Context:The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years.Objective:The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure.Design, Setting, and Participants:This was a multicenter, international, open-label study of 4550 women.Intervention:Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover).Main Outcome Measures:Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported.Results:Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture.Conclusion:Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Purpose: Despite the demonstrated efficacy of long-duration adjuvant tamoxifen and aromatase inhibitor use in breast cancer management, information on adherence to such therapy is limited. Therefore, we reviewed the published literature regarding hormonal therapy adherence in clinical trial and practice settings. Methods: A systematic search of the PubMed database, augmented by a review of manuscript references and conference proceedings, commonly identified adherence reports in clinical trials but identified only 9 adherence reports in clinical practice settings. Results: In adjuvant breast cancer clinical trials with longer (≧4 years) follow-up, hormonal therapy (tamoxifen or aromatase inhibitors) was prematurely discontinued by about 23–28% of the study participants. Adherence to aromatase inhibitors did not differ from adherence to tamoxifen in this setting. In breast cancer prevention trials, tamoxifen was prematurely discontinued by 20–46% of the participants. In clinical practice settings, only 2 reports addressed longer-duration (>4 years) adherence to adjuvant tamoxifen use. In these, tamoxifen was prematurely discontinued by 30–50% of the patients. Conclusion: Adherence to prescribed breast cancer hormone therapy has not received concerted attention. Current, albeit limited, evidence suggests long-term hormone therapy adherence may represent an area limiting optimal breast cancer patient treatment.

SummaryIn a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study.IntroductionThe purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.MethodsIn the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.ResultsOf the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.ConclusionContinued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Toth, P. P. et al. (2017) Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies. Circulation, 135(19), pp. 1819-1831. (doi:10.1161 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.