Associations of serum sclerostin with bone mineral density, markers of bone metabolism and thalassaemia characteristics in adult patients with transfusion-dependent beta-thalassaemia

Sapunarova, Katya; Goranova-Marinova, Vesselina; Georgiev, Pencho; Deneva, Tanya; Tsvetkova, Silvia; Грудева-Попова, Жанет

doi:10.1080/07853890.2020.1744708

Cited by 5 publications

(4 citation statements)

References 64 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Dkk-1 is an osteogenic cell-derived glycoprotein that inhibits Wnt/β-catenin signaling pathway, a key regulator of osteoblast function and bone formation. 15 In adults with β-thalassemia and TAO, increased sclerostin 16,17 and Dkk-1 18 concentrations were observed. Furthermore, serum Dkk-1 concentration was inversely associated with the lumbar spine (LS) BMD 18 as similarly observed in postmenopausal osteoporosis.…”

Section: Introductionmentioning

confidence: 97%

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Bone Mineral Density and Dickkopf-1 in Adolescents with Non-deletional Hemoglobin H Disease

Wiromrat

Rattanathongkom

Laoaroon

et al. 2023

Preprint

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Background: Low bone mineral density (BMD) is prevalent in individuals with β-thalassemia which might be related to increased circulating dickkopf-1 (Dkk-1). These data are limited in α-thalassemia. Objectives: To evaluate the prevalence of low BMD in adolescents with non-deletional hemoglobin (Hb) H disease. Additionally, we aimed to examine the association between serum Dkk-1 concentration and BMD. Methods: Participant medical records were reviewed. The lumbar spine (LS) and total body (TB) BMD were measured and converted into height-adjusted z-scores. Serum Dkk-1, osteocalcin and C-telopeptide of type-I collagen (CTX) concentrations were also analyzed. Results: Thirty-seven participants (59% female, 86% Tanner stage ≥2, 95% regularly transfused) had mean age 14.6 ± 3.2 years, and average pretransfusion Hb and ferritin concentrations of 8.8 ± 1.0 g/dL and 958 ± 513 ng/mL, respectively. No participants had experienced fracture. The prevalence of low LSBMD and TBBMD was 42% and 17%, respectively. LSBMD z-score was lower in males vs. females (p-value = 0.029). LSBMD and TBBMD z-scores were correlated positively with BA, Tanner stage, and BMI, and negatively with Dkk-1 (p-values <0.05). Dkk-1 was correlated positively with history of delayed puberty, and negatively with transfusion interval (p-values = 0.038). Osteocalcin and CTX did not correlate with BMD or Dkk-1. Multiple regression analysis showed Dkk-1 inversely associated with TBBMD z-score adjusting for confounders (p-value = 0.009). Conclusions: We demonstrated a high prevalence of low BMD in adolescents with non-deletional Hb H disease. Moreover, Dkk-1 inversely associated with TBBMD suggesting it may serve as bone biomarker in thalassemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Bone Mineral Density and Dickkopf-1 in Adolescents with Non-deletional Hemoglobin H Disease

Wiromrat

Rattanathongkom

Laoaroon

et al. 2023

Preprint

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“…A study of 62 subjects with major BTH (32 males/30 females) showed that RANKL (receptor activator of nuclear factor kappa-Β ligand) was higher ( p = 0.049) and OPG (osteoprotegerin)/RANKL ratio was lower ( p = 0.009) in patients with BTH versus a group of menopausal osteoporotic women, with similar results for sclerostin and CTX (C-terminal telopeptide), which suggests that traditional medication against OP should not be different in TBD [ 97 ]. A study on adults with major BTH showed a 10-fold increase in serum sclerostin versus controls, being correlated with pre-transfusion Hb levels, LIC (Liver Iron Concertation), splenectomy status, and prevalent fractures [ 98 ]. Another study from 2022 confirmed lower OPG, a respective lower OPG/RANKL ratio in 60 children with transfusion-dependent BTH (aged between 5 and 14 y) versus 60 age—and sex- matched healthy subjects, with a higher incidence of OPG rs2073618 (×2.3) and OPG rs2073617 genotypes (×1.9) among TBD [ 99 ].…”

Section: Thalassemic Endocrine Diseasementioning

confidence: 99%

New Entity—Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement

et al. 2022

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Beta-thalassemia (BTH), a recessively inherited haemoglobin (Hb) disorder, causes iron overload (IO), extra-medullary haematopoiesis and bone marrow expansion with major clinical impact. The main objective of this review is to address endocrine components (including aspects of reproductive health as fertility potential and pregnancy outcome) in major beta-thalassemia patients, a complex panel known as thalassemic endocrine disease (TED). We included English, full-text articles based on PubMed research (January 2017–June 2022). TED includes hypogonadism (hypoGn), anomalies of GH/IGF1 axes with growth retardation, hypothyroidism (hypoT), hypoparathyroidism (hypoPT), glucose profile anomalies, adrenal insufficiency, reduced bone mineral density (BMD), and deterioration of microarchitecture with increased fracture risk (FR). The prevalence of each ED varies with population, criteria of definition, etc. At least one out of every three to four children below the age of 12 y have one ED. ED correlates with ferritin and poor compliance to therapy, but not all studies agree. Up to 86% of the adult population is affected by an ED. Age is a positive linear predictor for ED. Low IGF1 is found in 95% of the population with GH deficiency (GHD), but also in 93.6% of persons without GHD. HypoT is mostly pituitary-related; it is not clinically manifested in the majority of cases, hence the importance of TSH/FT4 screening. HypoT is found at any age, with the prevalence varying between 8.3% and 30%. Non-compliance to chelation increases the risk of hypoT, yet not all studies confirmed the correlation with chelation history (reversible hypoT under chelation is reported). The pitfalls of TSH interpretation due to hypophyseal IO should be taken into consideration. HypoPT prevalence varies from 6.66% (below the age of 12) to a maximum of 40% (depending on the study). Serum ferritin might act as a stimulator of FGF23. Associated hypocalcaemia transitions from asymptomatic to severe manifestations. HypoPT is mostly found in association with growth retardation and hypoGn. TED-associated adrenal dysfunction is typically mild; an index of suspicion should be considered due to potential life-threatening complications. Periodic check-up by ACTH stimulation test is advised. Adrenal insufficiency/hypocortisolism status is the rarest ED (but some reported a prevalence of up to one third of patients). Significantly, many studies did not routinely perform a dynamic test. Atypical EM sites might be found in adrenals, mimicking an incidentaloma. Between 7.5–10% of children with major BTH have DM; screening starts by the age of 10, and ferritin correlated with glycaemia. Larger studies found DM in up to 34%of cases. Many studies do not take into consideration IGF, IGT, or do not routinely include OGTT. Glucose anomalies are time dependent. Emerging new markers represent promising alternatives, such as insulin secretion-sensitivity index-2. The pitfalls of glucose profile interpretation include the levels of HbA1c and the particular risk of gestational DM. Thalassemia bone disease (TBD) is related to hypoGn-related osteoporosis, renal function anomalies, DM, GHD, malnutrition, chronic hypoxia-induced calcium malabsorption, and transplant-associated protocols. Low BMD was identified in both paediatric and adult population; the prevalence of osteoporosis/TBD in major BTH patients varies; the highest rate is 40–72% depending on age, studied parameters, DXA evaluation and corrections, and screening thoracic–lumbar spine X-ray. Lower TBS and abnormal dynamics of bone turnover markers are reported. The largest cohorts on transfusion-dependent BTH identified the prevalence of hypoGn to be between 44.5% and 82%. Ferritin positively correlates with pubertal delay, and negatively with pituitary volume. Some authors appreciate hypoGn as the most frequent ED below the age of 15. Long-term untreated hypoGn induces a high cardiovascular risk and increased FR. Hormonal replacement therapy is necessary in addition to specific BTH therapy. Infertility underlines TED-related hormonal elements (primary and secondary hypoGn) and IO-induced gonadal toxicity. Males with BTH are at risk of infertility due to germ cell loss. IO induces an excessive amount of free radicals which impair the quality of sperm, iron being a local catalyser of ROS. Adequate chelation might improve fertility issues. Due to the advances in current therapies, the reproductive health of females with major BTH is improving; a low level of statistical significance reflects the pregnancy status in major BTH (limited data on spontaneous pregnancies and growing evidence of the induction of ovulation/assisted reproductive techniques). Pregnancy outcome also depends on TED approach, including factors such as DM control, adequate replacement of hypoT and hypoPT, and vitamin D supplementation for bone health. Asymptomatic TED elements such as subclinical hypothyroidism or IFG/IGT might become overt during pregnancy. Endocrine glands are particularly sensitive to iron deposits, hence TED includes a complicated puzzle of EDs which massively impacts on the overall picture, including the quality of life in major BTH. The BTH prognostic has registered progress in the last decades due to modern therapy, but the medical and social burden remains elevated. Genetic counselling represents a major step in approaching TH individuals, including as part of the pre-conception assessment. A multidisciplinary surveillance team is mandatory.

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“…Excessive RANKL activity favours osteoclastic bone resorption, leading to reduced BMD [116]. Sapunarova and colleagues report 10-fold higher serum levels of sclerostin, a secreted glycoprotein with anti-osteoblastic properties, in adults with transfusion-dependent beta thalassaemia compared to controls [117]. Given its correlation with both lumbar spine/femoral neck Z-scores and incidence of fragility fractures, it has been proposed to act as a biomarker of severe osteoporosis in advanced beta thalassaemia.…”

Section: Osteoporosismentioning

confidence: 99%

Investigation and Management of Endocrinopathies in Thalassaemia Major

Al-Hourani¹,

Hua²,

De³

2021

Human Blood Group Systems and Haemoglobinopathies

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A combination of sub-therapeutic chelation and subsequent iron overload are regarded as the principal drivers of endocrine dysfunction in thalassaemia. The clinical presentation of endocrine complications and their timing of onset can be highly variable, in part due to population heterogeneity but also variation in chelation strategies. Endocrinopathies commonly associated with thalassaemia include: growth delay; pubertal delay; gonadal dysfunction; thyroid disorders; parathyroid and adrenal gland impairment; impaired bone metabolism; and type 2 diabetes mellitus. In this chapter we summarise the main presentations of endocrine disorder in thalassaemia, summarising their epidemiology, clinical presentation and pathophysiologic basis. Furthermore, we review screening, monitoring and treatment strategies, with particular regard to the UK Thalassaemia Society’s 2016 National Standards.

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Associations of serum sclerostin with bone mineral density, markers of bone metabolism and thalassaemia characteristics in adult patients with transfusion-dependent beta-thalassaemia

Abstract: Grudeva-Popova (2020) Associations of serum sclerostin with bone mineral density, markers of bone metabolism and thalassaemia characteristics in adult patients with transfusion-dependent beta-thalassaemia,

Cited by 5 publications

References 64 publications

Bone Mineral Density and Dickkopf-1 in Adolescents with Non-deletional Hemoglobin H Disease

Bone Mineral Density and Dickkopf-1 in Adolescents with Non-deletional Hemoglobin H Disease

New Entity—Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement

Investigation and Management of Endocrinopathies in Thalassaemia Major

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