Denosumab in transfusion-dependent thalassemia osteoporosis: a randomized, placebo-controlled, double-blind phase 2b clinical trial

Abstract

Denosumab (DNM) is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) that has been licensed for the treatment of different types of osteoporosis. However, the prospective data for the evaluation of DNM efficacy on transfusion-dependent thalassemia (TDT)-induced osteoporosis are rather limited. Thus, we conducted a randomized, placebo-controlled, double-blind, phase 2b clinical trial to evaluate DNM in TDT osteoporosis. Patients were assigned to receive either 60 mg DNM (n = 32) or placebo (n = 31) subcutaneously on day 0 and 180 during a total of 12 months of follow-up. The percentage increase of L1-L4 bone mineral density was higher in the DNM group than the placebo group (5.92% ± 5.25% vs 2.92% ± 5.56%, respectively; P = .043), whereas the advantage of DNM regarding wrist bone mineral density was much higher compared with placebo (-0.26% ± 5.31% vs -3.92% ± 8.71%, respectively; P = .035). No grade 3 or 4 toxicity was observed. DNM reduced pain scores that remained unaltered in the placebo group. DNM showed a significant reduction of soluble RANKL (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase between baseline and the 12th month (P < .01 for all comparisons) without changes in dickkopf-1, sclerostin, and osteocalcin. On the contrary, placebo patients showed an increase in sRANKL, osteoprotegerin, dickkopf-1, sclerostin, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase during the study period (P < .01 for all comparisons). In conclusion, DNM increased lumbar spine and wrist bone mineral density and reduced pain and bone remodeling markers, and thus it is another valuable option for the management of TDT-induced osteoporosis. This trial was registered at www.clinicaltrials.gov as #NCT02559648.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study schema. On enrolment in the study after eligibility assessment, patients were randomly assigned in a 1:1 fashion to receive either 60 mg DNM or placebo sc, every 6 months for 12 months for a total of 2 doses (Day 0 ± 3 and Day 180 ± 3). Patients were followed every 3 months for clinical and laboratory evaluation.

Figure 2.

Consort flow diagram. Among the 80 patients assessed for eligibility, 63 were eventually randomized: 32 were allocated to and received DNM, whereas 31 were allocated to and received placebo. One patient from the placebo group was lost to follow-up, whereas 2 patients from the DNM group withdrew consent. The final analysis was made on an intent-to-treat basis.

Figure 3.

Analysis of covariance for the bone mineral density percentage change, defined as the dependent variable, with treatment group as a factor, defined as the independent variable consisting of 2 levels (DNM and placebo), and first baseline T score as covariate or nuisance variable. A significant difference on the percentage change (from baseline to 12-month visit) between the 2 groups was observed, after adjusting for the baseline T score (P = .043). DNM induced a significantly greater increase in bone mineral density compared with placebo.