Genetic polymorphisms of the wint receptor LRP5 are differentially associated with trochanteric and cervical hip fractures

Producción CientíficaPurpose. Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We planned to test the hypothesis that genetic factors have different influences on both types of fractures. Methods. Ten polymorphisms of genes known to play an important role in skeletal homeostasis (estrogen receptor alpha [ESR1], aromatase [CYP19A1], type I collagen [COL1A1], and lipoprotein receptor-related protein 5 [LRP5]) were analyzed in 471 Spanish patients with fragility hip fractures. Results. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (p-value 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci, in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with 1 or 2 rare alleles, and 7.5 in those with 3 or 4 rare alleles (p-value for trend 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1 and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or in an extended group of 818 patients. Conclusions. These results suggest LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies

Vertebroplasty and kyphoplasty as treatment for osteoporotic vertebral fractures

Summary Over the last decade vertebroplasty and kyphoplasty have become popular as therapeutic options for the treatment of vertebral fractures. In fact, numerous non-controlled studies have indicated that both procedures are very efficacious for the control of pain associated with fractures. However, some recently published randomised trials have cast doubt on the true effectiveness of these procedures. On the other hand, certain observations have suggested that the increase in the rigidity which is produced by the injection of metacrylate into a vertebral body could facilitate the collapse of the adjacent vertebra. Therefore, vertebroplasty and kyphoplasty should not be considered as a routine theraputic measure, but should be limited to carefully selected patients, in whom the potential benefits surpass the risks and costs of the procedure. In any case, the patients should be put on a global treatment programme which includes pharmaceutical measures and non-pharmaceutical care to reduce the risk of future vertebral and peripheral fractures. Various clinical trials have recently been published which were supposed to be an important contribution to knowledge regarding the effectiveness of vertebroplasty. The results have been rather contradictory both within themselves, and with earlier observational studies. For this reason it is worth reviewing this questions with the intention of helping clinicians who need to take decisions on the treatment of patients with osteoporotic fractures. We have not dealt with the possible utility vertebroplasty in other processes, such as fractures caused by tumours or by trauma

Hypercalcemia in patients with rheumatoid arthritis: a retrospective study

Objetivo: Investigar la prevalencia de hipercalcemia en pacientes con artritis reumatoide (AR) y analizar las características clínicas y las causas de la hipercalcemia. Material y métodos: Estudio retrospectivo de revisión basado en casos que incluyó 500 pacientes con AR. Se identificaron los pacientes con niveles de calcio aumentados en al menos dos ocasiones. Resultados: La hipercalcemia estuvo presente en 24 de los 500 pacientes con AR (4,8%). La edad osciló entre 50 y 80 años, con una media de 68±10 años. La duración media de la enfermedad fue de 10±7 años. De los pacientes con hipercalcemia, 22 eran mujeres postmenopáusicas (92%) y solo dos eran hombres (8%). El hiperparatiroidismo se encontró en 9 pacientes de la serie; solo un paciente tenía una hipercalcemia maligna debido a un mieloma múltiple, y un caso fue consecuencia de una intoxicación por vitamina D. En un paciente la hipercalcemia parecía relacionada con el síndrome calcio-alcalino. En el resto de pacientes, la hipercalcemia fue idiopática (8/24) o el estudio fue incompleto (4/24). No se encontró una relación evidente entre la actividad de la enfermedad y la aparición de hipercalcemia. Conclusión: Al igual que sucede en la población general, el hiperparatiroidismo primario es la causa más común de hipercalcemia en pacientes con AR. En algunos pacientes no se identificaron otros trastornos causantes de hipercalcemia, lo que plantea la posibilidad de una relación causal entre la AR y la hipercalcemia.Objetive: To investigate the prevalence of hypercalcemia in patients with rheumatoid arthritis (RA) and analyze the clinical features and causes of hypercalcemia. Material and methods: Retrospective case?based review study that included 500 patients with RA. Patients with increased calcium levels on at least two occasions were identified. Results: Hypercalcemia was present in 24 of the 500 RA patients (4.8%). The age ranged between 50 and 80 years, with a mean of 68±10 years. The mean duration of the disease was 10±7 years. Of the patients with hypercalcemia, 22 were postmenopausal women (92%) and only two were men (8%). Hyperparathyroidism was found in 9 patients in the series; only one patient had malignant hypercalcemia due to multiple myeloma, and one case was a consequence of vitamin D intoxication. In one patient, hypercalcemia appeared to be related to calcium?alkali syndrome. In the remaining patients, hypercalcemia was idiopathic (8/24) or the study was incomplete (4/24). No obvious relationship was found between disease activity and the appearance of hypercalcemia. Conclusion: As in the general population, primary hyperparathyroidism is the most common cause of hypercalcemia in patients with RA. In some patients, no other disorders causing hypercalcemia were identified, raising the possibility of a causal relationship between RA and hypercalcemia

Abnormal bone turnover in individuals with low serum alkaline phosphatase

The clinical spectrum of hypophosphatasia (HPP) is broad and variable within families. Along severe infantile forms, adult forms with mild manifestations may be incidentally discovered by the presence of low alkaline phosphatase (ALP) activity in serum. However, it is still unclear whether individuals with persistently low levels of ALP, in the absence of overt manifestations of HPP, have subclinical abnormalities of bone remodeling or bone mass. The aim of this study was to obtain a better understanding of the skeletal phenotype of adults with low ALP by analyzing bone mineral density (BMD), bone microarchitecture (trabecular bone score, TBS), and bone turnover markers (P1NP and ß-crosslaps). We studied 42 individuals with persistently low serum ALP. They showed lower levels of P1NP (31.4?±?13.7 versus 48.9?±?24.4 ng/ml; p?=?0.0002) and ß-crosslaps (0.21?±?0.17 versus 0.34?±?0.22 ng/ml, p?=?0.0015) than individuals in the control group. There were no significant differences in BMD, bone mineral content, or TBS. These data suggest that individuals with hypophosphatasemia have an overall reduction of bone turnover, even in the absence of overt manifestations of HPP or low BMD. We evaluated bone mineral density (BMD), bone microarchitecture, and bone turnover markers in patients with low serum levels of alkaline phosphatase. Our results show that these patients have low bone remodeling even in the absence of BMD abnormalities, thus supporting the recommendation of avoiding antiresorptives such as bisphosphonates in these subjects

Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians

<p>Abstract</p> <p>Background</p> <p>Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (<it>ESR1</it>) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians.</p> <p>Methods</p> <p>We analyzed those two SNPs and another neighbour SNP located on the exon 4 of <it>ESR1 </it>in 787 patients with hip fractures and 953 controls from Spain.</p> <p>Results</p> <p>The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.</p> <p>Conclusions</p> <p>This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of <it>ESR1 </it>and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.</p

Genetic and acquired factors influencing the effectiveness and toxicity of drug therapy in osteoporosis

Introduction: Osteoporosis is a highly prevalent skeletal disorder characterized by compromised bone strength, usually related to decreased bone mass and microstructural alterations of bone tissue, predisposing a person to an increased risk of fracture. As other prevalent disorders, osteoporosis is the result of a complex interplay of genetic and acquired factors. Areas covered: We provide an update of recent studies aimed at identifying the clinical and genetic factors that influence the response to drugs used to treat osteoporosis, as well as those determining the risk of two intriguing adverse effects of antiresorptives: osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). Expert opinion: Several clinical factors have been suggested to increase the risk of a poor drug response, such as advanced age and frailty. Candidate gene studies suggest that some common polymorphisms of the Wnt pathway and farnesyl diphosphate synthase (FDPS), the target enzyme for bisphosphonates, also influence the response to antiresorptives. However, they await for replication in large independent cohorts of patients. Similarly, some genetic and acquired factors may influence the risk of ONJ and AFF. Preliminary data suggest that the risk of suffering these adverse effects may have a polygenic basis

Association of aromatase and estrogen receptor gene polymorphisms with hip fractures

Producción CientíficaSummary Two polymorphisms of the aromatase and estrogen receptor genes appeared to interact to influence the risk of hip fractures in women. Introduction Allelic variants of the aromatase gene have been associated with bone mineral density and vertebral fractures. Our objective was to analyze the relationship between two polymorphisms of the aromatase and estrogen receptor genes and hip fracture

Relationship of sclerostin and secreted frizzled protein polymorphisms with bone mineral density: an association study with replication in postmenopausal women

Objectives.- Secreted frizzled-related protein and sclerostin, encoded by FRZB and SOST genes, respectively, are extracellular Wnt inhibitors that tend to decrease bone formation. The purpose of this study was to explore the association of sets of polymorphisms capturing common variations of these genes with bone mineral density (BMD). Methods.- Twelve polymorphic loci of the FRZB gene and 7 of the SOST gene were genotyped in postmenopausal women from two Spanish regions (Cantabria, n=1043, and Valencia, n=342). The polymorphisms included tagging SNPs and SNPs with possible functional consequences assessed in silico. Results.-The rs4666865 polymorphism of the FRZB gene was associated with spine BMD in the Cantabria cohort in the single-locus (p=0.008) and the haplotypic analysis. However, the results were not replicated in the Valencia cohort. Several polymorphisms at the 5´region of the SOST gene, and particularly rs851056, were associated with BMD in women from both cohorts (p=0.002 in Cantabria and 0.005 in Valencia). When the results of both cohorts were combined, the mean BMD difference across rs851056 genotypes was 47 mg/cm2 or 0.31 standard deviations (p<0.001). No differences in FRZB and SOST expression was detected across genotypes. Conclusions.- Polymorphisms in the 5’ region of SOST gene are associated with BMD in postmenopausal women, and consequently contribute to explain in part the hereditary influence on bone mass

Nuclear receptor NR5A2 and bone: gene expression and association with bone mineral density

ObjectiveThere is growing evidence for a link between energy and bone metabolism. The nuclear receptor subfamily 5 member A2 (NR5A2) is involved in lipid metabolism and modulates the expression of estrogen-related genes in some tissues. The objective of this study was to explore the influence of NR5A2 on bone cells and to determine whether its allelic variations are associated with bone mineral density (BMD).DesignAnalyses of gene expression by quantitative PCR and inhibition of NR5A2 expression by siRNAs were used to explore the effects of NR5A2 in osteoblasts. Femoral neck BMD and 30 single nucleotide polymorphisms (SNPs) were first analyzed in 935 postmenopausal women and the association of NR5A2 genetic variants with BMD was explored in other 1284 women in replication cohorts.ResultsNR5A2 was highly expressed in bone. The inhibition of NR5A2 confirmed that it modulates the expression of osteocalcin, osteoprotegerin, and podoplanin in osteoblasts. Two SNPs were associated with BMD in the Spanish discovery cohort (rs6663479, P=0.0014, and rs2816948, P=0.0012). A similar trend was observed in another Spanish cohort, with statistically significant differences across genotypes in the combined analysis (P=0.03). However, the association in a cohort from the United States was rather weak. Electrophoretic mobility assays and studies with luciferase reporter vectors confirmed the existence of differences in the binding of nuclear proteins and the transcriptional activity of rs2816948 alleles.ConclusionsNR5A2 modulates gene expression in osteoblasts and some allelic variants are associated with bone mass in Spanish postmenopausal women