Denosumab

Denosumab reversibly inhibits bone resorption by reducing osteoclast formation and differentiation and increasing osteoclast apoptosis. Denosumab increases BMD at the lumbar spine and hip, and reduces vertebral, nonvertebral and hip fractures.

Before starting denosumab, discuss with the patient the importance of adhering to a 6-monthly regimen, and explain that denosumab therapy must either be continued indefinitely (at the time of writing, the use of denosumab for more than 10 years has not been studied), or be replaced by bisphosphonate therapy if stopped.

Recent studies have demonstrated an increased incidence of multiple spontaneous vertebral fractures when denosumab is stopped or a dose is delayed for more than 4 weeks (ie it has been more than 7 months since the last dose). The risk of multiple vertebral fractures is particularly high in patients with a prior vertebral fracture. Unlike bisphosphonates, which have a long skeletal half-life, stopping denosumab leads to a rapid increase in bone turnover and loss of BMD. If denosumab is stopped, a replacement drug (typically a bisphosphonate) must be started to prevent rapid bone loss and vertebral fracture. At the time of writing, the optimal choice of bisphosphonate (oral or intravenous) to replace denosumab is not known; the optimal time to start the bisphosphonate after stopping denosumab, and how long it should be continued, are also not known. A suggested regimen based on limited clinical trial data is to start oral alendronate no more than 6 months after the last dose of denosumab, and continue for 12 to 24 months.

Serious skeletal adverse effects such as osteonecrosis of the jaw and atypical fracture of the femur have been rarely reported with denosumab.

If denosumab is suitable, use:

Throughout therapy, ensure the patient’s calcium intake is sufficient and they are vitamin D replete.

Denosumab can cause hypocalcaemia, particularly in patients with risk factors for hypocalcaemia such as vitamin D deficiency, kidney disease or a malabsorption disorder. Before the first dose, measure kidney function, serum corrected calcium concentration and serum 25-hydroxyvitamin D concentration. In patients at risk of hypocalcaemia, these parameters should also be measured before each subsequent dose. Administration of denosumab is safe provided that:

• serum 25-hydroxyvitamin D concentration is greater than 50 nanomol/L
• serum total calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
• creatinine clearance is greater than 30 mL/min.

For information about monitoring therapy, see here.