The breakthrough fully human monoclonal antibody denosumab (Prolia) received Food and Drug Administration approval for the treatment of postmenopausal osteoporosis following the agency's fast-track review and request for resubmission of data.
The approval is based primarily on the findings of a pivotal phase III clinical trial designed and funded by the drug manufacturer (Amgen), in which denosumab treatment was associated with a reduction in vertebral, nonvertebral, and hip fracture risk in women with osteoporosis.
Specifically, of the 7,808 women with osteoporosis between the ages of 60 and 90 years enrolled in the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, those who were assigned to receive twice yearly injections of 60 mg denosumab for 3 years were 68% less likely to develop a vertebral fracture and 40% less likely to develop a hip fracture than were women in the placebo group. Additionally, significantly increased bone mineral density was observed at all of the key sites measured.
By targeting the receptor activator of nuclear factor-kappaB ligand (RANKL), which is the primary mediator of osteoclast formation, denosumab blocks the production of the bone-destroying osteoclasts and by so doing improves the density, volume, and strength of both cortical and trabecular bone, according to the authors (N. Engl. J. Med. 2009;361:756–65).
Among the side effects reported in the FREEDOM and other clinical trials of denosumab, the most common include back pain, musculoskeletal pain, extremity pain, hypercholesterolemia, and urinary and bladder infections, according to a statement issued by the FDA. Serious adverse reactions include hypercalcemia, dermatologic conditions, and infections.
The significance of the long-term suppression of bone remodeling is unknown, according to a press release issued by Amgen.
“The long-term consequences of the degree of suppression of bone remodeling observed with [denosumab] may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing,” the release stated, warning that patients should be monitored for these adverse outcomes.
The FDA approval of denosumab includes a risk evaluation and mitigation strategy comprising a medication guide for patients and communications to health care providers explaining the risks and benefits of the drug.
The approval of denosumab was delayed in October 2009, when the FDA's Division of Reproductive and Urologic Products issued a Complete Response Letter for the biologics license application for denosumab in the treatment and prevention of postmenopausal osteoporosis, according to Amgen.