Discussion
Adolescents with non-deletional Hb H disease have many risk factors for
compromised bone health similar to their peers with β-TI whose disease
severity is comparable. In the present study, we demonstrated high
prevalence of low BMD in adolescents with non-deletional Hb H disease.
Notably, the majority of them receiving frequent blood transfusion. The
prevalence of low BMD was higher at the lumbar spine as compared to the
total body site. After adjusting for confounding factors, TBBMD was
inversely associated with serum Dkk-1 concentration, suggesting that
alteration in the Wnt signaling pathway might play an important role in
decreased bone mass and might be a potential bone biomarker in
non-deletional α-thalassemia.
Our study found that the prevalence of low LSBMD in adolescents with
non-deletional Hb H disease is slightly lower (42% vs. 50%) than the
report from the United States Thalassemia Clinical Research Network
(USTCRN) study.12 Moreover, when compared with USTCRN
study, the prevalence of low LSBMD in adolescents with deletional Hb H
disease was similar to their peers with β-TM (44%) and β-TI (44%),
lower than those with both transfusion-dependent and
nontransfusion-dependent forms of Hb E/β-thalassemia (58%), and higher
than those with Hb H disease (13%).12 Notably, the
high prevalence of low LSBMD in Hb E/β-thalassemia vs. other forms in
this study might be related to the clinical severity as demonstrated by
shorter height, more delayed BA, lower pre-transfusion Hb, and higher
serum transferrin receptor concentration. In addition, sex, race,
vitamin D status, blood transfusion and iron chelation protocols as well
as different methods used for calculating BMD z-score (i.e., height
adjusted vs. unadjusted BMD z-score) may also contributed to the
differences observed. Recently, Nakavachara et al. measured the
height-adjusted BMD z-score in Thai adolescents with
nontransfusion-dependent Hb E/β-thalassemia and found lower prevalence
of low LSBMD (23%) and TBBMD (9%)27 as compared to
peers with non-deletional Hb H disease or Hb E/β-thalassemia in our
study and USTCRN. Again, participants in the Nakavachara’s study seemed
to have less severity of anemia and lower ferritin concentration. As
expected, the prevalence of low BMD was higher at the trabecular lumbar
spine, where bone marrow expansion occurs in response to anemia,
compared to the total body site. Taken together, other studies and ours
confirm the high prevalence of low LSBMD in non-deletional
α-thalassemia, comparable to β-thalassemia of similar anemia severity
and blood transfusion requirement.
Our results are in line with other thalassemia studies that age, BMI
z-score (i.e., nutritional status) and pubertal
status5,12,28 are associated with BMD. Furthermore,
male adolescents had lower LSBMD z-score and a trend toward lower TBBMD
z-score compared to females despite having comparable blood transfusion
frequency, iron overload, and rates of endocrine complication, and even
higher Hb concentration. However, the latter is considered to be normal
physiology as healthy male vs. female adolescents have
~12% higher Hb concentration due to testosterone
effect.29 Previous literature in adults with
thalassemia major supports our findings by demonstrating that male vs.
female patients had an increased prevalence of low BMD particularly at
the LS site.30 Interestingly, a recent meta-analysis
showed men vs. women with anemia and otherwise healthy had higher rates
of fracture31 suggesting that anemia per se may have
different impacts on male vs. female skeletons. Moreover, there is
empirical evidence showing that males with β-thalassemia are more
susceptible to iron toxicity in many organs than
females32,33 which is linked to sex-related expression
of various pathways such as oxidative stress and
erythropoietin.33 In α-thalassemia, this information
remains unknown, thus, further research is needed.
Wnt/β-catenin pathway is crucial for the gain and maintenance of bone
mass. Several agonizing and antagonizing molecules involve in the
regulation of this intricate pathway.34 To date, many
studies have assessed sclerostin,16,17 another Wnt
inhibitor, in various causes of osteoporosis including thalassemia, but
only a few studies have evaluated serum Dkk-1 concentration in
thalassemia.18,35 Voskaridou et al. found that adults
with transfusion-dependent β-thalassemia vs. healthy controls had
elevated concentrations of Dkk-1 and sclerostin, both of which were
associated with lower BMD z-score at the lumbar spine, forearm and
femoral neck.17,18 They also found that among various
bone metabolism markers (including receptor activator of NF-kB (RANK)
ligand and osteoprotegerin), only Dkk-1 was an independent predictor for
severe low bone mass. In addition, a reduction in Dkk-1 but not
sclerostin was observed in their participants following bisphosphonate
therapy.18 In adolescents with non-deletional Hb H
disease, we demonstrated similarly that Dkk-1 was inversely correlated
with LSBMD and TBBMD z-scores. However, when adjusting for confounders,
Dkk-1 remained an independent negative predictor only for TBBMD z-score.
We also examined factors associated with Dkk-1 concentration and found
that interval of blood transfusion, a surrogate marker of anemia
severity, had a negative correlation, and the history of delayed puberty
had a positive correlation with Dkk-1. Multiple studies also found
people with hypogonadism had increased Dkk-1 and sclerostin
concentrations.36-39 However, the mechanism linking
sex hormone and Dkk-1 is incompletely understood. Whether circulating
Dkk-1 involves in the pathogenesis of decreased BMD in thalassemia needs
future research.
Our study had some limitations. First, our study design was
cross-sectional, thus, the association results must be interpreted with
caution. Further, our study also had a small sample size that may lead
to type II error. Finally, we did not measure sex hormone
concentrations, therefore, we could not determine their associations
with Dkk-1.
In conclusion, adolescents with non-deletional Hb H disease had a high
prevalence of low BMD with the lumbar spine being the prominent site.
Our reported prevalence is akin to that in β-thalassemia of similar
severity. Furthermore, Dkk-1 was independently associated with TBBMD
suggesting its potential bone biomarker in thalassemia. Whether Dkk-1
involves in the pathogenesis of low bone mass in non-deletional Hb H
disease requires further research.