Denosumab effective in transfusion-dependent thalassemia-induced osteoporosis

A twice-yearly injection of denosumab improved spinal bone mineral density among individuals with osteoporosis caused by transfusion-dependent thalassemia, according to a randomized phase 2b study published in Blood Advances.

The treatment also reduced pain and improved quality of life.

“Not only is denosumab associated with improved bone health and reduced pain, but its ease of administration may very well make this drug superior to bisphosphonates for the treatment of osteoporosis in patients with [transfusion-dependent thalassemia] and osteoporosis,” senior study author Evangelos Terpos, MD, researcher at the National and Kapodistrian University in Athens, Greece, said in a press release.

Osteoporosis affects 40% of patients with transfusion-dependent thalassemia, a congenital blood disorder that causes decreased production of hemoglobin and red blood cells.

The current standard therapy is IV administration of bisphosphonate agents, including pamidronate and zoledronic acid.

Denosumab (Xgeva, Amgen) — a fully human monoclonal antibody — inhibits receptor activator of nuclear factor kappa-B ligand (RANKL), which studies have shown is elevated in patients with transfusion-dependent thalassemia and is associated with low bone mineral density.

Denosumab is not yet approved by the FDA for use by patients with osteoporosis caused by transfusion-dependent thalassemia.

Terpos and colleagues conducted a single-site, placebo-controlled, double-blind phase 2b trial that included 63 patients with transfusion-dependent thalassemia and bone mineral density T scores between -2.5 and -4 in at least one of three examined areas — lumbar spine, femoral neck or wrist bone.

Researchers assigned patients to receive either 60 mg denosumab (n = 32) or a placebo (n = 31) subcutaneously on days 0 and 180. Follow-up continued until 1-year after initial treatment.

Each patient also was given a daily supplement of calcium and vitamin D throughout the study period.

All patients had at least eight transfusions per year in the three years preceding the study. Median number of blood transfusions in the 1-year period before the study was 15 (range, 8-60) in the denosumab group and 11 (range 8-48) in the placebo group.

The study’s primary objective was to evaluate the effect of treatment on lumbar spine bone mineral density compared with placebo. Secondary objectives included evaluation of the effect on femoral neck and wrist bone mineral density, pain scores and markers of bone remodeling, as well as safety.

Results at 1 year showed a mean 5.92% increase in lumbar bone density among patients who received denosumab, compared with a 2.92% increase among patients assigned placebo (P = .043).

Further comparison showed patients in the denosumab group lost less bone mineral density in the wrist (– 0.26% vs. – 3.92%; P = 0.35) and had increased density in the femoral neck (4.08% vs. 1.96%).

Patients assigned denosumab also reported a significant reduction in pain compared with patients assigned placebo.

Three serious adverse events occurred among patients who took denosumab. These included one case each of grade 3 pleural effusion, grade 4 supraventricular tachycardia and grade 3 atrial fibrillation. Researchers found no direct link between treatment and the adverse events.

Terpos and colleagues acknowledged study limitations, including the use of bone mineral density to evaluate osteoporosis and the wide range of blood transfusions among patients over the 3-year period before the study.

“[Denosumab] administration was associated with a significantly greater increase in the lumbar spine bone mineral density in patients with [transfusion-dependent thalassemia]-associated osteoporosis compared with placebo. [Denosumab] seemed also to reduce biomarkers promoting bone resorption,” Ersi Voskaridou, MD, PhD, director of the National Center for Thalassaemia and Haemoflobinopathies at Laikon General Hospital in Athens, and colleagues wrote. “However, there was evidence for a higher number of adverse events in the [denosumab] group compared [with] the placebo. Subsequently, more research is needed to clarify the effect of [denosumab] on other surrogate endpoints, to control for confounding factors, and to evaluate safety with a longer follow-up period.” – by John DeRosier

Reference:

Voskaridou E, et al. Blood. 2018;doi:10.1182/bloodadvances.2018023085.

Disclosure: The study was supported by Amgen. The authors report no relevant financial disclosures.