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.

Denosumab effects on serum levels of the bone morphogenetic proteins antagonist noggin in patients with transfusion-dependent thalassemia and osteoporosis

“…Increased levels of RANKL have been also identified among thalassemia patients [11]. In this context, we have evaluated the effect of denosumab on TDT-induced osteoporosis and we have found encouraging results pertaining to an improvement in BMD and a reduction in pain scores and markers of bone resorption [5].…”

“…This is a post hoc analysis of a phase 2b clinical trial evaluating the efficacy and safety of denosumab among patients with TDT-induced osteoporosis (Clini-calTrials.gov identifier: NCT02559648) [5]. This study was conducted at Thalassemia Reference Centre at Laiko General Hospital (Athens, Greece).…”

“…Study design, eligibility criteria, endpoints, randomisation and masking procedures, interventions, clinical and laboratory assessments have been previously described in detail [5]. In brief, this was a double-blind, placebo-controlled, single-site, randomized phase 2b clinical trial.…”

“…Although bisphosphonates have been traditionally considered the mainstay of TDT-induced osteoporosis, there is accumulating evidence suggesting denosumab as a promising drug in the field [3][4][5]. Denosumab is a fully human monoclonal antibody that strongly binds and inhibits receptor activator of nuclear factor kappa-B ligand (RANKL).…”

Zoledronik asit osteoporozlu β-talasemi hastalarında kemik mineral yoğunluğunu arttırır: Bir vaka kontrol çalışması

“…Several therapies including calcium, vitamin D, calcitonin, sex steroids, and strontium ranelate provide contribution to bone growth and remodeling [9][10][11] . Furthermore, in recently one phase 2b study was showed that denosumab 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 12,13 . Although this drug has been used for hypercalcemia in hematological malignancies, there is insufficient evidence for its use in osteoporotic patients with β-thalassemia.…”