Treatment with twice-yearly denosumab improved spinal bone mineral density (BMD) compared with placebo in patients with transfusion-dependent thalassemia (TDT)–induced osteoporosis, according to results of a phase IIb study published in Blood Advances.
Denosumab, which targets the RANK ligand (a mediator of bone resorption), also reduced pain scores and markers of bone remodeling, the authors, led by Ersi Voskaridou, MD, from the Thalassemia and Sickle Cell Disease Center at Laiko General Hospital, in Athens, Greece, reported.
"As [transfusion] and chelation therapy have significantly prolonged survival in [patients with TDT], osteopenia and osteoporosis significantly add to the morbidity burden in young adults" through both genetic and acquired factors, the investigators explained. "Although bisphosphonates are currently the mainstay of treatment in thalassemia patients with osteoporosis, denosumab may provide a more favorable efficacy and tolerability profile."
This randomized, placebocontrolled, double-blind trial enrolled 63 patients with TDTinduced osteoporosis, defined as a BMD T-score between –2.5 and –4.0 in either the lumbar spine, femoral neck, or wrist bone.
Patients with BMD T-scores <–4.0 in one of the two studied sites (lumbar spine, femoral neck) or those with previous administration of denosumab or bisphosphonates, fluoride, and strontium ranelate within one year of study enrollment were excluded. Patients were randomized to receive either subcutaneous denosumab 60 mg (n=32) or placebo (n=31), administered once every six months for 12 months. Participants also received daily supplementation with calcium 1,000 mg and vitamin D 400 IU or 800 IU. Randomization, treatment, and assessment occurred at a single center in Athens.
During the screening period and at the end of the study, the investigators measured BMD at the L1-L4 vertebrae, femoral neck, and wrist bone. Bone pain was assessed via the Huskisson's visual analogue scale (0 cm = no pain; 10 cm = worst pain possible) at both time points.
The researchers also measured the following four bone remodeling markers of osteoporosis at baseline and then at three-month increments during study treatment:
- bone resorption markers (e.g., C-terminal crosslinking telopeptide of type-I collagen and tartrate-resistant acid phosphatase isoform-5b)
- bone formation markers (e.g., bone-specific alkaline phosphatase and osteocalcin)
- osteoclast regulators (e.g., sRANKL and osteoprotegerin [OPG])
- osteoblast inhibitors (e.g., dickkopf-1 and sclerostin)
One year prior to study initiation, patients in each group required similar numbers of transfusions (15 in denosumab-treated patients vs. 11 in placebo-treated patients; p=0.714). The range of T-score values at each site also were similar between the denosumab and placebo groups:
- femoral neck: –3.20 and –0.50 vs. –3.30 and –0.40 (p=0.245)
- lumbar spine: –4.00 and –0.90 vs. –4.00 and –0.90 (p=0.587)
- wrist bone: –11.7 and –1.10 vs. –8.70 and –0.10 (p=0.367)
After 12 months of treatment, the increase in lumbar spine BMD from baseline (primary endpoint) was significantly higher in patients who received denosumab compared with those who received placebo (5.92% vs. 2.92%; p=0.043) as well as in wrist BMD (–0.26% vs. –3.92%; p=0.035)," the authors added.
Denosumab treatment also reduced the levels of bone resorption markers, beginning at three months after the injection of treatment or placebo; for example, C-terminal crosslinking telopeptide of type-I collagen decreased by 31.6 percent in the denosumab group but increased by 16.5 percent in the placebo group (p<0.001).
While all participants had mild to moderate pain at baseline, by 12 months, only those in the denosumab group experienced a significant reduction in pain:
- denosumab: 3.4 cm at baseline vs. 2.8 cm at 12 months (p<0.001)
- placebo: 3.0 cm vs. 2.8 cm (p=0.356)
Seventeen adverse events (AEs) occurred in 14 patients during the 12-month study period, with most of these events classified as grade 1. "Most mild AEs (n=11/14) concerned abnormalities on blood or biochemical test and only three of them a clinical symptom – specifically headache, diarrhea, and fever," the researchers reported. AEs were more common in the denosumab group, compared with the placebo-treated group (p=0.018), and the three serious AEs reported during the study duration all occurred in the denosumab group.
The patient population of the study was highly heterogenous, which the investigators cited as a potential limitation. In addition, the small number of participants and the single-center design also could limit the ability to extrapolate findings across the entire TDT and osteoporosis population.
"Denosumab seemed also to reduce biomarkers promoting bone resorption; however, there was evidence for a higher number of AEs in the denosumab group compared with placebo," the researchers concluded. "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."
The authors report no conflicts of interest. The study was supported by Amgen.
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 Advances.