Re-thinking the bone remodeling cycle mechanism and the origin of bone loss.

Proper bone remodeling necessarily requires that osteoblasts reconstruct the bone that osteoclasts have resorbed. However, the cellular events connecting resorption to reconstruction have remained poorly known. The consequence is a fragmentary understanding of the remodeling cycle where only the resorption and formation steps are taken into account. New tools have recently made possible to elucidate how resorption shifts to formation, thereby allowing to comprehend the remodeling cycle as a whole. This new knowledge is reviewed herein. It shows how teams of osteoclasts and osteoblast lineage cells are progressively established and how they are subjected therein to reciprocal interactions. Contrary to the common view, osteoclasts and osteoprogenitors are intermingled on the eroded surfaces. The analysis of the resorption and cell population dynamics shows that osteoprogenitor cell expansion and resorption proceed as an integrated mechanism; that a threshold cell density of osteoprogenitors on the eroded surface is mandatory for onset of bone formation; that the cell initiating osteoprogenitor cell expansion is the osteoclast; and that the osteoclast therefore triggers putative osteoprogenitor reservoirs positioned at proximity of the eroded bone surface (bone lining cells, canopy cells, pericytes). The interplay between magnitude of resorption and rate of cell expansion governs how soon bone reconstruction is initiated and may determine uncoupling and permanent bone loss if a threshold cell density is not reached. The clinical perspectives opened by these findings are discussed.