Vitamin D supplementation for sickle cell disease

Review question

We reviewed the evidence about the effect of giving vitamin D supplements to people with sickle cell disease (SCD).

Background

Vitamin D deficiency is common in people with SCD. Vitamin D regulates calcium levels and supports bone health and a lack of it make worse any bone health problems that people with SCD may have. We wanted to discover whether vitamin D supplements for people with SCD were better or worse than either a placebo (substance which contains no medication) or no vitamin D supplements and also if one dose schedule was better than another.

Search date

The evidence is current to: 14 January 2020.

Study characteristics

We looked at three studies where individuals were selected for different treatments at random. In one study, 39 people with SCD took either vitamin D or placebo tablets for six weeks and were then followed up for six months. In a second study, 62 people with SCD took either vitamin D 100,000 international units (IU)/month or 12,000 IU/month for two years. In the third study, 21 people with SCD took either 7000 IU/day or 4000 IU/day for three months.

Key results

Vitamin D versus placebo

People taking a vitamin D supplement had higher levels of vitamin D in their blood when it was measured after eight, 16 and 24 weeks. There were no differences in the number of people reporting side effects (tingling in the lips or hands). The vitamin D group had fewer days of pain. After eight weeks, the vitamin D group had a slightly worse score for health-related quality of life (physical functioning score); the difference was greater after 16 and 24 weeks. However, the quality of this evidence was low.

Different vitamin D doses compared

Only one of the two included studies which compared different doses of vitamin D supplementation provided any data for analysis. In the study with data, those taking a high-dose of vitamin D (100,000 IU/month) had higher levels of vitamin D in their blood when it was measured after one and two years. There were no differences in the number of people reporting side effects, respiratory events, lung function (forced expiratory volume in one second) and hand grip strength. But forced vital capacity (another measure of lung function) was lower in high-dose group.

The study comparing oral vitamin D3 7000 IU/day to 4000 IU/day reported that people taking the low-dose had lower average levels of vitamin D in the blood at both six and 12 weeks. At 12 weeks average levels of growth hormone were lower in the high-dose group.

Given the results from three small clinical trials with moderate to low-quality evidence, we do not think the results of our review are of sufficient quality to guide clinical practice. Until further evidence is available, clinicians should consider relevant existing guidelines for vitamin D supplementation, and recommendations for calcium and vitamin D intake.

Quality of the evidence

Vitamin D versus placebo

The risk of bias resulting from how people were put into the different groups was low. Also, neither those taking part or their doctor could guess which group they were in once the study started. Adverse events were not detailed in the original report, but the author provided the information when asked. More people dropped out of the placebo group (68.4%) than the vitamin D group (5%). The risk of bias from how the study reported results was high. We considered the evidence for vitamin D blood levels to be moderate quality, and for adverse events, days of pain and health-related quality of life to be low quality.

Different vitamin D doses compared

The risk of bias resulting from how people were put into the different dose groups was low in one study and unclear in the second. Neither those taking part nor their doctor could guess which group they were in once both studies started. The risk of bias from people taking part dropping out was low, but the risk was high for how the study reported results. Tthe quality of the evidence for vitamin D blood levels and side effects was low, and for respiratory events it was moderate.

Authors' conclusions: 

We included three RCTs of varying quality. We consider that the current evidence presented in this review 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 and dietary reference intakes for calcium and vitamin D. Well-designed RCTs of parallel design, are required to determine the effects and the safety of vitamin D supplementation as well as to assess the relative benefits of different doses in children and adults with SCD.

Read the full abstract...
Background: 

Sickle cell disease (SCD) is a genetic chronic haemolytic and pro-inflammatory disorder. With increased catabolism and deficits in energy and nutrient intake, individuals with SCD suffer multiple macro- and micro-nutritional deficiencies, including vitamin D deficiency. This is an update of a previous review.

Objectives: 

To investigate the effects of vitamin D supplementation in children and adults with SCD and to compare different dose regimens.

To determine the effects of vitamin D supplementation on general health (e.g. 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 (including lung function, acute chest syndrome, acute exacerbation of asthma and respiratory infections) and the safety of vitamin D supplementation.

Search strategy: 

We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 March 2020.

We also searched database such as PubMed, clinical trial registries and the reference lists of relevant articles and reviews. Date of last search: 14 January 2020.

Selection criteria: 

Randomised controlled trials (RCTs) and quasi-RCTs comparing oral administration of any form of vitamin D supplementation at any dose and for any duration to another type or dose of vitamin D or placebo or no supplementation in people with SCD, of all ages, gender, and phenotypes.

Data collection and analysis: 

Two authors independently extracted the data and assessed the risk of bias of the included studies. They used the GRADE guidelines to assess the quality of the evidence.

Main results: 

Vitamin D versus placebo

One double-blind RCT (n = 39) compared oral vitamin D3 (cholecalciferol) supplementation (20 participants) to placebo (19 participants) for six weeks. Only 25 participants completed the full six months of follow-up. The study had a high risk of bias due to incomplete outcome data, but a low risk of bias for randomisation, allocation concealment, blinding (of participants, personnel and outcome assessors) and selective outcome reporting; and an unclear risk of other biases.

Vitamin D supplementation probably led to higher serum 25(OH)D levels at eight weeks, mean difference (MD) 29.79 (95% confidence interval (CI) 26.63 to 32.95); at 16 weeks, MD 12.67 (95% CI 10.43 to 14.90); and at 24 weeks, MD 15.52 (95% CI 13.50 to 17.54) (moderate-quality evidence). There was little or no difference in adverse events (tingling of lips or hands) between the vitamin D and placebo groups, risk ratio 3.16 (95% CI 0.14 to 72.84) (low-quality evidence). Vitamin D supplementation probably caused fewer pain days compared to the placebo group at eight weeks, MD -10.00 (95% CI -16.47 to -3.53) (low-quality evidence), but probably led to a lower (worse) health-related quality of life score (change from baseline in physical functioning PedsQL scores); at both 16 weeks, MD -12.56 (95% CI -16.44 to -8.69) and 24 weeks, MD -12.59 (95% CI -17.43 to -7.76), although this may not be the case at eight weeks (low-quality evidence).

Vitamin D supplementation regimens compared

Two double-blind RCTs (83 participants) compared different regimens of vitamin D. One RCT (n = 62) compared oral vitamin D3 7000 IU/day to 4000 IU/day for 12 weeks, while the second RCT (n = 21) compared oral vitamin D3 100,000 IU/month to 12,000 IU/month for 24 months. Both RCTs had low risk of bias for blinding (of participants, personnel and outcome assessors) and incomplete outcome data, but the risk of selective outcome reporting bias was high. The bias from randomisation and allocation concealment was low in one study but not in the second. There was an unclear risk of other biases.

When comparing oral vitamin D 100,000 IU/month to 12,000 IU/month, the higher dose may have resulted in higher serum 25(OH)D levels at one year, MD 16.40 (95% CI 12.59 to 20.21) and at two years, MD 18.96 (95% CI 15.20 to 22.72) (low-quality evidence). There was little or no difference in adverse events between doses (low-quality evidence). There were more episodes of acute chest syndrome in the high-dose group, at one year, MD 0.27 (95% CI 0.02 to 0.52) but there was little or no difference at two years, MD 0.09 (95% CI -0.04 to 0.22) (moderate-quality evidence). At one year and two years there was also little or no difference between the doses in the presence of pain (moderate-quality evidence) or forced expiratory volume in one second % predicted. However, the high-dose group had lower values for % predicted forced vital capacity at both one and two years, MD -7.20% predicted (95% CI -14.15 to -0.25) and MD -7.10% predicted (95% CI -14.03 to -0.17), respectively. There were little or no differences between dose regimens in the muscle health of either hand or the dominant hand.

The study comparing oral vitamin D3 7000 IU/day to 4000 IU/day (21 participants) did not provide data for analysis, but median serum 25(OH)D levels were reported to be lower in the low-dose group at both six and 12 weeks. At 12 weeks the median serum parathyroid hormone level was lower in the high-dose group.

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