Odanacatib, a New Drug for the Treatment of Osteoporosis: Review of the Results in Postmenopausal Women

Osteoclasts are specialized cells that initiate the process of bone resorption, which has two phases, dissolution of the mineral component and degradation of the organic matrix, in which cathepsin K plays a key role. Cathepsin K inhibitors, which block the activity of cathepsin on bone resorption lacunae, may be a new therapeutic option in osteoporosis. Odanacatib is a nonpeptidic biaryl inhibitor of cathepsin K. Two studies have evaluated the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study of safety and efficacy. Due to the long half-life of odanacatib and the similar effects of different doses on bone remodeling markers, a weekly dosage was chosen for the phase II trail, with the best results being obtained with a dose of 50 mg. At 36 months, increases in bone mineral density similar to those produced by other powerful antiresorptive drugs (zoledronate and denosumab) were observed but there were differences in the behaviour of bone remodeling markers. Data on fractures from the phase III trial currently in development are required to confirm these possible advantages

Effects of Atorvastatin on Vitamin D Levels in Patients With Acute Ischemic Heart Disease

Producción CientíficaVitamin D deficiency is a risk factor for osteoporosis and other chronic diseases, including type 1 diabetes, hypertension, metabolic syndrome, and ischemic heart disease. Cholesterol and vitamin D share the 7-dehydrocolesterol metabolic pathway. This study evaluated the possible effect of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Eighty-three patients (52 men and 31 women) with an acute coronary syndrome (75 with acute myocardial infarction and 8 with unstable angina) were included. After diagnosis, patients received atorvastatin as secondary prevention. Serum vitamin D was measured by high-performance liquid chromatography at baseline and at 12 months. Atorvastatin treatment produced a statistically significant decrease in cholesterol and triglyceride levels and an increase in vitamin D levels (41 19 vs 47 19 nmol/L, p 0.003). Vitamin D deficiency was decreased by 75% to 57% at 12 months. In conclusion, atorvastatin increases vitamin D levels. This increase could explain some of the beneficial effects of atorvastatin at the cardiovascular level that are unrelated to cholesterol levels

Effect of the TNF -308 G/A Polymorphism on the Changes Produced by Atorvastatin in Bone Mineral Density in Patients with Acute Coronary Syndrome

Producción CientíficaAims: To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome depending on the tumor necrosis factor- (TNF )-308 G/A polymorphism. Methods: Sixty-two patients with acute coronary syndrome (35 males and 27 females), average age 60 8 10 years, were included. Patients were given low (10–20 mg) and high doses (40–80 mg) atorvastatin according to their baseline levels of cholesterol and triglycerides and their index of vascular risk. Patients were studied during hospital admission (baseline) and at 12 months of follow-up. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow-up. Densitometric studies were conducted in the lumbar spine (L 2 –L 4 ), femoral neck and trochanter using an X-ray densitometer. The TNF -308 G/A polymorphism was determined by the polymerase chain reaction. Results: Forty-five patients were homozygous for G/G (72.5%) and 17 were heterozygous for G/A (27.5%). The prevalence of osteoporosis (T score ^ 2.5 in the lumbar spineand/or hip) was 33% for the G/G genotype and 35% for the G/A genotype, with no statistically significant differences between groups. There was a statistically significant increase in bone mineral density (BMD) in the lumbar spine (1.107 8 0.32 vs. 1.129 8 0.23; p = 0.0001) in patients with the G/G genotype. No changes were observed in patients with the G/A genotype. Conclusion: In patients with acute coronary syndrome, atorvastatin increases lumbar spine BMD solely in patients with the G/G genotype of the TNF -308 G/A polymorphism

Levels of DKK1 in patients with acute myocardial infarction and response to atorvastatin

Producción CientíficaThe atherosclerosis that appears in coronary, cerebrovascular and peripheral arterial disease is responsible for most cardiovascular diseases. It is characterized by chronic arterial inflammation caused and exacerbated by disorders of the lipidic metabolism and other clearly identified risk factors [1]. Calcification, which is initiated by an active process in which inflammatory cytokines and other mediators that regulate the phospho-calcium metabolism intervene, is characteristic of atherosclerosis [2]. These mechanisms can intervene in an opposite phenomenon that takes place at the level of the bone characterized by a reduction in bone mineral content and alterations in the microarchitecture that define osteoporosis. The association between the two diseases, which share mechanisms but have a different expression, is noteworthy

Polymorphisms of the farnesyl diphosphate synthase gene modulate bone changes in response to atorvastatin

Producción CientíficaAlthough their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins

Association between vitamin D deficiency and heart failure in the elderly

Producción CientíficaVitamin D (25-OH-vitamin D) is a hormone which acts on the calcium-phosphorus metabolism and also has extraskeletal effects. In the cardiovascular system, it regulates the renin-angiotensinaldosterone system (RAAS), inhibits vascular smooth muscle proliferation, and suppresses cardiac hypertrophy and hypercontractility [1]. We assessed the relationship between vitamin D deficiency and heart failure (HF) in an elderly population. We carried out a prospective case-control study in the Internal Medicine Department, Rio Hortega Hospital, Valladolid in 2010. Twenty-five patients were diagnosed with HF and 19 were institutionalized controls with no history of cardiovascular disease (CVD). The age of patients and control group was similar (83±7 years vs. 85±8 years, pN0.05). The sex distribution don't show differences. HF was diagnosed according to clinical and laboratory criteria (B-type natriuretic peptideN400 pg/mL). Vitamin D insufficiency was defined as levelsb20 ng/ml and deficiency asb10 ng/ml. Two-dimensional echocardiography evaluated systolic and diastolic function, pulmonary artery systolic pressure (PASP), atrial fibrillation and valvular disease in the HF group

Bone mineral density, bone remodeling and osteoprotegerin in patients with acute coronary syndrome

Producción CientíficaThe objective of this study was to evaluate the relationship between coronary disease and osteoporosis and determine the effect of osteoprotegerin (OPG) on bone remodeling and bone mineral density (BMD) in a group of patients with acute coronary syndrome. Eightythree patients (52 males and 31 women) with acute coronary syndrome (75 patients with acute myocardial infarction and 8 with unstable angina) with an average age of 61±10 years were studied. Levels of osteocalcin, urinarydeoxypyridinoline, OPG and the receptor activator of nuclear factor-κB ligand (RANKL) were determined during the hospital stay. Femoral neck, trochanter and lumbar spine densitometry was carried out using a DXA densitometer. Thirty percent of patients presented osteoporosis (39% of females and 26% of males). Osteoporotic patients were older and had a lower weight and height and elevated serum levels of osteocalcin (3.6±2.25 2.63 versus ±1.55, p=0.05). Levels of OPG and RANKL were similar in both groups and showed no relationship with BMD. In conclusion, no relationship was observed between the OPG/RANKL system and BMD in these patients

Relationship Between Bone Mineral Density and Angiotensin Converting Enzyme Polymorphism in Hypertensive Postmenopausal Women

Producción CientíficaThe purpose of this study was to assess the relationship between bone mineral density and insertion/ deletion (I/D) angiotensin converting enzyme polymorphism (ACE) in hypertensive postmenopausal women.2015-09-0

Effect of Quinapril, Quinapril-Hydrochlorothiazide, and Enalapril on the Bone Mass of Hypertensive Subjects: Relationship With Angiotensin Converting Enzyme Polymorphisms

Producción CientíficaBackground: Many alterations in extracellular metabolism of calcium have been associated to hypertension, but the number of studies relating this disease with osteoporosis is extremely low. This study clarifies the therapeutic effect of three treatments— quinapril, quinapril hydrochlorothiazide (HCTZ), enalapril—on bone remodeling markers, bone mineral density (BMD) in hypertensive patients, and relationship with angiotensin converting enzyme (ACE) polymorphism.2015-09-0

Chemical compounds causing severe acute toxicity in heavy liquids used for intraocular surgery

Producción CientíficaPerfluorocarbon liquids (PFCLs) have been considered safe for intraocular manipulation of the retina, but since 2013 many cases of acute eye toxicity cousing blindness have been reported in various countries when using various commercial PFCLs. All these PFCLs were CE marked (Conformité Européenne), which meant they had been subjected to evaluation complying with the International Organization for Standardization (ISO) guidelines. These dramatic events raised questions about the safety of PFCLs and the validity of some cytotoxicity tests performed under ISO guidelines. Samples from toxic batches were analyzed by gas chromatography-mass spectrometry combined with Raman and infrared spectrometry. Perfluorooctanoic acid, dodecafluoro-1-heptanol, ethylbenzene and tributyltin bromide were identified and evaluated by a direct contact cytotoxicity test using ARPE-19 cell line, patented by our group (EP 3467118 A1). Perfluorooctanoic acid at a concentration of >0.06 mM and tributyltin bromide at a concentration of ≥0.016 mM were shown to be toxic, whereas the concentration found in the toxic samples reached 0.48 mM, and 0.111 mM, respectively. These finding emphasized the idea that determination of partially fluorinated compounds are not enough to guarantee the safety of these medical devices