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30 July 2010
Denosumab▼ subcutaneous injection (Prolia®), administered as a 60mg dose every six months, has been marketed in the UK for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The annual cost of the product is £366 (plus VAT).
Preliminary recommendations from NICE restrict its use to women who are unable to comply with the administration regimens for oral bisphosphonates, are intolerant of those drugs or for whom such treatment is contra-indicated. For primary prevention, NICE recommend that certain other criteria are met before considering using denosumab. This is not NICE’s final guidance which may change after consultation. The closing date for comments is 9th July 2010.
Action
NICE final guidance will be issued in due course. In the meantime, local decision making bodies should consider engaging with stakeholders and agree a protocol for implementation of those recommendations. This includes identifying those patients for whom the drug may be appropriate and ensuring audit or other monitoring arrangements are in place locally to permit effective implementation of NICE’s recommendations as well as monitoring patients closely for adverse effects.
Background information
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. It has been marketed in the UK recently and is administered as a 60mg dose by subcutaneous injection every six months at a cost of £366 per year (plus VAT). More details on the use of the drug can be found in the Summary of Product Characteristics. Administration should be performed by an individual who has been adequately trained in the appropriate injection technique. The pre-filled syringes must be stored in a refrigerator, but can be stored at room temperature if used within 30 days. Patients must be adequately supplemented with calcium and vitamin D.
The pivotal clinical trial, FREEDOM, was the subject of an On The Horizon blog in September 2009. The trial showed that 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 0.26 to 0.41, P<0.001, a number needed to treat (NNT) of 21 over 36 months).
The secondary endpoints of the study were the incidence of non-vertebral fracture and hip fractures over three years. 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). Other fracture rates reported included new clinical vertebral fractures at an incidence of 0.8% for denosumab and 2.6% for placebo (HR 0.31, 95% CI 0.20 to 0.47, P <0.001).
The mechanism of action of denosumab has led to concerns being expressed by the FDA about long term use of the drug. The product information in the US has identified the following for consideration: the occurrence of serious infection, the possible development of new malignancies (although a causal relationship has not been established). In addition, there is concern about possible complications such as delayed fracture healing, osteonecrosis of the jaw, and dermatologic adverse events.
NICE have issued an appraisal consultation document (ACD) setting out draft recommendations on the role of denosumab in both primary and secondary prevention of osteoporotic fractures in postmenopausal women. It should be noted that this document is not NICE’s final guidance which may change after consultation. The closing date for comments is 9th July 2010 and comments may be made online.
The preliminary recommendations are that denosumab is a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who:
- are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated, and
- also have a specific combination of T-score, age and number of independent clinical risk factors for fracture as defined within a table in the guidance.
Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who:
- are unable to comply with the special instructions for the administration of oral bisphosphonates, are intolerant of oral bisphosphonates or for whom treatment with oral bisphosphonates is contraindicated
There are a number of options available for the management of osteoporosis, including calcium and vitamin D, bisphosphonates and strontium. Information on these can be found on the osteoporosis section of NPC. A number of these products are available generically at relatively low acquisition cost with a range of dosage regimens, 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.
Denosumab has also been licensed in the UK for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. The drug has recently been approved by the FDA in the United States for the treatment of postmenopausal women with osteoporosis at high risk of fracture.
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