The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies

Abstract

SummaryThis post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.IntroductionThis analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment.MethodsIn FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM.ResultsDuring FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43–0.81]; P = 0.0012).ConclusionsThese data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.Electronic supplementary materialThe online version of this article (10.1007/s00198-018-4687-2) contains supplementary material, which is available to authorized users.

Evaluation of satisfaction and preference in patients with osteoporosis receiving Denosumab

“…Kendler et al [14] compared subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM. Their results showed that denosumab decreases the risk of subsequent fracture.…”

Should denosumab treatment for osteoporosis be continued indefinitely?

“…No currently available therapy completely eliminates the risk of sustaining a fracture, thus deciding to cease or switch away from denosumab due to the occurrence of an on-treatment fracture may not always be justified. A 2018 study by Kendler et al 55 assessed this issue based on the incidence rate of subsequent fracture in participants who sustained an "on-treatment fracture" whilst receiving either denosumab or placebo in FREEDOM or the extension study. The adjusted hazard ratio for subsequent fracture for the participants receiving denosumab compared with placebo was 0.59 (95% CI 0.43-0.81).…”

“…A 2018 study by Kendler et al . 55 assessed this issue based on the incidence rate of subsequent fracture in participants who sustained an “on-treatment fracture” whilst receiving either denosumab or placebo in FREEDOM or the extension study. The adjusted hazard ratio for subsequent fracture for the participants receiving denosumab compared with placebo was 0.59 (95% CI 0.43–0.81).…”

<p>A Review on the Role of Denosumab in Fracture Prevention</p>

“…Human studies that did not report the fracture incidence or risk are not included. There are two retrospective cohort studies utilizing national data; 25,26 seven articles from Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) clinical trial and FREEDOM extension; [27][28][29][30][31][32][33] nine articles on post hoc analysis of FREEDOM data 31,39 (wherein 2 articles reporting both post hoc analysis and FREEDOM extension); 32,33 one article from Austrian Breast Cancer Study Group study (ABCSG-18); 40 one article from Denosumab fracture Intervention RandomizEd placebo Controlled Trial (DIRECT); 41 two articles from FRActure study in postmenopausal woMen with ostEoporosis study (FRAME) 42,43 and two articles from a randomized controlled trial (RCT) by Saag et al 44,45 The denosumab was administrated at 60 mg subcutaneously once in every 6 months in these clinical trials. However, the treatment period, dose and compliance of denosumab are not known for retrospective cohort studies.…”

“…28,47 A continuation of FREEDOM trial (also known as FREEDOM extension) was conducted, wherein all subjects (both placebo and denosumab groups) who did not miss more than 1 dose of the investigational product were recruited to receive the denosumab up to an additional 7 years. 27,[29][30][31][32][33] The placebo of FREEDOM trial was noted as "cross-over group" because they received denosumab in the FREEDOM extension while denosumab group continued to receive denosumab up to 10 years and was named the "long-term group". 27,[29][30][31][32][33] ABCSG-18 study is a prospective, double-blind, placebo-controlled, multicentre phase 3 trial on 3420 postmenopausal women with hormone receptor-positive breast cancer and underwent aromatase inhibitor as treatment.…”