Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability

Abstract

Bisphosphonates stop bone loss by inhibiting the activity of bone-resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This prosurvival effect is strictly dependent on the expression of connexin (Cx) 43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant-negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90(RSK) kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The antiapoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack antiresorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone-forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anticatabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired.