Updates on mechanism of action and clinical efficacy of risedronate in osteoporosis

Risedronate is a heterocyclic orally active aminobisphosphonate and it belongs to the bisphosphonate category: these drugs are powerful bone resorption inhibitors, thanks to their affinity for hydroxyapatite crystals at bone mineral matrix level and to their inhibiting effects on osteoclast activity, using the ability of inhibiting enzyme FPPS. Recent observations have reported that risedronate can decrease resorption entity, not only of the trabecular bone, but also of the cortical bone, modifying therefore the (bone compact) thickness and the cortical porosity entity, which is largely responsible of femoral fracture especially among elderly patients. Various controlled studies have proved the efficacy of risedronate in reducing fragility fracture risk significantly. In particular, it is able to lower in a very significant way the incidence of vertebral, non-vertebral and femoral fractures, with precocity of effects after only six months of therapy. The extension of protocols, moreover, has marked its efficacy even after seven years of treatment. Under the metabolic profile, these studies have also shown that risedronate activity can reduce bone resorption markers and increase bone density values at lumbar and femoral level. Results emerged from a group of women aged over 80 are relevant: risedronate has proved capable of decreasing femoral fracture risk. Also in male and steroidal osteoporosis, clinical controlled studies have shown that risedronate is effective in decreasing vertebral fracture incidence. Lastly, tolerability: the main side effects concern the gastrointestinal tract and they are usually rare, of minor entity and can be solved by sospending the treatment. Acute phase reaction is rare, due to risedronate oral administration; it is also valid for osteonecrosis of the jaw and atypical fractures

Obesity and fracture risk.

Obesity and osteoporosis are two common diseases with an increasing prevalence and a high impact on morbidity and mortality. Obese women have always been considered protected against osteoporosis and osteoporotic fractures. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. Fat and bone are linked by many pathways, which ultimately serve the function of providing a skeleton appropriate to the mass of adipose tissue it is carrying. Leptin, adiponectin, adipocytic estrogens and insulin/amylin are involved in this connection. However, excessive body fat, and particularly abdominal fat, produces inflammatory cytokines which may stimulate bone resorption and reduce bone strength. This review aimed to examine the literature data on the relationships of BMI and fat mass with factures in adult and elderly subjects. Even though the more recent studies have shown conflicting results, there is growing evidence that obesity, and particularly severe obesity, may be related to an increased risk of fracture at different skeletal sites which is partially independent from BMD. Moreover, the relationship between obesity and fracture appears to be markedly influenced by ethnicity, gender and fat distribution. Even though the incidence and the pathogenesis of fracture in obese individuals has not yet been clearly defined, the growing evidence that obesity may be related to an increased risk of fracture has important public health implications and emphasizes the need to develop effective strategies to reduce fracture risk in obese subject

Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure

For patients presenting with acute dyspnea, an incorrect diagnosis could increase the mortality risk. When used in the evaluation of patients with acute symptoms, brain natriuretic peptide and N-terminal pro-brain natriuretic peptide (BNP and NT-proBNP, respectively) testing is highly sensitive for the diagnosis or exclusion of acute or chronic decompensated heart failure (HF). It has been demonstrated that BNP and proBNP levels can facilitate diagnosis and guide HF therapy. Natriuretic peptide (NP) levels are strictly related with HF severity; they are particularly increased in more advanced New York Heart Association (NYHA) classes and in patients with poor outcome. Therefore elevated NP levels were found to correlate with the severity of left ventricular systolic dysfunction, right ventricular dysfunction and pressures, and left ventricular filling alterations. However, the optimal use of NP determination agrees with patient history, physical examination, and all other diagnostic tools. There are some clinical conditions (ie, obesity, renal insufficiency anemia) for which the NP measurement is not diagnostic. Algorithm building taking into consideration all clinical and echocardiographic parameters, as well as NP measurements, may lead to the earlier identification and better risk stratification of patients with chronic HF, independently from etiology

Antibodies against specific extractable nuclear antigens (ENAs) as diagnostic and prognostic tools and inducers of a profibrotic phenotype in cultured human skin fibroblasts: are they functional?

Background: The importance of systemic sclerosis (SSc) autoantibodies for diagnosis has become recognized by their incorporation into the 2013 ACR/EULAR classification criteria. Clear prognostic and phenotypic associations with cutaneous subtype and internal organ involvement have been also described. However, little is known about the potential of autoantibodies to exert a direct pathogenic role in SSc. The aim of the study is to assess the pathogenic capacity of anti-DNA-topoisomerase I (anti-Topo-I) and anti-centromeric protein B (anti-Cenp-B) autoantibodies to induce pro-fibrotic markers in dermal fibroblasts. Methods: Dermal fibroblasts were isolated from unaffected and affected skin samples of (n = 10) limited cutaneous SSc (LcSSc) patients, from affected skin samples of diffuse cutaneous (DcSSc) patients (n = 10) and from healthy subjects (n = 20). Fibroblasts were stimulated with anti-Topo-I, anti-Cenp-B IgGs, and control IgGs in ratios 1:100 and 1:200 for 24 h. Cells were also incubated with 10% SSc anti-Topo-I+ and anti-Cenp-B+ whole serum and with 10% control serum for 24 h. Viability was assessed by MTT test, while apoptosis was assessed by flow cytometry. Activation of pro-fibrotic genes ACTA2, COL1A1, and TAGLN was evaluated by quantitative real-time PCR (qPCR), while the respective protein levels alpha-smooth-muscle actin (\u3b1-SMA), type-I-collagen (Col-I), and transgelin (SM22) were assessed by immunocytochemistry (ICC). Results: MTT showed that anti-Cenp-B/anti-Topo-I IgGs and anti-Cenp-B+/anti-Topo-I+ sera reduced viability (in a dilution-dependent manner for IgGs) for all the fibroblast populations. Apoptosis is induced in unaffected LcSSc and control fibroblasts, while affected LcSSc/DcSSc fibroblasts showed apoptosis resistance. Basal mRNA (ACTA2, COL1A1, and TAGLN) and protein (\u3b1-SMA, Col-1, and SM22) levels were higher in affected LcSSc/DcSSc fibroblasts compared to LcSSc unaffected and to control ones. Stimulation with anti-Cenp-B/anti-Topo-I IgGs and with anti-Cenp-B+/anti-Topo-I+ sera showed a better induction in unaffected LcSSc and control fibroblasts. However, a statistically significant increase of all pro-fibrotic markers is reported also in affected LcSSc/DcSSc fibroblasts upon stimulation with both IgGs and sera. Conclusions: This study suggests a pathogenic role of SSc-specific autoantibodies to directly induce pro-fibrotic activation in human dermal fibroblasts. Therefore, besides the diagnostic and prognostic use of those autoantibodies, these data might further justify the importance of immunosuppressive drugs in the early stages of the autoimmune disease, including SSc

B-type natriuretic peptide levels predict extent and severity of coronary disease in non-ST elevation coronary syndromes and normal left ventricular systolic function.

BACKGROUND: B-type natriuretic peptide (BNP) has been used recently as a biological marker in patients with coronary artery disease (CAD) with ST-elevation, as well as without ST-elevation. BNP is able to predict systolic dysfunction, adding new prognostic information to existing traditional markers. However is not known if there is a relation between the quantity of BNP levels and the severity of coronary artery disease. METHODS: This study compared B-type natriuretic peptide (BNP) levels in patients with stable angina (SA) and acute coronary syndromes (ACS) without ST-elevation in relation to angiographic lesions using TIMI and Gensini Scores. We studied 282 patients with CAD without ST elevation and preserved systolic function. BNP samples were measured in all recruited patients within 24 hours of hospitalization. RESULTS: BNP values were progressively increased in relation to the severity of diagnosis: SA (52.6±49.4 pg/mL ) UA (243.3±212 pg/mL) NSTE-ACS (421.7±334 pg/mL) (p<0.0001 and p<0.007 respectively). No statistically significant difference was observed between patients with SA and controls (21.2±6.8 pg/mL). The analysis of BNP levels in relation to the number of involved vessels demonstrated significantly increased levels in patients with multivessel disease compared to patients with 1 or 2 vessel disease (1-86.2±46.3 pg/mL; 2-127±297 pg/mL; 3-295±318 pg/mL; 4-297±347 pg/mL p<0.001 and p<0.003). Evaluation of BNP using Gensini Score showed a strong relation between BNP and coronary disease extension (r=0.38 p<0.0001).This trend was maintained in all CAD groups (SA=r 0.54; UA r=0.36 NSTE-ACS r=0.28). CONCLUSIONS: Circulating BNP levels appear elevated in ACS with diffuse coronary involvement, even in the absence of systolic dysfunction. BNP is also associated with multi-vessel disease and the extension of coronary disease

Bone Absorptiometry in Metabolic Bone Disease: Baseline Values and Long-Term Treatment with Calcitriol (Post-Menopausal Osteoporosis Versus Osteomalacia)

Total body bone absorptiometry reveals low mineral density in both postmenopausal osteoporosis and osteomalacia patients. The method was used to investigate the effect of calcitriol administration on patients suffering from one of these conditions. In osteomalacia, the administration of calcitriol resulted in a dramatic improvement in bone mineral density (sometimes up to 50% in 12 months), indicating the rapid mineralization of previously uncalcified bone tissue as a result of the normalization of the Ca x P product. In osteoporosis a similar treatment was seen to halt the progressive decrease in bone mineral levels and sometimes resulted in minor increases in density (up to 5%). This is likely to be due to a normalization of intestinal calcium malabsorption which halts secondary homeostatic bone resorption

Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders

Bisphosphonates are the first-choice treatment of osteoporosis and Paget’s disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5&nbsp;mg) or clodronic acid (1500&nbsp;mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget’s disease of bone. All patients were evaluated before, 1 and 6&nbsp;months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations

Natriuretic peptides and NGAL in heart failure: does a link exist?

In recent years there has been growing interest in the development of new diagnostic tools and particularly in laboratory tests for the identification of heart failure (HF) patients. Because of the rise in HF occurrence, it is necessary to use simple and reliable method to recognize those patients at risk before the onset of the clinical symptoms. To date HF diagnosis remains difficult: its symptoms and signs are often non specific as well as being poor sensitive indicators for HF severity. Throughout the last 10 years published literature has highlighted a boom in the use of biomarkers for HF. Both B-type and N-terminal pro-B-type natriuretic peptides have demonstrated specific role in heart failure diagnosis, as well as risk assessment. A single determination of BNP at any time during the development of chronic heart failure (CHF) provides a clinically useful tool to establish the outcome. Renal dysfunction is often associated with heart failure and predicts adverse clinical outcomes. Many studies have recently suggested the clinical use of serum neutrophil gelatinase-associated lipocalin (NGAL) levels in patients admitted to the hospital for acute HF can be used to estimate the risk of early worsening renal function. This could be potentially applied in clinical practice for early identification of renal dysfunction development in patients with HF. NGAL levels appear also to predict renal dysfunction in patients with chronic HF and preserved renal function. For all these reasons, BNP and NGAL are two emerging tools useful for diagnosis and prognosis in HF. The combination of two laboratory biomarkers could potentially identify patients with more elevated risks of both cardiac hemodynamic impairment and kidney dysfunction

Divergent effects of obesity on fragility fractures

Obesity was commonly thought to be advantageous for maintaining healthy bones due to the higher bone mineral density observed in overweight individuals. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. The effect of obesity on fracture risk is site-dependent, the risk being increased for some fractures (humerus, ankle, upper arm) and decreased for others (hip, pelvis, wrist). Moreover, the relationship between obesity and fracture may also vary by sex, age, and ethnicity. Risk factors for fracture in obese individuals appear to be similar to those in nonobese populations, although patterns of falling are particularly important in the obese. Research is needed to determine if and how visceral fat and metabolic complications of obesity (type 2 diabetes mellitus, insulin resistance, chronic inflammation, etc) are causally associated with bone status and fragility fracture risk. Vitamin D deficiency and hypogonadism may also influence fracture risk in obese individuals. Fracture algorithms such as FRAX® might be expected to underestimate fracture probability. Studies specifically designed to evaluate the antifracture efficacy of different drugs in obese patients are not available; however, literature data may suggest that in obese patients higher doses of the bisphosphonates might be required in order to maintain efficacy against nonvertebral fractures. Therefore, the search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with obesity might be considered a clinical priority which could improve the prevention of fracture in obese individual

Evaluation of FRAX® score use in Maltese osteoporosis management guidelines

Objectives: Recent years have brought a shift towards evidence-based fracture risk engines. Fracture Risk Assessment Tool (FRAX®) is one such diagnostic tool used to evaluate the ten-year probability of osteoporotic fracture risk. The aim of this study was to evaluate the Maltese FRAX® score-based osteoporosis management guidelines and identify the suitability of using such a risk factor engine-based protocol. Study design: Data from 702 patients presenting for bone mineral density (BMD) estimation in 2010- 2011 were collected. In this period, local guidelines were devised but not yet put into practice so all referred patients underwent BMD estimation. These patients were below 65 years of age and above the minimum age for FRAX® use: 40 years. Data included Age, Weight, Height, BMI and the presence of any risk factor components of the FRAX® score tool. BMD was assessed using Norland/Hologic densitometers. FRAX® scores (excluding BMD) for each patient were calculated using the online tool www.shef.ac.uk/FRAX as accessed in 2014. The resulting major osteoporotic fracture risk was compared to age-specific assessment thresholds as set by Kanis et al. (2013). Thus the appropriateness (or otherwise) of densitometry measurements as dictated by local guidelines was determined. Main outcome measures: The main outcome measures in this study were the femoral neck and vertebral body BMD. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of using the FRAX®-based guidelines in under 65 year olds were calculated. Results: Local guidelines for managing <65 year olds were found to have a PPV of 11.26% and a NPV of 94.38 % Conclusion: FRAX®-guided local guidelines are well suited at excluding non-osteoporotic patients (False omission rate of 5.62 %). Positive likelihood ratio for the protocol was found to be 1.27. This means that 1 in every 8.8 patients that would have been referred for BMD estimation were actually osteoporotic.peer-reviewe