Fracture Prevalence and Relationship to Endocrinopathy in Iron Overloaded Patients with Sickle Cell Disease and Thalassemia.
Authors: Fung Ellen B. , Harmatz Paul , Milet Meredith , Vichinsky Elliott 
Published: April 2020

Abstract
Transfused patients with hemoglobinopathies commonly develop iron overload. Iron toxicity in patients with thalassemia (Thal) often leads to gonadal failure, osteoporosis and increased incidence of fracture. However, the gonadal failure that occurs frequently in patients with Thal is scarcely reported in patients with sickle cell disease (SCD). A prospective, natural history, multi-center study was conducted to assess fracture history and iron related endocrine dysfunction in transfused Thal and SCD subjects compared to non-transfused subjects with SCD (NonTxSCD). Data were collected annually by patient interview and chart review at 30 clinical centers in the U.S., Canada and the U.K. Data collected from the first year are presented here and analyzed by ANOVA or χ2 . Logistic regression was used to develop multivariate models. 204 subjects with TxSCD (44% Male, 24.7±0.9 years: Mean ± SE), 152 subjects with Thal (52% Male; 25.6±0.7 yrs) and 62 NonTxSCD (50% Male, 22.2±1.3 yrs) were eligible and completed baseline assessment. Eligibility was based on age&gt;11 years and liver iron concentration (LIC) &gt; 10 mg/g dry wt (Thal or TxSCD) or serum ferritin &lt; 500 ng/mL (NonTxSCD). Despite similar LIC at baseline in transfused subjects (Overall: 20.0±1.0 mg/g dry wt), those with Thal had significantly more growth failure (24% vs. 6%; p&lt;0.001), hypogonadism (40% vs. 4%, p&lt;0.001), hypothyroidism (10% vs. 1.5%; p&lt;0.001) and were more likely to be taking growth hormone (p&lt;0.001), bisphosphonates (p=0.007) and sex hormone replacement therapy (p&lt;0.001) compared to TxSCD. There were no differences between TxSCD and NonTxSCD. 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%). The most common site of fracture was the arm/wrist (40% of all fractures). 82% of all fractures were treated with a cast/splint while 7.7% required surgery or hospitalization. For those who fractured, Thal subjects suffered their first fracture at an earlier age (11.9 yrs) compared to TxSCD (16.8 yrs) or NonTxSCD (13.7 yrs; p&lt;0.001). Fracture incidence was positively related to age, male gender, hypogonadism, hypothyroidism, transfusion duration and sex hormone replacement therapy (all p&lt;0.005). In multivariate analysis, the significant predictors of fracture 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 endocrinopathy and bone fracture than subjects with TxSCD. Male subjects with endocrine dysfunction are at particular risk for fracture. In contrast, transfused subjects with SCD had no greater risk of fracture or endocrinopathy compared to non-transfused SCD. Endocrine organs appear to be protected against iron related organ injury in SCD, which may also provide protection from high incidence of fracture. Analysis of the longitudinal data may assist in addressing questions related to iron loading and fracture incidence, and comparison of fracture incidence to reference healthy populations. Supported in part by NIH grants: R01DK057778 and M01RR01271.