Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

Osteoporosis is a frequent problem in disorders characterized by iron overload, such as the thalassemias and hereditary hemochromatosis. The exact role of iron in the development of osteoporosis in these disorders is not established. To define the effect of iron excess in bone, we generated an iron-overloaded mouse by injecting iron dextran at 2 doses into C57/BL6 mice for 2 months. Compared with the placebo group, iron-overloaded mice exhibited dose-dependent increased tissue iron content, changes in bone composition, and trabecular and cortical thinning of bone accompanied by increased bone resorption. Iron-overloaded mice had increased reactive oxygen species and elevated serum tumor necrosis factor-α and interleukin-6 concentrations that correlated with severity of iron overload. Treatment of iron-overloaded mice with the antioxidant N-acetyl-L-cysteine prevented the development of trabecular but not cortical bone abnormalities. This is the first study to demonstrate that iron overload in mice results in increased bone resorption and oxidative stress, leading to changes in bone microarchitecture and material properties and thus bone loss.

SummaryThis study aimed to determine differences in the rates of growth, endocrineand calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23AE2 years (range 6AE1-75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = )0AE73 ± 1AE24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12AE8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Although rare, cases of vitamin D intoxication that present with dramatic life-threatening symptoms still occur in children. Moreover, recent studies in infants raise a potential need for monitoring vitamin D levels when doses at or above the currently recommended upper range are used. Further studies are needed to clarify these findings. The Drugs and Therapeutics Committee of the Pediatric Endocrine Society suggests obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended.

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Summary Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β2-microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Historically, fractures are cited as a frequent problem in patients with Thalassemia prior to optimization of transfusion and chelation regimens. The aim of this study was to determine the prevalence of fractures in a contemporary sample of North American patients with Thalassemia. The North American Thalassemia Clinical Research Network (TCRN) database registry was used to gather historical data on 702 patients with common alpha and beta-Thalassemia diagnoses including Thalassemia Major (TM), Intermedia (TI), E/Beta, homozygous alpha Thalassemia (AT), Hemoglobin H disease (HbH) and HbH with Constant Spring (HbH/CS), who consented to a medical record chart review. Bone mineral density (BMD) measurements by DXA were available for review in a subgroup of patients (n = 312). The overall fracture prevalence among all Thalassemia syndromes was 12.1%, equally distributed between females (11.5%) and males (12.7%). Fractures occurred more frequently in TM (16.6%) and TI (12.2%) compared to E/Beta (7.4%) and alpha (2.3%). Prevalence increased with age (2.5% ages 0-10 years, 7.4% ages 11-19 years, 23.2% ages >20 years) and with use of sex hormone replacement therapy (SHRT) (P < 0.01). On average, BMD Z and T scores were 0.85 SD lower among patients with a history of fractures (mean Z/T score -2.78 vs. -1.93, 95% CI for the difference -0.49 to -1.22 SD, P = 0.02). Presence of other endocrinopathies (i.e. hypothyroidism, hypoparathyroidism and diabetes mellitus), anthropometric parameters, heart disease or hepatitis C were not significant independent predictors of fractures. These data indicate that fractures remain a frequent complication among the aging patients with both TM and TI beta-Thalassemia. However, the fracture prevalence has improved compared to published reports from the 1960s to 1970s. In addition, children with Thalassemia appear to have low fracture rates compared to the general population.

Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This study examines the impact of GH and LHRH analog (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Fourteen patients with CAH (eight males, six females) predicted to be more than 1.0 sd below their midparental target height received GH and LHRHa until final height. Each patient was matched at the start of GH therapy to a CAH patient treated only with glucocorticoids according to type of CAH, sex, and chronological age. Mean age, bone age, height, height prediction, and target height were the same in both groups at the beginning of GH therapy. Mean duration of GH treatment was 4.4 +/- 1.5 yr. Mean duration of LHRHa therapy was 4.2 +/- 2.0 yr. In the treatment group, final height sd score of -0.4 + 0.8 was significantly greater than both the initial prediction of -1.5 +/- 0.9 (P < 0.0001) and the final height sd score of the untreated group of -1.4 +/- 1.1 (P = 0.01). Our results indicate that the combination of GH and LHRHa improves final adult height in patients with CAH.