The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches

Anapliotou, Margarita; Kastanias, I.; Psara, Panagiota; Εvangelou, Εvangelos; Liparaki, M.; Dimitriou, P.

doi:10.1111/j.1365-2265.1995.tb01876.x

Cited by 116 publications

(104 citation statements)

References 29 publications

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“…This suggests that an important determinant of the often suboptimal bone response to testosterone replacement reported previously may be inadequate prior testosterone treatment, largely due to the pharmacological limitations and inconvenience of the available testosterone products. Our findings on the bone density benefits of sustained, adequate treatment are consistent with findings that AD thalassaemic adolescents taking regular testosterone treatment had higher BMD than others whose testosterone treatment was irregular (42,43). In most previous longer (.…”

Section: Discussionsupporting

confidence: 80%

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

Aminorroaya

Kelleher²,

Conway³

et al. 2005

eur j endocrinol

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Objective: Androgen deficiency (AD) leads to bone loss and contributes to osteoporotic fractures in men. Although low bone mineral density (BMD) in AD men is improved by testosterone replacement, the responses vary between individuals but the determinants of this variability are not well defined. Design and methods: Retrospective review of dual energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur in men with established AD requiring regular androgen replacement therapy (ART). After a DEXA scan all men were treated with testosterone implants (800 mg, , 6 month intervals). Patients were classified as having a congenital, childhood, or post-pubertal onset, as well as according to the adequacy of treatment prior to their first DEXA scan as untreated, partially treated or well treated. Results: Men with AD requiring regular ART (n ¼ 169, aged 46.3^1.1 years, range 22 -84 years) underwent a DEXA scan prior to being treated with testosterone implants (800 mg, ,6 month intervals). In cross-sectional analysis at the time of the first DEXA scan untreated men (n ¼ 24) had significantly reduced age-adjusted BMD at all four sites (L1 -L4, femoral neck, Ward's triangle and trochanter). Well-treated men (n ¼ 77) had significantly better age-adjusted BMD at all four sites compared with those who were partially treated (n ¼ 66) or untreated (n ¼ 24) with their ageadjusted BMD being normalized. In a longitudinal assessment of men (n ¼ 60) who had two or more serial DEXA scans, at the second DEXA scan after a median of 3 years, men who were previously partially treated (n ¼ 19) or untreated (n ¼ 11) had proportionately greater improvements in BMD, significantly for Ward's triangle (P ¼ 0.025) and the trochanter (P ¼ 0.044) compared with men (n ¼ 30) previously well treated. Conclusions: The present study demonstrates a positive relationship between adequacy of testosterone replacement and BMD in men with overt organic AD. Additionally, the BMD of well-treated AD men approximates that of age-matched non-AD controls. The greatest BMD gains are made by those who have been either untreated or partially treated, and optimal treatment over time (median 3 years) normalizes BMD to the level expected for healthy men of the same age.European Journal of Endocrinology 152 881-886

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Section: Discussionsupporting

confidence: 80%

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

Aminorroaya

Kelleher²,

Conway³

et al. 2005

eur j endocrinol

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“…Delayed or arrested puberty is common in patients with thalassaemia (4, 5) because of disturbed gonadotrophin-releasing hormone secretion (5, 34) with consequent deficiency of sex steroids. Sex steroids can influence growth through the modulation of IGF-Iinduced cellular response (35)(36)(37), and their deficiency adds significantly to the growth delay and osteoporosis of thalassaemic children (38). This may explain the relatively short upper segment, in addition to the mild vertebral changes observed in our thalassaemic group.…”

Section: Discussionmentioning

confidence: 69%

GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia

Soliman

Banna

Ansari

1998

European Journal of Endocrinology

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The causes of growth retardation of children with thalassaemia major are multifactorial. We studied the GH response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, IGF-I, IGF-binding protein-3 (IGFBP-3) and ferritin, and evaluated IGF-I generation after a single dose of GH (0.1 mg/kg per dose) in 15 prepubertal patients with thalassaemia, 15 age-matched children with constitutional short stature (CSS) (height standard deviation score less than ¹2, with normal GH response to provocation) and 11 children with isolated GH deficiency (GHD). Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (6:2 Ϯ 2:3 and 6:8 Ϯ 2:1 mg/l respectively) than the CSS group (18:6 Ϯ 2:7 and 16:7 Ϯ 3:7 mg/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP-3 (47:5 Ϯ 19 ng/ml and 1:2 Ϯ 0:27 mg/l respectively) compared with those with CSS (153 Ϯ 42 ng/ ml and 2:06 Ϯ 0:37 mg/l respectively), but the IGF-I and IGFBP-3 concentrations were not different from those with GHD (56 Ϯ 25 ng/ml and 1:1 Ϯ 0:32 mg/l respectively). These data demonstrate that the GH-IGF-I-IGFBP-3 axis in thalassaemic children is defective. Serum ferritin concentration correlated significantly with GH peak response to provocation (r ¼ ¹0:36, P < 0:05) and circulating IGF-I (r ¼ ¹0:47, P < 0:01) and IGFBP-3 (r ¼ ¹0:42, P < 0:01) concentrations. In the IGF-I generation test, after GH injection, the thalassaemic children had significantly lower IGF-I and IGFBP-3 levels 86:7 Ϯ 11:2 ng/ml and 2:05 Ϯ 0:51 mg/l respectively) than those in the CSS group (226 Ϯ 45:4 ng/ ml and 2:8 Ϯ 0:43 mg/l respectively). The IGF-I response was significantly higher in children with GHD (158 Ϯ 50 ng/ml) than in thalassaemic children. Six short (height standard deviation score less than ¹2) thalassaemic children who had defective GH response to provocation (<10 mg/l), all the children with GHD and eight short normal children (CSS) were treated for 1 year with human GH (18 units/m 2 per week divided into daily s.c. doses). After 1 year of GH therapy there was a marked acceleration of growth velocity in both thalassaemic children (from 3:8 Ϯ 0:6 cm/year to 7:2 Ϯ 0:8 cm/year) and controls. However, the linear acceleration of growth velocity on GH therapy was significantly slower in thalassaemic children (3:3 Ϯ 0:3 cm/year increment) compared with those with CSS (5:3 Ϯ 0:4 cm/year increment) and GHD (6:9 Ϯ 1:2 cm/year increment) (P < 0:05). Their circulating IGF-I concentration (105 Ϯ 36 ng/ml) was significantly lower than those for CSS (246 Ϯ 58 ng/ml) and GHD (189 Ϯ 52 ng/ml) after 1 year of GH therapy. These data prove that some children with b-thalassaemia major have a defective GH-IGF-I-IGFBP-3 axis and suggest the presence of partial resistance to GH.

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“…[1][2][3][4][5] Bone problems may be present even in welltransfused and chelated patients. Various factors contribute to the development of osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have been performed using dual energy X-ray absorptiometry (DEXA) to measure bone mineral density (BMD) in patients with transfusion-dependent thalassaemia. [1][2][3][4][5] The prevalence of reduced BMD varied, but Jensen et al 1 reported that half of their 82 patients had severely low BMD whereas the other 45% had low bone mass. Angastiniotis et al 5 showed that patients with thalassaemia intermedia were not spared, and 75% of them had BMD below À2 s.d.…”

mentioning

confidence: 99%

Bone mineral density in children with thalassaemia major: determining factors and effects of bone marrow transplantation

Leung

Hung

Lam

et al. 2005

Bone Marrow Transplant

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Summary:Osteoporosis and osteopenia affect up to half of patients with thalassaemia major (TM). We investigate the effects of acquired factors and BMT on bone mineral density (BMD) in these patients. In all, 53 patients on regular transfusion (BT group) and 33 patients at 5.771.9 years post transplant (BMT group) were recruited. BMD was measured by dual energy X-ray absorptiometry. Serum concentrations of osteocalcin, bone-specific alkaline phosphatase (ALP), beta-crossLap and urinary cross-linking deoxypyridinoline (DPD) were measured by chemiluminescence and enzyme immunoassay, respectively. Severe BMD deficit (Z-score oÀ2.5) at spine and hip were noted in 62 and 35% of BT group. Serum osteocalcin (b ¼ À0.463; P ¼ 0.006) was predictive of spine BMD, whereas age (b ¼ À0.843; P ¼ 0.007) and urine DPD (b ¼ À0.439; P ¼ 0.037) were associated with hip BMD in BT group. Among BMT patients, post transplant duration (b ¼ 0.450; P ¼ 0.009) and serum bone-specific ALP (b ¼ À0.495; P ¼ 0.013) were associated with spine BMD. Severe BMD deficit was less common among BMT than BT patients (6 vs 35%; P ¼ 0.036). The mean (s.d.) osteocalcin levels in BMT and BT groups were 96.4 (72.7) lg/l and 68.9 (40.3) lg/l, respectively (P ¼ 0.037).In conclusion, severe BMD deficit is common in Chinese TM patients and BMT may reverse BMD deficit in these patients. Osteoporosis and osteopenia are major long-term complications of thalassaemia major (TM). A number of studies have been performed using dual energy X-ray absorptiometry (DEXA) to measure bone mineral density (BMD) in patients with transfusion-dependent thalassaemia. [1][2][3][4][5] The prevalence of reduced BMD varied, but Jensen et al 1 reported that half of their 82 patients had severely low BMD whereas the other 45% had low bone mass. Angastiniotis et al 5 showed that patients with thalassaemia intermedia were not spared, and 75% of them had BMD below À2 s.d. even with transfusion started only later in life. BMD correlates with the risk of fractures. DEXA is currently the most reliable and widely used method for measuring BMD, and this technique assesses bone mass classically at the lumbar spine and proximal femur. 6,7 There are well-established normal standards for DEXA measurements for Caucasian and Chinese children. [6][7][8] Both genetic and acquired factors may contribute to the reduction in BMD in TM patients. Concerning the genetic regulation, Sp1 polymorphism in the gene encoding type 1 collagen (major) protein (COLIA1) was found to be associated with the severity of osteopenia at spine and hip in male thalassaemic patients, and the same genetic factor also predicted treatment failure to bisphosphonate. 3 Acquired factors contributing to skeletal morbidity include endocrinopathy, direct iron-induced toxicity, bone marrow expansion and the use of iron-chelating therapy. [9][10][11][12] However, the effects of BMT, being the only curative treatment for TM, on BMD measurements have not been reported. We hypothesise that the diminished BMD seen in TM patients may improve wh...

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The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches

Abstract: Hypogonadism seems to play an important role in the development of osteopenia-osteoporosis in thalassaemia major; continuous hormone replacement therapy with transdermal oestrogen for females or hCG for responding males best improves the bone density parameters.

Cited by 116 publications

References 29 publications

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia

Bone mineral density in children with thalassaemia major: determining factors and effects of bone marrow transplantation

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