Takashi Shigematsu1, Masafumi Fukagawa2, Keitaro Yokoyama3, Takashi Akiba4, Akifumi Fujii5, Motoi Odani6, Tadao Akizawa7. 1. Department of Nephrology, Wakayama Medical University, Wakayama, Japan. Electronic address: taki@wakayama-med.ac.jp. 2. Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan. 3. Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. 4. Sekikawa Hospital, Tokyo, Japan. 5. Clinical Development Planning, Ono Pharmaceutical Co, Ltd, Osaka, Japan. 6. Data Science, Ono Pharmaceutical Co Ltd, Osaka, Japan. 7. Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Abstract
PURPOSE: Secondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. METHODS: This study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1α,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FINDINGS: The etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. IMPLICATIONS: These results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665.
PURPOSE: Secondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. METHODS: This study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1α,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FINDINGS: The etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. IMPLICATIONS: These results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665.
Authors: Antonio Bellasi; Mario Cozzolino; Fabio Malberti; Giovanni Cancarini; Ciro Esposito; Carlo Maria Guastoni; Patrizia Ondei; Giuseppe Pontoriero; Ugo Teatini; Giuseppe Vezzoli; Marzia Pasquali; Piergiorgio Messa; Francesco Locatelli Journal: J Nephrol Date: 2019-12-18 Impact factor: 3.902