Erythropoietin-Induced Bone Loss Is Driven By an M-CSF Surge in the Bone Marrow As Assessed By Time-Course Studies in a Murine Model

Bone tissue constantly undergoes a process of remodeling that simultaneously involves bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclasts are multinuclear cells that originate primarily from myeloid precursors, while macrophage colony-stimulating factor (M-CSF) is essential for their survival and differentiation. Osteoblasts originate from mesenchymal cells and differentiate into osteocytes (mineralized bone resident cells). The balance between bone resorption and bone formation determines changes in bone mass.

A wide variety of therapeutic interventions can affect bone metabolism. Erythropoietin (EPO), a primary regulator of red cell lineage, is commonly used in the clinic to treat anemia in certain clinical conditions and is sometimes administered to non-anemic patients before surgery to reduce the need for perioperative blood transfusion. We have previously shown that multidose (2-week) exposure to EPO significantly reduces bone mass in mice.

In this study, we explored the dynamics of the response to a single high-dose EPO treatment in bone and bone marrow (BM) microenvironment in mice. Bone parameters were examined at four time points (16 hours, 48 hours, 1 week, and 2 weeks) following a single EPO injection (180 U) in young (9 weeks) female mice. We found that this single dose of EPO led to a 32% decrease in bone volume/total volume (BV/TV) in the distal femur within 1 week, as assessed by µCT analysis. Serum M-CSF levels increased by 180% 16 hours after EPO administration. This increase was accompanied by a 2-fold increase in soluble M-CSF in the BM extracellular matrix, which returned to baseline levels 48 hours after EPO administration. M-CSF-receptor (CD115) positive cells in the BM increased by 32% and 39% 48 hours and 1 week following EPO injection, respectively. Osteoclast precursor cells (Lin− CD11b− Ly6Chi CD115+) increased by 32%, 32% and 46%, two days, 1 week and 2 weeks after EPO injection, respectively. In line with these findings, serum levels of tartrate resistance acid phosphatase 5b (TRAP5b), a marker of bone-resorbing osteoclasts, increased in EPO-treated mice by ~20% 1 week after EPO injection, compared to diluent injected controls. Bone formation was also significantly affected by EPO treatment, as reflected by a ~80% decrease in procollagen type I N-terminal propeptide (P1NP) within 48 hours after EPO injection and returned to baseline one-week post-treatment.

This study sheds light on the dynamic bone response to EPO, showing for the first time that even a single dose of EPO may have significant implications for bone metabolism. These findings are highly relevant in the case of EPO administration to non-anemic patients before surgery for potential avoidance of allogeneic transfusions.

No relevant conflicts of interest to declare.