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Denosumab increases BMD in women with breast cancer receiving AI therapy, findings indicate

Monday, December 17 2007 | Comments
Evidence Grade 0 What's This?
Twice-yearly administration of denosumab consistently increased bone mineral density (BMD) during 24 months of treatment in women with nonmetastatic breast cancer who had low bone mass and were receiving adjuvant aromatase inhibitors (AI), data from the Phase III HALT Breast Cancer 135 study showed.

Although adjuvant therapy with AIs is common practice in postmenopausal women with hormone receptor (HR)-positive breast cancer, it can be complicated by accelerated bone loss and increased risk of fracture.

According to the researchers, bone loss is mediated by osteoclasts, which depend on receptor activator of NF-kB ligand (RANKL) for formation, function, and survival.

To evaluate the effect of denosumab, a fully human monoclonal antibody to RANKL, on BMD in women with histologically confirmed HR-positive, nonmetastatic breast cancer who were receiving AI therapy, researchers randomized patients to receive 60 mg of denosumab (n=127) or placebo (n=125) subcutaneously every 6 months for 4 doses.

Patients, who were stratified by duration of AI therapy (<=6 months vs >6 months), were told to take calcium and vitamin D daily. The patients all displayed evidence of bone loss at enrollment. None of the patients, however, had osteoporosis or T scores < -2.5 at the lumbar spine, total hip, or femoral neck.

The study's primary endpoint was percentage change from baseline at month 12 in lumbar spine BMD. This was obtained by dual-energy x-ray absorptiometry measurement.

At 12 months, lumbar spine BMD increased by 5.5% in patients who received denosumab as compared with patients who received placebo. At 24 months, this measure increased to 7.6% in patients who received denosumab versus those who were given placebo. The between-group differences were significant at both time points (P<.0001). Duration of AI therapy did not influence these increases, the researchers noted.

At both 12 and 24 months, increases in BMD were also seen elsewhere, including at the total hip and total body as well as predominantly cortical sites at the femoral neck and distal 1/3 radius (P<.0001 without multiplicity adjustment). At 12 months, the difference from placebo at the femoral neck and distal 1/3 radius was 2.5% and 3.8%, respectively.

Dr. Georgiana Ellis, the study's lead investigator, told VerusMed that the effect of the drug on the cortical bone of the distal 1/3 radius was unique because this area is generally not affected by biphosphonate therapy, the other alternative for bone loss treatment.

In addition, 97% of patients in the denosumab group had preservation of lumbar spine BMD at 12 months compared with 36% of patients in the placebo group (P<.0001). At 24 months, the same preservation was found for 95% of patients in the denosumab group and 34% of patients in the placebo group (P<.0001).

Between the groups, the overall incidence of treatment-emergent adverse events was similar, with 91% of the denosumab group and 90% of the placebo group reporting them. The number of grade III, IV, and V adverse events was also similar between the groups (23% with denosumab vs 23% with placebo). In the denosumab group, 19 patients (15%) had >=1 serious adverse event compared with 11 patients (9%) in the placebo group.

The authors said none of the serious adverse events were considered treatment related in either group and noted that "[n]o specific type of adverse event accounted for the slight imbalance in serious adverse events." Neither of the 2 deaths in the study (1 in each group due to metastatic breast cancer) was considered treatment related. (Abstract 47.)

This information concerns a use that has not been approved by the Food and Drug Administration.

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