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BACKGROUND AND AIMS: Since accelerated atherosclerosis has been reported in systemic lupus erythematosus (SLE), predictive biomarkers of cardiovascular disease (CVD) are needed. Among non-traditional risk factors, bone mineral density (BMD) has been related to CVD. However, its role in SLE remains controversial. This study aims to analyze the associations of subclinical atherosclerosis with traditional and non-traditional CV risk factors. METHODS AND RESULTS: In a cross-sectional study, atherosclerosis burden was compared between 112 female SLE patients and 31 controls. Plaque number and carotid intima-media wall thickness (cIMT) were assessed by ultrasonography. In a retrospective study, BMD determinations obtained 5-years before the ultrasonography assessment were analyzed in a subgroup of 62 patients. Plaque frequency was increased in SLE, even in patients without CV events or carotid wall thickening. cIMT was increased in patients with CVD, positively correlated with body mass index (BMI). Interestingly, a paradoxical effect of BMI on carotid parameters was observed. Whereas underweight patients (BMI < 20) showed increased prevalence of carotid plaques with low cIMT, those with BMI > 30 showed higher cIMT and plaque burden. Overweight patients (25 < BMI<30) exhibited both elevated cIMT and plaque number. BMI was an independent predictor of BMD. In our retrospective study, patients with either clinical or subclinical CVD exhibited lower BMD levels than their CV-free counterparts. A low lumbar spine BMD independently predicted CVD development after adjusting for confounders. CONCLUSION: SLE was associated with a higher subclinical atherosclerosis burden, a bimodal effect being observed for BMI. Decreased BMD can be a CV risk biomarker in SLE.

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UNLABELLED: Two matrix Gla protein (MGP) polymorphisms were associated with progression of aortic calcification and femoral neck bone loss in men. All these findings were also functionally corroborated in two vascular and bone in vitro systems indicating that MGP genetic variations can be partly responsible of higher risk of bone loss and vascular calcification. INTRODUCTION: MGP plays an important role in bone and vascular mineralization as confirmed by MGP-deficient murine model. We therefore aimed to find a genetic association among -138T>C, -7G>A, and Thr83Ala MGP single-nucleotide polymorphisms (SNPs), bone loss, and progression of aortic calcification in a randomly selected general population of 296 individuals who participated in the European Vertebral Osteoporosis Study. METHODS: To evaluate the rate of change in bone mineral density (BMD) and the progression of aortic calcification, dual X-ray absorptiometry and lateral spine X-rays were performed at baseline and after 4 years of follow-up. Genotyping for the three polymorphisms was carried out using polymerase chain reaction and restriction fragment length analysis. In addition, functional studies of MGP-7G>A and Thr83Ala SNPs were performed on transiently transfected osteoblast-like UMR-106 and vascular smooth muscle A7r5 cells. RESULTS: The proportion of men who had lost BMD in the femoral neck was higher among homozygous -7AA and 83Ala-Ala (p = 0.039 and p = 0.009, respectively), and also featured a higher risk of progression of aortic calcifications (OR = 5.6, 95% CI = 1.2-27.8 and OR = 6.8, 95% CI = 1.4-32.3, respectively). No effect was observed in women. The MGP-7A allele produced a reduction in luciferase activity compared to MGP-7G: 47% less in vascular cells and 34% less in bone cells (p = 0.001 and 0.012, respectively). In vascular cells under calcifying conditions, the MGP 83Thr allele showed a slightly higher, although not significant, inhibition than the MGP 83 Ala allele in calcium content suggesting functional differences between both variants. CONCLUSION: These results suggest that MGP genetic variations could predict a higher risk of bone loss and progression of vascular calcification in men.

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UNLABELLED: In this observational study, we found a positive relationship between low calcidiol levels and the risk of aortic calcification progression. A 10-ng/mL increase of calcidiol was associated with a decrease in the risk of progression by 44%. This figure was higher than that observed if we increased age by 10 years. 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 community-based sample of ambulatory subjects. METHODS: Three hundred two 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, parathyroid hormone, 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 and 20 ng/mL showed a higher risk of progression of aortic calcification (odds ratio (OR) = 3.95; 95% confidence interval (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.

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The chronic kidney disease-bone and mineral disorders (CKD-MBD) represents a dinamic area of research. Recently, new factors such as FGF-23 have been added to the classic list of regulators of bone metabolism, which include calcium, phosphorus, PTH and calcitriol. Vascular calcification, one of the most important complication of CKD-MBD is regulated by a complex variety of  promoters and inhibitors. The relationship between vascular calcification, bone loss and mortality, together with the existence of likely common signaling pathways are subject of interesting investigations.

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Las alteraciones del metabolismo óseo en el escenario de la enfermedad renal crónica (CKD-MBD) constituyen un dinámico campo de estudio. Al conjunto de reguladores clásicos del metabolismo óseo tales como calcio, fósforo, hormona paratiroidea (PTH) y calcitriol se ha añadido el factor de crecimiento fibroblástico 23 (FGF-23). La calcificación vascular, una de las complicaciones más importantes de la enfermedad renal crónica, está sujeta a una compleja regulación en la que intervienen factores promotores e inhibidores del proceso de mineralización. La asociación entre calcificación vascular, desmineralización ósea y mortalidad y la existencia de factores y vías de señalización comunes está siendo objeto de interesantes investigaciones (AU)

The chronic kidney disease-bone and mineral disorders (CKD-MBD) represents a dinamic area of research. Recently, new factors such as FGF-23 have been added to the classic list of regulators of bone metabolism, which include calcium, phosphorus, PTH and calcitriol. Vascular calcification, one of the most important complication of CKD-MBD is regulated by a complex variety of promoters and inhibitors. The relationship between vascular calcification, bone loss and mortality, together with the existence of likely common signaling pathways are subject of interesting investigations (AU)

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BACKGROUND: Osteoporosis is predominantly a condition of the elderly, and the median age for hip fracture in women is approximately 83 years. Osteoporotic fracture risk is multifactorial, and often involves the balance between bone strength and propensity for falling. OBJECTIVE: To present an overview of the available evidence, located primarily by Medline searches up to April, 2009, for the different management strategies aimed at reducing the risk of falls and osteoporotic fractures in the elderly. RESULTS: Frailty is an independent predictor of falls, hip fractures, hospitalisation, disability and death in the elderly that is receiving increasing attention. Non-pharmacological strategies to reduce fall risk can prevent osteoporotic fractures. Exercise programmes, especially those involving high doses of exercise and incorporating balance training, have been shown to be effective. Many older people, especially the very elderly and those living in care institutions, have vitamin D inadequacy. In appropriate patients and given in sufficient doses, vitamin D and calcium supplementation is effective in reducing both falls and osteoporotic fractures, including hip fractures. Specific anti-osteoporosis drugs are underused, even in those most at risk of osteoporotic fracture. The evidence base for the efficacy of most such drugs in the elderly is incomplete, particularly with regard to nonvertebral and hip fractures. The evidence base is perhaps most complete for the relatively recently introduced drug, strontium ranelate. Non-adherence to treatment is a substantial problem, and may be exacerbated by the requirements for safe oral administration of bisphosphonates. CONCLUSION: Evidence-based strategies are available for reducing osteoporotic fracture risk in the elderly, and include exercise training, vitamin D and calcium supplementation, and use of evidence-based anti-osteoporotic drugs. A positive and determined approach to optimising the use of such strategies could reduce the burden of osteoporotic fractures in this high-risk group.

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The mechanism of regulation of Parathyroid hormone (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 parathyroid gland.

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El mecanismo de regulación de los niveles de Parathormona (PTH) es complejo, y en él intervienen diversos factores: los fundamentales son el calcio, el calcitriol y el fósforo. El mecanismo de acción de calcio y calcitriol tiene lugar a través de sus receptores específicos, el Receptor-sensor de Calcio (CaR) y el Receptor de Vitamina D (VDR). Estos dos factores tienen efecto no sólo sobre sus receptores específicos sino que pueden modificar en sentido positivo al otro receptor, potenciando sus acciones y demostrando un efecto cooperativo entre ambos. Además de calcio y calcitriol, los fármacos que se utilizan en el tratamiento de las alteraciones del metabolismo óseo y mineral de la Enfermedad Renal Crónica (ERC) también actúan directa o indirectamente sobre CaR y VDR y, por tanto, también son responsables de la regulación de la paratiroides (AU)

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UNLABELLED: In this prospective study, we found a positive relationship between the prevalence of aortic calcifications and age. Aortic calcifications at baseline were positively associated with osteoporotic fractures. In addition, progression of aortic calcifications was also positively associated with the rate of decline in BMD at lumbar spine. INTRODUCTION: The aim of this study was to analyze the relationship between the progression of abdominal aortic calcification and osteoporosis in a Spanish cohort of men and women older than 50. METHODS: Men and women (n=624) aged 50 and over underwent two lateral X-rays of thoracic and lumbar spine and a dual X-ray absorptiometry (DXA) study at lumbar spine and hip, and were followed during 4 years. Abdominal aortic calcifications were classified as absent, mild-moderate and severe. RESULTS: There was a positive relationship between the prevalence of aortic calcifications and age. In both sexes, prevalent severe aortic calcifications were positively associated with prevalent osteoporotic fractures [odds ratio (OR)=1.93 (1.02-3.65)]. The association was stronger when only vertebral fracture was considered [OR=2.45 (1.23-4.87)]. In addition, progression of aortic calcifications showed a positive association with the rate of decline in bone mineral density (BMD) at lumbar spine. CONCLUSIONS: Aortic calcifications at baseline were positively associated with osteoporotic fractures. The progression of aortic calcifications was also positively associated with the rate of decline in BMD at lumbar spine.

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BACKGROUND: The aim of this experimental study was to analyze the histomorphometric changes observed when using different doses of estradiol, calcitriol and both treatments combined, in rats with both chronic kidney disease (CKD) and ovariectomy (OVX). METHODS: Six groups of rats with CKD+OVX were treated for 8 weeks with placebo, with different doses of 17beta-estradiol (E2), with calcitriol or with both treatments combined (E2+calcitriol). Histomorphometric studies were carried out at the proximal tibia segment. RESULTS: All groups that received active treatments showed a trabecular bone volume similar to those of rats with normal ovarian function. Treatment with E2 was effective, E2-10 diminished osteoid and eroded surfaces, and E2-30 was able to achieve a bone remodeling similar to that of the normal group. Calcitriol proved to have a positive effect on bone microarchitecture, achieving normal trabecular connectivity. The combined treatment with E2-30+calcitriol was the most effective treatment as it was not only capable of achieving normal trabecular remodeling and connectivity, but also normal trabecular bone volume. CONCLUSIONS: E2 and calcitriol seem to have independent effects on cancellous bone turnover in rats with CKD+OVX. In rats with chronic kidney disease and ovariectomy, these two agents are able to produce additive effects on bone and offer additional advantages as opposed to the use of both drugs independently.

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Anteriormente se había observado que el aluminio era capaz de inhibir la síntesis y la secreción de hormona paratiroidea, si bien los mecanismos moleculares subyacentes se desconocían. Estudios recientes han demostrado que dicha inhibición tiene lugar a través de un mecanismo post-transcripcional. Además, el aluminio disminuye la proliferación de las células de la glándula paratiroides de un modo similar al calcio, el principal regulador de la función paratiroidea. Por último, el aluminio es también capaz de activar el receptor-sensor de calcio a concentraciones micromolares, lo que demuestra que éste es el mecanismo por el que las glándulas paratiroides respondían al metal. En conjunto, estos resultados demuestran por primera vez que las acciones del aluminio sobre la función paratiroidea tienen lugar a través de un mecanismo similar al del calcio. Además, dicho efecto es consecuencia de la baja especificidad del receptor-sensor del calcio

Aluminum (Al) is able to inhibit parathyroid hormone (PTH) synthesis and secretion, although the subjacent molecular mechanisms are unknown. Recent studies have shown that this inhibition occurs through a post-transcriptional mechanism. Similarly to calcium, the main regulator of parathyroid function, Al also decreases parathyroid cell proliferation. Finally, Al is also able to activate the calcium-sensing receptor (CaR) at the micromolar level, thus demonstrating that this is the mechanism by which parathyroid glands sense the metal. In summary these results show for the firs time that Al-induced impairment of parathyroid function is a calcium-like mechanism. In addition, this effect is the consequence of a low specificity of the CaR

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En los últimos años se ha discutido el posible papel de los polimorfismos en el gen del receptor de la vitamina D en diferentes enfermedades. En este trabajo se revisan diferentes estudios realizados para determinar la influencia de varios polimorfismos del receptor de la vitamina D y del colágeno tipo I sobre diferentes aspectos relacionados con el metabolismo del hueso y de la glándula paratiroides. Los estudios epidemiológicos mostraron que la combinación alélica BAt de los polimorfismos BsmI, ApaI y TaqI del receptor de la vitamina D y el genotipo ss del polimorfismo sp1 del colágeno tipo I son predictores del riesgo de fracturas osteoporóticas. Los estudios experimentales llevados a cabo en los osteoblastos en cultivo indicaron que la combinación alélica baT en el receptor de la vitamina D confiere una mayor sensibilidad del osteoblasto ante el estímulo con calcitriol. Por el contrario, en las glándulas paratiroides en cultivo fue la combinación BAt la que respondió mejor al calcitriol. La combinación alélica más favorable en el hueso no lo es en la glándula paratiroides y viceversa, lo que indicaría un efecto tejido específico del receptor de la vitamina D en la respuesta al calcitriol

In the last years, the likely role of the vitamin D receptor polymorphisms in different diseases has been discussed. In this work we review several studies performed to investigate the influence of the vitamin D receptor polymorphisms and type I collagen in different aspects of bone and parathyroid gland metabolism. On one hand, the epidemiological studies showed that BAt haplotype from BsmI, ApaI and TaqI polymorphisms in the vitamin D receptor and SS genotype in sp1 polymorphism in type I collagen gene predicted the risk for osteoporotic fractures. On the other hand, experimental studies carried out in both human primary osteoblasts and parathyroid glands showed that while baT haplotype responded better to calcitriol in osteoblasts, BAt haplotype showed the best response in parathyroid glands. The most favorable allele combination in the bone is not in the parathyroid gland and vice versa. These findings are indicative of a tissue specific effect of the vitamin D receptor in the response to calcitriol

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Bone and cardiovascular disorders are common age-related disorders in the general population and also in patients suffering from chronic kidney disease (CKD). Recent studies have shown an association between these two disorders and the rate of mortality. This article addresses some limitations of the concept of osteoporosis in CKD and compares bone and vascular disorders and mortality between non-selected general population and dialysis patients from the same geographic area. In the general population, all metabolic disorders increase with age, as well as vascular calcifications. The progression of vascular calcification was associated with a higher prevalence and incidence of bone fractures. In addition, both vascular calcifications and vertebral fractures were associated with higher mortality. A similar pattern was observed in dialysis patients with no increments in vertebral fractures, although with higher prevalence of vascular calcifications also both associated with higher mortality. Age was the strongest variable associated with all the analysed parameters, but some of the associations remained significant after age adjustment indicating the likely role of other common factors in the pathogenesis of bone and vascular disorders.

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Secondary hyperparathyroidism-related disorders begin in the pre-dialysis period and progressively worsen during dialysis. In a high proportion of cases, therapeutic failure in the control of PTH secretion is related to a late start in medical treatment. This may happen because recovery of the functional control of the parathyroid gland, once some irreversible molecular and genetic changes have occurred, can be only partial. These irreversible changes include promotion of cell proliferation and failure of several pathways affecting the metabolism of DNA, RNA and proteins.

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Osteoporotic studies conducted exclusively in men have been limited by the discrepancies in defining densitometric osteoporosis and, also, because osteoporosis has traditionally been associated only with women. The aims of this study were to describe the prevalence of low bone mineral density (BMD) and osteoporotic fractures as well as the rate of bone loss. The analysis of some risk factors for accelerated bone loss was also evaluated. Men aged 50 years and over, randomly selected from the Oviedo municipal register (n = 308), completed a questionnaire regarding risk factors related to osteoporosis; they underwent two lateral radiographs of the dorsal and lumbar spine and a dual X-ray absorptiometry (DXA) study at the lumbar spine and hip. In the 4th year of the follow-up period, participants were invited to undergo repeats of the same tests that had been carried out in the initial study. The prevalence of densitometric osteoporosis in men older than 50 years, standardized by age, was 8.1% with regard to at least one of the four studied bone areas, with a slight increase with age. The prevalence of osteoporotic fracture, standardized by age, was 24.4%, with a marked increase with age. Osteoporotic prevalent fracture was independently associated only with the rate of change in lumbar spine BMD. From all the osteoporotic risk factors analyzed, only low milk consumption and regular smoking were independently associated with loss of bone mass. In summary, prevalent osteoporotic fracture was independently associated with the rate of change in the lumbar spine BMD but not in the other segments studied. Avoiding smoking and ensuring an adequate milk intake might prevent the loss of bone mass in men.

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A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.

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The parathyroid glands have a great sensitivity to small changes in the extracellular ionic calcium. The calcium-sensing receptor (CaR) is a G protein-coupled receptor that responds to extracellular ionic calcium changes activating several intracellular signalling systems (phospholipases C, A2 and D) finally inhibiting the PTH secretion. In addition to calcium, there are some other agonists and modulators such as the Mg2+, spermine, amyloid beta-peptides, a variety of aminoacids, especially aromatic aminoacids and ionic strength. In the uraemia, the sensitivity of the parathyroid glands to calcium is altered and higher values of calcium are necessary to suppress the PTH. In the secondary hyperparathyroidism the CaR expression is reduced. It has been found a negative correlation between cellular proliferation and the expression of the CaR in hyperplasic glands. Despite it is a calcium receptor, the expression of the CaR does not seem to be regulated by calcium and there is some controversy about the role of calcitriol regulating its expression. On the other hand, the phosphorous induces hyperplasia of the parathyroid gland increasing the cellular proliferation and a decrease of the CaR expression.

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Desferrioxamine and deferiprone are both metal-chelating drugs often used in aluminum-overloaded dialysis patients. In these patients, desferrioxamine produces an improvement on bone mineralisation without a relevant decrease in bone aluminum. Thus, desferrioxamine might have a direct effect on bone cells. The aim of this study was to assess the effect of desferrioxamine and deferiprone on 1,25(OH)2D3-stimulated osteocalcin secretion in osteoblast--like cells. The study was carried out in MG-63 cell cultures. Cells were seeded at a density of 15,000 cel/cm2 and grown to confluence for 72 hours in DMEM supplemented with 10% FCS. The medium was then replaced by another medium containing 1% BSA, 10(-9) M 1,25(OH)2D3 and desferrioxamine 5, 10, 20, 40, 60, 80 microM or deferiprone 15, 30, 60, 120, 180, 240 microM. Tris-HCl at pH 7.4 was used as control. After 48 hours, supernatants were collected for the measurement of secreted osteocalcin. Desferrioxamine and deferiprone, at high doses (desferrioxamine: 60 microM, 80 microM; deferiprone: 180 microM, 240 microM), inhibited the 1,25(OH)2D3-induced osteocalcin secretion. On the contrary, at lower doses (desferrioxamine 5 microM; deferiprone 15 microM) stimulated the secretion. In summary, these results suggest that desferrioxamine and deferiprone exert a direct effect on bone cell metabolism that might be independent from their metal-chelating properties.

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Between 1994-2001 we have performed 57 bone biopsies for diagnostic purposes in symptomatic CRF patients. We analyzed here 52 samples where the material was optimal for study, and divided them into 2 periods according to when the biopsy was performed: 1994-1996 and 1997-2001, to verify changes in the spectrum of renal osteodystrophy. Mean serum values were: serum calcium 9.9 +/- 1.8 mg/dl, phosphate 5.8 +/- 3.2 mg/dl, alkaline phosphatase 693.9 +/- 968.9 Ul/L, iPTH 562.0 +/- 598.5 pg/ml, serum aluminum 65.7 +/- 79.3 ug/L and bone aluminum 22.8 +/- 22.4 ug/g. Hyperparathyroidism was the most common histological diagnosis as severe in 13 patients (25%), or as mild in 14 (27%). Ten patients had osteomalacia (19%), adynamic bone disease was diagnosed in 5 (9.6%) and mixed renal osteodystrophy in 10 (19.2%). Low bone turnover patients showed higher bone and serum aluminum than high bone turnover patients. We observed a relative increment in high turnover bone disease in the later period (1997-2001) without changes in low turnover bone disease. These data showed a high prevalence of hyperparathyroidism and aluminum-related low turnover bone disease, with no significant changes between the two time-periods analyzed here.

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