FGF23-Klotho Axis and Fractures in Patients Without and With Early CKD: A Case-Cohort Analysis of CARTaGENE

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.

Keywords: FGF23; chronic kidney disease; fracture; parathyroid hormone; α-Klotho.

Figure 1.

Study flowchart. The number of patients included in the CKD group is lower than the sum of case and cohort patients since 7 patients were selected both as case and cohort. Abbreviation: eGFR, estimated glomerular filtration rate.

Figure 2.

Levels of bone and mineral parameters in CKD and non-CKD. Dots represents each individual value stratified by CKD status. Boxes indicate the interquartile range of a parameter, and the bold horizontal line indicates the median. Vertical lines below and above each box indicate the 5^th and 95^th percentile of each parameter. Bbreviations: CKD, chronic kidney disease; PTH, parathyroid hormone.

Figure 3.

Association of cFGF23, α-Klotho, and mineral parameters with fracture incidence. Dark lines represent associations with fracture incidence as hazard ratios compared to the point of lowest (or highest) risk for each parameter. They are adjusted for a fracture risk score (including age [treated flexibly with restricted cubic splines], sex, ethnicity, body mass index [treated flexibly with restricted cubic splines], prior fracture at any anatomical site, active smoking, diabetes, prevalent cardiovascular disease, alcohol consumption [treated flexibly with restricted cubic splines], secondary osteoporosis) and chronic kidney status. Shaded areas represent the 95% CI at each level. Associations and confidence intervals were generated from 10 multiply imputed datasets using Rubin’s rules. Lines below each plot represent the distribution of parameters for each patient. The x-axis for cFGF23 is displayed on the log scale. The y-axis is displayed on the log scale. Abbreviation: PTH, Parathyroid hormone.

Figure 4.

Association of cFGF23, α-Klotho, and mineral parameters with bone density measured by calcaneal ultrasound. Dark lines represent associations with bone density (measured as calcaneal QUS stiffness index) as betas compared to the point of lowest risk, highest risk, or the median for each parameter. They are adjusted for a bone density score (including age [treated flexibly with restricted cubic splines], sex, ethnicity, body mass index [treated flexibly with restricted cubic splines], prior fracture at any anatomical site, active smoking, diabetes, prevalent cardiovascular disease, alcohol consumption [treated flexibly with restricted cubic splines], secondary osteoporosis), and chronic kidney status. Shaded areas represent the 95% CI at each level. Associations and confidence intervals were generated from 10 multiply imputed datasets using Rubin’s rules. Lines below each plot represent the distribution of parameters for each patient. Abbreviations: PTH, parathyroid hormone; QUS, quantitative ultrasound.