Francesca De Vita

Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals

Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored. This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density - vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area - tCSA and cCSA) in older individuals. The study population consisted of 1038 subjects (452 men and 586 women) 65years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self-report of PPI use over the last 15days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7±7.4years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, BMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5±54.8 vs. 207.9±59.4, p=0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc, tCSA and cCSA between PPI users and nonusers. In community dwelling older persons, the use of PPIs is inversely associated with vBMDt, an early marker of the osteoporotic process. These findings suggest that PPI use might increase the risk of fractures in older subjects through its detrimental effects on trabecular bone.

Instrumental and non-instrumental evaluation of 4-meter walking speed in older individuals

Background Manual measurement of 4-meter gait speed by a stopwatch is the gold standard test for functional assessment in older adults. However, the accuracy of this technique may be biased by several factors, including intra- and inter-operator variability. Instrumental techniques of measurement using accelerometers may have a higher accuracy. Studies addressing the concordance between these two techniques are missing. The aim of the present community-based observational study was to compare manual and instrumental measurements of 4-meter gait speed in older individuals and to assess their relationship with other indicators of physical performance. Methods One-hundred seventy-two (69 men, 103 women) non-disabled community-dwellers aged ≥65 years were enrolled. They underwent a comprehensive geriatric assessment including physical function by Short Physical Performance Battery (SPPB), hand grip strength, and 6-minute walking test (6MWT). Timed usual walking speed on a 4-meter course was assessed by using both a stopwatch (4-meter manual measurement, 4-MM) and a tri-axial accelerometer (4-meter automatic measurement, 4-MA). Correlations between these performance measures were evaluated separately in men and women by partial correlation coefficients. Results In both genders, 4-MA was associated with 4-MM (men r = 0.62, p<0.001; women r = 0.73, p<0.001), handgrip strength (men r = 0.40, p = 0.005; women r = 0.29, p = 0.001) and 6MWT (men r = 0.50, p = 0.0004; women r = 0.22, p = 0.048). 4-MM was associated with handgrip strength and 6MWT in both men and women. Considering gait speed <0.6 m/s as diagnostic of dismobility syndrome, the two methods of assessment disagreed, with a different categorization of subjects, in 19% of men and 23% of women. The use of accelerometer resulted in 29 (13 M, 16 F) additional diagnoses of dismobility, compared with the 4-MM. Conclusions In an older population, the concordance of gait speeds manually or instrumentally assessed is not optimal. The results suggest that manual measures might lead to misclassification of a substantial number of subjects. However, longitudinal studies using standardized and validated procedures aimed at the comparison of different techniques are needed before recommending the use of accelerometers in comprehensive geriatric assessment.

Identification and treatment of older persons with sarcopenia

Abstract In the last decades, sarcopenia in older persons has been operationalized by the assessment of lean body mass, muscle strength and/or physical performance. Several definitions of sarcopenia, using different parameters and cut-offs, have been proposed. However, which is the best definition to describe and to assess this condition is still matter of debate. Hand grip strength has been suggested as better predictor of incident mobility impairment and mortality, than skeletal muscle mass. In the light of the current knowledge, we sought to propose an operative approach for identifying and treating sarcopenic older persons according to main categories of sarcopenia: the age-related or primary sarcopenia and disease-related or secondary sarcopenia. We suggest that a quantitative assessment of grip strength alone might be sufficient to identify patients with primary sarcopenia. When chronic diseases accompany the ageing process, the combined assessment of muscle strength plus a balance test could be more appropriate. The identification of tests and pathological relevant cut-offs that facilitates the entry of sarcopenia into the clinical practice, could step forward researchers and physicians. This could be important for planning multidisciplinary models to maximize the maintenance of locomotive abilities especially in older persons affected by chronic diseases such as Parkinson’s disease.

Multiple hormonal dysregulation as determinant of low physical performance and mobility in older persons

Mobility-disability is a common condition in older individuals. Many factors, including the age-related hormonal dysregulation, may concur to the development of disability in the elderly. In fact, during the aging process it is observed an imbalance between anabolic hormones that decrease (testosterone, dehydroepiandrosterone sulphate (DHEAS), estradiol, insulin like growth factor-1 (IGF-1) and Vitamin D) and catabolic hormones (cortisol, thyroid hormones) that increase. We start this review focusing on the mechanisms by which anabolic and catabolic hormones may affect physical performance and mobility. To address the role of the hormonal dysregulation to mobility-disability, we start to discuss the contribution of the single hormonal derangement. The studies used in this review were selected according to the period of time of publication, ranging from 2002 to 2013, and the age of the participants (≥65 years). We devoted particular attention to the effects of anabolic hormones (DHEAS, testosterone, estradiol, Vitamin D and IGF-1) on both skeletal muscle mass and strength, as well as other objective indicators of physical performance. We also analyzed the reasons beyond the inconclusive data coming from RCTs using sex hormones, thyroid hormones, and vitamin D (dosage, duration of treatment, baseline hormonal values and reached hormonal levels). We finally hypothesized that the parallel decline of anabolic hormones has a higher impact than a single hormonal derangement on adverse mobility outcomes in older population. Given the multifactorial origin of low mobility, we underlined the need of future synergistic optional treatments (micronutrients and exercise) to improve the effectiveness of hormonal treatment and to safely ameliorate the anabolic hormonal status and mobility in older individuals.

Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants

The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population.

SHBG and endothelial function in older subjects

BACKGROUND Endothelial dysfunction is predictor of cardiovascular diseases that have different prevalence in men and women before menopause. Sex hormones and sex hormone binding globulin (SHBG), novel risk factors for diabetes and cardiovascular diseases even in older individuals, might explain this difference. However, the relationship between these hormones and endothelial function has never been addressed in the elderly. METHODS AND RESULTS 430 men and,424 women 70 years older of Prospective Study of the Vasculature in Uppsala Seniors study, with complete data on SHBG, testosterone(T), estradiol(E2), endothelium-independent vasodilation (EIDV), endothelium-dependent vasodilation(EDV), flow-mediated vasodilation (FMD) and the pulse wave analysis (reflection index, RI) were evaluated. Multivariate regression analysis adjusted for confounders was used to assess the relationship between T, E2, SHBG and endothelial function. In men we found a positive relationship between SHBG and EDV (β ± SE 3.60 ± 0.83, p<0.0001), EIDV (2.42 ± 0.58, p<0.0001) but not with FMD. The relationship between SHBG and EDV and EIDV was maintained after adjustment for sex (1.64 ± 0.47, p<0.001 and 1.79 ± 0.35, p<0.0006, respectively). After adjustment for confounders, the relationship between SHBG and EDV and EIDV was still statistically significant (2.63 ± 0.90 and 1.86 ± 0.63, p = 0.004 for both). In women SHBG and EIDV were positively associated (1.58 ± 0.46; p = 0.0007), and this relationship was independent of sex (1.79 ± 0.35; p<0.001). No significant interaction SHBG * SEX was found for EIDV (p = 0.72). In a combined analysis in two sexes, SHBG and EIDV were positively associated (1.13 ± 0.45; p = 0.01). SHBG was not associated with EDV, FMD and RI. No significant relationship was found between T or E2 and EDV, EIDV, FMD or RI in both sexes. CONCLUSIONS In older men SHBG, but not T and E2, is positively and independently associated with EDV in resistance arteries. In both sexes, SHBG was positively and independently associated with EIDV.

Vitamin D and Endothelial Vasodilation in Older Individuals : Data From the PIVUS Study

CONTEXT Vitamin D plays a role in a wide range of extraskeletal processes, including vascular function. Endothelial dysfunction is a predictor of cardiovascular disease, especially in older subjects. However, the relationship between vitamin D levels and indexes of endothelial vasodilation has never been fully addressed in older individuals. OBJECTIVE The objective of this study was to examine the association between vitamin D and endothelial function in a large community-based sample of older subjects. METHODS This cross-sectional study involved 852 community-dwelling men and women aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), with complete data on vascular function and 25-hydroxyvitamin D. We evaluated endothelium-dependent vasodilation by an invasive forearm technique with acetylcholine, endothelium-independent vasodilation by sodium nitroprussiate, flow-mediated vasodilation, and the pulse wave analysis (reflectance index). Vitamin D levels were measured by chemiluminescence. We used multivariate regression models adjusted for body mass index (model 1) and for multiple confounders (high-sensitivity C-reactive protein, insulin, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, smoking, sex hormones, season of blood collection, hypertension, diabetes, cardiovascular medications and diseases, statin usage, plasma calcium and calcium intake, PTH, physical exercise, liver and kidney function tests, albumin; model 2). RESULTS In women, but not in men, vitamin D levels were positively associated with endothelium-independent vasodilation in both model 1 (β ± SE = 1.41 ± 0.54; P = .001), and model 2 (β ± SE = 2.01 ± 0.68; P = .003).We found no significant relationship between vitamin D levels and endothelium-dependent vasodilation, flow-mediated vasodilation, and reflectance index in both sexes. CONCLUSIONS In older women, but not in men, vitamin D is positively and independently associated with EIDV.

Effects of transdermal testosterone treatment on inflammatory markers in elderly males

OBJECTIVE During the male aging process, testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these 2 phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T. METHODS A total of 108 healthy males >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University and randomized to 60-cm2 T or a placebo patch for 36 months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of the inhibitory effect of T on inflammation. We evaluated 70 males (42 in the T group) who had banked specimens from multiple time points available for assays of T, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, soluble TNF-α receptor-1 (TNFR1), interleukin-6 (IL-6), and soluble IL-6 receptors (sIL6r and sgp130). RESULTS The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce significant decreases in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-α (P = .03) and sgp130 (P = .01). Significant differences in estimated means of TNFR1 (but not other inflammatory markers), with lower levels in the T group, were observed at the 36-month time point. In T-treated subjects we found an almost significant treatment x time interaction term TNFR1 (P = .02) independent of total body fat content as assessed by dual energy X-ray absorptiometry (DXA). No serious adverse effect was observed. CONCLUSIONS Transdermal T treatment of older males for 36 months is not associated with significant changes in inflammatory markers.

Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women

Background. In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. Methods. We examined 512 women ≥ 65 years from the InCHIANTI study. Retinol, α-caroten, β-caroten, β-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998–2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. Results. After adjustment for age, α-carotene (β ± SE = −0.01 ± 0.004, p = 0.02) and β-carotene (β ± SE = −0.07 ± 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. α-Carotene was also significantly and positively associated with T/E2 ratio (β ± SE = 0.07 ± 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between α-carotene (β ± SE = −1.59 ± 0.61, p = 0.01), β-carotene (β ± SE = −0.29 ± 0.08, p = 0.0009), and E2 persisted whereas the relationship between α-carotene and T/E2 ratio was attenuated (β ± SE = 0.22 ± 0.12, p = 0.07). In a fully adjusted model (Model 3), only β-carotene (β ± SE = −0.05 ± 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of α-carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. Conclusions: In older women, β-carotene levels are independently and inversely associated with E2.

The Role of the Multiple Hormonal Dysregulation in the Onset of “Anemia of Aging”: Focus on Testosterone, IGF-1, and Thyroid Hormones

Anemia is a multifactorial condition whose prevalence increases in both sexes after the fifth decade of life. It is a highly represented phenomenon in older adults and in one-third of cases is “unexplained.” Ageing process is also characterized by a “multiple hormonal dysregulation” with disruption in gonadal, adrenal, and somatotropic axes. Experimental studies suggest that anabolic hormones such as testosterone, IGF-1, and thyroid hormones are able to increase erythroid mass, erythropoietin synthesis, and iron bioavailability, underlining a potential role of multiple hormonal changes in the anemia of aging. Epidemiological data more consistently support an association between lower testosterone and anemia in adult-older individuals. Low IGF-1 has been especially associated with anemia in the pediatric population and in a wide range of disorders. There is also evidence of an association between thyroid hormones and abnormalities in hematological parameters under overt thyroid and euthyroid conditions, with limited data on subclinical statuses. Although RCTs have shown beneficial effects, stronger for testosterone and the GH-IGF-1 axis and less evident for thyroid hormones, in improving different hematological parameters, there is no clear evidence for the usefulness of hormonal treatment in improving anemia in older subjects. Thus, more clinical and research efforts are needed to investigate the hormonal contribution to anemia in the older individuals.