Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia

Abstract

Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age ≥12 years and liver iron concentration ≥ 10 mg/g dry wt or serum ferritin ≥ 2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin < 500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6±0.7 yrs), 203 subjects with TxSCD (44% Male, 24.7 ±0.9 years: Mean ± SE), and 65 NonTxSCD (50% Male, 22.2 ±1.3 yrs) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.

Low bone mineral density is associated with insulin resistance in bone marrow transplant subjects

“…Increased serum ferritin has been reported as associated with fractures and decreased bone mass in some studies. 12,19 Serum ferritin levels have been thought to reflect the body iron stores; however, it is also a secreted by-product of intracellular ferritin synthesis. 20 This last process is increased in some inflammation states as chronic diseases.…”

“…Fung et al reported that for serum ferritin levels over 2000 ng/ml subjects with more blood transfusions had a greater fracture risk which could be due to iron overload. 12 Nevertheless, the presence of inflammatory proteins such as IL7 has been linked to bone loss, and the high serum ferritin levels could be a marker of chronic inflammation. 20 No matter the main explanation, in this study the serum ferritin levels were higher in subjects with osteopenia/osteoporosis.…”

“…10 Besides the classical risk factors there are other possible ones: Rakel et al have recently published a study showing diabetes mellitus as a risk factor for bone fractures in recipients of solid organ transplantation, 11 and increased serum ferritin levels have also been reported as a risk factor for bone fractures in patients with thalassemia. 12 Nevertheless, until the present moment we do not know whether diabetes mellitus or impaired glucose metabolism, and high serum ferritin levels, have some effect in post-BMT osteopenia and osteoporosis. The aim of this study was to identify factors associated with osteopenia and osteoporosis in the recipients of allogeneic BMT.…”

Evaluation of Bone Mineral Density in Children with Thalassemia Major

“…Yakın zamandaki terapötik yaklaşımlarla talasemili hastalardaki yaşam süresi ve kalitesi artmış, bununla birlikte patolojik kırıklara sebep olabilen osteoporoz, hastalığın en önemli iskelet bulgusu ve morbidite sebebi haline gelmiştir (5,6). İyi tedavi edilen talasemi majörlü hastalarda bile osteoporoz prevalansının %40-50 (3,5), kırık prevalansının %38-41 olduğu bildirilmiştir (7,8). Bu çalışma da hastanemizde düzenli olarak takip ve tedavi edilen TM'li çocuk hastaların kemik sağlığının biyokimyasal parametreler ve kemik mineral yoğunluğu (KMY) ölçülerek değerlendirilmesi, gelişebilecek osteoporoz yönünden erken tanı ve önleyici tedbirlerin alınmasının vurgulanması amaçlandı.…”

Multiple pathologic fractures in a 19-month-old boy with sickle cell disease

“…Osteopenia and osteoporosis are associated with sickle cell disease [20][21][22][23][24] . Iron overload has been correlated with this complication [20,21,25] and the explanation for this might be the inhibition of osteoblast proliferation and differentiation by iron [26] .…”