Denosumab is a fully human monoclonal antibody which binds to receptor activator of nuclear factor-kB ligand (RANKL) with high affinity and specificity. It blocks the interaction of RANKL with receptor activator of nuclear factor-kB (RANK) on the cells of the osteoclastic lineage, and thus inhibits the proliferation, activation and survival of the osteoclast, resulting in a strong and rapid inhibition of bone resorption.
In postmenopausal women with low bone mineral density (BMD), 60mg of denosumab decreases bone turnover; e.g. serum CTX decreases more than 80% one week after injection and at 12 months BMD increases 1 to 7% according to the skeletal site McClung, M.R., et al., Denosumab in postmenopausal women with low bone mineral density. N Engl J Med, 2006. 354(8): p. 821-31.
. After 10 years of denosumab, compared to baseline, increase in BMD has been shown to continue, without plateau, by 22% at the lumbar spine, 9.2% at total hip, 9% at femoral neck Bone, H.G., et al., 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol, 2017. 5(7): p. 513-523.
In the FREEDOM trial, subcutaneous injections of 60mg of denosumab every 6 months for 36 months decreased the risk of vertebral fracture by 70%, of non-spine fractures by 20% and of hip fracture by 40% in postmenopausal women with osteoporosis Cummings, S.R., et al., Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med, 2009. 361(8): p. 756-65.
. This effect on fracture risk is observed up to 10 years.
Denosumab has also shown positive effects in older men receiving androgen-deprivation therapy for prostate cancer by slowing bone turnover, increasing BMD 4 to 7%, as well as decreasing the incidence of vertebral fractures by 60% and the incidence of multiple fractures by 70% Smith, M.R., et al., Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol, 2009. 182(6): p. 2670-5.
Gnant, M., et al., Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, 2015. 386(9992): p. 433-43.
. In postmenopausal women with breast cancer receiving aromatase inhibitors, denosumab increases BMD and reduces the risk of clinical fractures.
Recommendations and safety
In the absence of contraindications, denosumab is considered a second-line therapy (after bisphosphonates) in most countries for women with postmenopausal osteoporosis. Additionally, it has been approved in men for the treatment of bone loss with hormone ablation therapy for prostate cancer. However, it is contraindicated in people with hypocalcemia, and sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy.
Discontinuation of denosumab has been shown to be associated with a transient rebound effect: markers of bone turnover increase over baseline during the first year off therapy, BMD decreases to baseline values, and the rate of vertebral fracture increases to levels observed in non-treated patients Cummings, S.R., et al., Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res, 2018. 33(2): p. 190-198.
Miller, P.D., et al., Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone, 2008. 43(2): p. 222-9.
. Some patients discontinuing denosumab experience multiple and severe vertebral fractures Cummings, S.R., et al., Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res, 2018. 33(2): p. 190-198.
. In these cases transition to bisphosphonate treatment should be considered Tsourdi, E., et al., Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone, 2017. 105: p. 11-17.
. Despite the increase in vertebral fractures after denosumab treatment cessation, no increase in non-vertebral fracture has been observed.
No major safety issues have been were observed in clinical trials. Adverse events like skin rashes, increased risk of infections such as cellulitis, hypocalcemia have been reported. Rare cases of atypical femoral fracture and osteonecrosis of the jaw were documented, but these risks were non-significant. Read more about side effects.