Research News

Vertebral fractures in men receiving androgen-deprivation therapy for prostate cancer are associated with pain, loss of mobility, and decreased survival.

Landmark bone study addresses debilitating side effect of prostate cancer treatment

05/Jan/2010

Vertebral fractures in men receiving androgen-deprivation therapy for prostate cancer are associated with pain, loss of mobility, and decreased survival.

Did you know

33%: The approximate percentage of the 2 million prostate cancer survivors in the United States who receive androgen-deprivation therapy

In recent decades, the management of prostate cancer has changed dramatically. The broad use of screening allows physicians to identify men with early-stage disease and intervene earlier. Androgendeprivation therapy, now the standard treatment for men with locally advanced, recurrent, and metastatic prostate cancer, has contributed to improved cancer outcomes. However, with this form of hormone therapy prostate cancer survivors face increased challenges to quality of life.

Currently, about one-third of the 2 million prostate cancer survivors in the United States receive androgen-eprivation therapy. It has improved outcomes, but not without some adverse physiological effects. One key side effect is the deterioration of bone density, and the greater risk for osteoporosis and debilitating bone fractures.

These fractures can have serious consequences for a patient’s quality of life. In the case of vertebral fractures, a patient may experience pain, loss of height, and spinal curvature. In severe cases, vertebral fractures can impair respiratory function. In addition, vertebral fractures are linked to major fractures at other sites, such as the hip, which can affect mobility and mortality. Although these problems have become well-recognized in recent years, there has been little information about how best to prevent fracture in men with prostate cancer. Research on osteoporosis and bone fractures has, until recently, focused primarily on women. With the lack of large, adequately designed fracture-prevention studies in men, and little evidence that bisphosphonates, the standard treatment for women, are effective in men, these patients have had few treatment options.

Denosumab, a new targeted therapy to stop bone loss, increase bone density, and prevent spinal fractures in men being treated for prostate cancer, has shown promising results. International studies on the drug are being led by Matthew R. Smith, MD, PhD, of the Massachusetts General Hospital Cancer Center, as part of the Denosumab Hormone Ablation Bone Loss Trial prostate cancer study group.

Denosumab-Novel RANKL targeted therapy

In 2004, researchers at the Massachusetts General Hospital Cancer Center spearheaded a trial of a new agent, denosumab, to prevent bone loss and fractures in prostate cancer patients. Denosumab is a monoclonal antibody against the receptor activator of the nuclear factor-kappaB ligand, or RANKL.

The biologic utilizes the basic processes of bone remodeling, in which new bone is formed and old bone is resorbed. This allows the skeleton to maintain its strength.

Receptor Activator of Nuclear Factor kB Ligand (RANKL): Control of Bone Remodeling

There are two types of cells that govern the process of bone remodeling:

  • Osteoblasts, which form new bone
  • Osteoclasts, which break down old bone

In normal states, the two types of cells work in tandem to maintain the proper balance of bone formation and breakdown. But in pathological states, osteoclast activity is excessive, resulting in net bone loss and impaired bone strength over time. Signaling from osteoblasts—the bone builders—is key to the process of excessive activity from their osteoclast counterparts. The signaling, or communication, from the osteoblasts to the osteoclasts is mediated by RANKL. In other words, RANKL is the critical regulator of osteoclast recruitment, differentiation, and survival.

Denosumab is a human monoclonal antibody that specifically binds and inactivates RANKL, and it is the first RANKL-targeted therapy in clinical development. This mechanism of action is distinct from that of existing bone-targeted drugs. Recent clinical research in a variety of settings suggests that denosumab is more potent than existing bone-targeted drugs, including bisphosphonates.

Major journal publishes study

Led by Matthew R. Smith, MD, PhD, director of the Claire and John Bertucci Center for Genitourinary Cancers, researchers developed a landmark study called the Denosumab Hormone Ablation Bone Loss Trial (HALT). In the trial, denosumab was administered twice yearly subcutaneously at a 60 mg dose. The trial, which included 1,468 men receiving androgen-deprivation therapy, found that denosumab robustly increases bone density, a predictor of fracture risk, and reduces new vertebral fracture. Results were published in the August 20, 2009, issue of the New England Journal of Medicine. Specifically, the drug reduced the risk for new spinal fractures by 62 percent in men receiving androgendeprivation therapy. The magnitude of benefit in this high-risk population of men was comparable to the benefit of any agent for osteoporosis in women.

In late August 2009, an FDA advisory committee recommended approval of denosumab for prevention and treatment of bone loss in patients undergoing hormone ablation in either prostate cancer or breast cancer, as well as for the prevention and treatment of postmenopausal osteoporosis. FDA approval of denosumab is expected in 2010.

Ongoing investigations

Physician-scientists at the Massachusetts General Hospital Cancer Center continue to investigate denosumab in other areas of unmet medical need. One ongoing study is testing the agent to prevent bone metastases in men with high-risk prostate cancer. Designed and led by Dr. Smith, this global trial is completely accrued, with results expected in 2010.

In addition, another trial is investigating the drug to prevent complications of bone metastases in men with prostate cancer. This is a head-to-head trial comparing denosumab with other agents. It also is fully accrued, and researchers plan to report their findings in early 2010.

Key Points

  • Androgen-deprivation therapy, commonly used after primary treatment for prostate cancer, is associated with bone loss and fracture risk in men.
  • Without adequate data, clinicians interested in preventing bone loss in men receiving androgen-deprivation therapy have had to extrapolate from research conducted in women. RANKL is a key mediator of osteoclasts, the cells that break down bone.
  • Denosumab is a monoclonal antibody that binds to the receptor activator of nuclear factor RANKL, limiting excessive osteoclast activity.
  • A multicenter, randomized, double-blind, placebo-controlled trial, published in the New England Journal of Medicine, found that denosumab increased bone mineral density and reduced spinal fractures in men receiving androgen-deprivation therapy.
  • This is the first major study to investigate bone loss in this population of men.
  • At press time, an FDA advisory committee recommended approval of denosumab for prevention and treatment of bone loss in patients undergoing hormone ablation in either prostate cancer or breast cancer, as well as for the prevention and treatment of postmenopausal osteoporosis.
  • More research is under way studying denosumab as an agent to prevent bone metastases in men with high-risk prostate cancer.

Selected references

  • Smith M, Egerdie B, Toriz N, Feldman R, Tammela T, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder B, Goessl C. (2009). Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med, 361(8):745-55.
  • Gralow J, Biermann J, Farooki A, Fornier M, Gagel R, Kumar R, Shapiro, C, Shields A, Smith R, Srinivas S, Van Poznak C. (2009). NCCN task force report: bone health in cancer care. J Natl Compr Canc Netw, 7(3):S1-S32.
  • Michaelson M, Kaufman D, Lee H, McGovern F, Kantoff P, Fallon M, Finkelstein J, Smith M. (2007). Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol, 25(9):1038-42.

Contributor

Matthew R. Smith, MD, PhD

  • Director of the Claire and John Bertucci Center for Genitourinary Cancers, The Massachusetts General Hospital Cancer Center
  • Associate Professor of Medicine, Harvard Medical School
  • Contact Information:
    mrsmith@partners.org
    617-724-5257

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