Diuretics and Bone Loss in Rats With Aldosteronism

Law, Peter; Sun, Yao; Bhattacharya, Syamal K.; Chhokar, Vikram S.; Weber, Karl T.

doi:10.1016/j.jacc.2005.03.055

Cited by 62 publications

(45 citation statements)

References 49 publications

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“…It has been well reported that aldosteronism affects bone metabolism; for instance, bone mineral and bone strength are lost in the presence of a high level of aldosterone. (60,61) Interestingly, two (NR3C2 and PIK3R1) of four pathway genes from the cluster have been demonstrated to be involved in bone metabolism. NR3C2 encodes mineralcortical receptor (MR) that is expressed in osteocytes, osteoblasts, and osteoclasts, (62) and aldosterone activation of MR promotes osteoblastic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

Gupta

Cheung

Hsu

et al. 2011

Journal of Bone and Mineral Research

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Genome-wide association studies (GWAS) using high-density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single-nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene-set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes-SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP-phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross-sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene-set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis-related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk. ß

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Section: Discussionmentioning

confidence: 99%

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

Gupta

Cheung

Hsu

et al. 2011

Journal of Bone and Mineral Research

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“…11 As is the case with ischemia/reperfusion injury or excess circulating catecholamines, intracellular Ca 2+ overloading is accompanied by the appearance of oxidative stress. This is expressed as (1) an activation of nicotinamide adenosine dinucleotide phosphate oxidase, a source of superoxide in vascular tissues; (2) an activation of a redox-sensitive transcription factor (NF)-κB, together with upregulated expression of the proinflammatory genes it governs; (3) reactive oxygen (e.g., superoxide, H2O2) and nitrogen (e.g., peroxynitrite) species in diverse tissues; and (4) 22 Secondary hyperparathyroidism with hypercalciuria has been observed in patients with advanced CHF awaiting cardiac transplantation and who had received chronic furosemide treatment. 23,24 These persons were also found to have a reduction in bone mineral density in keeping with osteopenia or, in more advanced cases, with osteoporosis.…”

Section: Chf: a Salt-avid Statementioning

confidence: 99%

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

Alsafwah¹,

LaGuardia²,

Arroyo³

et al. 2007

Clinical Medicine & Research

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Congestive heart failure (CHF) is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensin-aldosterone system. More than this cardiorenal perspective, CHF is accompanied by a systemic illness whose features include an altered redox state in diverse tissues and blood, an immunostimulatory state with proinflammatory cytokines and activated lymphocytes and monocytes, and a wasting of tissues that includes muscle and bone. Based on experimental studies of aldosteronism and clinical findings in patients with CHF, there is an emerging body of evidence that secondary hyperparathyroidism is a covariant of CHF. The aldosteronism of CHF predisposes patients to secondary hyperparathyroidism because of a chronic increase in Ca 2+ and Mg 2+ losses in urine and feces, with a fall in their serum ionized levels and consequent secretion of parathyroid hormone. Secondary hyperparathyroidism accounts for bone resorption and contributes to a fall in bone strength that can lead to nontraumatic fractures. The long-term use of a loop diuretic with its attendant urinary wasting of Ca 2+ and Mg 2+ further predisposes patients to secondary hyperparathyroidism and attendant bone loss. Aberrations in minerals and micronutrient homeostasis that includes Ca 2+ , Mg 2+ , vitamin D, zinc and selenium appear to be an integral component of pathophysiologic expressions of CHF that contributes to its systemic and progressive nature. This broader perspective of CHF, which focuses on the importance of secondary hyperparathyroidism and minerals and micronutrients, raises the prospect that dietary supplements could prove remedial in combination with the current standard of care.

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“…(6) Furthermore, in an animal model with aldosteronism, due to aldosterone/salt treatment, loss of minerals and progressive reduction of cortical bone strength was observed, (7) subsequently rescued by spironolactone treatment. (8)(9)(10)(11) The aim of our study was to evaluate bone involvement in patients with primary aldosteronism (PA) consecutively recruited among the patients with adrenal incidentaloma (AI) referred to two tertiary care centers in Italy.…”

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confidence: 99%

Bone involvement in aldosteronism

Salcuni

Palmieri

Carnevale

et al. 2012

Journal of Bone and Mineral Research

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In rats with aldosteronism, a reduction of bone mineral density (BMD) and cortical bone strength has been reported. Our study was aimed to evaluate bone involvement in patients with primary aldosteronism (PA). A total of 188 consecutive subjects with adrenal incidentaloma, observed between November 2009 and October 2011, were screened for PA with aldosterone-to-renin ratio. After confirmatory tests, in those who screened positive, 11 patients were diagnosed as PA and 15 patients were not (nPA). A serum/urinary biochemical profile, parathyroid hormone (PTH), BMD measured at lumbar spine (LS) and total and femoral neck (TN and FN) by dual X-ray absorptiometry, and conventional spinal radiographs (T 4 -L 4 ) were obtained in all subjects. PA patients had a significantly higher 24-hour urinary calcium (6.28 AE 1.85 versus 4.28 AE 1.18 mmol/d; p < 0.01), and PTH (9. 8 [5.8-14.6 p ¼ 0.012; and OR, 30.4; 95%CI,, p ¼ 0.045, respectively) regardless of age, body mass index (BMI), and LS-BMD. In 9 of 11 PA patients, 6 months after beginning of treatment (surgery or spironolactone) there was a significant reduction of urinary calcium excretion (p < 0.01) and PTH (p < 0.01), whereas in 5 of 11 PA patients, 1 year after beginning of treatment, BMD was significantly increased at LS, p < 0.01). In conclusion, PA is associated with osteoporosis, vertebral fractures, and increased urinary calcium excretion. ß

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Diuretics and Bone Loss in Rats With Aldosteronism

Cited by 62 publications

References 49 publications

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

Bone involvement in aldosteronism

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