Long-term antifracture efficacy and safety of antiosteoporotic treatments: the hidden part of the iceberg

Long-term antifracture efficacy and safety are the two major goals of any antiosteoporotic treatments. So far, several drugs have proved to be effective and safe during the 2-3 years period of controlled clinical trials but only a few of them have shown bone protection up to 5 years, which is the minimum period in order to assume there is sustained fracture reduction. Raloxifene has shown efficacy in vertebral fracture risk reduction in up to 5 years but no effect in non-vertebral fracture. Risedronate and Alendronate have also shown anti-fracture efficacy in vertebral fracture risk reduction up to 7 and 10 years respectively, but no long-term benefit was observed in non-vertebral fracture. Strontium ranelate have demonstrated a sustained fracture risk reduction up to 5 years in vertebral and non-vertebral fractures. In addition, preliminary analyses of the 8 years treatment have shown the same trend in vertebral and non-vertebral fracture risk reduction. In summary, at least 4 drugs have demonstrated a sustained vertebral antifracture efficacy but only strontium ranelate has proved to be long-term efficient in non-vertebral fracture

The role of calcium, calcitriol and its receptors in

The mechanism of regulation of Parathyroidhormone (PTH)is complex, and diverse factors are involved: the fundamental ones are calcium, calcitriol and phosphorus. Calcium and calcitriol's mechanism of action takes place through its specific receptors, the calcium-sensing receptor (CaR) and the Vitamin D Receptor (VDR). These two factors have an effect not only on its specific receptors, but also they can modify the other receptor in a positive manner, promoting its actions and demonstrating a cooperative effect between the two. Along with calcium and calcitriol, drugs used in the treatment of Chronic Kidney Disease Mineral Bone Disorders (CKD-MBD) also act directly or indirectly on CaR and VDR and therefore are also responsible for the regulation of the parathyroidgland.Fondo de Investigaciones Sanitarias (FIS 02/0688) (ISCIII-Retic-RD06, REDinREN, (16/06) and Fundación Renal Íñigo Álvarez de Toled

Calcificación vascular y desmineralización: dos caras de una misma moneda

There is a clinic and epidemiological evidence suggesting that impaired bone turnover is associated with the progression of vascular calcification. Several factors have been identified as mediators and possible links between the observed changes in bone turnover and vascular calcification. Most of these factors have been found to be involved in both, bone and vascular mineralization. Among them, hyperphosphataemia has been the most studied factor. Maintenance of adequate serum phosphate control has been associated with good bone and cardiovascular health. Due to the fact that common factors have been involved in the pathogenesis of these alterations it has been suggested that both, disorders of bone turnover and vascular calcification may respond to common therapies. Bisphosphonates and denosumab have focused the attention of several clinical and experimental studies in this field.Existen estudios clínicos, epidemiológicos y experimentales que sugieren una relación entre las alteraciones del recambio óseo y la progresión de la calcificación vascular. La mayoría de estos estudios indican que un recambio óseo bajo se asocia a una mayor prevalencia y progresión de las calcificaciones vasculares. Se han identificado diversos factores que podrían ser mediadores y responsable de esta asociación. La mayoría de factores implicados en estos procesos son comunes y han sido involucrados tanto en la formación y recambio óseo como en la génesis de las calcificaciones vasculares. Alguno de ellos podría ser el nexo entre ambas alteraciones. De ellos la hiperfosfatemia es uno de los factores más estudiado y la mayoría de resultados indican que, probablemente, juegue un importante papel en el mantenimiento de una buena salud ósea y vascular, especialmente en pacientes con ERC

Dual-Specificity Phosphatases Are Implicated in Severe Hyperplasia and Lack of Response to FGF23 of Uremic Parathyroid Glands from Rats

Phosphate load accelerates the progression of secondary hyperparathyroidism (sHPT). In advanced stages of sHPT, there is amarkedhyperplasiaandresistance to classical regulatory endocrine factors such as calcium, calcitriol, or fibroblast growth factor 23 (FGF23), which suppresses PTH secretion by an ERK-dependent mechanism. Nephrectomized rats were fed with a high- or normal-phosphorus diet for different periods of time to induce sHPT. Biochemical parameters, parathyroid gland microarrays, quantitative real-time PCR, and immunohistochemistry (ERK/phospho-ERK) were performed. To test the role of dual-specificity phosphatases (Dusp) on parathyroid gland regulation, normal parathyroid glands were cultured with FGF23 and Dusp. Uremic rats fed with a high-phosphorus diet showed more severe sHPT, higher serum FGF23 levels and mortality, and decreased parathyroid Klotho gene expression. In all stages of sHPT, parathyroid microarrays displayed a widespread gene expression down-regulation; only a few genes were overexpressed,among them, Dusp5 and -6. In very severe sHPT, a significant reduction in phospho-ERK (the target of Dusp) and a significant increase of Dusp5 and -6 gene expression were observed. In ex vivo experiments with parathyroid glands, Dusp partially blocked the effect of FGF23 on PTH secretion,suggesting that Dusp might play a role in parathyroid regulation. The overexpression of Dusp and the inactivation of ERK found in the in vivo studies together with the ex vivo results might be indicative of the defense mechanism triggered to counteract hyperplasia, a mechanism that can also contribute to the resistance to the effect of FGF23 on parathyroid gland observed in advanced forms of chronic kidney disease.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS 090415), Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y Técnica (FICYT I30P06P), Instituto de Salud Carlos III (Retic-RD06), Red de Investigación Renal (REDinREN 16/06), and Fundación Renal Íñigo Álvarez de Toled

Natural antioxidants and vascular calcification: a possible benefit?

Background: Several studies have demonstrated the impact of vascular calcification on morbidity and mortality both in the general and chronic kidney disease populations. The process of vascular calcification involves complex mechanisms including the overexpression of genes and proteins associated with mineralization and increments of reactive oxygen species (ROS). Taking into account previous findings, we decided to analyze in vitro the likely inhibitory effect of natural antioxidants in the process of vascular calcification. Methods: Primary vascular smooth muscle cells (VSMCs) were cultured with either normal medium or normalmedium supplemented with calcium and phosphorus (P + Ca) in combination with several antioxidants. Mineralization,intracellular reactive oxygen species levels and the protein expression of Cbfa1/RUNX2 and Mn–superoxide dismutase-2 (SOD-2) were investigated. Results: Curcumin and silybin were the more effective,inhibiting both ROS increase and VSMC mineralization. Curcumin was able to prevent the increase in Cbfa1/ RUNX2 expression, but did not modify SOD-2 expression in the VSMCs cultured with the P + Ca medium. Conclusions: These findings support the importance of performing further studies in this field, as some antioxidants might have potential benefits in the management of vascular calcification.This work was supported by projects from FIS (070893, 09/00415 and PI11-00667), FICYT (I30P06P and IB09-033), Instituto de Salud Carlos III (Retic-RD06), RedInRen (16/06),and IRSIN-FRIAT

Low calcidiol levels and risk of progression of aortic calcification

Introduction: The aim of this study was to investigate the relationship between serum calcidiol levels and the onset and progression of aortic calcifications in a communitybased sample of ambulatory subjects. Methods: 302 men and women aged 50 and over underwent two lateral X-rays and were followed-up for 4 years. Abdominal aortic calcifications were classified as absent, mild-moderate, and severe. The biochemical measurements of serum calcium, phosphorus, PTH, total alkaline phosphatase, tartrate-resistant acid phosphatase, creatinine, calcidiol, calcitriol and osteocalcin were determined. Subjects who had received anti-osteoporotic treatments were excluded from the analysis. Results: Subjects with progression of aortic calcifications had significantly lower serum calcidiol levels than those without progression. In the multivariate analysis, using the agreed upon serum levels for calcidiol (> 30 ng/mL) as the reference, those subjects with calcidiol levels between 10 to 20 ng/mL showed a higher risk of progression of aortic calcification (OR = 3.95; 95% CI = 1.16 to 13.40). An even higher OR was observed in subjects with calcidiol values < 10 ng/mL (OR = 4.10; 95%CI = 1.12 to 14.99). In addition, an increase by 1 ng/mL in osteocalcin levels was associated with a 17% reduction of the risk of aortic calcification progression. Conclusions: An increase by 10 ng/mL of calcidiol was associated with a decrease in the risk of aortic calcifications progression by 44%. This figure was even higher than that observed if we increased age by 10 years. Levels of calcidiol higher than 30 ng/mL seem to be desirable to reduce the progression of aortic calcification and to maintain bone turnover.This study has been partially supported by European Vertebral Osteoporosis Study (EVOS), European Community (1991-1993); the European Prospective Osteoporosis Study (EPOS), European Community BIOMED 93-95. BMHI - CT 092 - 0182. (1993 - 1997); by Fondo de Investigaciones Sanitarias (FIS 94/1901-E), by Fundación Renal Iñigo Álvarez de Toledo (Spain) and by ISCIII-Retic-RD06, REDin REN (16/06). Language consultant was Marino Santirso Ruiz

Efecto del carbonato de lantano sobre sistema óseo y vascular y supervivencia

Fondos FEDER, ISCIII, REDinREN, FICYT y FRIA

Vascular Calcification in Patients with Chronic Kidney Disease: Types, Clinical Impact and Pathogenesis

Vascular calcification plays a major role in cardiovascular disease, which is one of the main causes of mortality in chronic kidney disease patients. Vascular calcification is determined by prevalent traditional and uraemia-related (non-traditional) risk factors. It occurs mainly in the arteries, which are classified into three types according to their size and structural characteristics. In addition, vascular calcification has been associated with bone loss and fractures in chronic kidney disease patients and the general population, stressing the fact that both disorders can share pathogenetic pathways. The strategies to control vascular calcification involve several measures, chief among them the control of hyperphosphataemia. Furthermore, it has been recently described that strategies that reduce bone resorption and increase bone mineralization may decrease the risk of vascular calcifications;however, this approach still remains controversial. The mechanisms involved in vascular calcification are complex and not yet fully understood. Phosphorus plays a major role,while other factors related to bone formation have been recently identified.The authors wish to thank the Fondo de Investigaciones Sanitarias, REDinREN del ISCIII (Redes Temáticas de Investigación Cooperativa en Salud; RD06/0016/1013), FYCIT (Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología) and Fundación Renal Iñigo Álvarez de Toledo (Spain

Vascular calcifications, vertebral fractures and mortality in haemodialysis patients

Background: Vascular calcifications and the bone fractures caused by abnormal bone fragility, also called osteoporotic fractures, are frequent complications associated to chronic kidney diseases (CKD). The aim of this study was to investigate the association between vascular calcifications, osteoporotic bone fractures and survival in haemodialysis (HD) patients. Methods: A total of 193 HD patients were followed up to 2 years. Vascular calcifications and osteoporotic vertebral fractures (quoted just as vertebral fractures in the text) were assessed by thoracic, lumbar spine, pelvic and hand X-rays and were graded according to their severity. Clinical, biochemical and therapeutical data gathered during the total time spent on HD were collected. Results: The prevalence of aortic calcifications was higher in HD patients than in a random-based general population (79% versus 37.5%, p<0.001). Total time on any renal replacement therapy (RRT) and diabetes were positively associated to a higher prevalence of vascular calcifications. In addition to these factors, time on HD was also positively associated to the severity of vascular calcifications, and higher haemoglobin levels were associated with a lower prevalence of severe vascular calcifications in large and medium caliber arteries. The prevalence of vertebral fractures in HD patients was similar to that of the general population (26.5% versus 24.1%). Age and time on HD showed a positive and statistically significant association with the prevalence of vertebral fractures. Vascular calcifications in the medium caliber arteries were associated to a higher rate of prevalent vertebral fractures. In women, severe vascular calcifications and vertebral fractures were positively associated to mortality [RR=3.2 (1.0-10.0) and RR=4.8 (1.7-13.4)[respectively]. Conclusions: Positive associations between vascular calcifications, vertebral fractures and mortality have been found in patients on HD.European Vertebral Osteoporosis Study (EVOS), European Community (1991-1993); the European Prospective Osteoporosis Study (EPOS), European Community BIOMED 93-95. BMHI - CT 092 - 0182. (1993 -1997); the Fondo de Investigaciones Sanitarias (FIS 94/1901-E, FIS 04/1576);REDinREN del ISCIII (Redes Temáticas de Investigación Cooperativa en Salud; RD06/0016/1013); FICYT (Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología), and Fundación Renal Iñigo Álvarez de Toledo (Spain). Language consultant was Marino Santirso. We would also like to thank L.Reyes and A. Rodríguez-Rebolla

Vascular calcification: pathogenesis, epidemiology anda clinical impact

Several studies suggest that vascular calcifications play a main role in the cardiovascular disease, which is one of the main causes of mortality in CKD patients. Vascular calcification is determined by prevalent traditional, uraemia-related and non-traditional risk factors such as cardiovascular disease or pro-inflammatory molecules and occurs mainly in the arteries, which are classified in three types according to their size and structural characteristics. Several epidemiological studies have linked vascular calcifications to bone loss and fractures in chronic kidney disease patients and also in the general population, stressing the fact that both can share pathogenetic pathways. The mechanisms behind vascular calcification are complex and not yet fully understood. Phosphorus plays a main role, while other elements related to bone formation have been recently identified, including the BMP-Wnt-Msx-2 axis. The strategies to control vascular calcifications involve several measures, chief among them the control of hyperphosphatemia. Furthermore, it has been recently described that strategies focusing on both reducing bone resorption and increasing bone mineralization may decrease the risk of vascular calcifications.Fondo de Investigaciones Sanitarias, REDinREN del ISCIII (Redes Temáticas de Investigación Cooperativa en Salud; RD06/0016/1013); FICYT (Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología), and Fundación Renal Iñigo Álvarez de Toledo (Spain). The authors also would like to extend their appreciation to Marino Santirso for the language editing of this articl