The human monoclonal antibody denosumab has been found to increase bone mineral density in postmenopausal women, results of a recent randomized phase II study suggest.
Evaluation of the primary end point—the percentage change in lumbar spine bone mineral density from baseline to 12 months—indicated that denosumab was active and significantly superior to placebo (N. Engl. J. Med. 2006;354:821–31).
Dr. Michael R. McClung, of the Providence Portland (Ore.) Medical Center, and his fellow researchers evaluated 12 months of denosumab, compared with open-label oral alendronate (70 mg once weekly) or placebo in postmenopausal women with low bone mineral density, as defined by a “T score of −1.8 to −4.0 at the lumbar spine or −1.8 to −3.5 at either the femoral neck or total hip,” the researchers reported.
Subjects randomized to the experimental arm received denosumab every 3 or 6 months.
Of the 412 study participants, 319 women were randomized to the seven denosumab groups, 47 to the alendronate group, and 46 to the placebo group; 369 women completed the 12-month treatment study.
At study end, women receiving denosumab had increases in bone mineral density at the lumbar spine of 3.0%–6.7%, compared with a 0.8% decrease with placebo, or a mean increase of 4.6% with alendronate. Bone mineral density was also found to be superior with denosumab, compared with placebo at the total hip (mean change, 1.9%–3.6% vs. −0.6%, respectively), the distal third of the radius (0.4%–1.3% vs. −2.0%), and the total body (0.6%–2.8% vs. −0.2%), the researchers reported.
They noted that “in exploratory comparisons, the observed mean changes in bone mineral density were at least as great with denosumab as with alendronate.”
Denosumab targets the receptor activator of nuclear factor-β ligand (RANKL). By specifically binding to RANKL with a high affinity, denosumab inhibits RANKL activity.
In an accompanying editorial, Dr. Michael P. Whyte expressed concern that inhibiting RANKL, a member of the “tumor necrosis factor superfamily,” might have unintended effects on the immune system (N. Engl. J. Med. 2006; 354:860–3). “Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications,” Dr. Whyte suggested.
During the study, an investigation into bone turnover indicated a significant decrease in serum C-telopeptide with denosumab that had a dose-dependent duration; a similar pattern was noted for the urinary N-telopeptide to creatinine ratio. These markers of bone turnover were at least equivalent with denosumab, compared with alendronate.
Adverse events were calculated in 406 study participants who received at least one dose of denosumab, alendronate, or placebo. Dyspepsia, however, was found to be greater in the alendronate group.
In the denosumab-treated group, 5.7% of study participants reported a serious adverse event, compared with 4.3% in the placebo group, and 2.2% in the alendronate group. In both the denosumab and placebo arms, 2.2% of the women withdrew from the study due to adverse events, and 3.8% of the denosumab group reported clinical fractures, compared with 2.2% in both the placebo and alendronate groups.
Dr. McClung and his investigators noted that their study was not designed to test equivalency, and denosumab should be further investigated for the treatment and prevention of bone-loss diseases.
The study was developed and supported by Amgen Inc., the manufacturer of denosumab. Dr. McClung disclosed having served as a consultant for, and having received grant support from, Amgen.