FDA committee vote: Denosumab benefits outweigh risks for postmenopausal osteoporosis

The FDA Advisory Committee for Reproductive Health Drugs voted unanimously that the benefit of denosumab treatment — an investigational fully human monoclonal antibody that targets RANK Ligand — likely outweighs the risk in various populations.

However, the committee did not recommend denosumab (AMG 162, Amgen Inc.) for preventive use in postmenopausal osteoporosis (12-3) until more long-term data are available. The general consensus was that denosumab should be limited to a high-risk subgroup of women with a history of fracture and patients who have failed or are intolerant to other therapeutic measures.

“This is a unique therapy and beneficial in women who do not tolerate other therapies,” Julia V. Johnson, MD, vice chair of gynecology in the department of obstetrics and gynecology at the University of Vermont/ Fletcher Allen Health Care, said during the meeting.

“Although the treatment may be effective, it is related to unknown risks that may not make the benefit of prevention worthwhile,” added Sanda Carson, MD, chair of the committee and professor of obstetrics and gynecology at Warren Alpert Medical School of Brown University.

“We know that when this drug stops, bone mineral density does plummet,” she said. “However, we are talking about long-term use here and we better be convinced of its safety.”

Other safety issues identified in clinical trials include occurrence of serious infection, development of new malignancies and potential for tumor progression in patients with cancer. In addition, data on histomorphometry suggest suppression of bone remodeling, which may lead to delayed fracture healing or atypical fracture with long-term use and dermatologic adverse events.

Committee members reviewed data from 30 studies that included more than 30,000 patients exposed to denosumab for about 5 years.

“Compared to some other drugs used for treatment of chronic diseases, the choices for treatment of osteoporosis have been limited,” said John D. Kaufman, MD, Musculoskelal Oncology & Metabolic Bone Disease section editor for Orthopedics Today. “Patients intolerant to bisphosphonates have few options. Either raloxifene or teriparatide may not be suitable for the patient with moderate osteoporosis or moderate fracture risk. Denosumab gives us a new alternative with a drug from an entirely new class.

“The fact that the drug is given every 6 months by sub Q injection is going to be well accepted by most patients and will help monitor compliance,” he added. “So far, the studies look good and the drug seems to have an excellent benefit/risk ratio. It should be a valuable addition to the present osteoporosis drug options.”

Elton Strauss, MD, an orthopedic surgeon from Mount Sinai Medical School in New York, remained more cautious.

“It may be utopia up front, but we do not know what long-term use complications it may bring,” he told Orthopedics Today. “It will pass, but we should keep an eye on it.”

The FDA is scheduled to make a decision about denosumab in October.