Erythropoietin in bone homeostasis-Implications for efficacious anemia therapy

Bone homeostasis and hematopoiesis are irrevocably linked in the hypoxic environment of the bone marrow. Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor, Epor, on erythroid progenitor cells. The continuous process of bone remodeling is achieved by the finely balanced activity of osteoblasts in bone synthesis and osteoclasts in bone resorption. Both osteoblasts and osteoclasts express functional Epors, but the underlying mechanism of Epo-Epor signaling in bone homeostasis is incompletely understood. Two recent publications have provided new insights into the contribution of endogenous Epo to bone homeostasis. Suresh et al examined Epo-Epor signaling in osteoblasts in bone formation in mice and Deshet-Unger et al investigated osteoclastogenesis arising from transdifferentiation of B cells. Both groups also studied bone loss in mice caused by exogenous human recombinant EPO-stimulated erythropoiesis. They found that either deletion of Epor in osteoblasts or conditional knockdown of Epor in B cells attenuates EPO-driven bone loss. These findings have direct clinical implications because patients on long-term treatment for anemia may have an increased risk of bone fractures. Phase 3 trials of small molecule inhibitors of the PHD enzymes (hypoxia inducible factor-prolyl hydroxylase inhibitors [HIF-PHIs]), such as Roxadustat, have shown improved iron metabolism and increased circulating Epo levels in a titratable manner, avoiding the supraphysiologic increases that often accompany intravenous EPO therapy. The new evidence presented by Suresh and Deshet-Unger and their colleagues on the effects of EPO-stimulated erythropoiesis on bone homeostasis seems likely to stimulate discussion on the relative merits and safety of EPO and HIF-PHIs.

Automated summary

Bone homeostasis and hematopoiesis are closely linked in the hypoxic bone marrow environment, with erythropoietin playing a key role in regulating erythropoiesis. Recent studies have shed light on the effects of EPO-stimulated erythropoiesis on bone homeostasis, highlighting potential implications for clinical practice. Further research is needed to better understand the role of Epo-Epor signaling in bone maintenance.