Proposed model of the effect of imatinib mesylate on bone remodeling. Imatinib suppresses osteoclast differentiation and function through inhibition of c-Fms, resulting in a decrease in dissolution of calcium and phosphate from bone. Concomitantly, imatinib promotes osteoblast function through inhibition of PDGF-R, resulting in de novo bone formation. Sequestration of calcium and phosphate to bone results in a net decrease in extracellular calcium and phosphate, which in turn stimulates a compensatory increase in parathyroid hormone (PTH) release. PTH liberates calcium and phosphate from bone by stimulating osteoclast activity. This process is potentially suppressed by imatinib. PTH also balances extracellular calcium and phosphate levels, resulting in a decrease in renal phosphate absorption. This decrease further depletes serum phosphate levels, leading to hypophosphatemia. Shaded boxes represent processes that have been confirmed in vivo and include observations made in previous studies.^15,16