Browsing by Subject "Secondary hyperparathyroidism"

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    Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis
    (Oxford University Press, 2019-04-26) Wolf, Myles; Block, Geoffrey A.; Chertow, Glenn M.; Cooper, Kerry; Fouqueray, Bruno; Moe, Sharon M.; Sun, Yan; Tomlin, Holly; Vervloet, Marc; Oberbauer, Rainer; Medicine, School of Medicine
    Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.
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    Prolonged secondary hyperparathyroidism in adenine-induced CKD leads to skeletal changes consistent with skeletal hyporesponsiveness to PTH
    (Public Library of Science, 2025-05-23) Metzger, Corinne E.; Tak, Landon Y.; Scholz, Samantha; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of Medicine
    High circulating parathyroid hormone (PTH) leading to secondary hyperparathyroidism is proposed to be a key driver of the skeletal phenotype of chronic kidney disease-mineral bone disorder (CKD-MBD) leading to high bone turnover and cortical bone deterioration. The association between high PTH and the skeletal phenotype is typically clearly demonstrated in preclinical models of CKD; however, clinical studies show the relationship between PTH and skeletal outcomes is not as clear. The clinical data have led to a proposed hyporesponsiveness to PTH in the CKD setting with unclear causes. In the current study, we assessed skeletally mature male C57BL/6J mice at 12-weeks and 21-weeks of adenine-induced CKD (Ad) with the second timepoint seven weeks longer than we have previously assessed. We found that serum BUN was high in Ad mice in both groups indicating the presence of kidney disease while PTH was higher in 21-wk Ad vs. 12-wk Ad. Despite the higher PTH, bone formation rate in 21-wk Ad mice was lower than 21-wk Ad mice. Additionally, immunohistochemical assessment of the PTH receptor, PTHR1, and RANKL, a key factor upregulated by PTH, showed a lower percentage of osteocytes positive for the proteins in 21-wk Ad vs. 12-wk Ad. Furthermore, regression analyses demonstrated a positive relationship between serum PTH and PTHR1 and RANKL at 12-weeks, but this relationship was lost by 21-weeks. Overall, these data indicate that prolonged exposure to continuously elevated PTH in adenine-induced CKD mice eventually led to an altered skeletal response indicating lower responsiveness of bone, particularly osteocytes, to the chronic PTH signal. This has implications for using PTH as a surrogate marker of bone outcomes in CKD as well as pointing to the need to better understand the time-based relationship between PTH and skeletal outcomes in CKD.