Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

Pharmacokinetic profile and effect on bone markers and muscle strength of two daily dosage regimens of calcifediol in osteopenic/osteoporotic postmenopausal women.

BACKGROUND: At present, although cholecalciferol represents the form of vitamin D of choice for the treatment of vitamin D deficiency, there is a growing interest in calcifediol. AIMS: This study aimed to evaluate the efficacy and the safety of two different daily doses of calcifediol. METHODS: Fifty osteopenic/osteoporotic women with serum levels of 25-hydroxyvitamin D (25OHD) between 10 and 20 ng/ml were randomized to a 6-month treatment with oral calcifediol 20 µg/day (n = 25) or oral calcifediol 30 µg/day (n = 25). In all, we measured the time course of the levels of 25OHD and other biochemical parameters. Moreover, we evaluated handgrip strength and serum levels of myostatin. RESULTS: The peak increase in 25OHD levels was reached after 90 days of treatment in group 1 (59.3 ng/ml) and after only 60 days in group 2 (72.3 ng/ml); thereafter in both groups, the levels of 25OHD showed a tendency towards stabilization. After 30 days, all the patients treated with 30 µg/day had values of 25OHD > 30 ng/ml. Handgrip strength showed a modest but progressive increase which reached the statistical significance in the 30 µg/day group. This latter group also presented a modest and non-significant decrease in serum levels of myostatin. CONCLUSIONS: Calcifediol is able to rapidly normalize the vitamin D deficiency, and the 30 µg daily dosage could be suggested in those patients who need to rapidly reach optimal 25OHD levels. Moreover, the 6-month treatment with calcifediol at a dose of 30 µg results in a modest but significant increase in upper limb strength.

Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with bone disease severity in Rett syndrome.

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.

Prognostic Significance of an Early Echocardiographic Evaluation of Right Ventricular Dimension and Function in Acute Heart Failure.

OBJECTIVE: Sparse and contradictory data are available on the prognostic role of an early echocardiographic examination in patients with acute decompensated heart failure (ADHF). We planned a prospective study to illustrate which early echocardiographic parameter would be better related to prognosis in such patients. METHODS: In a consecutive series of patients with ADHF with either reduced (n=209) or preserved (n=172) left ventricular ejection fraction (LVEF), a complete echocardiographic examination was performed within 12 hours of admission. The endpoint of the study was death or rehospitalization at 6 months from hospital discharge. RESULTS: After 6 months from discharge, 73 died and 96 were rehospitalized due to cardiovascular causes. In multivariable analysis, a right ventricular end-diastolic diameter (RVEDD) >40 mm (P = .02), a tricuspid annular plane systolic excursion (TAPSE) <19 mm (P= .004), and an inferior vena cava diameter >22 mm (P = .02) were associated with 6-month events. LVEF and LV diastolic function were not predictive of events. Pulmonary artery systolic pressure (PASP) >45 mmHg and TAPSE/PASP <0.425 were associated with prognosis in univariate but not in multivariable analysis. Conversely, the TAPSE/RVEDD ratio (dichotomized at its median value of 0.461) was an independent predictor of outcome in multivariable analysis (P< .001). CONCLUSIONS: In patients hospitalized for ADHF, early echocardiographic identification of right ventricular dilatation and dysfunction predicts a poor outcome better than LV systolic and/or diastolic dysfunction.

Congestion occurrence and evaluation in acute heart failure scenario: time to reconsider different pathways of volume overload.

Although congestion is considered to be the main reason for hospital admission in patients with acute heart failure, a simplistic view considering idro saline retention and total body volume accumulation did not provide convincing data. Clinical congestion occurrence is often the tip of the iceberg of several different mechanisms ranging from increased filling pressure to extravascular fluid accumulation and blood flow redistribution. Therefore, the clinical evaluation is often restricted to a simple physical examination including few and inaccurate signs and symptoms. This superficial approach has led to contradictory data and patients have not been evaluated according to a more realistic clinical scenario. The integration with new diagnostic ultrasonographic and laboratory tools would substantially improve these weaknesses. Indeed, congestion could be assessed by following the most recognized HF subtypes including primitive cardiac defect, presence of right ventricular dysfunction, and organ perfusion. Moreover, there is a tremendous gap regarding the interchangeable concept of fluid retention and redistribution used with a univocal meaning. Overall, congestion assessment should be revised, considering it as either central, peripheral, or both. In this review, we aim to provide different evidence regarding the concept of congestion starting from the most recognized pathophysiological mechanisms of AHF decompensation. We highlight the fact that a better knowledge of congestion is a challenge for future investigation and it could lead to significant advances in HF treatment.

Circulating Long Non-Coding RNA GAS5 Is Overexpressed in Serum from Osteoporotic Patients and Is Associated with Increased Risk of Bone Fragility.

Osteoporosis (OP) is a multifactorial disorder in which environmental factors along with genetic variants and epigenetic mechanisms have been implicated. Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of bone metabolism and OP aetiology. In this study, we analyzed the expression level and the genetic association of lncRNA GAS5 in OP patients compared to controls. Quantitative RT-PCR analysis of GAS5 was performed on the serum of 56 OP patients and 28 healthy individuals. OP subjects were divided into three groups of analysis: 29 with fragility fractures of lumbar spine (OP_VF), 14 with fragility fractures of femoral neck (OP_FF) and 13 without fractures (OP_WF). Genotyping of the rs145204276 insertion/deletion polymorphism has also been performed by Restriction fragment length polymorphism (RFLP) and direct sequencing analyses. Expression of circulating GAS5 is significantly increased in OP patients compared to controls (p < 0.01), with a statistically higher significance in fractured OP individuals vs. healthy subjects (p < 0.001). No statistically significant change was found in female OP patients; conversely, GAS5 is upregulated in the subgroup of fractured OP women sera (p < 0.01) and in all OP males (p < 0.05). Furthermore, a direct correlation between GAS5 expression level and parathyroid hormone (PTH) concentration was found in OP patients (r = 0.2930; p = 0.0389). Genetic analysis of rs145204276 revealed that the deletion allele was correlated with a higher expression of GAS5 in OP patients (0.22 ± 0.02 vs. 0.15 ± 0.01, ** p < 0.01). Our results suggest circulating GAS5 as a putative biomarker for the diagnosis and prognosis of OP and OP-related fractures.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Vitamin D Status in Paget Disease of Bone and Efficacy-Safety Profile of Cholecalciferol Treatment in Pagetic Patients with Hypovitaminosis D.

Adequate vitamin D status is essential for skeletal health. Paget's disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case-control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy-safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8 weeks until 25OHD levels reaches 70 nmol/L as primary therapy and 50.000 UI of cholecalciferol administered every 2 weeks for 52 weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50 nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70 nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70 nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

Bone status in relation to ambulatory performance in girls with Rett syndrome: a 10-year longitudinal study.

BACKGROUND: Low bone mass is a frequent and early complication of girls with Rett syndrome. As a consequence of the low bone mass, Rett patients are at an increased risk of fragility fractures. This study aimed to investigate the long-term influences of mobility on bone status in girls with Rett syndrome. METHODS: In 58 girls with Rett syndrome, biochemical parameters and quantitative ultrasound parameters at phalanges (amplitude-dependent speed of sound: AD-SoS and bone transmission time: BTT) were measured at baseline and after 5 and 10 years. The subjects were divided into two groups: nonambulatory (n = 28) and ambulatory (n = 30). RESULTS: In nonambulatory Rett subjects, the values of AD-SoS and BTT were significantly lower than in ambulatory Rett subjects at each time point. However, during the 10-year follow-up both ambulatory and nonambulatory Rett patients showed a similar worsening in their bone status. CONCLUSION: This longitudinal study suggests that both ambulatory and nonambulatory Rett subjects present a progressive deterioration of bone status as assessed by quantitative ultrasound parameters, and the ambulatory impairment and the nutritional status seem to play a key role in the deterioration of bone status.

Altered expression of RXFP1 receptor contributes to the inefficacy of relaxin-based anti-fibrotic treatments in systemic sclerosis.

OBJECTIVES: Relaxin is a potent anti-fibrotic hormone that has been tested to ameliorate fibrosis in systemic sclerosis (SSc), but with controversial results. The aim of the study is to sequence relaxin receptor gene RXFP1 and to assess its mRNA expression and protein levels in the skin of SSc patients and healthy subjects. METHODS: Fibroblasts were isolated from unaffected/affected skin samples of (n=16) limited-cutaneous-SSc-(LcSSc) and from affected ones of (n=4) diffuse-cutaneous-SSc-(DcSSc) patients. Fibroblasts from healthy subjects were used as controls. Sequencing of exonic target regions of interest for RXFP1 gene was performed, coupled with mRNA transcript variant analysis. RXFP1 mRNA and protein levels were assessed by quantitative-real-time-PCR-(qRT-PCR) and by immunocytochemistry-(ICC). Alpha-smooth-muscle-actin-(α-SMA) synthesis induced by transforming-growth-factor-beta-1-(TGF-ß1) stimulation was investigated in all fibroblasts with and without pre-treatment with serelaxin (a recombinant form of human relaxin-2 targeting the receptor RXFP1). RESULTS: Sequencing of RXFP1 gene showed no relevant mutations in all fibroblast populations. The analysis of mRNA transcripts revealed the presence of 13 different mRNA isoforms of RXFP1 (7 coding and 6 non-coding) upregulated in LcSSc/DcSSc-affected samples and not in LcSSc-unaffected and in healthy ones. On the contrary, ICC demonstrated the absence of RXFP1 in LcSSc/DcSSc-affected fibroblasts and the presence in LcSSc-unaffected and in healthy ones. To prove these findings, serelaxin pre-incubation was unable to counteract TGF-ß1-driven upregulation of α-SMA in LcSSc/DcSSc-affected fibroblasts only, but not in LcSSc-unaffected and healthy ones. CONCLUSIONS: The absence/altered expression of relaxin receptor RXFP1 in the affected fibroblasts of SSc patients could explain the inefficacy of relaxin-based anti-fibrotic treatments in the disease.

Helicobacter pylori Infection Does Not Impact on Lung Transplant Outcome.

BACKGROUND: Helicobacter pylori (HP) is a spiral, gram-negative, microaerophilic bacterium that colonises the human gastric mucosa and is associated with gastrointestinal and extragastrointestinal disorders. Since no data are yet available on HP infection in lung transplant patients, we evaluated the prevalence and impact of HP infection in a population of such patients. METHODS: Sixty-seven lung transplant patients were enrolled in the study (35 females and 32 males, age 48.4 ± 13.3 years), 54 underwent bilateral and 13 single lung transplant. Serum antibodies against HP and CagA were assayed in all subjects. RESULTS: The prevalence of HP infection in lung transplant patients was similar to that in the general population (49.25% vs. 51.4%), whereas HP-positive patients showed lower CagA positivity (9% vs. 50.2%, p < 0.0001). There was a higher prevalence of HP infection in patients who underwent lung transplant because of pulmonary fibrosis (p = 0.049), and a lower prevalence in COPD patients (p = 0.011). No correlation was found between HP infection in lung transplant patients and graft outcome. No differences in primary graft dysfunction, acute rejection or bronchiolitis obliterans syndrome-free survival were found. However, more patients who required three or more post-transplant re-hospitalisations were observed among HP-positive patients. CONCLUSIONS: The prevalence of HP infection in lung transplant patients was comparable to that of the general population and to that reported in heart and kidney transplant recipients. It did not seem to impact short-, mid- or long-term lung allograft outcome. H. pylori infection did not prove to be clinically relevant in lung transplant patients.

Sarcopenia in systemic sclerosis: the impact of nutritional, clinical, and laboratory features.

We evaluated the presence of sarcopenia in a population of systemic sclerosis (SSc) patients, with respect to nutritional, clinical, and laboratory features. A total of 62 patients who met the ACR/EULAR 2013 classification criteria were enrolled. Sarcopenia was defined according to the Relative Skeletal Mass Index (RSMI) and hand grip strength (HGS). Body composition was assessed with the calculation of the Body Mass Index (BMI), lean body mass (LBM) and fat mass (FM). Malnutrition was evaluated according to the ESPEN criteria. Clinical evaluation included nailfold capillaroscopy and skin evaluation by modified Rodnan Skin Score (mRSS), pulmonary function tests (PFT) with diffusing capacity for carbon monoxide adjusted for hemoglobin (DLCO), high-resolution computed tomography (HR-CT) of the lungs, echocardiography and high-resolution manometry (HRM) for esophageal involvement. Laboratory evaluation included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, creatinine, creatine kinase (CK), transaminases, lipid profile, glycemia, albumin, and vitamin-D. Antinuclear antibodies (ANA) and extractable nuclear antigens (ENA) were also assessed. Considering RSMI, the prevalence of sarcopenia is 42%. In this case, age, malnutrition, disease duration, mRSS, capillaroscopy score, esophageal involvement, ESR, and ANA titer are higher in the sarcopenic group, while DLCO and LBM are lower. Considering HGS, the prevalence of sarcopenia is 55%. Age, disease duration, malnutrition, FM, mRSS, capillaroscopy score, esophageal involvement, ESR, and ENA positivity are higher in the sarcopenic group, while DLCO is lower. By using both RSMI and HGS to assess sarcopenia in SSc, the results of this study demonstrated that this condition correlates with different nutritional, clinical, and biochemical parameters associated with the worsening of the disease.

Retrospective evaluation of persistence in osteoporosis therapy with oral bisphosphonates in Italy: the TOBI study.

The patients' persistence with osteoporosis treatments is low. This retrospective, multicenter survey showed that almost 30% of osteoporotic patients discontinued the treatment within the first 6 months and that those taking drinkable bisphosphonates were less likely to interrupt the therapy; instead, the use of generic bisphosphonates was associated to a more precocious interruption. PURPOSE: Low persistence with osteoporosis medications is associated with higher fracture risk. This study aimed to assess the persistence to treatment with oral bisphosphonates among Italian osteoporotic patients under treatment for at least 6 months and to evaluate whether the different oral formulations of bisphosphonates may influence the interruption of the therapy. METHODS: 723 consecutive osteoporotic patients, aged 50 years or over, referred as outpatients for a follow-up visit after receiving a prescription of an oral bisphosphonate for the first time for at least 6 months were enrolled in this retrospective, multicenter survey carried out under conditions of usual clinical practice. All the patients enrolled were submitted to a standardized interview. RESULTS: 191 patients turned out to have discontinued treatment (28.7%), the more common causes for interruption being the adverse events (43.9%), fear of adverse events (23.3%) and perceived absence of efficacy of the treatment (15.8%). The osteoporotic patients taking drinkable bisphosphonate or on treatment with aromatase inhibitors or under the age of 70 years were less likely to interrupt the treatment. However, these associations were no longer significant when the pharmaceutical formulation (generic vs branded) was included into the multivariate logistic regression model. CONCLUSION: This study suggests that the new drinkable formulations of bisphosphonates could be an interesting option able to reduce upper GI adverse events, thus increasing persistence; whereas the generic formulations of bisphosphonates were associated to a premature discontinuation.

Molecular Dysfunction and Phenotypic Derangement in Diabetic Cardiomyopathy.

The high incidence and poor prognosis of heart failure (HF) patients affected with diabetes (DM) is in part related to a specific cardiac remodeling currently recognized as diabetic cardiomyopathy (DCM). This cardiac frame occurs regardless of the presence of coronary artery diseases (CAD) and it can account for 15-20% of the total diabetic population. The pathogenesis of DCM remains controversial, and several molecular and cellular alterations including myocardial hypertrophy, interstitial fibrosis, oxidative stress and vascular inflammation, have been postulated. The main cardio-vascular alterations associated with hyperglycemia comprise endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation. High glucose concentrations lead to a loss of mitochondrial networks, increased reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) activation and a reduction in cGMP production related to protein kinase G (PKG) activity. Current mechanisms enhance the collagen deposition with subsequent increased myocardial stiffness. Several concerns regarding the exact role of DCM in HF development such as having an appearance as either dilated or as a concentric phenotype and whether diabetes could be considered a causal factor or a comorbidity in HF, remain to be clarified. In this review, we sought to explain the different DCM subtypes and the underlying pathophysiological mechanisms. Therefore, the traditional and new molecular and signal alterations and their relationship with macroscopic structural abnormalities are described.

Clinical impact of oral antidiabetic medications in heart failure patients.

Heart failure (HF) is a common complication in patients with type 2 diabetes and it is closely associated with high morbidity and mortality rate. The incidence of cardiovascular events in patients with diabetes is related to high levels of glycemia, expressed by increase of HbA1c levels. However, there is little evidence to indicate that glycemic control can reduce the incidence of HF events in this population. Recently, several new antidiabetic drugs have been proposed although the exact clinical impact on heart failure occurrence and deterioration is under debate. Most common oral antidiabetic medication such as SGLT2, GLP-1 receptor agonist, metformin, and DPP4 inhibitor revealed peculiar metabolic and biomolecular signal effects. Moreover, the negative effects of thiazolidinediones on HF prognosis, on cardiac function, and exercise tolerance is of great interest. Conversely, several studies on GLP-1RA have highlighted many positive effects on cardiac myocytes, reducing apoptosis through cAMP/PKA/CRCB-mediated pathways protecting against oxidative stress. DPP-4 inhibitors have a controversial effect: saxagliptin and alogliptin may increase the risk of HF as opposed to vildagliptin and sitagliptin. Metformin increases myocardial ATP levels due to activation of 5-AMPK and this could explain the positive link between the drug and events rate reduction in diabetic patients with HF. The more interesting class of new drugs is SGLT2 inhibitors, that seems to have a positive effect on cardiac function by 38% reduction of HF incidence and mortality with empagliflozin treatment. In this review, we would analyze the specific effects of each class so as to better elucidate the clinical impact of antidiabetic drug on HF for guiding the clinicians in the choice of a best individualized therapy.

Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

In Type-2 Diabetes Subjects Trabecular Bone Score is Better Associated with Carotid Intima-Media Thickness than BMD.

Literature data reported that in elderly subjects, carotid intima-media thickness (IMT) was negatively associated with bone mineral density (BMD). Paradoxically, type-2 diabetes (T2DM) patients, despite having higher BMD, present an increased risk of fragility fractures and cardiovascular complications. Some studies have reported trabecular bone score (TBS), an index of trabecular bone quality, as possibly being reduced in T2DM. This study aimed to evaluate whether in T2DM subjects TBS was better associated with IMT with respect to BMD. In 131 consecutive T2DM subjects (55 men and 76 women; mean age: 60.0 ± 7.3 years) and 265 consecutive non-T2DM subjects (107 men and 158 women; mean age: 58.9 ± 7.8 years) we measured carotid IMT by high-resolution ultrasonography and BMD at lumbar spine (LS-BMD), at femoral neck FN-BMD and total hip TH-BMD; TBS was calculated using TBS iNsight software. LS-BMD, FN-BMD, and TH-BMD were all significantly higher in T2DM than in non-T2DM subjects, whereas TBS was significantly lower in T2DM subjects than in controls and inversely correlated with diabetes duration. In T2DM subjects multiple regression analysis showed that IMT was positively associated with age (b = 0.017; p < 0.001) and inversely associated with TBS (b = -0.473; p = 0.038). In non-T2DM subjects, only age was positively associated with IMT. To sum up, T2DM subjects present higher values of BMD and lower values of TBS with respect to non-diabetic controls. Moreover, in T2DM subjects TBS was found to be independently associated with carotid IMT. These findings suggest that TBS may not only capture bone fragility-related factors, but also some information associated with greater risk of developing cardiovascular diseases.

Vitamin D levels in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Besides its well known function on bone metabolism, vitamin D role in cerebrovascular pathologies including cerebral small vessel disease has been confirmed by recent meta-analysis. In this study, we measured vitamin D levels in 56 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients (mean age 49.9) with no or minimal disability (modified Ranking Score, mRS ≤2) and in 56 age, sex and seasonality matched healthy controls. History of ischemic events was recorded and cognitive functions were assessed using the Mini-Mental State Examination. White matter hyperintensities on brain T2-weighted magnetic resonance images were classified according to a modified Fazekas scale. Comparison of vitamin D levels between patients and controls showed significant lower values (p < 0.05) in no-to-mild CADASIL patients and a higher number of subjects with severe deficiency [25(OH)D <10 ng/ml]. Vitamin D levels did not correlate with vascular risk factors, clinical data or Fazekas score. The role of vitamin D is worth to be further explored in prospective studies.

Prescription of anti-osteoporosis medications after hospitalization for hip fracture: a multicentre Italian survey.

PURPOSE: Literature data indicate that the proportion of patients with recent hip fracture who receive a prescription for anti-osteoporotic drugs is low and does not seem to increase over time. This study aimed to obtain data on the prescription for anti-osteoporotic drugs in Italian patients discharged after a recent hip fracture and to assess which variables could have influenced the decision for prescribing osteoporosis medication. METHODS: A total of four Italian centres located in four different geographical areas (Siena, Verona, Naples and Palermo) participated in this retrospective study. In each centre, experienced clinicians gathered the data of up to 200 consecutive patients discharged after a recent low-trauma hip fracture. The analysis was carried out on 697 patients (540 women and 157 men; mean age 81.9 ± 8.6 years). RESULTS: The percentage of patients who were receiving any type of treatment for osteoporosis before the hip fracture was 8.8% (ranging from 2.4% in Naples to 17.4% in Verona). After the index hip fracture, only 23.2% of patients (namely 10.5% of men and 27.2% of women) received prescription for any pharmacological treatments for osteoporosis. Both female gender and previous use of medications for osteoporosis were positively associated with the likelihood of receiving prescription for anti-osteoporotic treatment at discharge. CONCLUSIONS: This study showed that less than 25% of the elderly Italian patients discharged after a hip fracture received a prescription for any type of treatment for osteoporosis and highlights the urgent need for implementing new strategies in the management of hip fracture patients.

How the knowledge of fracture risk might influence adherence to oral therapy of osteoporosis in Italy: the ADEOST study.

UNLABELLED: The patients' adherence to osteoporosis treatments is low. In our study population a history of osteoporotic fractures was associated to better compliance and persistence; however, a 12-month randomized study carried out on 816 osteoporotic women showed that providing the patients with their individual fracture risk information did not prove effective. PURPOSE: Several drugs are currently available for the treatment of osteoporosis, but the patients' compliance and persistence with these treatments are low. This study aimed to both analyze the adherence to oral osteoporosis medications among Italian osteoporotic patients (cross-sectional study) and evaluate if providing patients with their individual fracture risk information may improve compliance and persistence (prospective study). METHODS: A total of 3379 osteoporotic patients referred as outpatients for a visit 1 year after receiving a prescription of oral osteoporosis medications for the first time, were enrolled for the retrospective study. Moreover, 816 postmenopausal women receiving an oral prescription for osteoporosis for the first time, were randomized into two groups: group 1 (managed according to standard clinical practice) and group 2 (managed with greater patient involvement and information on the individual risk of major osteoporotic fractures calculated by DeFRA algorithm). RESULTS: In the retrospective study, a history of osteoporotic fractures, the frequency of drug administration and a condition of being overweight/obese had a significant influence on both compliance and persistence. Of the 816 patients enrolled in the longitudinal study, 731 (374 of group 1 and 357 of group 2) attended the 1 year follow-up visit. The percentage of women with high compliance or persistence was greater in group 2 (64.2 vs. 58.1 % and 66.8 vs. 62.6 %, respectively), but without reaching any statistical significance. CONCLUSIONS: Although providing the patients with their individual fracture risk information was not statistically effective, further studies on additional interventions able to improve the patients' perceived risk of fracture are warranted.