Denosumab

Prolia (Amgen)
vials containing 60 mg/mL solution for injection
Approved indication: osteoporosis
Australian Medicines Handbook section 10.3.3

Denosumab is a humanised monoclonal antibody approved for the treatment of osteoporosis in postmenopausal women. This antibody works by binding RANKL (receptor activator of nuclear factor-κβ ligand) and blocking the interaction with its receptor on the surface of osteoclasts. This inhibits the development and activity of osteoclasts and leads to decreased bone resorption and increased bone density.

Following a subcutaneous dose of denosumab 60 mg, maximum serum concentrations are typically reached one to four weeks later. Denosumab has a half-life of 25–30 days. It is not eliminated via hepatic metabolism and dose adjustment is not needed in patients with renal impairment.

The approval of denosumab for osteoporosis is mainly based on a large phase III randomised trial which enrolled 7868 women aged 60–90 years. These women had to have a bone mineral density T score of less than –2.5 at the lumbar spine or total hip before being randomised to receive subcutaneous denosumab 60 mg or placebo every six months. After three years of treatment, the incidence of new vertebral fractures (measured radiolographically) was significantly lower for denosumab than for placebo (2.3% vs 7.2%). Denosumab also significantly reduced the cumulative incidence of hip fractures (0.7% with denosumab vs 1.2% with placebo) and nonvertebral fractures (6.5% with denosumab vs 8% with placebo). Over the same time period, denosumab was associated with a relative increase in bone mineral density at the lumbar spine (9.2%) and hip (6%) in a subset of 441 women. Markers of bone turnover (serum C-telopeptide) and bone formation (serum procollagen type I N-terminal propeptide) were also decreased in women receiving denosumab.¹ Although the efficacy data from this trial looks promising, a meta-analysis of three randomised controlled trials found that denosumab was not associated with a significant reduction in fracture risk in postmenopausal women.²

The efficacy of denosumab in reducing fractures has not been compared to other treatments for osteoporosis. However, a phase III trial looking at bone mineral density compared denosumab (six-month dose) to alendronate (70 mg orally each week) in women with low bone mass (T score ≤ –2.0). After 12 months, bone mineral density of the hip had increased more with denosumab than with alendronate (3.5% vs 2.6%). Although this was statistically significant, the clinical significance of this change is unclear. This increase was associated with a more pronounced decrease in markers for bone turnover in the denosumab group.³

In the placebo-controlled trial, eczema and flatulence were more common with denosumab than placebo (3% vs 1.7% and 2.2% vs 1.4%). Cellulitis, a serious adverse event, was also more frequent in women receiving denosumab (12/3886) compared to those receiving placebo (1/3876).¹ This may not be so surprising as RANKL is expressed on immune cells and its inhibition could make people more susceptible to infections. When a larger safety cohort (over 8000 people) was analysed, serious infections were more common with denosumab than placebo (3.4% vs 2.8%) and included abdominal, ear and urinary tract infections as well as cellulitis. Endocarditis, infected arthritis and skin ulcers were also more frequently reported. Malignancies are also a concern with denosumab and cancers were slightly more common with denosumab than with placebo (7.8% vs 7.1%). These risks should be considered when prescribing denosumab and patients should be informed of them.

In the safety cohort, serious pancreatitis occurred more commonly with denosumab than with placebo (9 cases vs 1 case). This proved fatal in two people.

Low osteoclast and osteoblast counts have been observed with denosumab. This could potentially delay healing of fractures. Transient hypocalcaemia can occur with denosumab and is a contraindication to treatment. Calcium and vitamin D supplementation is recommended for all patients. Neutralising antibodies were not found in women who received denosumab.

Denosumab seemed to reduce fractures in postmenopausal women with low bone density in a large placebo-controlled trial. However, because of lack of head-to-head trials it is not known how this efficacy compares with current treatments for osteoporosis. Women may prefer the six-monthly dosing of denosumab but will need to consider its increased risks of infections and malignancies. Postmarketing surveillance for these adverse effects is needed.

Manufacturer provided the clinical evaluation

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.