Denosumab

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Denosumab is a synthetic human IgG2 monoclonal antibody. Its therapeutic target is a receptor required for survival and activity of osteoclasts called receptor activator of nuclear factor-κB ligand (RANKL). The presumed mechanism of action of denosumab is that blockage of the receptor reduces osteoclast-mediated bone resorption, thereby maintain bone mineral density[1]. It has been shown to be effective in reducing all major types of osteoporotic fractures in women[2] and in men receiving androgen-deprivation therapy for prostate cancer[3]. The discovery in 2016 that it inhibits RANKL signaling in pre-neoplastic BRCA1 mutant breast tissue reducing progesterone-induced proliferation is likely to rapidly lead to preventive clinical trials as current prevention strategies include prophylactic mastectomy[4].

Contents

Indications

  • Osteoporosis
  • Prevention of skeletal-related events in men with prostate cancer being treated with hormone ablation
  • Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours.
  • Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Therapy

s/c twice yearly (osteoporosis) but four weekly in some cancer indications. Do not get the two different formulations and treatment regimes confused. See summary of product characteristics.

Issues

  • Unclear if long term therapy could be associated with undesired immune modulation (eg eczema and cellulitis seem to be increased)
  • There is strong evidence that where teriparatide is a treatment option for an individual it should be given first[5]. The economics of such a strategy is challenging.

Monitoring

  • Before treatment check Vitamin D levels
  • Especially with borderline renal function needs post treatment bloods to exclude hypocalcaemia

Side-effects

References

  1. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31
  2. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. The New England journal of medicine. 2009 Aug 20; 361(8):756-65.(Link to article – subscription may be required.)
  3. Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. The New England journal of medicine. 2009 Aug 20; 361(8):745-55.(Link to article – subscription may be required.)
  4. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nature medicine. 2016 Jun 20.(Epub ahead of print) (Link to article – subscription may be required.)
  5. Leder BZ, Tsai JN, Uihlein AV, Wallace PM, Lee H, Neer RM, Burnett-Bowie SM. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet (London, England). 2015 Jul 2.(Epub ahead of print) (Link to article – subscription may be required.)