Differential effects of 19-nor-1,25-(OH)2D2 and 1α-hydroxyvitamin D2 on calcium and phosphorus in normal and uremic rats

Slatopolsky, Eduardo; Cozzolino, Mario; Finch, Jane

doi:10.1111/j.1523-1755.2002.kid573.x

Cited by 73 publications

(21 citation statements)

References 45 publications

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“…For example, in CKD clinical studies, paricalcitol's therapeutic index (efficacy vs. hypercalcemic toxicity) is about 3- to 4-fold better than calcitriol, which is reproduced in this kidney disease animal model [37,42]. Consistent with reports by others [37,43], we have previously demonstrated that paricalcitol and doxercalciferol effectively suppress serum PTH at 0.021-0.33 μg/kg in the 5/6 NX rats, but both drugs also induce an increase in serum Ca in the same dose range [39,44]. As a comparison, we show in this report that VS-411, similar to calcitriol, affects serum PTH and Ca in the same dose range, but VS-110 significantly suppresses serum PTH at 0.01-1.0 μg/kg without affecting serum Ca.…”

Section: Discussionsupporting

confidence: 77%

Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5/6 Nephrectomized Uremic Rats

et al. 2013

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Background/Aims: Vitamin D receptor modulators (VDRMs) are indicated for secondary hyperparathyroidism in chronic kidney disease (CKD). Clinical observations demonstrate that VDRM therapy provides cardiovascular (CV) benefit in CKD. Current on-market VDRMs have a narrow therapeutic index at 1- to 4-fold [hypercalcemic toxicity vs. parathyroid hormone (PTH)-suppressing efficacy]. Hypercalcemia leads to the need for frequent drug dose titration and serum calcium (Ca) monitoring. A VDRM with a wider therapeutic index and beneficial CV effects will be clinically useful. Methods: Two structurally similar VDRMs were tested in the 5/6 nephrectomized (NX) rats with elevated PTH, endothelial dysfunction and left ventricular hypertrophy. Results: VS-110 and VS-411 at 0.01-1 μg/kg (i.p. 3 times/week for 2 weeks) suppressed serum PTH effectively. VS-411 raised serum Ca with an 11% increase at 0.01 μg/kg (therapeutic index = ∼1-fold), while VS-110 did not raise serum Ca even at 1 μg/kg (therapeutic index >50-fold). VS-110 improved endothelium-dependent aortic relaxation in a dose-dependent manner and significantly reduced left ventricular fibrosis without affecting serum Ca. VS-411 also exhibited effects on the CV parameters, but was less potent at the high doses with severe hypercalcemia. VS-110 and VS-411 specifically activated the reporter gene via a chimeric receptor containing the VDR ligand binding domain with EC₅₀ <0.1 nM. Conclusions: Structurally similar VDRMs can exhibit distinctly different hypercalcemic effects in 5/6 NX uremic rats. While differences exist for the Ca and CV effects of VS-110 and VS-411, the clinical implications are unclear. VS-110's results are promising but clinical outcome studies need to be performed.

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Section: Discussionsupporting

confidence: 77%

Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5/6 Nephrectomized Uremic Rats

et al. 2013

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“…91,92 Despite clinically important PTH suppression, Tan et al found doxercalciferol therapy unacceptably raised serum mineral levels by 13 times in half the ESRD patients in the observational study, totaling 4.9 hypercalcemic episodes and 10.1 hyperphosphatemic episodes per 100 weeks of treatment. 93 In a double-blind RCT investigating doxercalciferol therapy in dialysis patients suffering from moderate-to-severe SHPT, Frazao et al found that 82 of the 99 patients (83%) studied achieved PTH targets but with concomitant mild hypercalcemia and hyperphosphatemia.…”

Section: Doxercalciferolmentioning

confidence: 98%

“…22 In a preclinical murine model, Slatopolsky et al demonstrated that paricalcitol treatment causes reduced intestinal absorption of calcium and phosphorus versus equipotent doses of calcitriol. 109 The cause of this clinical advantage has been investigated on the molecular level and appears to be mediated by transcription of genes in enterocytes. Vitamin D compounds are believed to increase intestinal calcium absorption by up-regulating calcium-transporter-1 (CaT1) on the luminal membrane, calbindin in the cytosol, and plasma membrane calcium ATPase-1 (PMCA1) on the basolateral membrane of enterocytes.…”

Section: Molecular Mechanisms Differentiating Vitamin D-based Therapiesmentioning

confidence: 99%

Outcomes of Secondary Hyperparathyroidism in Chronic Kidney Disease and the Direct Costs of Treatment

Joy¹,

Karagiannis²,

Peyerl³

2007

JMCP

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What is already known about this subject• SHPT is highly prevalent in the hemodialysis patient population.It is often treated with vitamin D analogs. There is a need for evidence of the treatment effect of vitamin D analogs on hard endpoint skeletal and cardiovascular outcomes in predialysis CKD patients. What this study adds• The financial expense of treating SHPT (as a complication of CKD) may be cost effective, based on observational data. In addition to the need to establish a causal link between drug therapy for SHPT and reduction in hard endpoint cardiovascular outcomes, future randomized studies are needed to determine the preferred agent, PTH treatment goal, stage of the disease at which to initiate treatment, and impact on mortality.ABSTRACT BACKGROUND: There has been an emphasis over the last several years to identify and treat chronic kidney disease (CKD) and its complications as they evolve rather than waiting until the patient reaches end-stage renal disease (ESRD), also known as CKD stage 5. The number of patients who will be identified and prescribed therapies for complications such as secondary hyperparathyroidism (SHPT) is greater than initially proposed.OBJECTIVE: To review the pathways, complications, management, and estimated treatment costs of CKD-related SHPT.METHODS: An electronic literature search of MEDLINE (January 1980 through January 2007) was conducted for English-language publications using the base search term secondary hyperparathyroidism. To refine subsequent searches, the authors added Boolean operators to the following secondary and tertiary search terms: parathyroid hormone, chronic kidney disease, renal osteodystrophy, adynamic bone disease, vascular calcification, cardiovascular disease, vitamin D, vitamin D analogs, hypercalcemia, hyperphosphatemia, calcimimetics, costs, prevalence, and economics.RESULTS: The initial MEDLINE search produced 278 relevant articles. After refining the search terms, the authors triaged the results for English-language publications relevant to the discussion of SHPT and its complications in CKD, eliminating 149 publications. The remaining 129 publications were accepted for review. These articles represent a growing body of primarily observational evidence that demonstrates that elevated intact parathyroid hormone (PTH) levels cause deleterious physiological results across a variety of organ systems, including the cardiovascular and skeletal systems. Specific complications associated with SHPT are left ventricular hypertrophy (LVH), renal osteodystrophy (ROD), and extraskeletal calcification. Medical management of the PTH/vitamin D/calcium and phosphorus imbalances in SHPT focus on regulating PTH levels via vitamin D therapy. The class of calcimimetics is a newer treatment modality that has favorable effects on biochemical laboratory values, such as serum calcium and phosphorus levels, but current data do not show differences on hard endpoint patient-oriented outcomes compared with standard generic agents. CONCLUSIONS: SHPT causes skeletal and ca...

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“…However, nonselective activation of VDR pathways can cause hypercalcemia and hyperphosphatemia by enhanced intestinal absorption of calcium and phosphorus [15] which is associated with increased mortality in dialysis patients [16]. Ideally, management of SHPT in dialysis patients should control PTH levels, while maintaining serum calcium and phosphorus within the normal range, and correct active vitamin D deficiency and inactivation of VDR pathway transcription.…”

Section: Discussionmentioning

confidence: 99%

Oral Paricalcitol for the Treatment of Secondary Hyperparathyroidism in Patients on Hemodialysis or Peritoneal Dialysis

et al. 2007

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Background/Aims: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). Methods: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week’s intact PTH (iPTH) level as well as calcium and Ca × P product levels. The primary end points were efficacy (two consecutive iPTH decreases of ≧30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed. Results: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH ≤500 pg/ml and iPTH >500 pg/ml were 3.9 and 7.6 µg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive ≧30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. Conclusion: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

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Differential effects of 19-nor-1,25-(OH)2D2 and 1α-hydroxyvitamin D2 on calcium and phosphorus in normal and uremic rats

Cited by 73 publications

References 45 publications

Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5/6 Nephrectomized Uremic Rats

Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5/6 Nephrectomized Uremic Rats

Outcomes of Secondary Hyperparathyroidism in Chronic Kidney Disease and the Direct Costs of Treatment

Oral Paricalcitol for the Treatment of Secondary Hyperparathyroidism in Patients on Hemodialysis or Peritoneal Dialysis

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