A new study appearing in the July 9 issue of Blood discussed a potential therapeutic treatment that focuses on osteoblasts, the cells responsible for bone formation.

Myeloma patients commonly have high serum DKK1 levels, which may decrease with response to therapy for myeloma. DKK1, an important regulator of bone formation, has previously been associated with bone disease in cancers of the esophagus, lungs, prostate, and colon. However, DKK1 has recently emerged as a therapeutic target for suppressed bone formation. The study analyzed the effect of an antibody that neutralizes DKK1, called BHQ880 ^[1], which has been shown to increase bone formation.

Myeloma bone disease, one of the hallmark clinical features of multiple myeloma, is frequently recognized by damaged bone structure and, particularly, by bone lesions. Appearing as “holes” in a standard bone x-ray, bone lesions occur when bone dissolves, often due to the loss of calcium from bone.

Bone destruction in multiple myeloma patients is caused by rapid production of myeloma cells that inhibit bone formation. Likewise, myeloma increases production of osteoclasts, cells that dissolve old bone and work with osteoblasts to repair bone. However, increased osteoclast activity in myeloma results primarily in bone loss since the disease suppresses bone formation. Bisphosphonates, the most common treatment for bone disease, trigger osteoclasts to undergo cell death and inhibit bone loss.

BHQ880, by contrast, focuses on osteoblasts and bone formation. Multiple myeloma cells significantly inhibit maturation of osteoblasts, which are consequently no longer able to properly function. Treatment with BHQ880 reestablishes maturation and restores bone formation.

Maturation of osteoblasts has important consequences for the continued growth of multiple myeloma cells. Immature osteoblasts produce a significant amount of IL-6, one of the key factors that prevent multiple myeloma cells from dying. However, upon maturation of osteoblasts, IL-6 production decreases substantially.

DKK1 also augments production of IL-6. Therefore, although BHQ880 has no direct effect on myeloma cell growth, its connection to DKK1 may indirectly inhibit myeloma cell growth or survival.

The production of DKK1 is also controlled by several novel therapeutic drug agents, including dexamethasone ^[2] (Decadron), thalidomide ^[3](Thalomid), and Revlimid ^[4] (lenalidomide). Treatment with dexamethasone results in a time and dose-dependent increase in production of DKK1. As a result, dexamethasone also inhibits bone formation. It is therefore suggested that concomitant treatments of BHQ880 and dexamethasone may minimize dexamethasone-induced osteoporosis and stimulate bone formation.

For more information about BHQ880, see the article in the July 9 issue of the journal Blood (abstract ^[5]).