Denosumab
October 18, 2010
Denosumab (Prolia) was approved in June 2010 for the treatment of post-menopausal osteoporotic women at high risk for fracture. Denosumab is a fully human monoclonal antibody directed against Receptor Activator for Nuclear Factor κ B Ligand (RANKL); it interferes with the formation, activation and survival of osteoclasts.
The Data
Information on the efficacy and safety of denosumab comes primarily from the FREEDOM trial, a randomized, double-blind, placebo-controlled trial with a primary endpoint of new vertebral fracture at 36 months and preplanned secondary endpoints of times to first nonvertebral fracture and hip fracture (1). The study population included 3886 women treated with denosumab and 3876 women who received placebo. Women with severe osteoporosis (one severe or more than 2 moderate vertebral fractures or a T-score below -4.0) were excluded from the trial because of the ethical concern for exposing this very high-risk group to placebo.
All subjects received vitamin D supplementation and ≥1000 mg of calcium daily. At 3 years, relative to placebo, denosumab led to a 68% reduction in new vertebral fractures, a 40% reduction in hip fractures and a 20% reduction in non-vertebral fractures. In the denosumab group, the increase in bone mineral density over 3 years was 8.8% in the lumbar spine, 6.4% in the hip and 5.2% in the femoral neck. Bone turnover, measured by serum type 1 C-telopeptide (CTx), a marker of bone resorption, was shown to be reduced during the 6-month dosing interval in another trial. The decrease in CTx was attenuated by the end of the dose interval, however, reflecting the reversibility of denosumab’s effect on bone resorption as serum levels decline (2).
Safety
Adverse events in the FREEDOM trial were balanced between the denosumab and the placebo groups. Pre-defined “adverse events of interest” of infection, cancer, hypocalcemia and osteonecrosis of the jaw were evenly distributed between the two groups. Adverse events occurring in at least 2% of subjects and with a significant difference between the groups included eczema (3% in the denosumab group vs. 1.7% in the placebo group), falls that were not associated with fracture (4.5% in the denosumab group and 5.7% in the placebo group) and flatulence (2.2% in the denosumab group and 1.4% in the placebo group). Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with denosumab (4% vs. <0.1% in the placebo group); these infections were not always at the site of injection. The overall incidence of infections, including opportunistic infections, was similar between the treatment groups. As with any therapy targeting components of the immune system, there is a theoretical risk of increased infection; of note, in clinical trials of patients with advanced malignancies, therapy with denosumab did not appear to increase the prevalence of infections (3).
RANKL is a member of the TNF super family. The use of denosumab in patients taking other DMARDs or biologics, including other medications directed against this family of proteins, has only been studied in a limited manner (4), so there is no available information to guide the timing of denosumab administration relative to other agents.
Practical Considerations
Denosumab is administered as a 60 mg subcutaneous injection every 6 months in by a healthcare professional. The wholesale cost of a single injection is $825. For commercially insured patients, access may be through either medical or pharmacy benefits; for Medicare patients it is a part B covered service, requiring purchase of the drug by the physician’s office.
The Bottom Line
Denosumab, a monoclonal antibody directed against RANKL, is the first in a new class of anti-resorptive agents for the treatment of post-menopausal women with osteoporosis at high risk of fracture.
- Denosumab is approved for first-line therapy in this population.
- Patients at highest risk for fracture were excluded from the Phase 3 trial, and so there are no data on the efficacy of denosumab in this group.
- Denosumab is the first anti-resorptive agent shown to be safe and effective in patients with renal impairment. Based on data referenced in the package insert, it has been suggested that denosumab may be safely used in patients with impaired renal function or on dialysis; these patients should be monitored for hypocalcemia.
- No dose adjustment is necessary in patients with renal insufficiency, but monitoring of calcium, phosphorus, and magnesium is highly recommended in patients with severe renal impairment.
- In patients who develop a serious infection while taking denosumab, the benefits of continued therapy should be weighed against the risks.
- The "Medication Guide for Patients" lists the most common adverse reactions as back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia and cystitis.
References
- Cummings SR et al, N Engl J Med. 2009; 361: 756-765.
- McClung MR et al. N Engl J Med. 2006; 354: 821-831
- Fizazi K et al. J Urol. 2009; 182: 509-516.
- Dore RK et al., Ann Rheum Dis. 2010; 69: 872-875.
Hotline Author: Robin K. Dore, MD
Disclosure: Dr. Dore has disclosed the following information relevant to potential conflicts of interest regarding the material in the ACR Hotline. Dr. Dore is a paid consultant, on the speakers’ bureau and has performed clinical trials for Amgen, the manufacturer of Prolia (denosumab).
Hotline Editors: Arthur Kavanaugh, MD and Eric Ruderman, MD
Disclosures: Dr. Kavanaugh has served as an investigator on clinical trials of denosumab. Dr. Ruderman has nothing to disclose.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the author(s) and does not represent a position statement of the American College of Rheumatology.
