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What is known and the objective Low-grade evidence supports the use of newer biologics for otherwise refractory juvenile idiopathic arthritis (JIA)-associated uveitis, such as tocilizumab. Case summary This report details the cases of two adolescents whose severe JIA-associated uveitis was unresponsive to the first-line therapeutic approach. Tocilizumab therapy led to the remission of uveitis after a mean time of 3 weeks, and methotrexate was safely discontinued 1.5 years later. What is new and conclusion To our knowledge, these are the first reports of successful methotrexate withdrawal during tocilizumab treatment of JIA-associated uveitis. The administration of tocilizumab without methotrexate could be considered in patients with JIA-associated uveitis unresponsive to conventional therapy.

Background: Aseptic osteonecrosis of the hip is a clinical entity in which the necrotic process of the bone leads to pain and progressive disability. Objective: Pamidronate seems to reduce drastically the activation of the osteoclasts so that it can be useful only in the early stage of the disease, delaying the time of bone collapsing. Method: A 27-years-old male was treated with pamidronate for three consecutive days every four weeks. Results: After three months the patient came back at control showing a marked improvement in clinical condition, referred full recover from pain and dysmotility with improvement of the quality of life, which was confirmed by the result of MRI he had for control. Conclusion: We reported a case of aseptic osteonecrosis of the hip which was successfully treated pamidronate at dosage of 45 mg.

Introduction: Drug combination is widely used to treat chronic inflammatory diseases. A similar strategy might be worth of interest to design plant-derived natural products to treat inflammatory conditions. Curcumin is a natural phenolic compound which shares anti-inflammatory activity with both flavocoxid, a flavonoid mixture of baicalin and catechin, and β-caryophyllene, a bicyclic sesquiterpene. The aim of this study was to investigate the synergy potential of curcumin with both flavocoxid and β-caryophyllene in human articular chondrocytes triggered with lipopolysaccharide (LPS), in an experimental in vitro model of osteoarthritis.Materials and Methods: Human articular chondrocytes were stimulated with LPS alone or in combination with different treatments. Total RNA was extracted 4 h after treatment to study interleukin 1β (IL-1β), NF-κB, and STAT3 mRNA expression. A drug combination study was designed choosing 5 doses to demonstrate a synergistic effect of compounds, according to Chou and Talalay method. A median-effect equation was applied and finally, the combination index (CI) was used to clarify the nature of the compounds interaction (synergistic versus additive versus antagonistic inhibitory effects); CI < 1, CI = 1, and CI > 1 indicated synergistic, additive, and antagonistic effects, respectively.Results: LPS prompted IL-1β expression. Curcumin, flavocoxid and β-caryophyllene suppressed IL-1β expression with different IC50. A synergistic action for the reduction of the inflammatory phenotype in human chondrocytes was observed for the combination curcumin-flavocoxid with a percentage from 10% to 90%, and for the combination curcumin-β-caryophyllene from 50% to 90%. IC50 doses of either flavocoxid, β-caryophyllene and curcumin alone or in combination were safe and did not affect cell vitality. Moreover, the same IC50 doses reduced the transcription factors NF-κB and STAT3 mRNA expression and interestingly the effects of the combinations were greater than the natural products alone, thus suggesting that the site where the synergy takes place could be at the signal transduction level.Discussion: The results suggest that curcumin synergizes with either flavocoxid or β-caryophyllene, exerting an anti-inflammatory activity and thus strongly suggesting the potential of a dual combination of these compounds for the management of osteoarthritis and unmasking a new feature of these natural products.

Background: Evidence suggests that proteinuric diseases, such as primary or secondary glomerulonephritis, increase cardiovascular risk, but few studies confirmed this association. Methods: This is a cross-sectional, observational study on 32 patients, 17 with Primary Glomerulonephritis (PG) and 15 with Lupus Glomerulonephritis (LG). The control group consisted of 32 healthy individuals. Intima-media thickness (IMT) of the left common carotid artery, carotid bifurcation and internal carotid artery was measured by ultrasound. Left ventricular myocardial deformation was assessed by the use of the Global Circumferential Strain (GCS) and the Global Longitudinal Strain (GLS) following 2-Dimensional (2D) echocardiography in all participants. Results: Patients with glomerulonephritis in both groups showed significantly lower GLS compared with controls (p=0.0005). There was also a significant difference in common carotid IMT values between the LG and GP group (0.45±0.09 vs. 0.58±0.17 mm, respectively; p=0.01), but there was no difference with the control group. In patient group (n=32), a significantly positive correlation was observed between C-reactive protein and proteinuria (r=0.98; p Conclusion: Subclinical systolic myocardial dysfunction is present early in the course of glomerular disease. The use of 2D GLS revealed that LG and PG patients with no cardiovascular symptoms or history and a preserved left ventricle ejection fraction on conventional echocardiography had subclinical reduction in LV global longitudinal systolic function compared with controls.

Background: cardiovascular (CV) disease morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas accelerated subclinical atherosclerosis and endothelial dysfunction have been widely studied, less attention has been paid to myocardial function. RA patients with established disease who develop heart failure often have impaired left ventricular (LV) diastolic functionality with preserved LV ejection fraction (EF) and present fewer signs than non-RA patients. Then, additional and more sensitive screening tools as myocardial strain imaging are needed. In this sense, speckle-tracking echocardiography (STE) has been demonstrated to be suitable for detecting impaired systolic function. Although CV risk is increased at disease onset, whether abnormal myocardial functionality could be found already in the early phase of IJD remains unknown. Objectives: to evaluate the myocardial functionality by STE in recent onset RA and PsA patients and its associations with clinical features. Methods: STE was used to assess the myocardial functionality in patients with very early RA (n=41) (2010 EULAR/ACR criteria) and PsA (n=35) (CASPAR criteria) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) were estimated. Results: RA patients exhibited impaired GLS (-18.13±1.36%) and GCS (-20.15±1.34%) compared to HC (-23.25±1.80%, p 0.050). DAS28 was correlated to GLS (r=0.908, p 2.9) compared to HC (GLS: p=0.066 and GCS: p=0.007). Conclusions: a subclinical myocardial dysfunction can be observed in IJD patients with preserved LV function and without traditional CV risk factors. The subclinical impairment of the myocardial function was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Strain imaging by STE may detect early myocardial dysfunction in IJD. Disclosure of Interest: None declared

Background increased cardiovascular (CV) risk in inflammatory joint diseases (IJD) such as rheumatoid (RA) or psoriatic arthritis (PsA) is linked to an impaired vascular homeostasis. Chronic inflammation and immune dysregulation prompt endothelial damage and impair reparative mechanisms. Among them, circulating CD34 +bone marrow-derived progenitors are known to participate in endothelial turnover and improve myocardial neovascularization and ventricular remodelling, likely delaying CV disease development. Among factors related to CD34 +cells mobilisation, a role for vitamin D has emerged in other scenarios. Whether impaired CD34 +cells or vitamin D levels underlie endothelial and myocardial dysfunction in IJD patients remains unknown. Objectives to evaluate the associations between CD34 +cells and vitamin D levels with markers of subclinical atherosclerosis and myocardial functionality in IJD patients. Methods CD34 +cells counts were assessed by flow cytometry in peripheral blood samples from 41 RA (2010 EULAR/ACR criteria) and 35 PsA (CASPAR criteria) patients recruited at onset and 58 matched healthy controls (HC). Vitamin D levels were quantified in serum by HPLC. PWV and cIMT were evaluated as markers of subclinical atherosclerosis, whereas myocardial dysfunction was assessed by speckle-tracking echocardiography (STE). Results vitamin D was decreased in RA (23.68±6.42) and PsA (23.53±4.84) compared to HC (31.75±5.05 ng/ml, both p Conclusions vitamin D was negatively associated with cIMT and risk factors in HC and PsA patients with low disease activity, but not in those with active disease or RA. Vitamin D was an independent predictor of CD34 +cell depletion in IJD. CD34 +cells, negatively associated with risk factors in HC, were altered in RA in relation to disease activity and the duration of symptoms. CD34 +cells were associated with myocardial dysfunction in RA. Disclosure of Interest None declared

Klippel-Trenaunay syndrome (KTS) is described as a complex syndrome characterized by various combinations of capillary, venous, and lymphatic malformations associated with bone and soft tissue hypertrophy. We report a case of a 67-year-old postmenopausal Caucasian women with KTS that shows elevated levels of sclerostin and Dickkopf-related protein 1 (DKK1). Dual-energy X-ray absorptiometry (DXA) BMD T-scores at lumbar spine and femur were normal. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD)

Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34 STE was used to assess the myocardial functionality in patients with very early RA (n = 41) and PsA (n = 35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34 RA patients exhibited impaired GLS and GCS (both p0.001) as compared to HC, GLS being also altered in PsA (p = 0.020 vs. HC). DAS28 was correlated to GLS (r = 0.908, p0.001) and GCS (r = 0.868, p0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (r = -0.308, p = 0.026) but not in PsA or RA, although decreased levels were observed (both p0.001). Vitamin D was an independent predictor of decreased CD34 Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity.

Glucocorticoid-induced osteoporosis (GIO) is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP) for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN), an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist), or vehicle (0.9% NaCl). Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days) PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist), or zoledronate (as control for gold standard treatment), or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

Genistein has a preventive role against bone mass loss during menopause. However, experimental data in animal models of osteoporosis suggest an anti-osteoporotic potential for this isoflavone. We performed a post-hoc analysis of a previously published trial investigating the effects of genistein in postmenopausal women with low bone mineral density. The parent study was a randomized, double-blind, placebo-controlled trial involving postmenopausal women with a femoral neck (FN) density

During menopause, an increased prevalence of metabolic syndrome (MetS) and central obesity seems to increase hot flashes (HFs). Visfatin is an inflammatory adipokine secreted by visceral fat. We investigated visfatin levels and its relationship with hot flash number and BMI, in postmenopausal women with MetS. We also evaluated the effect of genistein, an isoflavone effective in reducing HFs, on visfatin levels and HFs after 1 year of treatment. This was a randomized, double-blind, placebo-controlled trial. Postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein (n = 60), daily for 1 year. As main outcome measures, hot flashes number and circulating visfatin levels were evaluated. Visfatin significantly correlated with BMI and HFs number in women with MetS at basal. After 6 and 12 months, our results indicate a strong correlation and a significant effect of genistein in reducing both HFs and visfatin in women with MetS. The present study suggests that visfatin plays a role in the vasomotor symptoms, at least in postmenopausal women with metabolic syndrome. Genistein may reduce HFs decreasing the circulating levels of this inflammatory adipokine.

Denosumab has been proven to reduce fracture risk in breast cancer (BC) women under aromatase inhibitors (AIs). Quantitative ultrasound (QUS) provides information on the structure and elastic properties of bone. Our aim was to assess bone health by phalangeal QUS and by dual-energy X-ray absorptiometry (DXA), and to evaluate bone turnover in AIs-treated BC women receiving denosumab. 35 Postmenopausal BC women on AIs were recruited (mean age 61.2 ± 4.5 years) and treated with denosumab 60 mg administered subcutaneously every 6 months. Phalangeal QUS parameters [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), Bone Transmission Time (BTT)] and DXA at lumbar spine and femoral neck were performed. Serum C-telopeptide of type 1 collagen (CTX) and bone-specific alkaline phosphatase (BSAP) were also measured. The main outcomes were compared with a control group not receiving denosumab (n = 39). In patients treated with denosumab, differently from controls, QUS and DXA measurements improved after 24 months, and a reduction of CTX and BSAP was detected at 12 and 24 months in comparison to baseline (P

OBJECTIVE Phalangeal quantitative ultrasound (QUS) measurements provide surrogate information on bone quality. The aim of the present study was to assess bone status by phalangeal QUS and by dual-energy x-ray absorptiometry (DXA), and to evaluate bone turnover in breast cancer (BC) women receiving aromatase inhibitors (AIs). METHODS Sixty postmenopausal BC women and 42 matched controls were recruited (mean age 61.64 ± 8.33 y). Amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), Ultrasound Bone Profile Index, as QUS parameters, L1-L4 and femoral neck BMD by DXA were assessed at baseline and after 18 months; serum bone-specific alkaline phosphatase (BSAP) and C-telopeptide of type 1 collagen were measured at baseline, 9 and 18 months. RESULTS FRAX (without BMD) derived 10-years probability of major fractures and hip fractures were significantly associated with AD-SoS (r = -0.381, P =

In hemodialysis patients, vertebral fractures were associated with elevated sclerostin levels, suggesting that sclerostin could reflect bone fragility in these patients. Fragility fractures are common in hemodialysis patients. The aims of our study were to determine the prevalence of vertebral fracture and analyze associations between sclerostin serum levels and vertebral fractures in hemodialysis patients. Ninety-two hemodialysis patients and 100 controls matched for age and sex were studied. Bone mineral density was measured by ultrasonography at non-dominant heel. The markers of bone turnover included serum osteocalcin, C-terminal telopeptide, and sclerostin. All participants underwent radiography of the thoracic and lumbar spine to ascertain the presence of vertebral fractures. Bone ultrasound parameters at calcaneus were significantly lower in hemodialysis patients compared with controls; bone turnover markers and parathyroid hormone level were significantly higher, while serum of 25-OH-D3 was significantly lower in hemodialysis group. One or more moderate or severe vertebral fractures were found in 38 hemodialysis patients, whereas in control group, 10 patients had a vertebral fracture. In hemodialysis group, the comparison between patients with and without vertebral fractures showed that the patients with vertebral fractures had the serum sclerostin levels statistically higher than patients without vertebral, while serum levels of 25-OH-D3 was significantly lower in patients with vertebral fractures compared to the patients without vertebral fractures. Multivariate analysis disclosed that sclerostin levels were associated with an increased risk of vertebral fractures in hemodialysis patients after adjusting for multiple variables. Our data shows high prevalence of vertebral fractures in hemodialysis patients and that it is associated with elevated sclerostin levels, reflecting bone fragility in these patients.

Vitamin D status has been linked to immune system and autoimmune disorders; in fact, low levels of vitamin D are common in many autoimmune disorders. The aims of our study were to assess the prevalence of vitamin D insufficiency and the possible correlation with clinical parameters in systemic sclerosis (SSc). We recruited 40 patients (38 female and two male) with scleroderma and 40 healthy controls matched for age and gender. Demographic and clinical parameters were recorded and the 25-hydroxivitamin D3 serum levels were measured. Serum 25-hydroxivitamin D3 levels were significantly lower in patients with systemic sclerosis than in the control group. The prevalence of 25-hydroxivitamin D3 insufficiency was 50% in the patients and 22.5% in the control group. A statistically significant association was observed between the insufficiency of 25-hydroxivitamin D3 and skin involvement (p = 0.02) and echocardiography systolic pulmonary artery pressure >35 mmHg (p = 0.02). Our data show that the systemic sclerosis group has significantly lower serum 25-hydroxivitamin D3 concentrations compared to the control group; skin involvement and pulmonary hypertension are associated with vitamin D3 insufficiency.

Multiple factors may contribute to the pathogenesis of postmenopausal osteoporosis including environmental, life-style and genetic factors. Common variants in ESR2 gene encoding for ER-beta, highly expressed in bone tissue, have recently been proposed as candidates for affecting bone phenotype at the population level, particularly in postmenopausal women. In this study, we examined the genetic background at ESR2 AluI (rs4986938, 1730G>A) locus in 89 osteopenic, postmenopausal women (age range 49–56 years) together with BMD at lumbar spine and femoral neck sites as well as variations in plasma levels of bone metabolism and turnover markers. Genotyping for ESR2 G1730A polymorphism showed that the frequency of A mutated allele accounted for 0.4 in our cohort of postmenopausal women; moreover, the GA1730 heterozygous individuals were the most represented (50.6%) compared with GG (37.8%) and AA homozygous ones (14.6%). A regression analysis showed that lumbar spine BMD values were significantly associated with both ESR2 AA1730 genotype (p = 0.044) and time since the onset of menopause (p = 0.031), while no significant association was detected between biochemical markers and genetic background. Interestingly, 85% of patients with AA1730 genotype presented the smallest lumbar spine BMD values. These findings first indicate a worsening effect of ESR2 AluI polymorphism on lumbar spine BMD reduction in postmenopause, suggesting that the detection of this ESR2 variant should be recommended in postmenopausal women, particularly in populations with a high prevalence of ESR2 AA1730 homozygous genotype.

This study was aimed at evaluating the occurrence of DLB in a population sample recovered in assisted sanitary residence (RSA=from the Italian name of "Residenza Sanitaria Assistita") in the Province of Catania. We considered 126 patients from a randomized population recovered in RSA of Viagrande (Catania) in the period from 1st March, 2005 and 31st March, 2007. Those who proved to be demented according to the DSM-III diagnostic protocols, and having a mini mental state examination (MMSE)-score

Background and Aim Recent evidence suggests that genistein aglycone may act beneficially on surrogate cardiovascular risk markers in postmenopausal women. We assessed the effects of genistein aglycone on some cardiovascular risk factors and homocysteine levels after 3-years of continued therapy in a cohort of osteopenic, postmenopausal women. Methods and Results The parent study was a randomized, double-blind, placebo-controlled trial involving 389 postmenopausal women with low bone mass for 24 months. Subsequently, a subcohort (138 patients) continued therapy for an additional year. Participants received 54mg of genistein aglycone ( n =71) or placebo ( n =67), daily. Both arms received calcium and vitamin D 3 in therapeutic doses. Moreover, 4 weeks before randomization procedures and during our follow-up study, all patients received dietary instructions in an isocaloric fat-restricted diet. Blood lipid profiles, fasting glucose and insulin, insulin resistance (HOMA-IR), fibrinogen, osteoprotegerin (OPG) and homocysteine at baseline and after 24 and 36 months of treatment were measured. Compared to placebo, genistein significantly decreased fasting glucose and insulin, HOMA-IR, fibrinogen and homocysteine after 24 and 36 months of treatment. By contrast, isoflavone administration did not affect high-density lipoprotein cholesterol and triglycerides though serum OPG was higher in the genistein recipients. There were no differences in adverse events or discomfort between groups. Results on routine biochemical, liver function, and hematologic testing did not change over time in placebo or genistein group. Conclusions After 3-years of treatment, genistein aglycone plus calcium, vitamin D 3 and a healthy diet showed positive effects on some cardiovascular risk factors and homocysteine levels in a cohort of postmenopausal women with low bone mass.

Context and Objective: Genistein aglycone positively affects postmenopausal symptoms. However, questions about its long-term safety on the thyroid gland still remain. Design: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24 months. A subcohort (138 patients) continued therapy for an additional year. Setting: Patients received ambulatory care. Patients and Interventions: Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67), plus calcium and vitamin D3 at therapeutic doses. Circulating thyroid hormones (TSH, free T3, free T4) and autoantibodies (thyroid peroxidase, thyroglobulin, and thyroid microsomal antigen) were assessed in 40 genistein and 37 placebo subjects who completed 3 yr. Thyroid hormone receptor (THRα and THRβ) and retinoid receptor (RARα, RARγ, and RXRα) expression from peripheral blood monocytes was also evaluated at baseline, 12, 24, and 36 months in all 3-yr completers. Results: Genistein administration over 3 yr did not affect serum thyroid hormones or autoantibodies. In addition, there were no differences in THRα, THRβ, RARα, RARγ, or RXRα mRNA expression between groups. Conclusion: These data suggest that genistein aglycone intake does not significantly increase the risk of clinical or subclinical hypothyroidism at the dose of 54 mg/d.

Context: Genistein aglycone improves bone metabolism in women. However, questions about the long-term safety of genistein on breast as well as its continued efficacy still remain. Objective: We assessed the continued safety profile of genistein aglycone on breast and endometrium and its effects on bone after 3 yr of therapy. Design: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24-months. Subsequently, a subcohort (138 patients) continued therapy for an additional year. Patients and Interventions: Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67). Both treatment arms received calcium and vitamin D3 in therapeutic doses. Main Outcomes: Mammographic density was assessed at baseline, 24 and 36 months by visual classification scale and digitized quantification. BRCA1 and BRCA2, sister chromatid exchange, and endometrial thickness were also evaluated. Lumbar spine and femoral neck bone mineral density were also assessed. Secondary outcomes were biochemical levels of bone markers. Results: After 36 months, genistein did not significantly change mammographic breast density or endometrial thickness, BRCA1 and BRCA2 expression was preserved, whereas sister chromatid exchange was reduced compared with placebo. Bone mineral density increases were greater with genistein for both femoral neck and lumbar spine compared to placebo. Genistein also significantly reduced pyridinoline, as well as serum carboxy-terminal cross-linking telopeptide and soluble receptor activator of NF-κB ligand while increasing bone-specific alkaline phosphatase, IGF-I, and osteoprotegerin levels. There were no differences in discomfort or adverse events between groups. Conclusions: After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.

Introduction Genistein is an isoflavone phytoestrogen derived from the soybean which acts as natural selective estrogen receptor modulator. Various studies have pointed out its cardioprotective role. The aim of the study was to evaluate the haemostatic effects of genistein in postmenopausal women. Material and methods In this double-blind placebo-controlled trial we enrolled 104 healthy postmenopausal women with osteopenia. 53 patients (mean age 54.9 ± 4.2 yr; BMI 23.4 ± 3.2 Kg/m2) received genistein (54 mg/day) and 51 patients (mean age 55.4 ± 4.3 yr; BMI 23.6 ± 3.6 Kg/m2) received an identical placebo-tablet. Both groups received a calcium and vitamin D supplement. Plasma levels of D-dimer (DD), plasminogen activator inhibitor-1 (PAI-1) and prothrombin fragment 1 + 2 (F1 + 2) were measured at baseline and after 6 and 12 months of treatment. Results Baseline characteristics of the two groups were similar. Compared with placebo, genistein decreased significantly DD (p Conclusion The results of our study do not confirm effects of genistein on activation of the haemostatic system, but on the contrary the significant decrease of DD could indicate a possible cardioprotective role of genistein in postmenopausal women.

Recent pooled analyses have shown that strontium ranelate increases the incidence of venous thromboembolism and non-fatal myocardial infarction, but no explanations were given. The aim of our study was to assess the effects a 12-month treatment with strontium ranelate on hemostasis factors and markers of cardiovascular risk in postmenopausal osteoporotic women. Forty osteoporotic postmenopausal women received orally strontium ranelate 2 g daily, plus calcium and colecalcipherol for 12 months. Forty postmenopausal osteopenic women matched for age, menopausal age, and body mass index served as controls and received orally calcium and colecalcipherol for 12 months. Biochemical cardiovascular risk factors and hemostatic indices were assayed prior to treatment, and after 3, 6, and 12 months of therapy. These indices included fibrinogen, fasting glucose, total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, plasma levels of D-dimer, homocysteine, partial thromboplastin time, and prothrombin time. In addition, we evaluated possible changes in blood pressure and occurrence of venous thromboembolic events. At baseline, no statistically significance was observed between the two groups except for bone mineral density at lumbar spine, femoral neck, and total femur, which was lower in strontium ranelate group. After 12 months of treatment, there was no statistically significant change in cardiovascular risk factors and hemostatic parameters. None of the 40 women developed any clinical venous thromboembolic event. A 12-month treatment with strontium ranelate did not alter hemostasis factors or markers of cardiovascular risk, suggesting that reported increased risk of venous thromboembolism and myocardial infarction with strontium is mediated by other factors.

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p

Postmenopausal estrogen decline is implicated in several age-related physical and psychological changes in women, including decreases in perceived quality of life. The phytoestrogen genistein at a dose of 54 mg daily in osteopenic postmenopausal women after 2 years implies an improvement on quality of life and depression symptoms. Postmenopausal estrogen decline is implicated in several age-related physical and psychological changes in women, including decreases in perceived quality of life (QoL). A number of trials with hormone therapy showed beneficial effects of the intervention on quality of life parameters. However, because of known or suspected serious side effects of conventional hormone therapy, there is a need for alternatives. We conducted a double-blind randomized placebo-controlled trial using the isoflavone genistein, 54 mg, or placebo for 2 years. In this trial, we recruited 262 postmenopausal women aged 49 to 67 years. At baseline, after 1 year, and at final visit, participants filled in the Short Form of 36 questions (SF-36) and the Zung Self-rating Depression Scale (ZSDS). For the placebo group, scores on all dimensions of the SF-36 decreased after 1 and 2 years. The genistein group showed increases on all dimensions of the SF-36 at the end of the study. There were, however, statistically significant differences in changes of scores between the two intervention groups. For the ZSDS, similarly, significant differences were found between groups. In conclusion, the findings of this randomized trial showed that genistein improves quality of life (health status, life satisfaction, and depression) in osteopenic postmenopausal women.

Scleroderma or systemic sclerosis (SSc) is an autoimmune disease of the connective tissue, characterized by vascular abnormalities and progressive fibrosis of the skin and internal organs. Kidney, esophagus, heart and lung are most frequently involved. According to the extensive skin involvement and the internal organ injury, scleroderma is classified in limited and diffuse forms. Vascular injury is considered the first event in the pathogenesis of scleroderma. Vasculopathy primarily affects the microcirculation and the small vessels decreasing blood flow that results in chronic ischemia. Chronic vascular injury induces fibroblasts activation that leads to extensive fibrosis. Prevalence of renal involvement ranges from 10 to 40%. Its presentation can be very variable. The most serious renal complication is the scleroderma renal crisis associated or not with severe hypertension and acute renal failure. It is observed in 10% of the patients with scleroderma. Treatment with ACE-inhibitors modified significantly the prognosis of renal crisis. Other renal manifestations are chronic renal failure, nephrotic syndrome, ANCA-associated glomerulonephritis and isolated proteinuria.

Recent advances suggest that the cellular redox state may play a significantrole in the progression of fibrosis in systemic sclerosis (SSc). Another,and as yet poorly accounted for, feature of SSc is its overlap with thyroidabnormalities. Previous reports demonstrate that hypothyroidism reducesoxidant stress. The aim of this study was therefore to evaluate the effectof propylthiouracil (PTU), and of the hypothyroidism induced by it, on thedevelopment of cutaneous and pulmonary fibrosis in the oxidant stress murinemodel of SSc. Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneousinjections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25)were randomized into three arms: HOCl (n = 10), HOCl plus PTU(n = 10) or vehicle alone (n = 5). PTU administrationwas initiated 30 minutes after HOCl subcutaneous injection and continueddaily for 6 weeks. Skin and lung fibrosis were evaluated by histologicmethods. Immunohistochemical staining for alpha-smooth muscle actin(α-SMA) in cutaneous and pulmonary tissues was performed to evaluatemyofibroblast differentiation. Lung and skin concentrations of vascularendothelial growth factor (VEGF), extracellular signal-related kinase (ERK),rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforminggrowth factor (TGF) β were analyzed by Western blot. Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTUtreatment prevented both dermal and pulmonary fibrosis. Myofibroblastdifferentiation was also inhibited by PTU in the skin and lung. The increasein cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in micetreated with HOCl was significantly prevented in mice co-administered////with PTU. PTU, probably through its direct effect on reactive oxygen species orindirectly through thyroid function inhibition, prevents the development ofcutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERKpathway in the oxidant-stress animal model of SSc.

OBJECTIVE: The aim of our study was to elucidate the pathophysiology of systemic sclerosis-related osteoporosis and the prevalence of vertebral fragility fracture in postmenopausal women with systemic sclerosis (SSc). METHODOLOGY: Fifty-four postmenopausal women with scleroderma and 54 postmenopausal controls matched for age, BMI, and smoking habits were studied. BMD was measured by dual energy-x-ray absorptiometry at spine and femur, and by ultrasonography at calcaneus The markers of bone turnover included serum osteocalcin and urinary deoxypyridinoline. All subjects had a spine X-ray to ascertain the presence of vertebral fractures. RESULTS: bone mineral density at lumbar spine (BMD 0.78±0.08 vs 0.88±0.07; p

The development of cardiovascular pathologies is potentially connected to the surrounding environment, partly due to purely environmental factors, like exposition to pollutions, or anthropological ones, like the type of manual or stressing working activities. The relevant literature has already widely discussed the correlation between the acute and chronic exposition to atmospheric pollutants of different types and the pathogenetic events, such as the atherogenesis, thrombosis, and hypertension, The present study intends to verify this idea on a larger population exposed to different geographical conditions, comparing an agricultural village (Pachino-Siracusa) with an industrialized area (Augusta-Siracusa), both having identical sanitary services of basic importance. On the basis of the specific rates of hospitalizations, we compared the prevalence of cardiovasular pathologies in the resident populations. These studies confirmed the negative influence of the risk factors deriving from the environmental pollutions even on the cardiovascular aging, displaying an increased rate of hospitalization for angina pectoris, myocardial infarction and cardiac arrhytmias in the industrialized population.

The incidence of cardiovascular disease (CVD) and resultant morbidity and mortality are highly increased in postmenopausal women. Recent observations indicate the involvement of estrogen receptor beta in the pathogenesis of CVD, and the potential role of ESR2 gene polymorphisms as independent risk factors for CVD. We aimed to investigate the possible association between the ESR2 AluI 1730G>A gene polymorphism (rs4986938) with different CVD risk markers, such as body mass index (BMI), blood fibrinogen, glucose and insulin, homeostasis model assessment of insulin resistance and urinary F2-isoprostanes, in 89 postmenopausal women. Genotyping for ESR2 1730G>A polymorphism showed the higher prevalence of heterozygous GA1730 genotype than either wild-type GG1730 or homozygously mutated AA1730 genotype (50.6 vs 34.8 or 14.6%, respectively). Statistical analysis of between-group variability revealed that mean levels of the examined CVD risk markers, except BMI and fibrinogen, were within the normal range in all subjects grouped to different ESR2 1730G>A genotypes. Interestingly, only fibrinogen levels were statistically different in AA1730 carriers compared with other genotypes. The analysis of genotype relative risk showed a significant elevation of plasma fibrinogen in AA1730 carriers compared with GG + GA ones. The present data strongly indicate that genotyping for the ESR2 AluI 1730G>A gene variant should be included in a screening panel for assessment of cardiovascular risk in menopausal women.

The acute-phase response (APR) is a frequent occurrence after infusion of zoledronic acid and is caused by activation of γδ T cells. Vitamin D receptor is expressed in immune cells, and vitamin D has immunomodulatory properties. The aim of this prospective study was to test the effect of vitamin D (cholecalciferol) on the incidence of APR and intensity of pain in women undergoing infusion of zoledronic acid for postmenopausal osteoporosis. 60 women were enrolled and randomized into two groups. At baseline, 30 women received an oral bolus of cholecalciferol (300,000 IU), while another 30 women received placebo. On day 5 both groups were treated with a single infusion of zoledronic acid (5 mg) and received a daily supplementation of calcium (1,000 mg) and vitamin D (800 IU). Patients were clinically evaluated and inflammatory markers were assayed before zoledronic acid administration and every 24 h for the following 2 days. The onset of APR has been defined by the occurrence of fever or at least one of the typical symptoms, such as musculoskeletal pain after zoledronic acid infusion. Intensity of pain was measured by a one-dimensional scale (0 = no pain, 10 = unbearable pain). APR developed in 66.6% of patients, with no significant difference between groups. The vitamin group experienced less musculoskeletal pain [median 1 (0–4) vs. 2 (1–8), P

This study intended to evaluate the existing correlation between the cardiac compensation and the bone mass, investigating the bone mineral density (BMD) in a population suffering from CCD or chronic heart disease (CHD). We enrolled 171 patients, all over the age of 70, being in the functional N.Y.H.A. Class II (Population A: 85 patients) and in Class III (Population B: 86 patients). All patients underwent an analysis of their cardiac functions using a Doppler echo-cardiographic method measuring the ventricular ejection fraction (VEF), as well as the BMD by means of a computerized bone mineralometric DEXA method, performed in vertebral and femoral measurement sites. Both populations proved to be osteopenic, displaying reduced values of BMD. Higher bone mineral losses were measured in the patients who had more severe cardiac insufficiency. The present data revealed a significant reduction of BMD in the N.Y.H.A. Class III patients, in correlation with the VEF (p0.001), both in the lumbar vertebral area (p0.01) and even more in the femoral sites (p0.001), where a direct correlation exists between BMD and the VEF. On the basis of these findings one can suggest that the actual VEF level has an influence on the bone turnover, reducing the mineral content through various mechanisms of action.

The aim of our study was to investigate the effects of teriparatide on the hypophysis–adrenal axis in postmenopausal women. Treatment with teriparatide increased plasmatic and urinary levels of cortisol after 6 and 12 months. Our paper demonstrates a possible direct secretagogue effect of teriparatide on adrenals in osteoporotic postmenopausal women. Teriparatide, recombinant human parathyroid hormone (1-34) (rhPTH [1-34]), is approved for the treatment of osteoporosis in men and postmenopausal women at high risk for fracture. In literature, data regarding the secretagogue effect of PTH on adrenocortical cells are present on in vitro, but not on in vivo, studies. The aim of our study was to investigate the effects of teriparatide on the hypophysis–adrenal axis in postmenopausal women. Twenty postmenopausal women with severe osteoporosis were treated with teriparatide in a regimen of 20 μg daily, self-administered injections at bedtime for 12 months and a calcium and vitamin D supplementation. At the same time, 20 osteopenic women matched for age and body mass index with the patients were enrolled and treated only with calcium and vitamin D. In all subjects, calcium, adrenocorticotropic hormone (ACTH), and plasmatic and urinary cortisol were evaluated at baseline and after 6 and 12 months. Treatment with teriparatide increased plasmatic and urinary levels of cortisol after 6 and 12 months, reaching statistical significance only after 1 year. Plasmatic levels of ACTH did not change significantly. Our paper, for the first time, demonstrates a possible direct secretagogue effect of teriparatide on adrenals in osteoporotic postmenopausal women.

Objective To evaluate in a 24-month, prospective, randomized, double-blind, placebo-controlled study whether pure administration of the phytoestrogen genistein (54 mg/d) might reduce the number and severity of hot flushes in postmenopausal women, with no adverse effect on the endometrium and vagina. Methods A total of 389 participants met the parent study criteria and were randomly assigned to receive the phytoestrogen genistein (n = 198) or placebo (n = 191). About 40% of participants in both groups did not experience hot flushes, and the evaluation was performed in a subgroup of 236 participants (genistein, n = 119; placebo, n = 117). Reductions from the baseline in the frequency and severity of hot flushes were the principal criteria of efficacy. Endometrial thickness was evaluated by ultrasonography. The maturation value was also used to determine hormonal action on the vaginal cells. Results There were no significant differences in vasomotor symptoms between groups at the baseline (4.4 +/- 0.33 hot flushes per day in the genistein group and 4.2 +/- 0.35 hot flushes per day in the control group). After 12 months of genistein therapy, there was a significant reduction (-56.4%) in the mean number of hot flushes, with a significant difference compared with the control group. After 24 months, there was no further decrease in the number of hot flushes in both groups. No significant difference was found in mean endometrial thickness and the maturation value score between the two groups, either at the baseline or after 24 months. Conclusions The phytoestrogen genistein has been shown to be effective on vasomotor symptoms without an adverse effect on the endometrium and vagina, but after the first year, there was no further improvement in the decrease in hot flushes.

This study aimed at evaluating the effects of genistein (54 mg/die) on calcaneus and phalanges ultrasound (QUS) parameters and bone mineral density in osteopenic postmenopausal women. We concluded that genistein prevented bone loss in the osteopenic postmenopausal women and improves QUS parameters at the calcaneus and phalanges. The purpose of the study was to evaluate the effects of genistein (54 mg/die) on quantitative ultrasound (QUS) parameters of the calcaneus and hand phalange and on bone mineral density (BMD) in osteopenic postmenopausal women. One hundred thirty-eight women (age 49–67 years) were assigned to receive genistein or placebo. Bone status was assessed by measuring the anteroposterior lumbar spine and femoral neck BMD by dual energy X-ray absorptiometry and by ultrasound of the calcaneus (Achilles Plus, GE, Lunar) and of the phalanges (Bone Profiler. IGEA) at baseline and after a 1- and 2-year treatment. At the end of the experimental period, genistein had significantly increased BMD in the femur and lumbar spine (p

Introduction: RANKL and its decoy receptor osteoprotegerin (OPG) constitute a complex physiological mediator system involved in the regulation of bone resorption and may be responsible for the homeostatic mechanism of normal bone remodeling. Genistein, an isoflavone representing 1–5% of total phytoestrogen content in soybean products, may positively regulate cellular bone metabolism, but its mechanism of action on bone is not yet fully understood. Materials and Methods: We studied the serum levels of both soluble RANKL (sRANKL) and OPG and the sRANKL/OPG ratio in 389 postmenopausal women (age, 49–67 yr) with a femoral neck BMD

To evaluate in a twelve-month, randomized placebo-controlled study whether pure administration of phytoestrogen genistein (54 mg/day) might reduce cytogenetic biomarkers in peripheral lymphocytes of postmenopausal women. A total of 57 postmenopausal women met the criteria and were randomly assigned to receive phytoestrogen genistein (n = 30) or placebo (n = 27). There was no significant difference in age, length of time since menopause or body mass index between the two groups. After one year, plasma genistein level was 0.14 +/- 0.01 micromol/L in the control group and 0.72 +/- 0.08 micromol/L in the genistein group (P0.0001). At baseline, sister chromatid exchange rate was 4.97 +/- 2.17 in the control group and 4.96 +/- 1.83 in the genistein group (P = 0.89). After one year, sister chromatid exchange rate was 4.96 +/- 2.16 in the control group and 3.98 +/- 1.14 in the genistein group (P0.05). High frequency cells count was 3% in the genistein group and 5% in the control group (P0.05) at the end of the study. Chromosomal aberration frequency was 5.55% in the control group at time 0 and 5.75% in the genistein group; after one year, the figures were 5.86% in the control group and 4.5% in the genistein group (P0.05). After one year, there was a negative relationship between sister chromatid exchange rate and plasma levels (r = - 0.43; P0.05) in the genistein group. Phytoestrogen genistein has been shown in postmenopausal women to be effective in the reduction of cytogenetic biomarkers. The protective effect on genomic damage appears to be a particularly promising tool in reducing the risk of cancer.

Context:Genistein,asoyisoflavone,hasreceivedwideattentionover the last few years because of its potential preventive role for cardiovascular disease. Objective: Our objective was to assess the effects of genistein administration (54 mg/d) on some predictors of cardiovascular risk in osteopenic, postmenopausal women. Design and Setting: We conducted a randomized, double-blind, placebo-controlled trial at three Italian university medical centers. Intervention: After a 4-wk stabilization on a standard isocaloric, fat-reduced diet, participants were randomly assigned to receive genistein (n 198) or placebo (n 191) daily for 24 months. Both intervention and placebo contained calcium and vitamin D3. OutcomeMeasures:Bloodlipidprofiles,fastingglucoseandinsulin, homeostasis model assessment for insulin resistance, fibrinogen, soluble intercellular adhesion molecule-1, soluble vascular cellular adhesion molecule-1, F2-isoprostanes, and osteoprotegerin at baseline and after 12 and 24 months of treatment were measured. Results: Compared with placebo, genistein significantly reduced fasting glucose and insulin as well as homeostasis model assessment for insulin resistance after both 12 and 24 months of treatment. By contrast, genistein administration did not affect blood lipid levels although fibrinogen, F2-isoprostanes, soluble intercellular adhesion molecule-1, and soluble vascular cellular adhesion molecule-1 decreased significantly compared with placebo after 24 months. Serum osteoprotegerin was higher in the genistein group compared with placebo. At 24 months, the genistein group showed no change in endometrial thickness compared with placebo. Most treatmentrelated adverse events were moderate and composed of gastrointestinal side effects [genistein, n 37 (19%); placebo, n 15 (8%)]. Conclusions: These results suggest that 54 mg genistein plus calcium, vitamin D3, and a healthy diet was associated with favorable effectsonbothglycemiccontrolandsomecardiovascularriskmarkers in a cohort of osteopenic, postmenopausal women. (J Clin Endocrinol Metab 92: 3068–3075, 2007)

Objective: To evaluate in a 12-month, prospective, randomized, double-blind, placebo-controlled study whether pure administration of the phytoestrogen genistein (54 mg/d) might reduce the number and severity of hot flushes in postmenopausal women with no adverse effect on the endometrium. Design: A total of 389 participants met the main study criteria and were randomly assigned to receive the phytoestrogen genistein (n = 198) or placebo (n - 191). About 40% of participants in both groups did not suffer from hot flushes, and the evaluation was performed in a subgroup of 247 participants (genistein, n = 125; placebo, n = 122). Reductions from baseline in the frequency and severity of hot flushes were the principal criteria of efficacy. Endometrial thickness was evaluated by ultrasonography. The maturation value was also used to determine hormonal action on the vaginal cells. Results: There were no significant differences in age, time since menopause, body mass index, and vasomotor symptoms between groups at baseline (4.4 ± 0.33 hot flushes per day in the genistein group and 4.2 ± 0.35 hot flushes per day in the control group). The effect was already evident in the first month and reached its peak after 12 months of genistein therapy (-56.4% reduction in the mean number of hot flushes). Furthermore, there was a significant difference between the two groups at each evaluation time (1, 3, 6, and 12 months). No significant difference was found in mean endometrial thickness and maturation value score between the two groups, either at baseline or after 12 months. Conclusions: The phytoestrogen genistein has been shown to be effective on vasomotor symptoms without an adverse effect on endometrium.