Schematic diagram of development of sickle cell bone disease (SBD) in mice. SCD mice display increased osteoclast activity and reduced osteoblastogenesis, resulting in reduced osteoid formation compared with healthy mice. H/R stress depresses osteoblastogenesis and increases osteoclast activity and osteoclastogenesis, promoting bone impairment. Recurrent H/R stresses further worsen the imbalance between osteoblastogenesis and osteoclastogenesis/osteoclast activity, resulting in bone loss and severe bone impairment. Zoledronic acid (Zol) blocks osteoclast activity and osteoclastogenesis and is associated with increased osteoblast recruitment and osteoblastogenesis, preventing the development of SBD. AA, healthy mice; H/R, hypoxia reoxygenation stress; MSCs, mesenchymal stem cells; SS, sickle cell disease.