The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

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.

Adherence to endocrine therapy for breast cancer.

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 (> or =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.

HT and breast cancer risk.

Two large recent studies indicate an increased risk of breast cancer with use of menopausal hormone therapy (HT), particularly combinations of estrogen and progestogen. These studies also go against previous theories of the types of breast cancer that would be associated with HT use. Emerging information regarding the influence of estrogen plus progestin on breast cancer risk adds further weight to the recommendation against use for chronic disease risk reduction and raises additional questions regarding risks of even short-term use for vasomotor symptoms associated with menopause.