title: Vitamin D supplementation for sickle cell disease.
abstract: Sickle cell disease is a genetic chronic haemolytic and pro-inflammatory disorder. The clinical manifestations of sickle cell disease result from the presence of mutations on the beta globin genes that generate an abnormal haemoglobin product (called haemoglobin S) within the red blood cell. Sickle cell disease can lead to many complications such as acute chest syndrome, stroke, acute and chronic bone complications (including painful vaso-occlusive crisis, osteomyelitis, osteonecrosis and osteoporosis). With increased catabolism and deficits in energy and nutrient intake, individuals with sickle cell disease suffer multiple macro- and micro-nutritional deficiencies, including vitamin D deficiency. Since vitamin D maintains calcium homeostasis and is essential for bone mineralisation, its deficiency may worsen musculoskeletal health problems encountered in sickle cell disease. Therefore, there is a need to review the effects and the safety of vitamin D supplementation in sickle cell disease.
  
  
  
  To investigate the hypothesis that vitamin D supplementation increases serum 25-hydroxyvitamin D level in children and adults with sickle cell disease.To determine the effects of vitamin D supplementation on general health such as growth status and health-related quality of life; on musculoskeletal health including bone mineral density, pain crises, bone fracture and muscle health; on respiratory health which includes lung function tests, acute chest syndrome, acute exacerbation of asthma and respiratory infections; and the safety of vitamin D supplementation in children and adults with sickle cell disease.
  
  
  
  We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews.Date of last search: 15 December 2016.
  
  
  
  Randomised controlled studies and quasi-randomised controlled studies (controlled clinical studies) comparing oral administration of any form of vitamin D supplementation to another type of vitamin D or placebo or no supplementation at any dose and for any duration, in people with sickle cell disease, of all ages, gender, and phenotypes including sickle cell anaemia, haemoglobin sickle cell disease and sickle beta-thalassaemia diseases.
  
  
  
  Two authors independently extracted the data and assessed the risk of bias of the included study. They used the GRADE guidelines to assess the quality of the evidence.
  
  
  
  One double-blind randomised controlled study including 46 people with sickle cell disease (HbSS, HbSC, HbSβ+thal and HbSβ0thal) was eligible for inclusion in this review. Of the 46 enrolled participants, seven withdrew before randomisation leaving 39 participants who were randomised. Only 25 participants completed the full six months of follow up. Participants were randomised to receive oral vitamin D3 (cholecalciferol) (n = 20) or placebo (n = 19) for six weeks and were followed up to six months. Two participants from the treatment group have missing values of baseline serum 25-hydroxyvitamin D, therefore the number of samples analysed was 37 (vitamin D n = 18, placebo n = 19).The included study had a high risk of bias with regards to incomplete outcome data (high dropout rate in the placebo group), but a low risk of bias for other domains such as random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, selective outcome reporting; and an unclear risk of other biases.Compared to the placebo group, the vitamin D group had significantly higher serum 25-hydroxyvitamin D (25(OH)D) levels at eight weeks, mean difference 29.79 (95% confidence interval 26.63 to 32.95); at 16 weeks, mean difference 12.67 (95% confidence interval 10.43 to 14.90); and at 24 weeks, mean difference 15.52 (95% confidence interval 13.50 to 17.54). We determined the quality of the evidence for this outcome to be moderate. There was no significant difference of adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% confidence interval 0.14 to 72.84), but the quality of the evidence was low. Regarding the frequency of pain, the vitamin D group had significantly fewer pain days compared to the placebo group, mean difference -10.00 (95% confidence interval -16.47 to -3.53), but again the quality of the evidence was low. Furthermore, the review included physical functioning PedsQL scores which was reported as absolute change from baseline. The vitamin D group had a lower (worse) health-related quality of life score than the placebo group but this was not significant at eight weeks, mean difference -2.02 (95% confidence interval -6.34 to 2.30). However, the difference was significant at both 16 weeks, mean difference -12.56 (95% confidence interval -16.44 to -8.69) and 24 weeks, mean difference -12.59 (95% confidence interval -17.43 to -7.76). We determined the quality of evidence for this outcome to be low.
  
  
  
  We included only one low-quality clinical study which had a high risk of bias with regards to incomplete outcome data. Therefore, we consider that the evidence is not of sufficient quality to guide clinical practice. Until further evidence becomes available, clinicians should consider the relevant existing guidelines for vitamin D supplementation (e.g. the Endocrine Society Clinical Practice Guidelines) and dietary reference intakes for calcium and vitamin D (e.g. from the USA Institute of Medicine). Evidence of vitamin D supplementation in sickle cell disease from high quality studies is needed. Well-designed, randomised, placebo-controlled studies of parallel design, are required to determine the effects and the safety of vitamin D supplementation in children and adults with sickle cell disease.
authors.affiliation: Department of Community Medicine, Melaka-Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia, 75150.
authors.forename: Htoo Htoo Kyaw
authors.initials: HH
authors.lastname: Soe
authors.affiliation: Department of Community Medicine, Melaka-Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia, 75150.
authors.forename: Adinegara Bl
authors.initials: AB
authors.lastname: Abas
authors.affiliation: Department of Community Medicine, Melaka-Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia, 75150.
authors.forename: Nan Nitra
authors.initials: NN
authors.lastname: Than
authors.affiliation: Internal Medicine, Faculty of Medicine, SEGi University, Hospital Sibu, Jalan Ulu Oya, Sibu, Sarawak, Malaysia, 96000.
authors.forename: Han
authors.initials: H
authors.lastname: Ni
authors.affiliation: Faculty of Medicine, Melaka-Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia, 75150.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Singh
authors.affiliation: Melaka-Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia, 75150.
authors.forename: Abdul Razzak Bin Mohd
authors.initials: AR
authors.lastname: Said
authors.affiliation: Comprehensive Sickle Cell Program, Aflac Cancer and Blood Disorders Service, Emory University School of Medicine, 1405 Clifton Road, NE, Atlanta, Georgia, USA, GA 30322.
authors.forename: Ifeyinwa
authors.initials: I
authors.lastname: Osunkwo
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications*; D002762:Cholecalciferol / Q000008:administration & dosage*; D006801:Humans; D010146:Pain / Q000188:drug therapy; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D014807:Vitamin D / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood; D014808:Vitamin D Deficiency / Q000628:therapy
chemical_list: D014807:Vitamin D; D002762:Cholecalciferol; C104450:25-hydroxyvitamin D