Authors' objectives: Background Since 2010, denosumab (Prolia®) has been listed on the Spezialitätenliste for the treatment of osteoporosis in postmenopausal women, men with osteoporosis who have an increased fracture risk, women with breast cancer receiving adjuvant aromatase inhibitor therapy (AAIT), and men with prostate cancer on hormone ablation therapy (HAT). Pharmacovigilance reports in 2017 warned that discontinuation of denosumab therapy in patients with osteoporosis may lead to increased bone turnover, significant bone mineral loss and increased vertebral fracture risk. On the basis of these safety concerns, the Federal Office of Public Health (FOPH) is re-evaluating the available evidence for denosumab. Objective The objective of this Health Technology Assessment (HTA) is to evaluate the safety, effectiveness, cost-effectiveness and financial impact of denosumab (Prolia®) compared to placebo, bisphosphonates and selective oestrogen receptor modulators (SERMs) in four subgroups of patients. Legal, social, ethical and organisational impacts have also been considered.

Authors' results and conclusions: Results Postmenopausal women: Twelve RCTs (k = 22 publications) with low to high risk of bias were identified. Only risedronate was found to be statistically significant for the prevention of nonvertebral fractures compared to placebo after 12 to 84 months of treatment; risedronate was also ranked as the most effective treatment at preventing nonvertebral fracture, with denosumab ranking as the least effective (of six treatments). In relation to femoral neck (FN) bone mineral density (BMD), alendronate, ibandronate and risedronate were statistically significant relative to placebo at 19 (± 1 SD) months, ranking from first to third at increasing FN BMD, respectively. Denosumab was ranked as the fourth most effective treatment (of eight) at increasing FN BMD. However, the clinical relevance of the increases in BMD findings is unclear, as there is a lack of consensus on minimally clinically important differences (MCID) that associates changes in BMD to fracture risk. Vertebral fracture, mortality, adverse events (AEs), serious adverse events (SAEs) and withdrawal due to treatment-related AEs reported no significant differences for any intervention compared to placebo. Evidence for discontinuation effects related to denosumab use was limited and cannot be used to draw conclusions about possible rebound effects. Women with breast cancer receiving AAIT: Four RCTs (k = 5 publications) with moderate to high risk of bias were identified. There were no studies evaluating the treatment effects of zoledronate, alendronate, raloxifene or bazedoxifene to directly or indirectly contribute to the network metaanalyses of effectiveness or safety outcomes. Denosumab was associated with statistically significant reductions in vertebral fractures, and increases in BMD, relative to placebo. However, the clinical relevance of the increases in BMD is unclear. No statistically significant difference between denosumab and placebo was detected for nonvertebral fractures, mortality, AEs, SAEs or withdrawal due to treatment-related AEs. Evidence for discontinuation effects related to denosumab use was limited and cannot be used to draw conclusions about possible rebound effects. Men with osteoporosis: Four RCTs (k = 5 publications) with moderate to high risk of bias were identified. None of the included treatments demonstrated a significant treatment effect compared to placebo in relation to vertebral or nonvertebral fracture. For FN BMD, denosumab and zoledronate were statistically significant relative to placebo at 12 months, ranking first and second at increasing FN BMD, respectively. However, the clinical relevance of these BMD findings is unclear. After 12 to 24 months, alendronate and zoledronate showed a statistically significant increase in risk of AEs relative to placebo in men with osteoporosis who have increased fracture risk (ranked fourth and fifth, respectively, of five treatments). None of the included interventions was statistically significant relative to placebo for mortality, SAEs or withdrawal due to treatment-related AEs. No evidence was available for AEs upon discontinuation of denosumab (i.e. rebound effect). Men with prostate cancer undergoing HAT: Ten RCTs (k = 10 publications) with moderate to high risk of bias were identified. There were no studies evaluating ibandronate, raloxifene or bazedoxifene in this population. Denosumab was found to be statistically significant relative to placebo for the prevention of vertebral fracture in men with prostate cancer on HAT, ranked as the most effective treatment (of three treatments). None of the included interventions were statistically significant for nonvertebral fractures after 12 to 36 months of treatment. Denosumab was ranked as the most effective treatment at preventing nonvertebral fractures. For FN BMD, zoledronate, denosumab and alendronate were statistically significant relative to placebo at 12 months, ranking second to fourth (of five treatments) at increasing FN BMD, respectively. However, the clinical relevance of these BMD findings is unclear. None of the included interventions were statistically different to placebo in terms of mortality, AEs, SAEs or withdrawal due to treatment-related AEs. No evidence was available for AEs upon discontinuation of denosumab (i.e. rebound effect). Sensitivity analysis on a combined population: A sensitivity analysis combining all four populations was conducted to investigate how grouping the four populations together affects the precision of the analysis. When populations were combined, only the results associated with denosumab changed from being nonsignificant in many groups to statistically significant in relation to vertebral fracture, nonvertebral fracture and FN BMD. Costs and cost-effectiveness Time-to-fracture distributions for hip, clinical vertebral and non-hip nonvertebral (NHNV i.e. forearm, humeral) fractures—derived from Swiss-specific FRAX® (fracture risk assessment tool) probabilities of major osteoporotic fracture (MOF) in women of postmenopausal age at various risk levels— formed the backbone of the economic model. Reductions in the risk of vertebral and nonvertebral fracture due to treatment were informed by the network meta-analysis, while real-world adherence data were obtained from the literature. Cost-effectiveness was determined via cost-effectiveness frontier analysis. Additionally, pairwise comparisons between denosumab and each comparator were made. At a hypothetical willingness-to-pay (WTP) threshold of Swiss francs (CHF)100,000, IV ibandronate was the most cost-effective option in women aged 60 years at very high risk, and in women aged 70 or 80 years at any risk level. In women aged 60 years at lower risk levels, zoledronate was the most cost-effective option. Whilst cost-effectiveness frontier analysis did not find denosumab to be the most cost-effective antiresorptive therapy, some of the incremental cost-effectiveness ratios (ICERs) from pairwise comparisons between denosumab and individual comparators were below the hypothetical WTP threshold of CHF100,000. In women aged 70 years at high fracture risk, denosumab had ICERs of CHF15,927, CHF23,135, CHF86,776, CHF107,460, CHF166,451 and CHF615,149 when compared with no treatment, bazedoxifene, raloxifene, zoledronate, oral bisphosphonates and IV ibandronate, respectively. The higher intervention costs, smaller reduction in the risk of hip fracture and shorter duration of residual benefit associated with denosumab have contributed to the high ICER values seen in pairwise comparisons with oral bisphosphonates and IV ibandronate. The budget impact analysis explored the potential costs of denosumab from 2021 to 2024. In the base case, it was assumed that use of denosumab would continue to decline by 1.6% per annum, which reflects the average annual decline in use over the period 2018 to 2020. Under this assumption, the payer cost of denosumab was estimated to be CHF 26.6 million in 2024, representing a decrease of CHF 1.6 million compared to 2020 (CHF 28.2 million). While the utilisation of denosumab has declined in recent years, uptake of bisphosphonates has increased, suggesting a substitution may be occurring in practice. Crude analyses indicated the potential for cost savings through the natural substitution of denosumab with bisphosphonates (CHF0.36 million in 2021, increasing to CHF1.43 million in 2024). Social, legal, ethical and organisational issues No literature related to the legal implications of denosumab use was identified. Studies reported strong patient preferences and adherence to denosumab compared to bisphosphonates. Efforts to improve adherence would need to be considered if the reimbursement status of denosumab was altered. Conclusion Denosumab reported similar treatment effects and safety profile compared to comparator interventions in most populations; however, the analyses were largely limited by statistical imprecision due to the limited evidence in the four specific populations defined in the policy question. The evidence base investigating rebound effects in the Swiss policy context was severely limited and cannot be used to draw meaningful conclusions around the probability and severity of rebound effects upon discontinuation of denosumab therapy. Cost-effectiveness frontier analysis did not find denosumab to be the most cost-effective antiresorptive therapy; however, denosumab was found to be cost-effective over some comparators in pairwise comparisons.

Authors' methods: Methods A systematic literature search was conducted in eight biomedical databases, in conjunction with clinical trial registries and speciality websites. Safety, efficacy and effectiveness outcomes reported by at least two randomised controlled trials (RCTs), which in total reported three or more treatment arms, were evaluated using network meta-analysis; outcomes with only two comparison arms were evaluated using pairwise meta-analysis. Risk of bias of the included RCTs was evaluated using the Cochrane Risk of Bias 2.0 tool, and the overall strength of evidence for key outcomes was evaluated using the GRADE approach. A discrete event simulation (DES) model was developed to quantify the cost-effectiveness of denosumab versus oral bisphosphonates, intravenous (IV) ibandronate, zoledronate, raloxifene, bazedoxifene and no treatment for the management of osteoporosis in postmenopausal women. This population was chosen as an exemplar population because it represents the largest population in which denosumab is used in Switzerland, and it has the most robust clinical data supporting safety and efficacy of denosumab.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/denosumab.html

Year Published: 2022

URL for published report: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/denosumab.html

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health