Multiple myeloma is the most frequent cancer to involve the skeleton, with up to 80 percent of patients having bone disease. Although fewer patients appear to have bone involvement more recently, it is still a major source of both complications and death among patients with myeloma.

Bone disease is so severe in myeloma because the normal bone remodeling process is disrupted. In normal individuals, damaged bone is removed by bone-destroying cells, the osteoclasts, and then bone is replaced by bone-forming cells, the osteoblasts. In myeloma, the number and activity of the bone-destroying cells are increased, while the bone-building cells are decreased in number or nonexistent in areas affected with myeloma cells.

This bone destruction results in severe bone pain, pathologic fractures, and high calcium levels. It can require surgery and radiotherapy to bone. Bisphosphonates can also be used to impair the activity and formation of bone-destroying cells. The bisphosphonates Aredia ^[1] (pamidronate) and Zometa ^[2] (zoledronic acid) are the mainstay of treatment of myeloma bone disease.

The importance of bone involvement in myeloma has been highlighted by the recent results from the MRC Myeloma IX trial from England. In this clinical trial, almost 2,000 myeloma patients were treated with Zometa or a weaker bisphosphonate in addition to chemotherapy.

The results of this trial showed that targeting the bone with Zometa as part of treatment significantly improved survival of patients with myeloma. These results show that preventing and treating myeloma bone disease has beneficial effects beyond just controlling bone pain and preventing fractures; it also increases survival.

As myeloma becomes a chronic disease or a curable disease, reversing the bone destruction in myeloma will become even more important. This is because areas of bone affected by myeloma rarely fill in with new bone but fill in with fibrous tissue. This lack of bone healing occurs even though the myeloma cells may not be present in the bone for many years. Once bones become thin, patients will continue to be at risk for fracture.

Recent research has identified several factors that may be responsible for blocking new bone formation. These include DKK-1 and Activin A, which are produced or induced by myeloma cells in the bone marrow and inhibit development of osteoblast precursors to mature bone-building cells. Treatments to block DKK-1 or Activin A in myeloma have been developed and now are in clinical trial.

An antibody called BHQ880 ^[3] is one of the promising bone disease treatments under clinical development.  It targets DKK-1 and helps to restore bone formation.  Several ongoing Phase 2 studies are investigating the effect BHQ880, alone or in combination with Zometa, has on myeloma bone disease.

Another promising treatment being studied is called ACE-011 ^[4] (sotatercept ^[5]), which blocks Activin A.  Preclinical studies have demonstrated that it prevents the development of myeloma bone lesions in mice. A Phase 2 clinical trial is ongoing to determine the effects of blocking Activin A in myeloma patients with bone disease receiving melphalan ^[6] (Alkeran), thalidomide ^[7] (Thalomid), and prednisone ^[8].

In addition, a new inhibitor of bone destruction, Xgeva ^[9] (denosumab), has been approved for the treatment of bone disease in solid tumors and is being studied in clinical trials involving myeloma patients.  Xgeva blocks formation and survival of osteoclasts that break down bone.  Studies indicate that Xgeva may be at least as effective as Zometa.

Further, newer treatments for myeloma, such as Velcade ^[10] (bortezomib), can also stimulate new bone formation, although the increase in bone formation is only transient, rather than permanent, in most patients.

Studies in mice have shown that Forteo (parathyroid hormone), which is used to treat bone disease in patients with osteoporosis, may be safe for patients with myeloma. Clinical trials will have to determine whether this is the case.

Hopefully in the next several years, we will have agents that will help build bone in myeloma patients as we control their myeloma.

Major questions still remain, though, for treating bone disease in myeloma. Should all patients receive Zometa, regardless of whether they have bone disease? How often and how long should patients be treated with Zometa or other bisphosphonates? These and other important issues are ongoing areas of research.

Dr. David Roodman is director of the Multiple Myeloma Center at the University of Pittsburgh Cancer Institute and director of the Center for Bone Biology at the University of Pittsburgh Medical Center.  His research focuses on multiple myeloma and Paget’s disease. Dr. Roodman writes a quarterly column for The Myeloma Beacon.