Denosumab Appears to Help Patients With Transfusion-Dependent Thalassemia, Osteoporosis

Patients with transfusion-dependent thalassemia (TDT) and osteoporosis who were treated with denosumab had greater increases in bone mineral density in the femoral neck and lumbar spine, as well as lower pain scores and bone resorption biomarkers, compared with placebo, according to the results of a phase 2b trial.

Thalassemia is a blood disorder caused by abnormal hemoglobin production. In patients with TDT, transfusions have prolonged survival but also significantly increased the incidence of osteoporosis. Despite adequate treatment to normalize hemoglobin levels, bone resorption still occurred and greatly reduced bone mineral density.

Current evidence suggests that a combination of osteoblast dysfunction as well as increased osteoclast activation represents the proposed mechanism for osteoporosis in TDT. One area of interest is the receptor activator of nuclear factor κ-B (RANK) pathway that is known to activate osteoclasts and induce low bone mineral density.

Denosumab, a monoclonal antibody that inhibits RANK ligands, has been theorized to increase bone density. In this trial, investigators evaluated the safety and efficacy of denosumab in patients with TDT and osteoporosis to determine if it can be considered a viable treatment option in this population.

Patients in this trial received either denosumab 60 mg injected subcutaneously every 6 months or placebo. All patients who participated in this trial had TDT and a bone mineral density T score between —2.5 to –4 in at least one of these sites: lumbar spine, femoral neck, or wrist bone. Baseline ranges for T score were between –3.20 to –0.50 for the femoral neck, –4 and –0.90 for the lumbar spine, and –11.7 and –1.10 for the wrist bone, for patients in the denosumab group.

Ranges for T score were between —3.30 and –0.40 for the femoral neck, –4 and –0.90 for the lumbar spine, and –8.70 and –0.10 for the wrist bone for the placebo group.

After the 12-month trial period, the mean percentage increase of lumbar spine bone mineral density was significantly greater in the denosumab group versus the placebo group (5.92% vs 2.92%; P = .043). Increase in femoral neck bone mineral density was also greater in the denosumab group compared with placebo, although the difference was not significant (4.08 vs 1.96%; P = .870). Patients in both groups had decreases in wrist bone mineral density, but the decrease was significantly less in the denosumab group (—0.26% vs –3.92%; P =.035).

Patients who received denosumab had pain scores that were significantly lower than they were at baseline. In comparison, patients who received placebo did not have a change in pain scores. Patients who were administered denosumab also had a significant reduction in RANK ligands, C-terminal crosslinking telopeptide of type I collagen, tartrate-resistant acid phosphatase isoform-5B, RANK ligand/osteoprotegerin ratio, and bone specific alkaline phosphatase, in contrast to patients in the placebo group who had increases in each of these markers.

From this trial, investigators found that denosumab was associated with greater increases in lumbar and femoral neck bone mineral density in patients with TDT-associated osteoporosis. Furthermore, denosumab had fewer reductions in wrist bone mineral density and was able to reduce biomarkers that promoted bone resorption. Based on the results of this trial, investigators concluded that denosumab should be considered in patients with TDT and osteoporosis.

Reference

Voskaridou E, Ntanasis-Stathopoulos I, Papaefstathiou A, et al. Denosumab in transfusion-dependent thalassemia osteoporosis: a randomized, placebo-controlled, double-blind phase 2b clinical trial. Blood Adv. 2018;2(21):2837-2847. doi:10.1182/bloodadvances.2018023085.