particular, the DES model indicated that the optimal treatment at the common willingness-to-pay thresholds between $100,000 per quality-adjusted life-year (QALY) and $150,000 per QALY was denosumab. Analysis of patient heterogeneity in terms of low, medium, high, and very high risk of fractures resulted in a similar conclusion. DISCLOSURES: Funding for this study was received through the PhRMA Foundation Value Assessment Challenge Award. The author has no conflicts of interest to declare.

Association of RMND1/CCDC170-ESR1 single nucleotide polymorphisms with hip fracture and osteoporosis in postmenopausal women.

OBJECTIVE: This study aimed to investigate the association of seven single nucleotide polymorphisms (SNPs) on the RMND1, CCDC170, and ESR1 genes with osteoporosis or hip fracture in a postmenopausal Mexican population. METHODS: We included a group of 400 postmenopausal women from the Health Workers Cohort Study from the Mexican Institute of Social Security. As a replication sample, we recruited 423 postmenopausal women from the National Institute of Rehabilitation. Demographic data were collected through a structured questionnaire. Bone mineral density was assessed using dual X-ray absorptiometry. Individuals were classified as normal, osteopenia, osteoporosis, and fracture, according to World Health Organization criteria. Genotyping was performed using predesigned TaqMan Probes. Linear regression analysis was used to investigate association. RESULTS: All of the analyzed SNPs showed association with at least one of the phenotypes of the study groups. In addition, we observed a region with linkage disequilibrium within the ESR1 gene in all groups. CONCLUSION: This study shows that an association of the SNPs can exist with osteopenia, osteoporosis, or fragility fracture. Our results agree with data published elsewhere, supporting the potential of these loci for the identification of the population at risk. However, additional studies are required to determine the extent of this association for other geographic regions of Mexico.

Assessment of risk factors for low bone mineral density in Brazilian postmenopausal women.

OBJECTIVE: To assess risk factors associated with low bone mineral density (BMD) in postmenopausal women. METHODS: In this cross-sectional study, a total of 412 Brazilian postmenopausal women, aged 40-75 years, with BMD measured using central dual-energy X-ray absorptiometry, were included. The clinical risk factors assessed were: age, time since menopause, smoking, physical activity, use of hormone therapy (HT) or corticosteroids, personal fracture history, maternal history of fracture, and body mass index (BMI, weight/height(2)). Low BMD was considered when total spine and/or femoral neck T-score values were ≤ -2.0 standard deviations. Logistic regression was used to determine the odds ratio (OR) for low BMD in the presence of the influential variables analyzed. RESULTS: Low BMD, which occurred in 36.6% (151/412) of the participants, was observed in 22.4% of women aged 40-49 years, in 34.2% of those aged 50-59 years, and in 60.5% of those > 60 years (p < 0.001). Similarly, low BMD was observed in 21.9% of women with menopause duration ≤ 5 years, in 39.5% with a duration of 6-10 years, and in 57.7% with menopause duration of > 10 years (p < 0.001). Seventy percent of women with BMI < 20 kg/m(2) were osteopenic/osteoporotic (p < 0.001). The percentage of HT users was 37.4%; 27.7% took regular physical activity and 24.5% were smokers. The risk for low BMD detection increased significantly with age (OR 1.08; 95% confidence interval (CI) 1.02-1.14), time since menopause (OR 1.12; 95% CI 1.04-1.20), smoking (OR 3.43; 95% CI 1.67-6.96), fracture history (OR 2.05; 95% CI 1.11-3.78), and maternal history of fracture (OR 2.16; 95% CI 1.14-4.09). Physical activity, diet, corticotherapy and thyropathies did not influence risk. Contrarily, use of HT (OR 0.38; 95% CI 0.24-0.60) and high BMI (OR 0.89; 95% CI 0.84-0.96) reduced risk (p < 0.05). CONCLUSION: In postmenopausal women, age, time since menopause, smoking, and personal or maternal history of fracture were strong clinical indicators of risk for low BMD, whereas the use of hormone therapy and high BMI were shown to be protective factors.

Bone fractures after menopause.

BACKGROUND: Every year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and maintenance of bone strength. METHODS: PubMed searches were performed, for studies of the epidemiology of fractures, bone physiology, endocrine effects, osteoporosis measurement, genetics, prevention and effectiveness. Topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion. RESULTS: Ageing reduces bone strength in post-menopausal women because estrogen deficiency causes accelerated bone resorption. Bone mineral density (BMD) decreased more than 2.5 standard deviation below the mean of healthy young adults defines osteoporosis, a condition associated with an increased risk of fractures. Risk factors such as age and previous fracture are combined with BMD for a more accurate prediction of fracture risk. The most widely used assessment tool is FRAX™ which combines clinical risk factors and femoral neck BMD. General preventive measures include physical exercise to reduce the risk of falling and vitamin D to facilitate calcium absorption. Pharmacological interventions consist mainly in the administration of inhibitors of bone resorption. Randomized controlled trials show treatment improves BMD, and may reduce the relative fracture risk by about 50% for vertebral, 20-25% for non-vertebral and up to 40% for hip fractures although the absolute risk reductions are much lower. CONCLUSIONS: Although diagnosis of osteoporosis is an important step, the threshold for treatment to prevent fractures depends on additional clinical risk factors. None of the presently available treatment options provide complete fracture prevention.

Assessment of laboratory measurements and -308 TNFalpha gene promoter polymorphisms in normal bone mineral density.

The aim of this study was to identify and evaluate laboratory parameters associated with normal bone mineral density (BMD) and to test if -308 tumour necrosis factor (TNF) alpha gene promoter polymorphisms could influence BMD. We performed a comparative cross-sectional study of four main groups: young healthy individuals (20-30 years); subjects aged 50 years or over with normal BMD; osteoporotic subjects aged 50 years or over; osteoporotic women with active rheumatoid arthritis. Variables assessed included anthropometric features, diet intake, lifestyle, calcium-phosphorus balance, markers of bone turnover, sexual hormones, hormones related with body mass and growth, cytokines involved in inflammation and bone turnover, and -308 TNF alpha gene promoter polymorphisms. One hundred fifty-nine subjects were evaluated. Across the four groups, zinc serum levels were higher in men as compared to women. In addition, zinc serum levels were also higher in individuals with normal BMD as compared to osteoporotic subjects. Serum calcium levels were higher in normal BMD group. On the other hand, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were significantly higher in normal bone mass postmenopausal women and men as compared to age-matched osteoporotic groups. Finally, leptin was significantly lower in men, after correcting these results for body mass index values. The remaining variables assessed had a similar distribution among the different studied groups. In our population, low serum levels of leptin and high serum levels of zinc, calcium, FSH, and LH were associated with a higher BMD.

The implication of assessing a polymorphism in estrogen receptor alpha gene in the risk assessment of osteoporosis using a screening tool for osteoporosis in Asians.

Both genetic and environmental factors interact to determine bone mass and the risk for developing postmenopausal osteoporosis. Recently, an Asian-specific tool, the Osteoporosis Self-Assessment Tool for Asians (OSTA), has been developed to assess the risk of osteoporosis in women. An index is calculated by multiplying the difference in body weight in kilograms and age in years by 0.2 and disregarding the decimal digits. The risk of osteoporosis is classified as high, intermediate or low according to the OSTA index less than -4, -4 to -1 and greater than -1. In the present study we examined how a single nucleotide polymorphism (SNP) in exon 8 of the estrogen receptor alpha (ERalpha) gene affected the predictive value of the OSTA index. Subjects consisted of 358 postmenopausal women who were at least 55 years old. BMDs were measured by DXA, and the SNP in the ERalpha gene was assessed by PCR-RFLP. When considering both the OSTA index and ERalpha genotype in a logistic regression model, it was found that both the OSTA index and the ERalpha genotype independently contributed to the risk of osteoporosis. The odds ratios were 1.58 (95% CI 1.26-1.91) and 2.51 (95% CI 1.42-4.44) for one unit decrement in the OSTA index and each copy of the A allele of the ERalpha genotype, respectively. The joint effect conformed more to a multiplicative model of interaction than an additive model. This suggests that persons with the high-risk genotype are at far greater risk of developing osteoporosis with advancing age or decreasing body weight, the two variables from which the OSTA index is derived. Targeting preventive measures for osteoporosis subjects with risk factors and also disease-susceptibility alleles is likely to be more cost effective.