15 September 2009
In the FREEDOM study, subcutaneous denosumab was compared with placebo given at 6 monthly intervals over 36 months to almost 8,000 women with postmenopausal osteoporosis. While denosumab was more effective than placebo at reducing the risk of new radiographic vertebral fractures, its effect on patient-oriented outcomes such as non-vertebral fractures was not assessed.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Denosumab is in licensing with the EMEA and its exact indication will be clear once that process is complete. Concerns regarding the safety of long-term use have already been raised in the USA. The predominant competitors to subcutaneous denosumab administered twice yearly are bisphosphonates. NICE guidance on denosumab is planned, but commissioners who are planning ahead may wish to take into account that there are no head to head comparator trials for antifracture efficacy. The cost of denosumab is not yet known, but will be critical if clinical differences are marginal with its competitors.
What is the background to this?
Denosumab is the first of a new class of agents for bone conditions such as osteoporosis. It is a fully human monoclonal antibody to RANKL, a cytokine which is involved in mediating osteoclast activity. The manufacturer, Amgen, has submitted a marketing application for denosumab in the EU.
Further information on the management of osteoporosis is available on the osteoporosis section of NPC.
What does this study claim?
In this study of almost 8,000 postmenopausal women with osteoporosis, subcutaneous denosumab was more effective than placebo at reducing the risk of new radiographic vertebral fracture (cumulative incidence over 36 months: 2.3% in the denosumab group and 7.2% in placebo patients, relative risk 0.32, 95% confidence interval [CI] 0.26 to 0.41, P<0.001, number needed to treat (NNT) of 21 over 36 months).
How does this relate to other studies?
Currently, there are no trials comparing denosumab with other treatments for osteoporosis in terms of fracture reduction. Several phase III trials with active controls have been completed or are planned, with the endpoint of a disease-orientated outcome of change in bone mineral density. For example, a non-inferiority trial has compared denosumab with alendronate. Trials of denosumab with ibandronate or risedronate are planned.
NICE guidance on secondary prevention of osteoporotic fractures estimates that more than 2 million women have osteoporosis in England and Wales. The prevalence is approximately 2% at 50 years rising to more than 25% at 80 years. Osteoporotic fragility fractures are associated with reduced quality of life and substantial disability and pain.
As discussed on the osteoporosis section of NPC, there are already a number of options for the management of osteoporosis, including calcium and vitamin D, bisphosphonates and strontium. A number of these are available generically at low cost. A range of dosage regimens exist, including weekly, monthly and yearly. Oral bisphosphonates have precise administration regimens to minimise the risk of interactions with drugs and minerals, and to reduce the risk of gastro-intestinal adverse effects. As denosumab is given subcutaneously twice yearly it may be possible for patients, or their carers, to be taught to administer it at home. Whilst this might encourage compliance, the wide range of formulations available for bisphosphonates already provides opportunities to address this problem.
An FDA advisory committee recently recommended denosumab for the treatment of postmenopausal osteoporosis in women at high risk of fracture and for prevention and treatment of bone loss in men undergoing hormone ablation for prostate cancer. The manufacturer has been asked to provide a Risk Evaluation and Mitigation Strategy. The committee has recommended against approval to prevent bone loss in low-risk patients.
As discussed in the FREEDOM study, RANKL is expressed by a variety of lymphoid cells so theoretically inhibition by denosumab may increase the risk of cancer and infections. This had led to concerns about long term use of the drug and the Fda’s advisory committee has identified the following for discussion: the occurrence of serious infection, the possible development of new malignancies and the potential for tumour progression in patients with cancer. In addition, there is concern about possible complications such as delayed fracture healing, osteonecrosis of the jaw, and dermatologic adverse events.
Questions remain on the role of denosumab in a market where antiresorptive drugs are numerous, many with evidence of benefit in patient-oriented outcomes such as hip fracture. The FREEDOM trial examines the effect on silent radiographic vertebral fractures and does not study the effect on non-vertebral fractures or symptomatic vertebral fractures. Nor do we know if the bone gained would be lost when treatment is stopped.
It is not known if denosumab should be administered in a particular sequence in relation to other drugs for osteoporosis or if it is more effective in treatment-naïve patients. We do not know if it would be more effective if combined with other agents, but a trial in combination with teriparatide has just started.
The cost of denosumab is not yet available but given the variety of costs for bisphosphonates, and the seemingly marginal clinical differences, this may have a bearing on place in therapy.
Denosumab is also in development for other conditions such as bone loss in patients being treated for breast cancer, multiple myeloma and rheumatoid arthritis.
Design: Randomised, double-blind, placebo-controlled Phase 3 trial.
Patients: Although 7,868 patients were enrolled, 60 were excluded from analyses due to concerns re study procedures at one centre. Women aged 60 – 90 years (mean 72.3) with osteoporosis (T score less than -2.5, but not less than -4.0) were included. It is not known what proportion of patients was treatment-naïve.
Intervention and comparison: Denosumab 60mg subcutaneously every six months (n=3,902) was compared to placebo (n=3,906) over 36 months. Patients also received at least 1,000mg of calcium daily, and vitamin D if needed.
Outcomes and results: The primary outcome was new radiographic vertebral fracture. Secondary outcomes included time to first non-vertebral fracture and time to first hip fracture. The primary endpoint was seen in 2.3% of denosumab patients and 7.2% of placebo patients: difference 4.8% (95% CI 3.9 to 5.8), P<0.001. Reductions in risk were similar during each year. Non-vertebral fractures were seen in 6.5% and 8.0% of patients in the denosumab and placebo groups (hazard ratio [HR] 0.80, 95% CI 0.67 to 0.95, P=0.01) and hip fracture in 0.7% and 1.2%, respectively (HR 0.60, 95% CI 0.37 to 0.97, P=0.04).
Adverse events occurred in similar numbers of patients in each group. Serious adverse events were seen in 25.8% of denosumab patients and 25.1% of those on placebo. Infections were seen in 52.9% and 54.4% of patients, and cancer in 4.8% and 4.3%, respectively. Eczema was seen more frequently in patients receiving denosumab (3.0% versus 1.7%, P<0.001). Serious cellulitis (including that needing hospital admission) occurred in 0.3% of denosumab patients compared to less than 0.1% of placebo patients, P=0.002. No cases of osteonecrosis of the jaw were reported.
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