Inhibition of osteoclast function abolishes Epo-induced bone remodeling and blunts the erythroid response to Epo. (A) Percentage of bone volume per total volume (BV/TV) as measured by μCT analysis of tibias from mice treated with PBS (P) or osteoclast-inhibiting ZA (Z) before PBS and Epo (E) treatment, respectively. (B) Number of cells per femur and (C) spleen weight of the same mice as in panel A. (D) B-lymphopoiesis as analyzed by FACS. (E-H) Quantification of the peripheral (E) RBC, (F) hemoglobin, (G) hematocrit, and (H) mean cellular volume (MCV), in ZA-treated mice. Data are mean ± SEM; n = 5 per treatment. (I) A mechanistic figure illustrating that: (1) Epo directly stimulates early erythroblasts in the BM to induce an erythroid response; (2) Epo treatment indirectly results in an osteoclast-dependent decrease of trabecular bone and increased bone remodeling; and (3) Epo treatment impairs B-cell development through unknown actions of Epo-responsive erythroblast in the BM microenvironment.