CLINICAL STUDY Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men Richard Marsell, Elin Grundberg 1 , Tijana Krajisnik 1 , Hans Mallmin, Magnus Karlsson 2 , Dan Mellstro ¨m 3 , Eric Orwoll 4 , Claes Ohlsson 3 , Kenneth B Jonsson, O ¨ sten Ljunggren 1 and Tobias E Larsson 1 Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden, 1 Department of Medical Sciences, Uppsala University Hospital, Ing. 70, 3 tr., UAS, 75185 Uppsala, Sweden, 2 Clinical and Molecular Osteoporosis Research Unit, Departments of Clinical Sciences and Orthopaedics, Malmo ¨ University Hospital, Lund University, 20502, Malmo ¨, Sweden, 3 Center for Bone Research at the Sahlgrenska Academy, Department of Internal Medicine, Gothenburg University, 41345, Gothenburg, Sweden and 4 Oregon Health and Science University, Portland, Oregon 97239-3098, USA (Correspondence should be addressed to T E Larsson; Email: tobias.larsson@medsci.uu.se) Abstract Objective: Fibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease. Design: Serum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70–80 years were randomly selected from the population. Methods: Intact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D 3 were measured. Association studies were performed using linear univariate and multivariate regression analyses. Results: The median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (rZK0.21; P!0.00001) and log PTH (rZ0.13; P!0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (bZ0.082; P!0.05) and eGFR (bZK0.090; P!0.05) were associated with log FGF23 in subjects with eGFRO60 ml/min. Only eGFR (bZK0.35; P!0.0001) remained as a predictor of log FGF23 in subjects with eGFR!60 ml/min. Conclusions: Serum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi. European Journal of Endocrinology 158 125–129 Introduction Fibroblast growth factor-23 (FGF23) is a circulating phosphaturic factor that plays a critical role in renal phosphate (Pi) reabsorption (1). Numerous activating and inactivating mutations in the human FGF23 gene have been identified, causing two clinical disorders of disturbed Pi homeostasis: autosomal dominant hypophosphatemic rickets (OMIM#193100) (2) and hyperphosphatemic familial tumoral calcinosis (OMIM#211900) (3, 4). The interaction between FGF23 and parathyroid hormone (PTH) in physiology as well as in states of disease is not completely understood. Importantly, we recently showed that FGF23 negatively regulates PTH mRNA expression and protein secretion in vitro (5). High serum FGF23 in chronic kidney disease (CKD) is a predictor of secondary hyperparathyroidism (6), although it is unknown whether increased FGF23 is a cause of, or a protective response to, an emerging hyperparathyroidism. In addition, overexpression of FGF23 in transgenic mice causes secondary hyperparathyroidism (7, 8), which could be due to low calcitriol levels and/or hypocalcemia. Finally, serum FGF23 correlates to PTH in pre-dialysis CKD patients (9, 10), and it was also recently shown that FGF23 and PTH were associated in a subgroup of patients with early CKD (10). However, such an association remains to be established in a larger group of subjects with normal or mild impairment of renal function. The role of FGF23 in CKD has been subject to thorough investigation. Initial reports demonstrated elevated serum FGF23 in CKD, although measurements were performed using an assay detecting both intact, as well as inactive, European Journal of Endocrinology (2008) 158 125–129 ISSN 0804-4643 q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0534 Online version via www.eje-online.org