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1.  Inadequate Dietary Intake in Patients with Thalassemia 
Background
Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.
Objective
Assess dietary intake in a large contemporary sample of patients with thalassemia.
Design
Prospective, longitudinal cohort study using a validated food frequency questionnaire
Participants
221 patients (19.7±11.3 yrs, 106 female) categorized into three age groups: young children (3–7.9 y), older children/adolescents (8–18.9 yr), and adult (≥ 19 yr). 78.8% β-thalassemia; 90% chronically transfused.
Setting
10 hematology outpatient clinics in the United States and Canada.
Main outcome measures
Comparison of intake with U.S. Dietary Reference Intakes, and correlation with serum 25-OH vitamin D and total body iron stores.
Statistical Analyses Performed
Intake was defined as inadequate if less than the estimated average requirement (EAR). Chi-square, Fisher’s exact and Student’s t-test were utilized to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, gender and race.
Results
Over 30% of patients consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which >90% of patients consumed adequate amounts were riboflavin, vitamin B12 and selenium. Dietary inadequacy increased with increasing age group (p<0.01) for vitamins A, C, E, B6, folate, thiamin, calcium, magnesium and zinc. Over half the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of patients. Dietary iron intake was not related to total body iron stores.
Conclusion
Patients with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy is concerning and supports the need for nutritional monitoring to determine which patients are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.
doi:10.1016/j.jand.2012.01.017
PMCID: PMC3419338  PMID: 22551675
Thalassemia; dietary intake; iron; vitamin D
2.  The effect of whole body vibration therapy on bone density in patients with thalassemia: A pilot study 
American journal of hematology  2012;87(10):10.1002/ajh.23305.
Patients with thalassemia (Thal) have low bone mass which can lead to fracture and decreased quality of life. There are no noninvasive anabolic therapies available to improve bone health in Thal. A longitudinal cross-over pilot trial was conducted to evaluate the effectiveness of low magnitude whole body vibration (WBV) therapy on bone in 18 patients with Thal (9 adults, 10 male, 22.1 ± 10.7 years). Subjects were asked to stand on a vibrating platform (30 Hz, 0.3 g) for 20 min/day for 6 months. Areal bone mineral density (aBMD) by DXA and volumetric BMD by peripheral quantitative computed tomography (pQCT) was assessed at baseline, 6 and 12 months. Adherence in the first 3 months was greater when compared with the second 3 months (14 ± 6 vs. 10 ± 7 min/day, P=0.007). Intention to treat analysis revealed a significant increase in whole body BMC (2.6%; P = 0.021), BMC/Ht (2.6%, P = 0.02) and aBMD (1.3%; P = 0.036), as well as a net increase in serum markers of bone formation (Osteocalcin/CTx, P = 0.027) in the adult subjects. These preliminary findings suggest that vibration therapy may be an effective nonpharmacologic intervention in Thal. Future research is needed to confirm these findings in a larger sample for longer duration.
doi:10.1002/ajh.23305
PMCID: PMC3845963  PMID: 22886910
3.  Characterization of Low Bone Mass in Young Patients with Thalassemia by DXA, pQCT and Markers of Bone Turnover 
Bone  2011;48(6):1305-1312.
Previous reports using dual x-ray absorptiometry (DXA) suggest that up to 70% of adults with thalassemia major (Thal) have low bone mass. However, few studies have controlled for body size and pubertal delay, variables known to affect bone mass in this population. In this study, bone mineral content and areal density (BMC, aBMD) of the spine and whole body were assessed by DXA, and volumetric BMD and cortical geometries of the distal tibia by peripheral quantitative computed tomography (pQCT) in subjects with Thal (n=25, 11 male, 10 to 30 yrs) and local controls (n=34, 15 male, 7 to 30 yrs). Z-scores for bone outcomes were calculated from reference data from a large sample of healthy children and young adults. Fasting blood and urine were collected, pubertal status determined by self-assessment and dietary intake and physical activity assessed by written questionnaires. Subjects with Thal were similar in age, but had lower height, weight and lean mass index Z-scores (all p<0.001) compared to controls. DXA aBMD was significantly lower in Thal compared to controls at all sites. Adult Thal subjects (>18 yrs, n=11) had lower tibial trabecular vBMD (p=0.03), cortical area, cortical BMC, cortical thickness, periosteal circumference and section modulus Z-scores (all p<0.01) compared to controls. Cortical area, cortical BMC, cortical thickness, and periosteal circumference Z-scores (p=0.02) were significantly lower in young Thal (≤18 yrs, n=14) compared to controls. In separate multivariate models, tibial cortical area, BMC, and thickness and spine aBMD and whole body BMC Z-scores remained lower in Thal compared to controls after adjustment for gender, lean mass and/or growth deficits (all p<0.01). Tanner stage was not predictive in these models. Osteocalcin, a marker of bone formation, was significantly reduced in Thal compared to controls after adjusting for age, puberty and whole body BMC (p=0.029). In summary, we have found evidence of skeletal deficits that cannot be dismissed as an artifact of small bone size or delayed maturity alone. Given that reduced bone density and strength are associated with increased risk of fracture, therapies focused on increasing bone formation and bone size in younger patients are worthy of further evaluation.
doi:10.1016/j.bone.2011.03.765
PMCID: PMC3095710  PMID: 21443975
4.  Relationship between Chronic Transfusion Therapy and Body Composition in Subjects with Thalassemia 
The Journal of pediatrics  2010;157(4):641-647.e2.
Objective
To measure body composition in patients with thalassemia and explore its relationship to abnormal growth and bone mass.
Study design
Cross-sectional, multi-center study. Fat, lean, and bone mineral density (BMD) were assessed by DXA. Medical history, food frequency and physical activity questionnaires were conducted in 257 transfused thalassemia patients (23.7 ± 11 yr, Mean±SD, 51% male) compared with 113 non-transfused patients (21.3 ± 13 yr, 44% male).
Results
Subjects with thalassemia were leaner compared with healthy Americans from NHANES III data. Transfused subjects had higher percentage body fat compared with non- transfused after controlling for age, sex and ethnicity; 11.8% of non-transfused pediatric subjects were considered underweight, significantly lower than NHANES data (p=0.03). Hemoglobin level was positively related to lean mass (p=0.008). Body fat and lean mass were positive predictors for both height and BMD Z-scores after adjustment for transfusion status, age, sex, ethnicity, calcium intake and physical activity (all p<0.001).
Conclusions
Though the majority of adult patients with thalassemia had healthy body composition with rare obesity, young, non-transfused patients appear at risk for being underweight. Optimizing physical activity and appropriate use of transfusion therapy may improve growth and bone health in these at risk patients.
doi:10.1016/j.jpeds.2010.04.064
PMCID: PMC2936667  PMID: 20547400
DXA; lean mass; fat mass; body mass index (BMI); calcium
5.  Bone density assessment in patients with mucopolysaccharidosis: A preliminary report from patients with MPS II and VI 
Enzyme replacement therapy has been successful in alleviating morbidity and improving endurance in Mucopolysaccharidosis (MPS) type I, II, and VI, however little attention has been paid to the effects on bone mineralization. Brief case reports in MPS type III and IV suggest that bone mineral density (BMD) is diminished, but did not account for patient size. In this report, BMD was evaluated by quantitative computed tomography and by dual-energy x-ray absorptiometry (DXA) in separate studies involving 10 patients with MPS type VI (7 Female; 7.0 to 21.0 y) and 4 male patients with MPS II (8.1 to 35.5 y). Vitamin D intake met the current RDA (200 IU) for most, though 25-OH vitamin D was insufficient (< 30 ng/mL) in 87.5% of patients tested. Ht Z-score was low −5.8 ± 3.6, with height deficits greatest in MPS VI. Spine and whole body BMD Z-scores by DXA were considered normal for chronological age in all MPS II, and after correction for Ht Z-score, in all but one subject with MPS VI. These results suggest that vitamin D insufficiency is quite common in MPS. BMD by DXA is within normal range for most, particularly after correction for short stature. A review of bone health assessment is provided as well as a discussion of these results.
PMCID: PMC2898152  PMID: 20617160
DXA; Bone mineral density; low bone mass; vitamin D; MPS II; MPS VI
6.  Fracture Prevalence and Relationship to Endocrinopathy in Iron Overloaded Patients with Sickle Cell Disease and Thalassemia 
Bone  2008;43(1):162-168.
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.
doi:10.1016/j.bone.2008.03.003
PMCID: PMC2500183  PMID: 18430624
Fracture; Endocrinopathy; Iron Overload; Thalassemia; Sickle Cell Disease
7.  Markers of Bone Turnover Are Associated With Growth and Development in Young Subjects With Sickle Cell Anemia 
Pediatric blood & cancer  2008;50(3):620-623.
Children with sickle cell anemia (SCA) have low bone mass though bone turnover has not been well described. In this study, growth and pubertal development were assessed twice, 1 year apart, in 80 young subjects with type-SS SCA, while whole body bone mineral content (BMC) and density where measured in a subset (n = 46). Markers of bone turnover were measured at the second visit. Bone formation (alkaline phosphatase) was elevated, whereas bone resorption (deoxypryidinoline) was decreased compared to published data in healthy children. Markers of bone turnover correlated with growth velocity and pubertal development but not with changes in bone mass.
doi:10.1002/pbc.21147
PMCID: PMC2561913  PMID: 17243130
bone markers; bone mineral content; bone mineral density; growth; sickle cell anemia
8.  Rapid Re-Mineralization of the Distal Radius Following Forearm Fracture in Children 
Journal of pediatric orthopedics  2011;31(2):138-143.
Background
Bone mineral content (BMC) and density (BMD) have been shown to diminish following fracture and immobilization in adults. Distal radius fractures (DRFx) are common in children, and unlike adults, there is a low incidence of re-fracture. The primary aim of this study was to assess the change in radial BMC and BMD following upper extremity fracture and casting in healthy pediatric patients.
Methods
Subjects were recruited at the time of DRFx casting. The non-fractured (non-Fx) distal radius was initially scanned by dual energy x-ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), as well as 4, 8, 12, 24 and 52 weeks post cast removal.
Results
Twenty-one subjects were enrolled (13 Male, 13 Caucasian, 10.4±2.5 yrs) with an average length of casting of 38 ± 11 days. Eighteen subjects (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the fractured and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was +4.2% and +0.2%, respectively; while for the Fx arm, the change was +8.3% and +3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error and p<0.05). However, by 52 weeks, these differences were no longer significant. The increased mineralization was unrelated to age, gender, arm dominance or calcium intake.
Conclusions
This data shows that there is rapid re-mineralization following a simple forearm fracture in children, with a transient elevation in BMD in the fractured arm after casting. This novel finding suggests that bone may be stronger around the site of fracture and could significantly change how we counsel young patients recovering from forearm fracture. Future research should focus on children immobilized for varying lengths of time, as well as those with repeat fractures, employing volumetric techniques of bone geometry and strength assessment.
doi:10.1097/BPO.0b013e3182093ddd
PMCID: PMC3079274  PMID: 21307706
DXA; bone mineral content; bone mineral density; forearm fracture; children
9.  Evidence of Associations Between Feto-Maternal Vitamin D Status, Cord Parathyroid Hormone and Bone-Specific Alkaline Phosphatase, and Newborn Whole Body Bone Mineral Content 
Nutrients  2012;4(2):68-77.
In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status (25(OH)D), parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose of the present study was to investigate the relationships between maternal and cord 25(OH)D, PTH, BALP, and WBBMC in newborns in a multiethnic population in Oakland, California and to evaluate the predictive value of the biochemical indices as indicators of WBBMC. Maternal and cord blood were collected from 80 mother-infant pairs and infant WBBMC was measured by dual energy X-ray absorptiometry 8–21 days post-birth. Cord PTH and BALP were each inversely correlated with infant WBBMC (r = −0.28, p = 0.01 and r = −0.26, p = 0.02) and with cord 25(OH)D (r = −0.24, p = 0.03 and r = −0.34, p = 0.002), while cord 25(OH)D and unadjusted or weight-adjusted WBBMC were not significantly correlated with one other. In multivariate regression modeling, infant WBBMC was most strongly predicted by infant weight (p < 0.0001), while either PTH or BALP contributed modestly but significantly to the model (p = 0.006 and p = 0.03 respectively). Cord 25(OH)D was not a significant predictor of infant WBBMC. This study provides evidence of associations between feto-maternal 25(OH)D, cord PTH and BALP, and early infant WBBMC, though neither feto-maternal 25(OH)D nor the measured biochemical indices were suitable indicators of WBBMC.
doi:10.3390/nu4020068
PMCID: PMC3296991  PMID: 22413062
infant; vitamin D; dual X-ray absorptiometry; bone mineral content
10.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
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.
doi:10.1359/jbmr.080505
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia
11.  Vitamin C treatment reduces elevated C-reactive protein 
Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. We investigated whether vitamins C or E could reduce CRP. Healthy nonsmokers (n=396) were randomized to three groups:1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for two months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants are included. However, significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (≥1.0 mg/L), vitamin C reduced median CRP by 25.3% vs. Placebo (p=0.02), (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not E significantly reduced CRP among individuals with CRP ≥ 1.0 mg/L. Among the obese, 75% had CRP ≥ 1.0 mg/L. These data extend previous results in smokers, and identify CRP levels susceptible to reductions. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.
doi:10.1016/j.freeradbiomed.2008.09.030
PMCID: PMC2631578  PMID: 18952164
C-reactive protein; inflammation; vitamin C; vitamin E; obesity; cardiovascular risk; antioxidants; oxidation; randomized controlled trial
12.  Effect of vitamins C and E on biomarkers of oxidative stress in nonsmokers 
Free radical biology & medicine  2008;45(4):377-384.
Background
Oxidative stress is elevated in obesity, and may be a major mechanism for obesity-related diseases.
Methods
Nonsmokers (n=396) were randomized to 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for two months. Treatment effect was examined in multiple regression analyses using an intention-to-treat approach.
Results
Vitamin C (p=0.001) and vitamin E (p=0.043) reduced plasma F2-isoprostanes. In the overall sample, changes from baseline were +6.8%, −10.6%, and −3.9% for placebo, vitamin C, and vitamin E groups, respectively. However, a significant interaction with baseline F2-isoprostane was found. When baseline F2-isoprostane was > 50 μg/mL, vitamin C reduced F2-isoprostane by 22% (p=0.01). Vitamin E reduced it by 9.8% (p=0.46). Below that cut-point, neither treatment produced further reductions. F2-isoprostane > 50 μg/mL was strongly associated with obesity, and was present in 42% of the sample. Change in malondialdehyde concentration was minimal.
Discussion
These findings suggest a role for vitamin C in reducing lipid peroxidation. Future research on effects of vitamins C or E on plasma F2-isoprostane should limit participants to those with baseline levels > 50 μg/mL. Further studies are needed to establish whether treatment with vitamins C or E in persons with concentrations above that cut-point could slow the development of cardiovascular disease.
doi:10.1016/j.freeradbiomed.2008.04.005
PMCID: PMC2750000  PMID: 18455517
Antioxidants; biomarkers; F2-isoprostane; obesity; oxidative stress; vitamin C; vitamin E; oxidative stress
13.  Oxidative stress and inflammation in iron-overloaded patients with β-thalassaemia or sickle cell disease 
British journal of haematology  2006;135(2):254-263.
Summary
Blood transfusion therapy is life-saving for patients with β-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although α-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, γ-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and γ-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.
doi:10.1111/j.1365-2141.2006.06277.x
PMCID: PMC2185791  PMID: 17010049
iron overload; thalassaemia; sickle cell disease; oxidative stress; inflammation; cytokines; non-transferrin bound iron; malondialdehyde; lipid peroxidation; vitamin E

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