Pharmacology Update
Denosumab Injection (Prolia)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The first receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor has been approved for the treatment of osteoporosis. RANKL is a cytokine essential for the function of osteoclasts. Inhibiting RANKL inhibits osteoclast formation, function, and survival, thereby reducing bone turnover. Denosumab is a human IgG2 monoclonal antibody that binds to RANKL. It is marketed by Amgen as Prolia.
Indications
Denosumab is approved for the treatment of postmenopausal women with osteoporosis at high risk for fractures.1 These include patients with a history of fractures or multiple risk factors for fractures, or those who have failed or are intolerant to available therapy.1
Dosage
The recommended dose is 60 mg given subcutaneously every 6 months. The injection sites should be upper arm, upper thigh, or abdomen. Patients should take 1000 mg of calcium and at least 400 IU of vitamin D daily.1
Denosumab is available as a 60 mg single-use prefilled syringe or single-use vial.
Potential Advantages
Denosumab inhibits bone resorption by blocking the formation of osteoclasts. This is a different mechanism of action than other marketed medications for osteoporosis. The drug is administered every 6 months, which may improve compliance for some women.
Potential Disadvantages
Serious adverse events associated with denosumab include hypocalcemia (< 8.5 mg/dL; 1.7% vs 0.4% for placebo), serious infections (4.2% vs 3.5%), dermatologic events (10.8% vs 8.2%), and new malignances (4.8% vs 4.3%).1 Osteonecrosis of the jaw has been reported with denosumab. RANKL is a member of the TNF family of cytokines; the inhibition of RANKL may increase the risk of serious infection.1
Comments
Denosumab is the first RANKL inhibitor to be approved. Binding RANKL prevents its binding to RANK on osteoclasts and their precursors. This inhibits the formation, function, and survival of osteoclasts and results in inhibition of bone resorption and increased bone mass.1 The efficacy of denosumab was shown in a 3-year, randomized, double-blind, placebo-controlled study in women with a baseline lumbar spine or total hip BMD T-score between -2.5 and -4.0 (mean, -2.8).1,2 Twenty-three percent had a vertebral fracture. Study subjects were randomized to placebo (n = 3906) or denosumab 60 mg (n = 3902) given once every 6 months. The primary endpoint was the incidence of new vertebral fractures at 3 years. Secondary endpoints were the incidences of hip and nonvertebral fractures. At 3 years, vertebral fractures were reduced by 68% (2.3% vs 7.2%). Hip fractures were reduced by 40% (0.7% vs 1.2%), and nonvertebral fractures by 20% (6.5% vs 8.0%). BMD increased by 8.8%, 6.4%, and 5.2% for lumbar spine, total hip, and femoral neck, respectively. There was no significant difference between the two groups in terms of adverse events or discontinuation of treatments.2 There are currently no published comparative trials between denosumab and any bisophosphate in terms of reducing fractures. However, in a large study in postmenopausal women (n = 1189), denosumab (60 mg every 6 months) was compared to alendronate (70 mg weekly) with change in BMD as the endpoint. At 12 months, denosumab produced larger increases in BMD at the total hip (3.5% vs 2.6%, P < 0.001) as well as other skeletal sites (treatment difference of 0.6%-1%).3
Clinical Implications
Denosumab appears to be an effective agent for reducing the risk of fracture in postmenopausal women. The magnitude of fracture risk reduction is similar to that reported for once-yearly injections of zoledronic acid and at least numerically higher than that reported for oral bisphosphonates.4-7 The long-term safety of denosumab remains to be determined.
References
1. Prolia Product Information. Thousand Oaks, CA: Amgen; June 2010.
2. Cummings SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765.
3. Brown JP, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: A randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153-161.
4. Black DM, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822.
5. Black DM, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.
6. Wells G, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;(1):CD004523.
7. Wells G, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008;(1):CD001155.
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