Association of matrix Gla protein gene functional polymorphisms with loss of bone mineral density and progression of aortic calcification.

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.

Low calcidiol levels and risk of progression of aortic calcification.

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.

Progression of vascular calcifications is associated with greater bone loss and increased bone fractures.

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.

Determinants of incidence of osteoporotic fractures in the female Spanish population older than 50.

It is well known that the adoption of preventive measures for osteoporosis may contribute to minimizing its impact as a result of bone fractures. However, there are well-recognized risk factors involved in the onset of osteoporosis that are not possible to modify. Better knowledge of these non-modifiable factors could aid prevention in subjects at high risk of fractures. The aim of this study was to evaluate the likely association between gynecological, reproductive and family history of hip fracture with the incidence of vertebral and nonvertebral osteoporotic fractures in women older than 50. We studied 255 women aged 50 and over, randomly selected from a Spanish population that had participated in a study of prevalence of vertebral fractures (EVOS study). This cohort was prospectively followed for 8 years by means of four postal questionnaires, in order to find out the incidence of nonvertebral fractures. Concerning the incidence of vertebral fractures, participants were invited to repeat the lumbar spine X-rays 4 years after the initial study. A total of 31 women had incident osteoporotic fractures. The analysis of gynecological variables showed that an increase in the age at menarche was a risk factor for all incident osteoporotic fractures [OR=1.57 (1.04-2.37)]. The presence of amenorrhea at any age during the fertile period was associated with higher incidence of all osteoporotic fractures [OR=6.30 (1.61-24.70)]. Among all the reproductive variables analyzed (pregnancy, number of live births and breast-feeding) only pregnancy was an important protective factor in preventing incident Colles fracture [OR=0.15 (0.03-0.62)]. A family history of hip fracture was associated with a higher incidence of all osteoporotic fractures [OR=3.59 (1.01-12.79)]. In summary, a late age at menarche, the presence of amenorrhea and having close relatives with hip fracture were all risk factors which, independently of bone mineral density (BMD) and age, were associated with higher incidence of all osteoporotic fractures. Pregnancy was an important protective factor for the incidence of Colles fractures.

Prevalence of osteoporosis in men and determinants of changes in bone mass in a non-selected Spanish population.

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.

[Osteoporosis, estrogens, and bone metabolism. Implications for chronic renal insufficiency]. / Osteoporosis, estrógenos y metabolismo óseo. Implicaciones en la insuficiencia renal crónica.

The relationship between estrogens, bone metabolism and osteoporosis is well known. Chronic renal failure in women is associated with menstrual disorders, lower bone mineral density and increased risk of fractures. However, most studies on renal osteodystrophy have not taken into account the role of oestrogen deficiency, its interaction, and the possible benefits of hormone replacement therapy (HRT) in uremic women. According to these limitations and the actual evidence of benefits and risks of HRT, we conclude that: a) Osteoporosis must be evaluated as a part of renal osteodystrophy; b) HRT would be considered in women with climateric symptoms and osteoporosis, and should not be used for prevention of cardiovascular disease, and c) Clearly we need to do more studies related to osteoporosis and estrogens in CRF, but right now we have to try to optimize bone turnover in our uremic patients.

[Prevalence of vertebral fractures and aortic calcifications in hemodialysis patients: comparison with a population of the same age and sex]. / Prevalencia de fracturas vertebrales y calcificaciones aórticas en pacientes en hemodiálisis: comparación con una población de la misma edad y sexo.

Dialysis patients have bone metabolic disorders and a higher prevalence of fractures, principally peripheral fractures. However, there are few studies focusing on the prevalence of vertebral fractures. Moreover, aortic calcifications are very common and are an independent predictive factor of vascular morbidity and mortality. The objective of this study was to assess the prevalence of vertebral fractures and vascular calcifications in haemodialysis (HD) patients (n = 99), in comparison with a random sample of general population of similar age and from the same geographical area (n = 624) and study their relationship with clinical, biochemical and therapeutical data. The prevalence of vertebral fractures in HD patients and general population was 19.1% and 24.1% respectively (non-significant statistical differences). In both, sexes, the presence of vertebral fractures was positively associated with age, mean maximum Ca, mean maximum CaxP. In women, time in HD was positively associated as well. On the other hand, the prevalence of aortic calcifications was much higher in HD patients (77.9% vs 37.5%, p < 0.001). HD was a risk factor for aortic calcification in women [OR = 7.7 (IC 95% = 2.6-22.9)] as in men [OR = 5 (IC 95% = 1.9-12.9)]. Severe vascular calcifications were more frequent in HD patients, it reached 57.4% compared with 17% of general population (p < 0.001). Both, in women (64.5% vs 13.3% p < 0.001) and in men (51.4% vs 20.9%), respectively (p < 0.001). In conclusion, the prevalence of vertebral fractures was similar in HD patients and in general population. Nevertheless, frequency and severity of aortic calcifications was higher in HD patients.

The effect of vertebral fracture as a risk factor for osteoporotic fracture and mortality in a Spanish population.

There is little data concerning the morbidity, mortality, and epidemiology of vertebral fracture. The aim of this study was to evaluate the effect of prevalent and incident vertebral fractures as risk factors for further osteoporotic fractures and mortality. The study was performed on a cohort of 316 women and 308 men older than 50 belonging to the EVOS study, randomly selected from our city register. At the beginning of the study and 4 years later, lateral dorsal and lumbar X-rays were performed. In addition, evaluation of the incidence of osteoporotic nonvertebral fractures was performed throughout 8 years. The incidence of all osteoporotic fractures was higher in women than in men (two-fold increase in vertebral fracture incidence and five-fold increase in Colles' and femur incidence). Vertebral fracture was a strong risk factor for a new vertebral fracture [RR=4.7 (1.8-11.9)], hip fracture [RR=6.7 (2.0-22.7)] and Colles' fracture [RR=3.0 (1.1-7.8)]. Prevalent and incident vertebral fractures were associated with a higher risk of having a hip fracture [RR=10.0 (2.0-50.2)] and Colles' fracture [RR=5.5 (1.3-23.4)]. In addition, in women, the vertebral fracture was associated with a higher mortality. By contrast, no association was found in men. These results demonstrate the association between a previous vertebral fracture with increments in the incidence of osteoporotic fractures of any type. In addition, we found a significantly higher mortality rate in women having vertebral fractures. These findings support the necessity of preventing the occurrence of vertebral fractures to limit their strong negative impact on mortality.

[Effect of vertebral fracture on health related quality of life in a Spanish population older than 54 years]. / Efecto de la fractura vertebral sobre la calidad de vida relacionada con la salud en población asturiana mayor de 54 años.

BACKGROUND: Effect of vertebral fracture on the perceived health using the SF-36 Health Questionnaire in a representative population older than 54 years. SUBJECTS AND METHOD: Randomly cohort from the register of the city Hall of Oviedo. All the 299 subjects (147 men and 152 women) completed the traduced and validated Spanish SF-36 questionnaire four years after radiologic studies were performed to evaluate prevalent vertebral fractures. RESULTS: Vertebral fracture decreased the health related quality of life, particularly in physical function dimension in males and in mental health dimension in women. This effect was increased when osteopenia was present. CONCLUSIONS: This first study performed in both sexes shows worse perceived health in people with fractures.

[Prevalence of vertebral fracture in population older than 50 years in Asturias (Spain) defined following different radiological criteria]. / Prevalencia de fractura vertebral en población asturiana mayor de 50 años de acuerdo con diferentes criterios radiológicos.

BACKGROUND: In spite of vertebral fracture is one of the most frequent osteoporotic fracture, the epidemiology of this entity remains unknown. The aim of this study was to know the prevalence of vertebral fracture in Oviedo (Spain), according to the most used radiologic criteria in research. SUBJECTS AND METHODS: A random sample of 624 men and women older than 50 years from the Oviedo's municipality took part in this analysis. All participants performed two thoracic and lumbar spinal lateral radiographs. In 615 subjects the presence of vertebral fracture was performed using a semicuantitative radiological criteria (Genant) and two morphometric criteria (Eastell and McCloskey). RESULTS: Prevalence of vertebral fracture varies between 17.4 and 24.6%, according to the radiological criteria used. The prevalence was higher in women than in men, but the differences were lower than expected, and there was a relative high frequency of vertebral fractures in men from 50 to 65 years old. In both sexes, prevalence of vertebral fracture increased with age, although in a steeper manner in women. The incidence of vertebral fracture in women was almost twice than in men. The incidence increased with age. Every ten years the prevalence of vertebral fracture increased two times. CONCLUSIONS: Prevalence of vertebral fracture was high in women and men older than 50 years, mainly in women older than 70 years, independently of the radiological criteria used. The average prevalence of vertebral fracture in Oviedo (Spain) has been similar to that observed in studies of American, European and Asian populations.

[Study of incidence of osteoporotic fractures in a cohort of individuals older than 50 years from Asturias, Spain, after a 6 year follow-up period]. / Estudio de incidencia de fracturas osteoporóticas en una cohorte mayor de 50 años durante un período de 6 años de seguimiento.

BACKGROUND: The present work, performed as follow-up of the prevalence study of vertebral fractures (EVOS Study), evaluates in a 6 year period the incidence of vertebral fractures and other osteoporotic fractures in Oviedo (Asturias, Spain) in people older than 50 years. SUBJECTS AND METHODS: The study was performed in a cohort from the Oviedo's local registry in 1986. 624 men and women were followed by 3 postal questionnaires. The first questionnaire referred to the history of falls and fractures that happened during the follow-up period performed. Between the 2nd and 3rd follow-up subjects were invited to repeat the X-rays previously performed in the initial study. RESULTS: The incidence of osteoporotic fractures was higher in women than in men. In both sexes, vertebral fracture was the one which reached the highest incidence. Compared with men, Colles' fracture in women occurred earlier, with 5 times higher incidence. The incidence of hip fracture was twice higher in women than in men. A prevalent vertebral fractures increased until 5 times the incidence of vertebral and hip fracture. CONCLUSIONS: Among the osteoporotic fractures, vertebral fracture had a highest incidence values in both sexes. Although vertebral and hip fractures were twice incident in women compared with men, the incidence of Colles fracture was five times higher in women. A pre-existing vertebral fracture is an important risk factor to develop a new vertebral or hip fracture.

Mortality associated with vertebral deformity in men and women: results from the European Prospective Osteoporosis Study (EPOS).

Clinically apparent vertebral deformities are associated with reduced survival. The majority of subjects with radiographic vertebral deformity do not, however, come to medical attention. The aim of this study was to determine the association between radiographic vertebral deformity and subsequent mortality. The subjects who took part in the analysis were recruited for participation in a multicentre population-based survey of vertebral osteoporosis in Europe. Men and women aged 50 years and over were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Radiographs were evaluated morphometrically and vertebral deformity defined according to established criteria. The participants have been followed by annual postal questionnaire--the European Prospective Osteoporosis Study (EPOS). Information concerning the vital status of participants was available from 6480 subjects, aged 50-79 years, from 14 of the participating centres. One hundred and eighty-nine deaths (56 women and 133 men) occurred during a total of 14,380 person-years of follow-up (median 2.3 years). In women, after age adjustment, there was a modest excess mortality in those with, compared with those without, vertebral deformity: rate ratio (RR) = 1.9 (95% confidence interval (CI) 1.0,3.4). In men, the excess risk was smaller and non-significant RR = 1.3 (95% CI 0.9,2.0). After further adjusting for smoking, alcohol consumption, previous hip fracture, general health, body mass index and steroid use, the excess risk was reduced and non-significant in both sexes: women, RR = 1.6 (95% CI 0.9,3.0); men RR = 1.2 (95% CI 0.7,1.8). Radiographic vertebral deformity is associated with a modest excess mortality, particularly in women. Part of this excess can be explained by an association with other adverse health and lifestyle factors linked to mortality.

Binding of aluminium to plasma proteins: comparative effect of desferrioxamine and deferiprone (L1).

Ultramicrofiltration techniques were used to study both the binding of aluminium to high molecular weight proteins in the presence of different concentrations of desferrioxamine and deferiprone (L1) and the kinetics of aluminium release from human serum proteins. Human serum from healthy volunteers was used in all studies. The serum was spiked with aluminium (100 micrograms/l) and different concentrations of chelators. Ultramicrofiltration was performed with Amicon YMT membranes which had a nominal cut-off of 30,000 Da. Aluminium was measured by graphite furnace atomic absorption spectrometry in total serum and ultrafiltered fluid. Deferiprone shows a higher capability to displace aluminium from serum proteins (80%) than desferrioxamine (60%) at equivalent concentrations of the chelators. The kinetics of the release were also faster for deferiprone, taking 20 min to achieve its maximum effect, whereas, desferrioxamine achieved only 80% of its maximum effect after 2 h. Thus, deferiprone could be an attractive alternative to desferrioxamine, as an aluminium chelator agent.

Reproducibility of a questionnaire on risk factors for osteoporosis in a multicentre prevalence survey: the European Vertebral Osteoporosis Study.

BACKGROUND: The European Vertebral Osteoporosis Study Group (EVOS) developed a questionnaire, back translated into 14 different European languages, for use in a multinational epidemiological study of vertebral osteoporosis. We investigated the reproducibility of this questionnaire in four of the participating study centres. METHODS: In all 151 men and women, aged 50-85 years, from Lubeck (Germany), Malmo (Sweden), Warsaw (Poland) and Oviedo (Northern Spain), were retested with the questionnaire on two occasions using a different observer within a 28-day period. RESULTS: Questions relating to personal or medical history were more reproducible than questions concerning subjective symptoms or aspects of lifestyle. The level of agreement for the non-ordinal categorical variables, as estimated by kappa, varied from 0.38 to 1.00 across the four centres. Agreement for the multicategory ordinal, mainly lifestyle, questions was in general poorer though improved when a weighted analysis was performed. For continuous data the 95% limits of agreement were narrow, and there was no evidence of bias between interviewers. There were no important differences in reproducibility across the four centres for either categorical or continuous data. CONCLUSION: The study indicates that the questionnaire may produce useful and comparable information concerning risk factors for osteoporosis across different countries and in different languages. It also highlights that questionnaire instruments designed for use in multinational population-based studies may provide data of comparable quality across a range of settings.

Serum aluminum transport and aluminum uptake in chronic renal failure: role of iron and aluminum metabolism.

Several factors have been blamed for increasing gastrointestinal absorption of aluminum. The likely role of iron metabolism was suggested some years ago. As iron and aluminum share many chemical properties, it is reasonable to think they also share biological pathways. The aim of this study was: (a) to evaluate serum aluminum transport and its relationship with iron-binding capacity, and (b) to investigate aluminum hydroxide absorption as a function of iron and aluminum. We investigated 127 patients with chronic renal failure undergoing hemodialysis in a study divided into two phases: phase 1, a basal study to investigate serum iron and aluminum status, and phase 2 in which an aluminum absorption test was performed. In phase 1, we found that the lower basal serum iron and iron transferrin saturation the greater serum aluminum (p < 0.001). In phase 2, we found a negative relationship between serum aluminum increments after the test and basal levels of serum aluminum and iron (r = -0.70; p < 0.001). These results suggest that the amount of either aluminum or iron carried by transferrin may influence the transferrin capacity to bind the other element and also may modulate, together with other factors, the gastrointestinal absorption of iron and aluminum.