C onsidering the special relation of human multiple myeloma (MM) to bones, it is of importance to clarify the early steps of bone involvement in this disease. In this work, using bone histomorphometry (including histoenzymologic and kinetic studies for the first time), we have evaluated the bone remodeling (i.e., bone resorption and bone formation rates) of 16 individuals with early MM in comparison with that of 10 with benign monoclonal gammopathy (BMG) and that of 17 patients with previously untreated overt MM. A significantly increased osteoblastic recruitment was observed in the individuals with early MM when compared with those with BMG (P less than 0.01). A significant (P less than 0.01) increased bone resorption (i.e., eroded surfaces, osteoclast numbers and surfaces) was observed from the early stage of MM in comparison with the BMG status where bone resorption remained within the normal range. At the tissue level, there was no difference in terms of bone resorption between early and overt MM. On the other hand, osteoblast activity was significantly reduced in patients with overt MM (P less than 0.05 by comparison with those with early MM). A significant enhancement of osteoblastic recruitment with an increased generation of new osteoclasts is an early critical event in the pathogenesis of human MM. Of particular importance is the early stimulation of osteoblasts, since these cells produce high amounts of IL-6, a potent myeloma cell growth factor and a critical cytokine for the formation of osteoclasts in the bone marrow.