Influence of vitamin D on non-communicable disease outcomes in South African schoolchildren: the ViDiKids-NCD sub-study

'Non-communicable disease' (NCD) is a term used to describe any illness that is not caused by infections. NCDs are becoming more common worldwide, particularly among less wealthy city-dwellers living in lower- and middle-income countries such as South Africa. Most research on NCDs focuses on illnesses that primarily affect adults, such as heart disease and cancer. However, children are also affected by NCDs including thinning of the bones leading to fractures (broken bones), and reduced muscle mass. 20% of urban South African schoolchildren suffer a bone fracture by the age of 15, compared with 13% in England. There is an urgent need to identify a way to improve bone health and muscle mass in children.

Low levels of vitamin D ('the sunshine vitamin') are common among children living in disadvantaged urban environments such as the townships around Cape Town, due to decreased time outdoors, poor diets and obesity (which leads to vitamin D being stored in fat so that it is not available to the organs that need it). A growing body of research suggests that low levels of vitamin D may be a risk factor for developing thinning of the bones and reduced muscle mass. However, there is a lack of large, well-conducted research studies designed to find out whether vitamin D supplementation could strengthen children's bones and boost their muscle mass.

We are already conducting a large MRC-funded clinical trial (the ViDiKids study) in 5,400 Cape Town schoolchildren to see if vitamin D supplementation can prevent TB. In this application, we propose to conduct a sub-study in which we will measure additional outcomes including bone density, muscle mass and physical fitness in a sub-set of 400 children who are also taking part in the main VidiKids trial.

2) Aims and objectives

The aim of this research is to determine whether a weekly vitamin D supplement, taken by mouth for 3 years, can improve bone density, muscle mass and physical fitness in children living in townships around Cape Town. We will achieve this by conducting a sub-study in 400 children. At the start of the sub-study we will measure participants' bone density, muscle mass and physical fitness. Participants will then be allocated to receive weekly doses of vitamin D or placebo (dummy medication) at random, supervised by study staff. At the end of the study we will repeat assessments of bone density, muscle mass and physical fitness, and compare these outcomes between children who received vitamin D vs placebo over the previous 3 years.

3) Potential applications and benefits

We already know that improvements in bone density in children translate into reduced risk of bone fractures: if we show that bone density is boosted by vitamin D, then supplements could be routinely given to children to prevent bone fractures. 1 billion people worldwide have inadequate vitamin D levels: results of our study could therefore have global importance.

Several groups could benefit from the study. Children could benefit from the discovery of a cheap, safe method of reducing their risk of fractures; public health doctors could benefit from the discovery of a new tool for control of non-communicable diseases; and medical researchers could benefit from new scientific insights into the effects of vitamin D on children's health.

1. Background

Laboratory investigations and observational studies suggest that vitamin D has favourable effects on calcium homeostasis, muscle function and metabolism that may translate into improved bone mineral density, increased lean mass and improved physical fitness. Randomised controlled trials (RCTs) powered to test minimum clinically important differences in these outcomes in children are lacking.

2. Aim and Objectives

We aim to determine the effect of a 3-year course of oral vitamin D supplementation on diverse non-communicable disease (NCD) outcomes in South African schoolchildren by conducting a sub-study nested within the MRC-funded ViDiKids study - a n=5,400 RCT of vitamin D for the prevention of TB infection.

Our objective is to conduct a sub-study (n=400 children aged 9-10 years at baseline, 12-13 years at follow-up) to evaluate:

i) bone mineral density (primary outcome, measured by DXA)

ii) physical fitness (VO2max derived from results of a 20 metre multi-stage shuttle run test)

iii) muscle strength (grip strength and explosive leg strength, assessed with grip dynamometry and long jump from standing respectively)

iv) body composition (fat mass and mean fat-free soft tissue mass, measured by DXA)

v) biochemical parameters (serum concentrations of 25(OH)D, PTH, ALP, P1NP and CTX).

3. Application of results

Vitamin D supplementation is cheap and safe. Positive findings from this research could have a major public health impact: 1 billion people worldwide are estimated to have inadequate vitamin D status, and an epidemic of osteroporosis is emerging in many low- and middle-income countries.

1. Who will benefit from this research?

The following groups have potential to benefit from this research:

a) Children at risk of osteopaenia, reduced muscle mass and allergic disorders - particularly those living in urban settings in low- and middle-income countries

b) Public health policy-makers, particularly those involved with community paediatric health, at international, national and local levels

c) The bone, sports medicine and allergy research communities

d) The commercial private sector, in particular companies manufacturing vitamin D supplements

e) Partner academic institutions

f) Study participants

g) Study staff

2. How will they benefit from this research?

If the results of this trial are positive, the primary beneficiaries will be children at risk of osteopaenia, allergic disease and low vitamin D status. We will disseminate results of the trial widely, along with advice on how children can improve their vitamin D status. Vitamin D status can be improved at relatively low cost to the public (e.g. via food fortification programmes) - thus results of the study could have a real impact on the health of the very poorest people who are at most at risk of osteopaenia and allergic diseases.

Public health policy-makers will also stand to benefit. Findings from the trial could identify vitamin D supplementation as a new tool to combat the emerging epidemic of NCDs that is particularly acute in urban environments in low- and middle-income countries. Interested parties include those working internationally (e.g. the International Osteoporosis Foundation), nationally (e.g. South African governmental ministries of health and education) and locally (e.g. local governmental departments with responsibility for child health in schools). Results are potentially relevant for large numbers of the global population: 1 billion people worldwide are estimated to have inadequate vitamin D status, and both osteoporosis and atopic diseases are set to become major global problems as low- and middle-income countries undergo demographic transition.

The commercial sector (e.g. businesses making vitamin D supplements) could also benefit from a positive result.

Several parties involved in the conduct of the study will also benefit. Individual participants will benefit from screening for rickets, which they would not otherwise receive. Research staff will benefit from training in GCP, clinical trials methods, phlebotomy, computer skills and sub-study assessments, all of which could be applicable in the wider healthcare or academic sectors. Participating institutions will also benefit from the establishment of research infrastructure and links between researchers and schools that could be used to conduct further collaborative projects.

These benefits could all be realised rapidly. In our experience, people find micronutrient supplementation very acceptable, and weekly administration of vitamin D via schools would be inexpensive, safe and easily observed. Positive results from this trial could result in widespread implementation of vitamin D supplementation to improve children's bone mineral density (and thereby reduce fracture risk) within a relatively short period of time.