Proposed pathways of sickle cell bone disease in mice. Hemoglobin SS mice display increased osteoclast activity and reduced osteoblastogenesis, resulting in reduced osteoid formation compared with hemoglobin AA mice. Hypoxia/reoxygenation stress depresses osteoblastogenesis and increases osteoclast activity, promoting bone impairment. Recurrent stress further worsens the imbalance between osteoblastogenesis and osteoclastogenesis, resulting in bone loss and severe bone impairment. Zoledronic acid blocks osteoclast activity and osteoclastogenesis and is associated with increased osteoblast recruitment and osteoblastogenesis, preventing sickle bone disease. H/R, hypoxia reoxygenation stress; MSCs, mesenchymal stem cells. See Figure 6 in the article by Dalle Carbonare et al on page 2320.