A Comparison of Calcium to Zoledronic Acid for Improvement of Cortical Bone in an Animal Model of CKD

Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.

doi:10.1002/jbmr.2089

Cited by 75 publications

(116 citation statements)

References 43 publications

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“…In rodents with CKD, calcium treatment increases FGF23 but also lowers PTH. 24 Thus, it is unclear whether the FGF23 lowering is directly mediated by calcium or indirectly 25 The analyses shown here are consistent with observations in rodents that calcium may be involved in the regulation of FGF23.…”

Section: Discussionsupporting

confidence: 75%

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

et al. 2015

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Background-Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. Methods and Results-This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). Conclusions-Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23are associated with lower rates of cardiovascular death and major cardiovascular events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

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Section: Discussionsupporting

confidence: 75%

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

et al. 2015

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“…[7][8][9][10] Biochemical measurements taken at the time of euthanasia in this study are consistent with our previous publications in this model. 7,8,11,12 Table 1 shows that the CKD rats had elevated BUN, phosphorus, and fibroblast growth factor 23 (FGF23) compared with normal (NL) rats. However, there was no statistical difference in calcium and potassium concentrations.…”

Section: Assessment Of Ckdmentioning

confidence: 99%

“…The Langendorff heart preparation requires prolonged (2 hours or more) perfusion and thus, alters histology and PCR. Therefore, tissue for histology was analyzed from sections of CKD and NL rats from a previous study, 11 with confirmation from rats that underwent the electrophysiology studies to directly correlate the results to the presence and absence of fibrosis. For real-time PCR and Western blots, we used previously frozen samples from these latter animals 11 and additional samples from previously frozen tissue.…”

Section: Animal Modelmentioning

confidence: 99%

“…Sections were stained with picrosirius red stain to assess fibrosis using animal hearts from a previous study. 11 Heart sections from the animals undergoing electrophysiology studies were stained with a Trichrome/elastin method. The fibrosis score was determined from picrosirius red stain-stained sections by V.H.G., and the percentage of fibrosis was evaluated using a semiquantitative 1+ to 4+ score (1, Rad).…”

Section: Histologymentioning

confidence: 99%

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Pathogenesis of Arrhythmias in a Model of CKD

Hsueh

Chen²,

Lin

et al. 2014

Journal of the American Society of Nephrology

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Patients with CKD have an increased risk of cardiovascular mortality from arrhythmias and sudden cardiac death. We used a rat model of CKD (Cy/+) to study potential mechanisms of increased ventricular arrhythmias. Rats with CKD showed normal ejection fraction but hypertrophic myocardium. Premature ventricular complexes occurred more frequently in CKD rats than normal rats (42% versus 11%, P=0.18). By optical mapping techniques, action potential duration (APD) at 80% of repolarization was longer in CKD rats (7864ms) than normal rats (6363 ms, P,0.05) at a 200-ms pacing cycle length. Calcium transient (CaT) duration was comparable. Pacing cycle length thresholds to induce CaT alternans or APD alternans were longer in CKD rats than normal rats (10067 versus 8063 ms and 9366 versus 7664 ms for CaT and APD alternans, respectively, P,0.05), suggesting increased vulnerability to ventricular arrhythmia. Ventricular fibrillation was induced in 9 of 12 CKD rats and 2 of 9 normal rats (P,0.05); early afterdepolarization occurred in two CKD rats but not normal rats. The mRNA levels of TGF-b, microRNA-21, and sodium calcium-exchanger type 1 were upregulated, whereas the levels of microRNA-29, L-type calcium channel, sarco/endoplasmic reticulum calcium-ATPase type 2a, Kv1.4, and Kv4.3 were downregulated in CKD rats. Cardiac fibrosis was mild and not different between groups. We conclude that cardiac ion channel and calcium handling are abnormal in CKD rats, leading to increased vulnerability to early afterdepolarization, triggered activity, and ventricular arrhythmias. CKD affects more than 26 million individuals; 15% of American adults have some degree of CKD. 1 Cardiovascular events account for 40% of deaths in CKD patients. In patients on dialysis, 25% of cardiovascular deaths are caused by sudden cardiac death, a 100-fold rate compared with the general population. 2,3 Although the increased frequency in dialysis patients has often been attributed to electrolyte imbalances induced by the dialysis procedure in patients with underlying cardiac disease, recent data have highlighted the increased risk with CKD in patients not yet on dialysis, indicating that other factors in these patients with CKD may lead to sudden cardiac death. 4 The Multicenter Automatic Defibrillator Implantation Trial-II showed that the risk for sudden cardiac death was 17% higher for every 10 ml/min per 1.73 m 2 decrease in eGFR. 5 The result was comparable even when patients considered low risk for sudden cardiac death were analyzed. 6 The pathogenesis by which CKD predisposes to sudden cardiac death remains unknown. Our rat model of CKD, the Cy/+ rat, accurately represents many of the changes associated with human CKD, including hypertension, left ventricular hypertrophy, and CKD-mineral bone disorder. Furthermore, we have occasionally

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“…Nunes has suggested that it is the deranged metabolism of calcium and phosphorus, rather than the intake, which may be promoting CV calcification, particularly in CKD 31 . Animal studies have shown that low calcium intake induces higher nephrocalcinosis and aortic calcium content, while high calcium intake is not generally associated with calcification in health [32][33][34] but in rats with chronic kidney disease (CKD) and secondary hyperparathyroidism calcium supplementation increased arterial calcification 35 .…”

Section: Calcificationmentioning

confidence: 99%

Cardiovascular Calcification and Bone: A Comparison of The Effects of Dietary and Serum Calcium, Phosphorous, Magnesium and Vitamin D

Nicoll¹

2015

ICFJ

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This comparison of the effects of calcium, phosphorus, magnesium and vitamin D on cardiovascular (CV) calcification and bone has shown that in general the micronutrients that promote bone health also protect the arteries. We have shown that adequate amounts of all three minerals should be ingested, paying particular attention to supplementing calcium to bind high phosphorus and to ensure the maximum benefit from supplementing vitamin D. It appears that the optimum intake for bone is >800 mg/d calcium, with postmenopausal women possibly requiring a total intake of >1100mg/d. Both CV and bone studies suggest achieving a serum 25(OH)D level of >75nmol/l. These relationships are valid for a Caucasian population, however, and may not hold in African Americans and Asians. The recent concerns that calcium supplementation may increase CV disease risk has largely proved groundless, with higher calcium intake improving dyslipidaemia, hypertension and mortality. With respect to higher serum phosphate, there is an association with CV calcification and CVD risk even within the normal range, suggesting that the reference ranges may need to be redefined for ‘at risk’ patients. CV calcification was reduced in CKD patients with magnesium intake in the range 384-669mg/d. When considering the complex interplay of the action of the minerals together with their regulators vitamin D, PTH and FGF23, it is clear that this is a very sophisticated system which attempts to maintain calcium homeostasis to the possible detriment of bone and arteries. This reinforces the need to ensure adequate calcium intake before supplementing vitamin D.

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A Comparison of Calcium to Zoledronic Acid for Improvement of Cortical Bone in an Animal Model of CKD

Cited by 75 publications

References 43 publications

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

Pathogenesis of Arrhythmias in a Model of CKD

Cardiovascular Calcification and Bone: A Comparison of The Effects of Dietary and Serum Calcium, Phosphorous, Magnesium and Vitamin D

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