Inhibition of osteocyte apoptosis does not prevent iron overload-induced bone resorption and bone loss.

Iron overload leads to apoptosis and increased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in osteocytes, which in turn accelerates osteoclastogenesis. Since osteocytes are the main RANKL producers, we hypothesized that apoptotic osteocytes increase RANKL expression in osteocytes, which in turn stimulates osteoclastogenesis and bone resorption. In this study, alendronate or IG9402, a bisphosphonate (BP) analog which does not inhibit bone resorption, inhibited iron overload-induced osteocyte apoptosis and increased RANKL expression. Both BPs also prevented osteoblast apoptosis but did not inhibit the increase in osteoblastic RANKL. Alendronate, but not IG9402, prevented the increase in osteoclastogenesis and serum levels of the bone resorption marker C-telopeptide of type I collagen (CTX) in iron-overloaded mice. Alendronate also prevented the iron overload-induced reduction in femoral bone mineral density, disruption of bone microstructure, and weakness of bone strength. Although IG9402 did not prevent bone loss due to iron overload, it partially prevented reduction of strength, suggesting that osteocyte viability contributes to the maintenance of bone strength. In conclusion, although osteocyte apoptosis in the presence of iron overload leads to an increase in osteocytic RANKL production. However, blocking these events was not sufficient to inhibit iron overload-induced osteoclastogenesis and bone loss.