in a Different Vein
Research from ASH’s online peer-reviewed
journal, Blood Advances
Evaluating Twice-Yearly Denosumab for Transfusion-
Dependent, Thalassemia-Induced Osteoporosis
Treatment with twice-yearly deno-
sumab improved increased spinal
bone mineral density (BMD)
compared with placebo in patients
with transfusion-dependent thalas-
semia (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 signifi-
cantly 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, deno-
sumab may provide a more favorable
efficacy and tolerability profile.”
This randomized, placebo-
controlled, double-blind trial
enrolled 63 patients with TDT-
induced 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 previ-
ous administration of denosumab
or bisphosphonates, fluoride, and
strontium ranelate within one year
of study enrollment were excluded.
Patients were randomized to
receive either subcutaneous deno-
sumab 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 investiga-
tors measured BMD at the L1-L4
vertebrae, femoral neck, and wrist
bone. Bone pain was assessed via the
Huskisson’s visual analogue scale
38
ASH Clinical News
(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 telo-
peptide of type-I collagen and
tartrate-resistant acid phosphatase
isoform-5b)
• bone formation markers (e.g.,
bone-specific alkaline phospha-
tase 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 reduc-
tion 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 biochemi-
cal test and only three of them a clini-
cal 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 limi-
tation. 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
“Denosumab
may provide a
more favorable
efficacy and
tolerability
profile [than
current
mainstays of
treatment].”
—ERSI VOSKARIDOU, MD
evidence for a higher number of AEs
in the denosumab group compared
with placebo,” the researchers
concluded. “Subsequently, more re-
search is needed to clarify the effect
of denosumab on other surrogate
endpoints to control for confound-
ing factors, and to evaluate safety
with a longer follow-up period.” ●
The authors report no conflicts of
interest. The study was supported by
Amgen.
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 Advances.
November 2018