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Denosumab Associated With Marked Increases in Bone Mineral Density in Patients With Nonmetastatic Breast Cancer Receiving Aromatase Inhibitors

Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875-4882. doi: 10.1200/JCO.2008.16.3832.
Background

In postmenopausal women with hormone receptor–positive, early-stage breast cancer, tamoxifen has long been the standard for adjuvant hormone therapy, as it significantly reduces tumor recurrence risk and has been shown to improve patient survival. Although tamoxifen has been reported to have a weak mitigating effect on bone mass loss resulting from estrogen deficiency, it is associated with several potentially life-threatening adverse effects (AEs)—thromboembolic events and endometrial cancer, for example. In more recent years, aromatase inhibitors (AIs) have been shown to have fewer life-threatening AEs compared with tamoxifen, while also improving progression-free survival in women with hormone receptor–positive, early-stage breast cancer. However, despite their proven benefit and decreased incidence of potentially life-threatening AEs, AIs are associated with bone loss and increased fracture risk.1

Osteoclasts mediate bone loss, and their formation, function, and survival depend on the receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL activates and maintains osteoclast-mediated bone resorption via binding to the RANK receptor on preosteoclasts and mature osteoclasts. Denosumab is a fully human monoclonal antibody that suppresses bone resorption by specifically inhibiting RANKL, ultimately inhibiting osteoclast formation, function, and survival.1

The results of a previous placebo-controlled study showed that denosumab treatment for up to 2 years was associated with increased bone mineral density (BMD) in postmenopausal women with low bone mass. Based on these findings, Ellis et al investigated the effects of denosumab on BMD in women with nonmetastatic breast cancer who were receiving adjuvant AI therapy.1

Study Design

This randomized, double-blind, placebo-controlled, phase 3 trial was conducted over a 24-month period at 53 sites in the United States and Canada. Patients enrolled in the study were adult women (≥18 years of age) with early-stage, histologically or cytologically confirmed receptor-positive breast cancer. Participants included in the study were also receiving adjuvant AI therapy and had completed treatment with surgery and/or radiation and chemotherapy at least 4 weeks before study entry. At study enrollment, patients were required to have evidence of low bone mass (lumbar spine, total hip, or femoral neck BMD corresponding to a T-score of −1.0 to −2.5) and a serum 25-hydroxyvitamin D level ≥12 ng/mL. Patients with osteoporosis (T-score <−2.5), prior vertebral fracture, current use of bisphosphonates, and use of any antineoplastic therapy (apart from AIs) were excluded from the study.1

Eligible patients were randomized (1:1) to receive denosumab (60 mg every 6 months for 4 doses) or placebo; randomization was stratified by duration of prior AI therapy (£6 months vs >6 months). All patients were instructed to take calcium (1 g/day) and vitamin D (400 U/day) supplements. Denosumab or placebo was administered subcutaneously on study day 1 and at months 6, 12, and 18. Bone turnover markers (serum C-telopeptide [CTX] and N-terminal propeptide of type 1 procollagen [P1NP]) were evaluated at baseline and at months 1, 6, 12, and 24. Safety was assessed in all study participants every 6 months for up to an additional 24 months following study completion or termination of study participation.1

The primary efficacy end point was the percentage change from baseline in lumbar spine BMD at 12 months compared with placebo. Exploratory end points included percentage changes in lumbar spine, total hip, and femoral neck BMD at 1, 3, and 24 months; the percentage changes from baseline in total body, one-third radius, and trochanter BMD at 12 and 24 months; percentage changes from baseline in CTX and P1NP at 1, 6, 12, and 24 months; and incidence of vertebral and nonvertebral fractures.1

Results

A total of 252 patients were enrolled in the study, 127 in the denosumab group and 125 in the placebo group. Baseline demographics, BMD measurements, and duration of prior AI use were well balanced between the treatment groups. Most patients were white and the mean age was 59.5 years. Overall, 63% of patients received prior AI therapy for more than 6 months.1

For the primary end point, lumbar spine BMD increased by 5.5% in the denosumab group compared with the placebo group after 12 months of treatment (P <.0001). After 24 months of treatment, lumbar spine BMD increased by 7.6% with denosumab compared with placebo (P <.0001). Increases were observed at 1 month and were not influenced by the duration of prior AI therapy. Additionally, when covariates (eg, age, race, weight at baseline, body mass index, prior chemotherapy, prior selective estrogen receptor modulator use, and time from last menstrual period) were added to the primary efficacy model, the treatment effect of denosumab on lumbar spine BMD at 12 months was still significantly different from placebo (P <.0001).1

Compared with placebo, denosumab was associated with significant increases in BMD at all measurement sites, including the one-third radius, which is predominately cortical bone. The percentage changes from baseline in BMD at 24 months in the total hip, femoral neck, trochanter, one-third radius, and total body are listed in the Table.1

Denosumab was associated with rapid reductions in markers of bone remodeling. Serum CTX levels reached their lowest point at the earliest evaluation (1 month), with a median percentage reduction from baseline of 91% compared with 9% in the placebo group (P <.0001). At 1 month, the median percentage reduction in P1NP was 29% with denosumab and 2% with placebo (P <.0001). P1NP levels continued to decrease with ongoing denosumab treatment, then stabilized, with reductions of 71% to 73% observed between 6 months and 24 months.1

Although no vertebral fractures were reported for either treatment group through 24 months, nonvertebral fractures occurred in 8 patients in each treatment group during this timeframe. Major nonvertebral fractures (eg, those occurring in the pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, or hip) were reported in 3 patients given denosumab and 5 patients given placebo.1

The overall incidence of AEs was similar between the denosumab and placebo groups— 91% and 90% of patients, respectively. The most common AEs were arthralgia, pain in extremity, back pain, and fatigue. The proportion of patients who experienced a grade 3 or higher AE was the same in both treatment groups (23%). Serious AEs occurred in 19 patients given denosumab and 11 patients given placebo, although none were considered to be related to treatment.1

Conclusions

In patients with breast cancer at risk for AI-induced bone loss, denosumab was associated with rapid, marked, and sustained increases in lumbar spine BMD through 24 months. These increases in lumbar spine BMD were observed regardless of the duration of prior AI therapy. Twice-yearly treatment with denosumab was generally well tolerated, significantly increased BMD, and reduced bone turnover in women with nonmetastatic breast cancer who were at risk of developing osteoporosis and fracture.1

Reference

1. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875-4882. doi: 10.1200/JCO.2008.16.3832.

 
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