Response to bortezomib and activation of osteoblasts in multiple myeloma.

Histomorphometry and biochemical markers of bone turnover have shown that, although osteoclast activity is increased in multiple myeloma (MM), mostly through the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin axis, the key element in vivo to determine the presence or absence of osteolytic lesions resides on the presence and activity of osteoblasts. The loss of bone observed in MM is the result of an uncoupling of bone formation and bone resorption. Bortezomib is a first-in-class proteasome inhibitor developed as an antineoplastic agent with marked activity in relapsed/refractory MM. Response to bortezomib has been related to a significant increase in alkaline phosphatase (ALP). Increased ALP in patients responding to bortezomib was associated with a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in MM is closely associated with osteoblastic activation. Variation in markers of osteoblastic activation (such as ALP) have also predicted response and response duration in patients with myeloma treated with bortezomib (P < 0.0001). This clinical observation has been confirmed in an experimental mouse model for primary human myeloma. The consequences of increased bone anabolism on myeloma growth need to be closely evaluated in prospective trials.