MO058INHIBITION OF OSTEOCLAST DIFFERENTIATION BY 1.25-D AND THE CALCIMIMETIC KP2326 REVEALS 1.25-D RESISTANCE IN ADVANCED CKD

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Julie Bernardor ◽  
Sacha Flammier ◽  
Bruno Ranchin ◽  
Segolene Gaillard ◽  
Diane Platel ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Resorption ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Active Vitamin ◽  
Vitamin D Analogs ◽  
Active Vitamin D ◽  
Ckd Stage ◽  
Osteoclastic Differentiation

Abstract Background and Aims Active vitamin D analogs and calcimimetics are cornerstones for managing secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Their direct effects on bone cells remain to be determined. Method Peripheral blood mononuclear cells (PBMCs) of 19 pediatric CKD patients and 6 healthy donors (HD) were differentiated into osteoclasts in presence of M-CSF and RANKL. Effect of combined or single treatment with active vitamin D (1.25-D) and/or the calcimimetic KP2326 were evaluated onto osteoclast differentiation and osteoclast mediated bone resorption. Results 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when CKD worsens. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through an activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited human osteoclast-mediated bone resorption. Conclusion Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however to a different extent. Whilst 1.25-D has no significant effect on bone resorption, KP2326 inhibits bone resorption. Recent data showed that calcimimetics also have a direct anabolic effect on bone, through the stimulation of osteoblastic differentiation and mineralization in human mesenchymal stem cells in vitro. All these results provide a strong rationale for a global positive effect of calcimimetics on bone remodeling. Calcimimetics also significantly decrease FGF23 levels. In the setting of global systematic deleterious effects of high FGF23 levels in CKD, and keeping in mind that active vitamin D analogs stimulate FGF 23 production, all these data could favor the use of decreased doses of 1.25-D with low-doses of calcimimetics in SHPT in dialysis, the combination of these two therapies already being proposed in the 2017 K-DIGO guidelines.

Design and synthesis of active vitamin D analogs

2010 ◽  
Vol 121 (1-2) ◽  
pp. 7-12 ◽  
Author(s):  
Silvina Eduardo-Canosa ◽  
Ramón Fraga ◽  
Rita Sigüeiro ◽  
Maria Marco ◽  
Natacha Rochel ◽  
...  
Keyword(s):  
Vitamin D ◽  
Active Vitamin ◽  
Vitamin D Analogs ◽  
Design And Synthesis ◽  
Active Vitamin D

scholarly journals Inhibitory effect of aspirin on bone resorption by active vitamin analogues in vitamin D deficient rats

1979 ◽  
Vol 29 ◽  
pp. 95
Author(s):  
Koichi Ueno ◽  
Minoru Hayashi ◽  
Norio Ohnuma ◽  
Seizi Kurozumi ◽  
Yoshinobu Hashimoto ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Resorption ◽  
Inhibitory Effect ◽  
Active Vitamin

scholarly journals Non-classical Vitamin D Actions for Renal Protection

2021 ◽  
Vol 8 ◽  
Author(s):  
Adriana S. Dusso ◽  
Kevin T. Bauerle ◽  
Carlos Bernal-Mizrachi
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Endocrine System ◽  
Active Vitamin ◽  
Renal Protection ◽  
Ckd Progression ◽  
Skeletal Health ◽  
Independent Manner ◽  
Vitamin D Analogs ◽  
Active Vitamin D

Chronic Kidney Disease (CKD), a disorder that affects 11% of the world's population, is characterized by an acceleration in skeletal, immune, renal, and cardiovascular aging that increases the risk of cardiovascular mortality by 10- to 20-fold, compared to that in individuals with normal renal function. For more than two decades, the progressive impairment in renal capacity to maintain normal circulating levels of the hormonal form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) was considered the main contributor to the reduced survival of CKD patients. Accordingly, calcitriol administration was the treatment of choice to attenuate the progression of secondary hyperparathyroidism (SHPT) and its adverse impact on bone health and vascular calcification. The development of calcitriol analogs, designed to mitigate the resistance to calcitriol suppression of PTH associated with CKD progression, demonstrated survival benefits unrelated to the control of SHPT or skeletal health. The exhaustive search for the pathophysiology behind survival benefits associated with active vitamin D analogs has identified novel anti-inflammatory, anti-hypertensive, anti-aging actions of the vitamin D endocrine system. A major paradigm shift regarding the use of calcitriol or active vitamin D analogs to improve survival in CKD patients emerged upon demonstration of a high prevalence of vitamin D (not calcitriol) deficiency at all stages of CKD and, more significantly, that maintaining serum levels of the calcitriol precursor, 25(OH)vitamin D, above 23 ng/ml delayed CKD progression. The cause of vitamin D deficiency in CKD, however, is unclear since vitamin D bioactivation to 25(OH)D occurs mostly at the liver. Importantly, neither calcitriol nor its analogs can correct vitamin D deficiency. The goals of this chapter are to present our current understanding of the pathogenesis of vitamin D deficiency in CKD and of the causal link between defective vitamin D bioactivation to calcitriol and the onset of molecular pathways that promote CKD progression independently of the degree of SHPT. An understanding of these mechanisms will highlight the need for identification of novel sensitive biomarkers to assess the efficacy of interventions with vitamin D and/or calcitriol(analogs) to ameliorate CKD progression in a PTH-independent manner.

scholarly journals Standards of care for hypoparathyroidism in adults: a Canadian and International Consensus

2019 ◽  
Vol 180 (3) ◽  
pp. P1-P22 ◽  
Author(s):  
Aliya A Khan ◽  
Christian A Koch ◽  
Stan Van Uum ◽  
Jean Patrice Baillargeon ◽  
Jens Bollerslev ◽  
...  
Keyword(s):  
Vitamin D ◽  
Patient Education ◽  
Serum Calcium ◽  
Standards Of Care ◽  
Close Monitoring ◽  
Active Vitamin ◽  
Vitamin D Analogs ◽  
Diagnosis And Management ◽  
Active Vitamin D

Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults. Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism. Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults. Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.

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