Louis-Charles Desbiens1,2, Aboubacar Sidibé1,3, Roth-Visal Ung1, Fabrice Mac-Way1,2. 1. CHU de Québec Research Center, L'Hôtel-Dieu-de-Québec Hospital, Endocrinology and Nephrology Axis, Quebec City, QC G1R 2J6, Canada. 2. Department and Faculty of Medicine, Université Laval, Quebec City, QC G1V 5C3, Canada. 3. Department of Social and Preventive Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 5C3, Canada.
Abstract
CONTEXT: Whether fibroblast growth factor-23 (FGF23) and α-Klotho are associated with fractures, especially in chronic kidney disease (CKD), remains controversial. OBJECTIVE: We evaluated how FGF23, α-Klotho, and traditional mineral parameters predict fractures in individuals with and without early CKD. METHODS: We conducted a stratified case-cohort analysis using CARTaGENE, a population-based survey from Quebec, Canada. Individuals aged 40 to 69 years were selected according to outcome and CKD status (non-CKD: eGFR > 60 mL/min/1.73 m2; CKD stage 3: eGFR 30-60 mL/min/1.73 m2]). Baseline levels of c-terminal FGF23 (cFGF23), α-Klotho, parathyroid hormone (PTH), phosphate, and calcium were analyzed for associations with osteoporotic fracture incidence from recruitment (2009-2010) through March 2016. Adjusted Cox models were used, and predictors were treated linearly or flexibly using splines. RESULTS: A total of 312 patients (159 non-CKD; 153 CKD) were included; 98 had ≥ 1 fracture at any site during a median follow up of 70 months. Compared with non-CKD, CKD patients had increased levels of cFGF23 but similar levels of α-Klotho. cFGF23 was linearly associated with increased fracture incidence (adjusted HR = 1.81 [1.71, 1.93] per doubling for all participants). The association of α-Klotho with fracture followed a U-curve (overall P = 0.019) but was attenuated by adjustment for potential mediators (bone mineral density, phosphate, PTH). PTH and phosphate also had U-shaped associations with fracture. Associations were mostly similar between non-CKD and CKD. Adjustment for cFGF23 strongly attenuated the association between CKD status and fractures. CONCLUSION: cFGF23 is associated linearly with fracture incidence while α-Klotho, PTH, and phosphate levels have a U-shaped association.
CONTEXT: Whether fibroblast growth factor-23 (FGF23) and α-Klotho are associated with fractures, especially in chronic kidney disease (CKD), remains controversial. OBJECTIVE: We evaluated how FGF23, α-Klotho, and traditional mineral parameters predict fractures in individuals with and without early CKD. METHODS: We conducted a stratified case-cohort analysis using CARTaGENE, a population-based survey from Quebec, Canada. Individuals aged 40 to 69 years were selected according to outcome and CKD status (non-CKD: eGFR > 60 mL/min/1.73 m2; CKD stage 3: eGFR 30-60 mL/min/1.73 m2]). Baseline levels of c-terminal FGF23 (cFGF23), α-Klotho, parathyroid hormone (PTH), phosphate, and calcium were analyzed for associations with osteoporotic fracture incidence from recruitment (2009-2010) through March 2016. Adjusted Cox models were used, and predictors were treated linearly or flexibly using splines. RESULTS: A total of 312 patients (159 non-CKD; 153 CKD) were included; 98 had ≥ 1 fracture at any site during a median follow up of 70 months. Compared with non-CKD, CKD patients had increased levels of cFGF23 but similar levels of α-Klotho. cFGF23 was linearly associated with increased fracture incidence (adjusted HR = 1.81 [1.71, 1.93] per doubling for all participants). The association of α-Klotho with fracture followed a U-curve (overall P = 0.019) but was attenuated by adjustment for potential mediators (bone mineral density, phosphate, PTH). PTH and phosphate also had U-shaped associations with fracture. Associations were mostly similar between non-CKD and CKD. Adjustment for cFGF23 strongly attenuated the association between CKD status and fractures. CONCLUSION: cFGF23 is associated linearly with fracture incidence while α-Klotho, PTH, and phosphate levels have a U-shaped association.
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