Vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children

Review question

To assess the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children.

Background

Nutritional rickets is a disease of the bones that affects mostly children in low- and middle-income countries. Children with nutritional rickets typically have deformed bones, may not grow well and experience other health problems. A lack of vitamin D is the most common cause of nutritional rickets. As such, nutritional rickets is usually treated by giving the child vitamin D with or without calcium. In some sunny countries, however, calcium alone has been used to treat nutritional rickets in children who are believed to have adequate vitamin D from their exposure to sunlight but who lack adequate calcium in their diet. This review was conducted to find out whether vitamin D, calcium or a combination of vitamin D and calcium is best for the treatment of nutritional rickets in children.

Study characteristics

We found four randomised controlled trials (clinical trials where people are randomly put into one of two or more treatment groups) that compared vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children. The 286 children in the studies were aged six months to 14 years. Following treatment, the children were monitored for between 12 and 24 weeks.

This evidence is up to date as of 25 July 2019.

Key results

We found evidence that using calcium alone or vitamin D plus calcium to treat nutritional rickets may improve healing when compared to using vitamin D alone. We are uncertain about the effects on fractures of calcium alone compared to vitamin D alone. We are uncertain about the effects on fractures or other side effects of vitamin D plus calcium compared to vitamin D alone. We are uncertain about the effects of vitamin D plus calcium compared to calcium alone on healing of rickets, fractures and side effects.

None of the studies reported on growth pattern (differences in height, weight, height for age, weight for age), death from any cause, socioeconomic effects (cost of treatment, resources lost due to illness or due to absence of the caregiver from work, cost of visits to hospital or health facility) and health-related quality of life.

Reliability of the evidence

The reliability of the evidence for all the outcomes in our review is low or very low. The reason for the uncertainty is mostly due to the low number of participants in the studies and the low number of studies included in the review. Imprecise results and the potential to arrive at wrong conclusions because of the way the trials were conducted in some of the studies also contributed to the level of uncertainty.

Authors' conclusions: 

This review provides low-certainty evidence that vitamin D plus calcium or calcium alone improve healing in children with nutritional rickets compared to vitamin D alone. We are unable to make conclusions on the effects of the interventions on adverse events or morbidity (fractures).

Read the full abstract...
Background: 

Nutritional rickets is a disease which affects children, especially in low- and middle-income countries. It causes problems such as skeletal deformities and impaired growth. The most common cause of nutritional rickets is vitamin D deficiency. Vitamin D administered with or without calcium is commonly regarded as the mainstay of treatment. In some sunny countries, however, where children are believed to have adequate vitamin D production from exposure to ultraviolet light, but who are deficient in calcium due to low dietary intake, calcium alone has also been used in the treatment of nutritional rickets. Therefore, it is important to compare the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children living in different settings.

Objectives: 

To assess the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children.

Search strategy: 

We searched CENTRAL, MEDLINE, LILACS, WHO ICTRP Search Portal and ClinicalTrials.gov. The date of the last search of all databases was 25 July 2019. We applied no language restrictions.

Selection criteria: 

We included randomised controlled trials (RCT) involving children aged 0 to 18 years with nutritional rickets which compared treatment with vitamin D, calcium or a combination of vitamin D and calcium.

Data collection and analysis: 

Two review authors independently screened the title and abstracts of all studies, extracted data and assessed the risk of bias of included studies. We resolved any disagreements by consensus or recourse to a third review author. We conducted meta-analyses for the outcomes reported by study authors. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI) and, for continuous outcomes, we calculated mean differences (MD) with 95% CIs. We assessed the certainty of the evidence of the included studies using GRADE.

Main results: 

We identified 4562 studies; of these, we included four RCTs with 286 participants. The studies compared two or more of the following: vitamin D, calcium or vitamin D plus calcium. The number of participants randomised to receive vitamin D was 64, calcium was 102 and vitamin D plus calcium was 120. Two studies were conducted in India and two were conducted in Nigeria. None of the included studies had a low risk of bias in all domains. Three studies had a high risk of bias in at least one domain. The age of the participants ranged between six months and 14 years. The duration of follow-up ranged between 12 weeks and 24 weeks.

Two studies compared vitamin D to calcium. There is low-certainty evidence that, at 24 weeks' follow-up, calcium alone improved the healing of rickets compared to vitamin D alone (RR 3.26, 95% CI 1.59 to 6.69; P = 0.001; 1 study, 71 participants). Comparing vitamin D to calcium showed no firm evidence of an advantage or disadvantage in reducing morbidity (fractures) (RR 0.27, 95% CI 0.03 to 2.32; P = 0.23; 1 study, 71 participants; very low-certainty evidence). Adverse events were not reported.

Two studies compared vitamin D plus calcium to vitamin D at 12 or 24 weeks. Vitamin D plus calcium improved healing of rickets compared to vitamin D alone at 24 weeks' follow-up (RR 3.06, 95% CI 1.49 to 6.29; P = 0.002; 1 study, 75 participants; low-certainty evidence). There is no conclusive evidence in favour of either intervention for reducing morbidity (fractures) (RR 0.24, 95% CI 0.03 to 2.08; P = 0.20; 1 study, 71 participants; very low-certainty evidence) or adverse events (RR 4.76, 95% CI 0.24 to 93.19; P = 0.30; 1 study, 39 participants; very low-certainty evidence).

All four included studies compared vitamin D plus calcium to calcium at different follow-up times. There is no conclusive evidence on whether vitamin D plus calcium in comparison to calcium alone improved healing of rickets at 24 weeks' follow-up (RR 1.17, 95% CI 0.72 to 1.90; P = 0.53; 2 studies, 140 participants; very low-certainty evidence). Evidence is also inconclusive for morbidity (fractures) (RR 0.89, 95% CI 0.06 to 13.76; P = 0.94; 1 study, 72 participants; very low-certainty evidence) and adverse events (RR 4.29, 0.22 to 83.57; P = 0.34; 1 study, 37 participants; very low-certainty evidence).

Most of the evidence in the review is low or very low certainty due to risk of bias, imprecision or both.

None of the included studies assessed all-cause mortality, health-related quality of life or socioeconomic effects. One study assessed growth pattern but this was not measured at the time-point stipulated in the protocol of our review (one or more years after commencement of therapy).

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