Postmenopausal women who've had an osteoporotic fracture are usually advised to take an osteoporosis drug. Almost all such medications are antiresorptive — that is, they work by slowing the breakdown phase (resorption) of normal bone turnover. The most widely prescribed antiresorptives are oral bisphosphonates — alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva) — which are taken daily, weekly, or monthly. Bisphosphonates all improve bone mineral density (BMD) and reduce fracture risk, but many women dislike taking them because of side effects, including trouble swallowing, heartburn, and upset stomach. Soon, they may have another option — a new kind of drug taken in a different way.
Results from a large, industry-sponsored controlled trial published Aug. 11, 2009, on the Web site of The New England Journal of Medicine indicate that this drug, called denosumab, significantly reduces the risk of spine, hip, and other fractures (compared with a placebo) in women with osteoporosis. Denosumab targets a protein required for the development and proliferation of osteoclasts, the cells that break down bone. The protein is known as RANKL, for receptor activator of nuclear factor-kappaB ligand. Denosumab counters the activity of RANKL, preventing the formation of osteoclasts. (Bisphosphonates block the activity of osteoclasts but not their formation.)
Researchers with the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months trial randomized 7,868 postmenopausal women with osteoporosis, ages 60 to 90, to denosumab or a placebo taken twice yearly by injection for three years. None of the women were taking other osteoporosis drugs, and all received daily calcium and vitamin D. Spine x-rays were taken yearly to check for vertebral fractures, and reports of other broken bones were confirmed with imaging or a radiologist's report. BMD was measured at the beginning of the trial and then annually at the hip and after 36 months at the lumbar spine. Results showed that vertebral fractures occurred in 2.3% of the women taking denosumab, compared with 7.2% of the placebo group — a 68% reduction. The drug also lowered the risk of hip fracture by 40%.
The rate of serious adverse events was similar in the denosumab and placebo groups. There were no cases of osteonecrosis of the jaw (a problem seen mostly in people taking bisphosphonates who've had complicating health problems), nor were there any unusual thigh fractures, which have been linked to long-term Fosamax use. The problems with bisphosphonates didn't emerge until they had been used for several years, so the researchers are continuing to monitor the denosumab takers for long-term effects.
For reasons that aren't entirely clear, eczema and cellulitis (a serious skin infection) occurred more often in the denosumab takers. RANKL plays a role in the immune system, and there's some concern that inhibiting it might increase the risk of infection and possibly cancer.
There have been no head-to-head fracture-risk trials comparing the various osteoporosis drugs, so it's hard to say exactly how denosumab stacks up. Preliminary evidence suggests that it may be about as effective as the best-performing bisphosphonate, zoledronic acid (Reclast), which is given intravenously once a year to prevent fractures in women with osteoporosis.
Amgen, denosumab's maker and the sponsor of this trial, is seeking FDA approval for the drug to treat or prevent osteoporosis in postmenopausal women. Citing insufficient long-term safety data, an FDA advisory committee has endorsed denosumab only for osteoporosis treatment, not prevention.