Bisphosphonates Remain Mainstays in Managing Bone Disease: Development of New Agents Is Continuing

G. David Roodman, MD, PhD

Although several types of cancer involve the bone, patients with multiple myeloma (MM) are at the highest risk of developing complications. Between 80% and 90% of patients with MM develop osteolytic bone lesions that can result in debilitating bone pain and fractures, and approximately 60% experience a bone fracture at some point during their lifetime.

As it stands now, intravenous bisphosphonates, particularly zoledronic acid (Zometa), remain the preferred bone-targeting therapy for patients with MM, while several promising new agents are in development.

Researchers have identified more than a dozen pathways and factors involving bone disease in MM. Some pathways promote osteoclasts—bone cells that cause resorption, a process whereby bones break down and cells move from the bone to the bloodstream—while others suppress osteoblasts, the cells needed for the formation of bone.

“You have multiple factors at work,” said G. David Roodman, MD, PhD, director of the Division of Hematology/ Oncology and a professor of Medicine at the Indiana University School of Medicine in Indianapolis, in an interview. “It’s a purely destructive process.”

Roodman said that patients with MM who experience a fracture due to bone disease have a 20% increased mortality risk, and that managing bone health issues in these patients costs approximately $50,000 per patient over the course of treatment in addition to what is spent to manage a patient’s myeloma.

Although lifestyle modifications and surgical interventions are helpful, intravenous bisphosphonates have been shown to inhibit osteoclast activity and markedly reduce the incidence of skeletal-related events (SREs), Roodman noted in an article in the American Society of Clinical Oncology Educational Book (Spring 2011; 316-319).

ASCO guidelines call for starting bisphosphonate therapy in patients with MM when evidence of bone involvement is detected on plain radiographs or imaging studies. The guidelines suggest either intravenous pamidronate 90 mg administered over at least two hours or zoledronic acid 4 mg delivered over at least 15 minutes every three to four weeks (J Clin Oncol. 2007;25(17):2464-2472).

“The major benefit of zoledronic acid over pamidronate is that it can be administered over a shorter period of time,” Roodman said in his article.

The National Comprehensive Cancer Network (NCCN) guidelines include a category 1 recommendation, the highest level, for administering bisphosphonates to all patients receiving primary therapy for MM.

The NCCN said clinical trial results show zoledronic acid is equivalent to pamidronate in reducing the risk of SREs but superior to another bisphosphonate, clodronic acid, in reducing mortality and extending median overall survival. In addition, zoledronic acid is the preferred agent to treat hypercalcemia.

Despite the effectiveness of bisphosphonates, SREs are still possible, and there are a number of serious adverse events associated with the use of these drugs, including renal failure and osteonecrosis of the jaw (ONJ). However, Roodman said that through proper monitoring, ONJ has not been as serious an issue among patients as it once was.

Among the agents in development for MM is denosumab (Xgeva), a RANK ligand inhibitor the FDA has approved for the prevention of SREs in patients with bone metastases from solid tumors (but not MM). An ongoing phase III trial is evaluating the efficacy of denosumab compared with zoledronic acid in patients with MM and other forms of advanced cancer.

Kenneth C. Anderson, MD

“This drug could provide a solution for treating multiple myeloma patients with renal failure, since the risk is lower when using denosumab,” said Kenneth C. Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute in Boston, Massachusetts.

Anderson also pointed to several new other therapies designed to specifically address bone disease in patients with MM in the earliest phases of testing. Novartis Oncology is developing BHQ880, a fully human antibody that targets dickkopf-1 (DKK-1). DKK-1 is an antagonist of the Wnt pathway, which aids in the development of osteoblasts. BHQ880 is currently in phase I/II trials.

“This drug has the potential to restore bone formation in patients with multiple myeloma,” Anderson said.

Eli Lilly and Company is working on tabalumab (LY2127399), a human monoclonal antibody that inhibits B-cell activating factor (BAFF), a protein associated with cell growth in the development of MM and the interruption of the formation of osteoblasts. The agent is under investigation in combination with bortezomib in relapsed or refractory MM.

Roodman said that any new therapies would not be a cure-all. He noted that in addition to bone-targeted therapies, patients should be advised to keep up with their bone health through supplements and everyday activity that can aid in the production of vitamin D and calcium.

For his part, Anderson is optimistic about the prospect for advances in managing bone complications in MM.

“This is the furthest we’ve ever been in terms of treating bone health in these patients,” he said. “We’re seeing patients living longer and experiencing a higher quality of life.”