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 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

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

Natriuretic peptides in heart failure: where we are, where we are going.

Tremendous advances have been made in understanding the pathophysiology and treatment of congestive heart failure (CHF). However, diagnosis still remains difficult, even with a comprehensive physical examination. Symptoms such as dyspnea are non-specific and poorly sensitive indicators for early CHF that can be largely undetected. The discovery of natriuretic peptides (BNP) as diagnostic biomarkers has been one of the most critical advances for heart failure diagnosis. Therefore, both B-type and N-terminal pro-B-type have potential role in the diagnosis of heart failure, as well as in prognostic risk assessment. A single determination of BNP at any time during the progression of chronic HF provides a clinically useful tool for risk stratification. The hypothesis that repeated measurements might carry prognostic information beyond a single measure was confirmed in different settings. One of the main interests is given to the values of repeated determinations for monitoring progression of disease, and for the evaluation of the clinical effects of medical therapy. Nevertheless, despite thousands of papers describing their potential utility, current guidelines have not endorsed the highest level of recommendation for their use, in part, because the application in clinical practice is often limited for the absence of well codified cut off. Recently, European guidelines emphasized the role of natriuretic peptides as potential laboratory markers. In the near future, algorithm building will take into consideration clinical and echocardiographic parameters as well as NP measurements, and this may lead to a correct diagnosis and identification of patients at high risk. The purpose of this review is to discuss the clinical approaches and future applications of natriuretic peptides in heart failure and coronary diseas

Undiagnosed vertebral fractures influence quality of life in postmenopausal women with reduced ultrasound parameters.

Osteoporosis, a multifactorial systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to increased bone fragility, is a worldwide public health problem. Vertebral fractures affect approximately 20% of postmenopausal women and are a hallmark of osteoporosis, but they may pass unnoticed, although they may lead to long-term immobility and disability. The aims of the present study were (1) to determine the prevalence and the severity of vertebral fractures in a large cohort of Italian women aged 60 years or older with reduced values of quantitative ultrasound parameters; and (2) to assess whether vertebral fractures and other variables may be associated with health-related quality of life. A total of 2450 women without back pain aged 60 years or older, after the completion of the Quality of Life Questionnaire of the European Foundation for Osteoporosis QUALEFFO, underwent quantitative ultrasound evaluation of the calcaneus; in those with a stiffness t-score of a parts per thousand currency sign -2 (n = 1194), radiographic evaluation of the thoracic and lumbar spine was carried out and then quantitative morphometry was performed by dedicated software (MorphoXpress). The radiographic analysis was carried out on 885 women who presented films of adequate quality. Multivariate regression was used to adjust for confounding variables. Of those who underwent radiographic analysis, 681 had no vertebral fractures, and 204 women (23.1%) had one or more previously undiagnosed vertebral fractures. The prevalence of previously undiagnosed vertebral fractures increased with advancing age with more than 30% of women older than 75 years having at least one fracture. Older age, body mass index, and severe vertebral fractures were independently associated with a worse total QUALEFFO score. We found that approximately one in four women showed evidence of undiagnosed vertebral fractures, and there was a strong age effect trend. Moreover, the severity grade of vertebral fractures, more than the number of fractures, was associated with a worsening of health-related quality of life as assessed by QUALEFFO. These findings confirm the clinical relevance of an early diagnosis of vertebral fractures and seem to support the usefulness of quantitative ultrasound measurements in the stratification of postmenopausal women at increased fracture risk

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