Osteoclast function in Pagetʹs disease and multiple myeloma

Pagetʹs disease of bone and multiple myeloma are characterized by increased numbers of osteoclasts and markedly increased bone resorption at the sites of the disease. In Pagetʹs disease the osteoclasts are abnormal morphologically and contain viral-like nuclear inclusions, but in multiple myeloma the osteoclasts are normal. The bone lesions in both Pagetʹs disease and multiple myeloma appear to be due to local stimulation of osteoclast formation and bone resorption. In situ hybridization techniques, bone marrow cultures, and cytokine assays have been used to examine osteoclast function in Pagetʹs disease and multiple myeloma. Interleukin-6 (IL-6) has been implicated as a potential mediator for the increased osteoclast activity in both diseases. In Pagetʹs disease, IL-6 is produced by the osteoclasts, the osteoclasts express IL-6 receptors and IL-6 mRNA, and increased levels of IL-6 are present in the marrow plasma and serum of these patients. Similarly, increased levels of IL-6 have been detected in sera from some patients with multiple myeloma. Multiple myeloma cells do not produce IL-6 in vivo but marrow stromal cells or the osteoclasts may be the source of IL-6 in multiple myeloma. IL-6 is a growth factor for multiple myeloma cells, and treating patients with anti-IL-6 decreases the tumor burden in some patients. Thus, IL-6 may be an autocrine/paracrine factor in both Pagetʹs disease and in multiple myeloma. Multiple myeloma cells also produce osteoclast activating factors (OAFs) that can stimulate osteoclast formation and activity. In vitro studies have suggested IL-1, TNF-α, and lymphotoxin as potential OAFs, but the identity of the OAF produced by multiple myeloma cells in vivo remains uncertain. Thus, osteoclast function is markedly enhanced in Pagetʹs disease and multiple myeloma, but the basis for the increased osteoclast activity remains to be clearly defined.