High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort

Abstract

Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean AE SD EPO was 11.5 AE 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = −0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray-verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35-1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08-1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00-2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function.

Effects of Erythropoietin in White Adipose Tissue and Bone Microenvironment

“…Consistent with EPO promoting bone healing in animal models of fracture, a pilot study in 60 patients with tibiofibular factures who received either EPO or saline showed patients in the EPO receiving arm having faster union rates by a couple of weeks and reduced nonunion fracture (Bakhshi et al, 2013). However, in a recent study, high EPO level was also associated with higher fracture risk independent of hemoglobin and age in elderly Swedish men (Kristjansdottir et al, 2020), suggesting that, as observed in mice, EPO may also affect bone homeostasis, and chronic EPO treatment may impact on bone health. EPO stimulated FGF23 production in mouse and human, increasing serum FGF23 and reducing serum phosphate, and may contribute to elevated FGF23 in chronic kidney disease patients receiving EPO (Clinkenbeard et al, 2017).…”

Erythropoietin signaling in osteoblasts is required for normal bone formation and for bone loss during erythropoietin‐stimulated erythropoiesis

“…We previously showed that absence of EPO signaling in non‐erythroid cells results in reduced trabecular bone in male and female mice 5 . In elderly men in Sweden with normal renal function, high plasma EPO associated with higher incidence of fracture risk 17 . Here, we assessed the effect of endogenous EPO signaling specifically on bone forming osteoblasts using Tg mice with targeted deletion of Epor in osteoblasts.…”

High platelet count is associated with low bone mineral density: The MrOS Sweden cohort

“…Serum and plasma samples were frozen within 1 h, and stored at − 80°C until required for analysis. Methods regarding concentrations of EPO, iFGF23, serotonin, osteocalcin, N-terminal propeptide of type I collagen (P1NP), iron, ferritin, total iron-binding capacity (TIBC), 25(OH)D, ALP, C-reactive protein (CRP), intact parathyroid hormone (iPTH), estradiol, estimated glomerular filtration rate (eGFR), and calculation using a cystatin C-based formula have previously been described [18][19][20][21][22][23][24][25]. Iron deficiency was defined as ferritin < 20 μg/L or transferrin saturation < 15%.…”