First antibody treatment for osteoporosis

Prolia (denosumab) is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.

PHARMACOLOGY

Denosumab is a fully human monoclonal antibody specific for the RANK ligand.1 This molecule regulates the differentiation, function and survival of osteoclasts. These cells are responsible for bone resorption – a process that is typically accelerated in osteoporosis. Denosumab is given as a 60mg subcutaneous injection twice a year.

CLINICAL STUDIES

The efficacy of denosumab was demonstrated in two pivotal randomised, double-blind, Phase III trials.

In the FREEDOM trial, 7,868 women received either denosumab or placebo for three years.2 Participants were aged between 60 and 90 years, and had a bone mineral density (BMD) T score less than –2.5 (but not less than –4.0) at the lumbar spine or total hip.

At 36 months, denosumab reduced the relative risks of vertebral fracture (the primary endpoint) by 68% (p<0.001), hip fracture by 40% (p=0.04) and non-vertebral fracture by 20% (p=0.01) compared with placebo. Absolute risk reductions were 4.8%, 0.3% and 1.5%, respectively. At all sites assessed, BMD increased significantly in women who received the antibody compared with those who received placebo, with relative increases of 9.2% at the lumbar spine and 6.0% at ?the total hip.

The HALT study enrolled 1,468 men with non-metastatic prostate cancer who were receiving androgen-deprivation therapy.3 Participants were aged at least 70 years, or had either a low BMD (T score at the lumbar spine, total hip, or femoral neck of less than –1.0) at baseline or a history of osteoporotic fracture.

After 24 months, BMD was 6.7% higher at the lumbar spine (the primary endpoint) and 4.8% higher at the total hip in men who received denosumab than in those who received placebo (p<0.001 for both). Similar differences in favour of denosumab were observed at all other BMD sites measured. Denosumab was associated with a 62% lower incidence of spine fractures than placebo (1.5% vs 3.9%; p=0.006).

Denosumab had a similar adverse effect profile to placebo in both the FREEDOM and HALT studies. Investigators observed no cases of osteonecrosis of the jaw in either trial, although this event did occur occasionally in other studies of denosumab.1

One head to head trial has compared denosumab directly with a bisphosphonate. These agents – the current mainstay of osteoporosis treatment – inhibit bone resorption by binding to the mineralised surface of bone.

Investigators randomised 1,189 postmenopausal women with low bone mass to receive oral alendronate plus subcutaneous placebo, or subcutaneous denosumab plus oral placebo, for one year.4 Total hip BMD (the primary endpoint) increased significantly more in denosumab-treated patients than in patients who received alendronate (3.5% versus 2.6%; p<0.0001), as did BMD at all other sites assessed. Conversely, markers of bone turnover decreased significantly more with denosumab than with alendronate.

A separate randomised, double-blind study examined the consequences of switching from alendronate to denosumab in postmenopausal women with reduced BMD.5 The study recruited 504 women who had been receiving the bisphosphonate for at least 6 months. Those who switched to denosumab experienced a 1.90% increase in total hip BMD over one year, whereas those who continued alendronate treatment experienced an increase of only 1.05% (p<0.0001).

View Prolia drug record

REFERENCES

  1. Prolia Summary of Product Characteristics, May 2010.
  2. Cummings S et al. N Engl J Med 2009: 361; 756–65.
  3. Smith M et al. N Engl J Med 2009: 361; 745–55.
  4. Brown J et al. J Bone Miner Res 2009: 24; 153–61.
  5. Kendler D et al. J Bone Miner Res 2010: 25; 72–81.

Further information: Amgen

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