Comparison of the Effect of Denosumab and Alendronate on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized, Blinded, Phase 3 Trial

Abstract

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, doubleblind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty-nine postmenopausal women with a T-score Յ −2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n ‫ס‬ 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n ‫ס‬ 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one-third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12-mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one-third radius; p Յ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab-and alendronate-treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.

Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: The OCEAN study

“…We excluded subjects with low bone resorption because in previous studies with antiresorptive drugs, such as alendronate and denosumab, low bone resorption was associated with a smaller BMD response. (20) The effect of such an exclusion would be greater increases in BMD for both alendronate and ONO-5334, but the relative change should not differ. This study was conducted at 13 study sites in 6 European countries and was conducted in accordance with applicable regulations and International Conference on HarmonisationGood Clinical Practice (ICH-GCP) and local legal requirements.…”

Cost Effectiveness of Denosumab Compared with Oral Bisphosphonates in the Treatment of Post-Menopausal Osteoporotic Women in Belgium

“…Therefore, 57.6% of patients received 3 years of treatment. In the case of discontinuation with denosumab after 6 months, fracture efficacy was assumed during this period given the large gains in BMD previously reported [65,66] and a declining effect over the subsequent 6 months. We also assumed, for both treatments, that if patients discontinued therapy, they received no further treatment.…”

Denosumab for bone diseases: translating bone biology into targeted therapy

“…Mild and asymptomatic hypocalcaemia has been reported in 0.1% (vs 0% in the placebo group) in the HALT study (41) and in 0% (vs 0.1% in the placebo group) in the DECIDE study (39). Patients with impaired renal function are particularly prone to hypocalcaemia after denosumab administration.…”

“…However, denosumab lacked superiority, after adjustment for multiple comparisons (44) and has not received approval for treatment of myeloma bone disease. In light of the clinical hypocalcaemic effects of denosumab (39,42,43) and evidence from preclinical animal models of RANKL blockade (45)(46)(47)(48), hypercalcaemia associated with malignancies might be another indication for denosumab, although this required formal testing in clinical trials.…”