Higher Fibroblast Growth Factor 23 Levels Are Causally Associated With Lower Bone Mineral Density of Heel and Femoral Neck: Evidence From Two-Sample Mendelian Randomization Analysis

Background: Previous observational studies have indicated that high levels of fibroblast growth factor 23 (FGF23), a phosphoric hormone that inhibits calcitriol synthesis, in the blood is associated with the reduced bone mineral density (BMD); however, whether this association is causal remains unclear. In this study, we conducted a Mendelian Random (MR) study to investigate whether the genetic predisposition of higher FGF23 levels was causally associated with lower BMD in adults. Methods: A two-sample MR was performed with five single nucleotide polymorphisms significantly associated with FGF23, selected as instrumental variables. Two-sample MR estimates were derived from summary-level data of large-sample genome-wide association studies for BMD and the levels of bone metabolism characteristics. Results: The two-sample MR analysis showed that for every 1-unit increase in the log-transformed blood FGF23 level (pg/mL), the decreased levels of adult heel BMD (β = −0.201, se = 0.084, P = 0.016) and femoral neck BMD (β = −0.286, se = 0.126, P = 0.022) were noted, indicative of a causal relationship based on the inverse variance weighting method. However, FGF23 levels were not correlated with adult lumbar spine BMD (β = −0.166, se = 0.193, P = 0.389), and forearm BMD (β = −0.186, se = 0.366, P = 0.610). Moreover, the two-sample MR analysis suggested that there was no evidence for associations between FGF23 and adult calcium, phosphorus, 25(OH)D, creatinine, and magnesium levels. Conclusions: This study suggests that there may be a causal relationship between blood FGF23 levels and BMD of the heel and femoral neck in adults; however, more investigations are necessary to determine whether FGF23 may be a potential biomarker and/or therapeutic target for diseases that affect bone mineralization.