Molecular Basis of Metastasis

n engl j med 360;16 nejm.org april 16, 2009 1678 after treatment with nitrogen-containing bisphosphonates. Our data indicate that although the number of normal-appearing osteoclasts is significantly increased in patients receiving bisphosphonate therapy, as compared with those receiving placebo, the decrease in biochemical markers and increase in bone density suggest that even normal-appearing osteoclasts may resorb bone poorly. Jobke’s micrograph of an osteoclast in a shallow resorption lacuna could represent a cell that has just begun to erode or one that has no current resorptive capability at all. Only in diseases involving very high rates of bone turnover can the rate of resorption be revealed by means of dynamic histomorphometry. For example, in Paget’s disease, direct measurement of the rate of bone erosion in individual osteoclasts is possible when pagetic osteoclasts bore through the double-tetracyclinelabeled cancellous perimeter while excavating a cavity. From the mean depth of the erosion cavity, dates of tetracycline administration, and time of the biopsy procedure, the minimum initial rate of bone erosion can be calculated in micrometers per day just as precisely as the mineral appositional rate.2 Such an opportunity did not arise in our study. We believe that Roos and Cox have misunderstood our statements about the production of multinuclear osteoclasts by the fusion of mononuclear precursors to form polykaryons. We did not suggest that this fusion occurred between existing multinuclear osteoclasts. Considerable evidence indicates that osteoclasts are formed by fusion of mononuclear precursors. These findings are from studies that use quail–chick chimeras with some osteoclasts containing nuclei with morphologic features of both quail and chicks,3 as well as from experiments using 3H-thymidine and autoradiography to show that osteoclasts form by the fusion of mononuclear precursors,4,5 not by nuclear replication. The fate of all cells that originate in the hematopoietic environment is to leave, do their work, and die. Finally, it is highly unlikely that the apoptotic nuclei in the giant osteoclasts that we described could divide.