Source: Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G, Cao X, Wang P. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014 Apr 15;7(5):2113-22. eCollection 2014.
Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al.; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361:756-65.
Study Population: Postmenopausal women with documented osteoporosis
Efficacy Endpoints: Prevention of new vertebral and non-vertebral fractures
Harm Endpoints: Infection, neoplasm, death
Narrative: As bone density decreases people are at an increased risk for fractures.1 Denosumab is a fully human monoclonal antibody that binds the receptor activator of nuclear factor-κB ligand (RANKL), which prevents its interaction with the osteoclast and osteoclast precursor surface receptor, RANK. This inhibits osteoclast-mediated bone resorption by blocking osteoclast function, formation, and survival.2, 3 Prior studies have demonstrated an increase in bone mineral density with the administration of denosumab in post-menopausal women.4, 5 This review assesses whether the increase in bone mineral density translates into a reduction in the risk of osteoporosis-related fractures.
The FREEDOM trial2 is the largest randomized control trial to compare denosumab vs placebo in the prevention of fractures in postmenopausal women with osteoporosis. Women between the ages of 60 and 90 years with a bone mineral density T score of less than -2.5 (consistent with the typical definition of osteoporosis) at the lumbar spine or total hip were included in the trial. Patients were randomly assigned to receive subcutaneous injections of either 60 mg of denosumab or placebo every 6 months for 36 months. In this trial, the primary endpoint was new vertebral fractures based on semi-quantitative grading scales of lateral spine radiographs.2 The treatment with denosumab was associated with significantly lower risk of new vertebral fractures (Relative risk [RR]: 0.32, 95% confidence interval [CI], 0.26 - 0.41]; Absolute risk difference [ARD]: 4.8%; NNT 21). Secondary outcomes included non-vertebral fractures (NNT 71), hip fractures (NNT 230), new clinical vertebral fractures (NNT 62), and multiple (≥2) new vertebral fractures (NNT 103). The study found no significant difference in the incidence of infection, death, or neoplasm.2
A meta-analysis3 published in 2014 examined the safety of denosumab in 15,263 postmenopausal women from 13 trials with documented osteoporosis who were followed between 9 months to 3 years after initiation of therapy. This meta-analysis found a non-significant reduction in the risk of non-vertebral fractures with the administration of denosumab (RR: 0.86, 95%CI, 0.74 - 1.00; ARD: 0.83%; NNT 121). The meta-analysis found the difference in incidence of death or neoplasm to be non-significant. However, a non-statistically significant difference in rates of infection (RR: 1.23, 95%CI, 1.00 - 1.52; ARD: 0.60%; NNH 167) was seen.2 We used this information to calculate the number-needed-to-harm (NNH) because the sample size for the meta-analysis was larger than the FREEDOM trial2 and also the objective of the meta-analysis specifically was to assess the safety of the treatment.3 Another systematic review6 published in 2014 compared the efficacy of various pharmacologic treatments in reducing the risk of fractures. This analysis also confirmed the efficacy of denosumab in reducing the risk of fractures in postmenopausal women. For different pharmacologic treatments including various bisphosphonates, bisphosphate derivatives, teriparatide, raloxifene, or denosumab; NNT for vertebral fractures was in the range of 60-89 and NNT for non-vertebral fracture was 50-60.6 The review also found denosumab to have an NNH of 118 for infection.6
Caveats: While the meta-analysis by Zhou et al3 included 11 randomized controlled trials, the FREEDOM trial2 was by far the largest study with their sample size accounting for about 60% of the total number of participants in all studies.
While the existing evidence supports the safety of denosumab, the follow-up period for the trials (ranging from 9 months to 3 years) may have been too short for assessing the harm endpoints of neoplasm, death, or infection. Longer-term follow-ups are needed to understand the long-term safety profile of this treatment. One longer-term follow-up was for the patients in the FREEDOM trial who were followed for an additional 7 years, and in this follow up study, the rates of serious adverse events for the participants treated with denosumab remained low (11·5 and 14·4 per 100 participant-years).7 Denosumab is marketed under brand names Prolia and Xgeva. As of October 2018, the price of one 60 mg syringe or vial, which has to be administered every 6 months, is approximately $1200-1400.8
The manufacturer’s website lists some examples of possible infections associated with it as infections of “skin, lower stomach, bladder, ear, or the inner layer of the heart (endocarditis)”.9
In conclusion, denosumab appears to be effective in reducing the risk of vertebral and non-vertebral fractures in premenopausal women with osteoporosis. Treatment with denosumab does not increase the risk of cancer or death but might increase the risk for infection. However, given the non-statistically significant impact on non-vertebral fractures and the uncertainty of longer-term harms due to relatively short follow up periods, we assign a color recommendation of Yellow (unclear benefit; more studies required) to this treatment.
Author: Peter Song, MD; Shahriar Zehtabchi, MD
Published/Updated: April 15, 2019
The title bar is color-coded with our overall recommendation.