Interventions for the prevention of nutritional rickets in term born children

  • Review
  • Intervention

Authors


Abstract

Background

Nutritional rickets is a disease of growing children leading to bone deformities, bone pain, convulsions or delayed motor development. Today, high-incidence of nutritional rickets is mainly found in low-income countries.

Objectives

To assess the effects of various interventions on the prevention of nutritional rickets in term born children.

Search methods

Studies were obtained from computerised searches of The Cochrane Library, MEDLINE, EMBASE, LILACS and reference lists of relevant articles. We contacted authors of studies or reviews to obtain further studies.

Selection criteria

Studies were included if they were randomised controlled clinical trials, controlled clinical trials or prospective cohort studies comparing any intervention for the prevention of nutritional rickets in term born children with placebo or no intervention. Minimum duration of the intervention was three months for children under 12 months or six months for children over 12 months.

Data collection and analysis

Two authors independently extracted data and assessed study quality. Authors of studies were contacted to obtain missing information.

Main results

Four studies enrolled approximately 1700 participants. Trials lasted between nine months to two years. Three studies were randomised controlled trials, two of which showed a cluster randomised design; one trial probably was a controlled trial with researcher controlled group assignment. In children up to three years of age in Turkey, Vitamin D compared to no intervention showed a relative risk of 0.04 (95% confidence interval (CI) 0 to 0.71). Despite a marked non-compliance, a Chinese trial in children up to three years of age comparing a combined intervention of supplementation of vitamin D, calcium and nutritional counselling showed a relative risk of 0.76 (95% CI 0.61 to 0.95) compared to no intervention. In two studies conducted in older children in China and in France no rickets occurred in both the intervention and control group.

Authors' conclusions

There a only few studies on the prevention of nutritional rickets in term born children. Until new data become available, it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers; children living in Africa, Asia or the Middle East or migrated children from these regions into areas where rickets is not frequent. Due to a marked clinical heterogeneity and the scarcity of data, the main and adverse effects of preventive measures against nutritional rickets should be investigated in different countries, different age groups and in children of different ethnic origin.

摘要

背景

預防足月孩童之營養性佝僂病之介入

營養性佝僂病是生長中孩童的疾病,會造成骨骼畸形、骨疼痛、抽搐或運動發展延遲。今日,高發生率之營養性佝僂病主要在低收入國家

目標

評估預防足月孩童之營養性佝僂病的各種介入措施的效益

搜尋策略

研究的獲取是由電腦搜尋Cochrane書庫、MEDLINE, EMBASE, LILACS與參考文獻表單之相關文章。聯絡研究或評論之作者以取得更深入的資料。

選擇標準

研究的收錄,包括隨機控制之臨床試驗、控制之臨床試驗或前瞻性的世代研究,預防足月孩童營養性佝僂病之任一種介入法與安慰組或無介入組比較,介入的期間在小於12個月大的幼童最少三個月、大於12月者至少六個月。

資料收集與分析

兩位作者分別獨立擷取數據和評估研究品質。聯絡研究的作者獲取缺漏的資料

主要結論

四個研究收錄將近1700個受試者。試驗期間從9個月到2年。三篇研究為隨機控制試驗,其中兩個為群集隨機設計,另一篇可能是控制試驗由研究者控制團體的分配。土耳其三歲以下孩童,維生素D與無介入組相比,顯示相對風險0.04 (95% 信心區間 (CI) 0 to 0.71)。一個中國三歲以下孩童的試驗,即使明顯的沒有遵囑性,使用維生素D、鈣補充與營養諮詢合併介入,與無介入組相比顯示其相對風險0.76 (95% CI 0.61 to 0.95)。兩個在中國與法國施行之年齡較大孩童的試驗,介入組與控制組均無佝僂症發生。

作者結論

預防足月兒童營養性佝僂病的研究不多。除非有可用之新資料,否則提供預防措施(維生素D或鈣)給高風險組群,如嬰兒與幼兒;生長在非洲、亞洲、中東的兒童或由這些地方移民到少有佝僂病地方的兒童,看來是合理的。由於臨床的異質性很高而且資料又很少,應該調查對抗營養佝僂病之預防措施在不同國家、不同年齡層與不同種族來源的主要效果與不良反應。

翻譯人

本摘要由慈濟醫院吳篤安翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

雖然只有少數研究且存在不同的結果,除非有新資料,對抗高風險族群營養性佝僂病之預防措施應為合理。佝僂病是影響兒童骨骼生長的疾病。鈣與磷是構成骨骼的重要成分。營養性佝僂病,在剛開始其可獲得的鈣減少,後來磷的障礙也會發生。鈣的缺乏可能因為攝取不足或腸道胃吸收不足所致。後者乃由維生素D高度調控,維生素D經陽光曝曬後由皮膚製造或由飲食獲取,如鱈魚肝。因此,缺乏鈣、維生素D或兩者都缺會造成營養性佝簍病,此病主要特徵是骨頭變形、骨頭疼痛、抽搐或發育遲緩。從1930年代,主要在高收入國家,採用補充維生素D預防兒童佝僂病;一些其他措施,如補充鈣或較長皮膚日曬也採用過。經過一段時間許多因素有了改變,例如提供鈣的營養,空氣污染會吸走陽光使得皮膚維生素D製造減少,或社會因素如童工也會造成陽光的曝曬不足。因為這些改變我們尋找過去五十年所做過的研究,調查病患相關的結果。依病患相關的結果,我們界定佝僂病的發生率、介入治療的不良反應、死亡率、健康相關之生活品質以及花費。4個試驗納入1700個受試者,為期九個月到兩年。受試者年齡從1個月大到15歲。營養性佝僂病依不同背景有不一樣的結果;其中只有一個研究有調查不良反應。考慮到營養性佝僂病的部分高發生率,明顯實施補充維生素D或鈣的方式,其風險利益之比是有利的,預防性措施在高風險的嬰兒與幼兒是合理的。新的試驗調查預防措施對抗營養性佝僂病之主要效果與副作用在不同的年齡層與不同國家是必要的。

Plain language summary

Interventions for the prevention of nutritional rickets in term born children

Although only a few studies with different results exist, preventive measures against nutritional rickets appear reasonable in high risk groups until new data become available.

Rickets is a disease which affects the bone of growing children. Calcium and phosphate are important elements which form the bone. In nutritional rickets, initially the availability of calcium is diminished, later disturbances in phosphate occur. The shortage of calcium may be caused by limited intake or limited resorption in the gut. The latter is highly regulated by vitamin D, which can be synthesised from the skin after sun exposure or can be acquired from dietary sources, for example cod liver. Therefore, shortage of calcium, vitamin D or both may lead to nutritional rickets, which is mainly characterized by deformed bones, bone pain, convulsions or delayed development. Since the 1930s supplementation of vitamin D is used for the prevention of rickets in children, mainly in high-income countries; several other measures like supplementation of calcium or longer exposure of the skin to sunlight are also used. Over the time many factors have changed, for example nutrition, which provides calcium, air pollution, through which sun light is absorbed leading to a diminished synthesis of vitamin D in the skin, or social issues, for example child labour, again leading to limited sun exposure. Because of these changes we looked for studies conducted in the last 50 years which investigated patient-relevant outcomes. As patient-relevant outcomes we defined the occurrence of rickets, adverse effects of the intervention, mortality, health-related quality of life and costs.
Four trials enrolled approximately 1700 participants and lasted between nine months and two years. Study participants were aged from one month to 15 years. There were different results on the occurrence of nutritional rickets in different settings. Adverse effects were investigated in one study only.
Considering the partial high frequency of nutritional rickets, the obvious way of action of supplementation of vitamin D or calcium and the favourable risk-benefit ratio, preventive measures are reasonable in high risk groups like infants and toddlers. New studies investigating main and side effects of preventive measures against nutritional rickets in different age groups and in different countries are indicated.

Background

Description of the condition

Rickets comprises a group of disorders characterised by defective mineralization and disorganisation of the epiphyseal growth plates. Therefore, rickets is a disease limited to growing children. Mineralisation of the bone matrix is also defective, called osteomalacia.
The main components of the bone mineral matrix are calcium and phosphate. Rickets is classified depending on the lacking mineral. Nutritional rickets is the main form of calcipenic rickets, nevertheless alterations in phosphate also occur in the course of the disease. The clinical presentation of nutritional rickets depends on the age of the child, it includes soft skull bone, called craniotabes; hypocalcaemic convulsions; typical bone deformities like deformation of the weight-bearing limbs; swelling of the wrist, knee or ankle; swelling of the costochondral junction of the ribs, called rachitic rosary or the deformity of the soft rib cage due to pulling of the diaphragm, called Harrison's sulcus. Furthermore, muscular hypotonia or delayed motor development may occur.
The biochemical findings of nutritional rickets include a normal or decreased blood level of calcium, a normal, decreased or increased blood level of phosphate as well as elevated blood levels of alkaline phosphatase, parathyroid hormone or both. In vitamin D-deficiency rickets 25-hydroxyvitamin D blood levels are decreased.
Radiologically, there is an irregular metaphyseal outline like cupping, widening or fraying due to diminished calcification of the growth plate. In younger children the radiological changes can best be visualised in the wrist, in older children the area above and below the knee is most useful (Pettifor 2005; Shaw 2004; Thacher).

Vitamin D and calcium
In general, nutritional rickets is the result of either calcium or vitamin D deficiency, or both.
The exposure of the skin to ultraviolet light (wavelengths from 290 to 315 nm, called UV-B) is crucial for the beginning of the endogenous syntheses of vitamin D. Provitamin D3 (7-dehydrocholesterol), stored in the skin, is photolysed by the absorbed energy of UV-B to previtamin D3. Previtamin D3 converts to vitamin D3 (cholecalciferol) rapidly. Thus, low UV-B irradiation due to northern or southern latitude, high air pollution, short outdoors exposure time, veiling of the skin, the use of sunscreens or high amounts of the skin pigment melanin lower the production of vitamin D3. As vitamin D3 is synthesised due to sunlight exposure, it is not a vitamin in the strict sense of definition.
Exogenous sources of vitamin D provide vitamin D2 (ergocalciferol) and vitamin D3. Very few foods contain a reasonable amount of vitamin D. Human breast milk has only a low concentration of vitamin D, which is an important factor for infants being solely breast fed for a long time.
Vitamin D, which denotes both vitamin D2 and vitamin D3, is hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol). A further hydroxylation, mainly in the kidneys, leads to 1,25-dihydroxyvitamin D (calcitriol), the final active form of vitamin D.
1,25-dihydroxyvitamin D acts via the vitamin D receptor (VDR), an intracellular protein which belongs to the steroid-hormone-thyroid hormone-retinoic acid receptor gene superfamily. Conflicting data exist for the role of polymorphisms of VDR for the pathogenesis of rickets.
The target of VDR is the vitamin D response element regulating gene transcription which evokes in the intestine the synthesis of proteins necessary for the transfer of calcium from the intestinal lumen to the capillaries. It is assumed that only ten percent of the calcium entry is vitamin D independent. The availability of calcium is lowered by complexation with oxalate or phytate. Inadequate low intake of calcium leads to inactivation of calcidiol.
A high-fibre diet results in degradation of calcitriol, as does elevated parathyroid hormone resulting from hypocalcaemia.
In state of dietary calcium deficiency, vitamin D also interacts with VDR in bone tissue. The thereby induced maturation of osteoclasts leads to dissolving of bone tissue and thus, release of calcium. It is not clear whether there is a direct effect of vitamin D on bone formation, too.
There are many other actions of vitamin D besides the regulation of calcium homeostasis, for example regulation of cell growth and apoptosis being associated with several forms of cancer. Furthermore, the modulation of immune reactions is associated with autoimmune diseases like type 1 diabetes mellitus or multiple sclerosis. There are influences on the functions of muscles and the nervous system, too (Bronner 2003; Dusso 2005; Pettifor 2003; Thacher 2003).

Frequency of nutritional rickets
To describe the frequency of nutritional rickets in term infants three aspects have to be considered. First, due to different diagnostic criteria reported frequencies are not directly comparable (Peach 1984). Secondly, frequency is extremely time dependent. In the 1920s and 1930s the prevalence of nutritional rickets was between 75% to 98% in Europe and the United States of America based on autopsies, clinical examination or radiographs (Chesney 2001). Thirdly, three groups have to be distinguished:

  • Infants with fair skin

  • Infants with intermediate or dark skin living in their indigenous area

  • Infants with intermediate or dark skin living in an area with lower UV-B irradiation than in their indigenous area

In the first group nutritional rickets mostly is due to pure vitamin D deficiency. Only few recent data for incidence or prevalence are known. For example, in a study in the West Midlands, United Kingdom, in which the overall incidence was 7.5 per 100,000 children under five years, only 1 of 24 children with rickets (defined by radiological changes or hypocalcaemic convulsions) was classified as 'white' which approximates an incidence of 0.4 per annum per 100,000 children under five years (Callaghan 2006). In Turkey, 10% of children from 3 to 36 months had clinical and biochemical changes consistent with rickets (Beser 1994). Fifteen per cent of children under one year showed biochemical changes in Greece (Lapatsanis 1968), nine per cent of children between 12 and 24 months showed radiological changes in the United Kingdom (Richards 1968).
In the second group, nutritional rickets may be due to calcium or vitamin D deficiency. For example, in Nigeria nine per cent of children between six months and three years showed clinical signs of rickets (Pfitzner 1988). In Tibet, 66% of children over 24 months showed clinical features of rickets (Harris 2001).
Children of immigrants or immigrated infants represent the third group. The study in the West Midlands, United Kingdom mentioned above showed an incidence for children of south Asian ethnic origin of 38 and for children of black African or African-Caribbean ethnic origin of 95 per annum per 100,000 children under the age of 5 five years (Callaghan 2006).

Development of prevention
Although early descriptions of rickets reach back to antiquity, rickets became more frequent in the 17th century. During and after the industrialisation in Europe and North America, rickets was a disease of high frequency, presumably because of the changing socio-economic and nutritional circumstances. Cod liver oil was first used traditionally, in the 19th century the specific action against rickets was noted. After its discovery vitamin D was used in different formes for the treatment and later the prevention of rickets (Rajakumar 2003).
In the 20th century rickets was considered to be a disease which affects children up to approximately five years of age. After the recognition of rickets in older immigrant children in the United Kingdom, cross-sectional studies showed that native children were also affected. Therefore, preventive measures need had to be considered (Cooke 1973).
Because of the relationship of sun light and synthesis of vitamin D, rickets were considered not be prevalent in tropical areas. Reports starting in the 1930s showed that rickets was a frequent disease in these regions and still is today. That is why preventive measures need to be considered in these areas as well (Jelliffe 1968; Thacher 2006).

Diagnostic criteria used for the review
There are no generally accepted diagnostic criteria for nutritional rickets. Therefore, we extracted data according to authors' definition of rickets. The different diagnostic criteria may produce significant variability in the clinical characteristics of the people with rickets included as well as in the results obtained. We planned to explore these differences in a sensitivity analysis.
Ideally, three diagnostic criteria would be encountered:
1. Clinical signs or radiological findings of rickets.
2. Elevated blood levels of alkaline phosphatase, parathyroid hormone or both.
3. Exclusion of disorders mimicking nutritional rickets (like phosphopenic rickets, vitamin D deficiency or lack of calcium due to gastrointestinal or renal diseases, inborn disorders of vitamin D or calcium metabolism).

Description of the intervention

Interventions for the prevention of nutritional rickets include supplementation of vitamin D, for example on a daily basis, as a "stossprophylaxis" (intermittent application of large amounts) or in fortified food, especially milk; calcium supplementation or advice on sun exposure.

How the intervention might work

Since paucity of calcium is crucial in nutritional rickets it is essential to increase the resorption of calcium. Therefore, there are three possibilities of intervention: First, increasing the calcium intake; secondly, increasing the endogenous syntheses of vitamin D; thirdly, increasing the vitamin D intake.

Adverse effects of the intervention
Reported adverse effects of vitamin D supplementation are hypercalcaemia or nephrocalcinosis (Markestad 1987; Rönnefarth 2000). Overexposure of the skin to sunlight may lead to skin cancer.

Why it is important to do this review

There are still many countries in Africa, Asia and the Middle East with high frequency of nutritional rickets. Furthermore, the incidence of rickets seems to be reincreasing in countries with a formerly low incidence. The latter might be linked to reduced acceptance of preventive measures. Considering the worldwide high burden of nutritional rickets leads to the question whether there are any effective measures for the prevention of nutritional rickets. As far as we know there is no systematic review, meta-analysis or health-technology assessment report about the prevention of nutritional rickets.

Objectives

To assess the effects of various interventions on the prevention of nutritional rickets in term born children.

Methods

Criteria for considering studies for this review

Types of studies

Randomised, quasi-randomised and non-randomised controlled clinical trials and prospective cohort studies.

Types of participants

Healthy term born children or children with diseases not increasing the risk of developing rickets.

Types of interventions

Intervention
Any intervention used for the prevention of nutritional rickets like vitamin D supplementation via tablets, liquids or fortified food; calcium supplementation, advice to get more sunlight or combinations of these interventions.

Comparison
Placebo or no intervention.

Types of outcome measures

Primary outcomes
  • occurrence of rickets;

  • adverse effects.

Secondary outcomes
  • all-cause mortality;

  • quality of life (ideally measured by a validated instrument);

  • costs.

Covariates, effect modifiers and confounders
  • different groups of children (mentioned under 'Frequency of nutritional rickets');

  • compliance;

  • nutrition (for example phytate or oxalate intake);

  • age.

Timing of outcome assessment

We had planned to include prospective studies only if observation lasted longer than three years. This observation period was considered to be long enough to definitely exclude rickets clinically, radiologically, or both. As we failed to identify these, we adapted the criteria: for children younger than 12 months of age, observation had to last three months or longer; for children older than 12 months of age, observation had to last six months or longer.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases:

  • The Cochrane Library (issue 3, 2006);

  • MEDLINE (via OVID interface, until August 2006);

  • EMBASE (via OVID interface, until August 2006);

  • LILACS (until August 2006).

We also searched the metaRegister of Clinical Trials (www.controlled-trials.com/mrct) to identify ongoing studies.

Studies published in any language were included. For details on the search strategy see Appendix 1. This strategy was used for MEDLINE and adapted for the other databases.

Reference lists
We tried to identify additional studies by searching the reference lists of included trials and reviews identified.

Correspondence
We contacted authors of studies and reviews as experts in the field to obtain additional references or unpublished trials.

Data collection and analysis

Selection of studies

First, one author (CL) scanned the title or abstract, or both sections of every record retrieved to eliminate all records not dealing with nutritional rickets or unequivocally not reporting comparative studies. Secondly, both authors scanned the title or abstract, or both sections of the selected records to determine which studies require further assessment. All potentially relevant articles were investigated as full text. Interrater agreement for study selection was measured using the kappa statistic (Cohen 1960). Consensus about variation in rated records was reached by discussion. An adapted QUOROM (quality of reporting of meta-analyses) flow chart of study selection (Moher 1999) is attached (see (Figure 1).

Figure 1.

QUOROM (quality of reporting of meta-analyses) flow-chart of study selection

Data extraction and management

For studies fulfilling the inclusion criteria, both authors independently extracted relevant population and intervention characteristics using standard data extraction sheets. Consensus about differently extracted data was reached by discussion. Any relevant missing information on the study was sought from the authors of the study. For details, please see 'Characteristics of included studies' and Table 1, Appendix 2, Appendix 3 and Appendix 4.

Table 1. Risk of bias
CharacteristicBeser 2004Du 2004Duhamel 2000Strand 2002/2003
Intervention 1 (I1) / intervention 2 (I2) / control 1 (C1)I1. vitamin D 400 IU/day per os
C1. no placebo or other intervention
I1: fortified milk, averaged calcium 245 mg/day per os
I2: fortified milk, averaged calcium 245 mg/day per os, vitamin D3 133 IU/day per so
C1: no placebo or other intervention
I1. vitamin D3 100,000 IU every 3 months per os
C1. placebo
I1: promoting of exclusive breastfeeding from birth, supplementation of solid foods at age 5 months, weaning at 12 to 18 months, vitamin D 300 IU/day per os during the first 12 months, calcium 378 mg/day per os from age 5 months to 24 months
C1: no placebo or other intervention.
Randomised controlled clinical trial (RCT)NYYY
Controlled clinical trial?
(presumed Y)
NNN
Prospective cohort studyNNNN
Method of randomisation (specify)N/A???
Unit of randomisation (individuals, cluster - specify)N/Acluster (pupils of matched 3 x 3 schools)individualscluster (children of 16 matched villages )
Randomisation stratified for centresN/AN/A?N/A
Randomisation ratioN/A???
(intervention group: 14 villages, control group: 2 villages)
Concealment of allocation (specify)N/A???
Study population representative of populationY??
(recruited from hospital)
Y
Method of selection of controls (specify) (*)N/AN/AN/AN/A
Patients in different groups form same population (*)N/AN/AN/AN/A
Exposed/unexposed over same period of time (*)N/AN/AN/AN/A
Ascertainment of group determination (specify) (*)N/AN/AN/AN/A
Ascertainment of outcome (specify)direct measurementdirect measurementdirect measurementdirect measurement
Stated blinding (open; single, double, triple blind)??double?
Actual blinding: participant/parentsN/A?YN/A
Actual blinding: caregiver / treatment administratorN/A??N/A
Actual blinding: outcome assessor???N
Actual blinding: others????
Blinding checked: participant????
Blinding checked: caregiver / treatment administrator????
Blinding checked: outcome assessor????
Primary endpoint definedYNNY
[n] of primary endpoint(s)1??1
[n] of secondary endpoints0??2
Total [n] of endpoints112
(no distinction made between primary and secondary outcomes)
8
(no distinction made between primary and secondary outcomes)
3
Prior publication of study design????
Power calculation????
[n] participants per group calculated????
Intention-to-treat analysis (ITT)Y
(no summary statistic in analysis)
Y
(no summary statistic for rickets in analysis)
Y
(no summary statistic for rickets in analysis)
N
(based on analysed patients)
Per-protocol-analysisNNNN
(based on analysed patients)
ITT definedNNNN
Dealing with missing data????
(imputing for birth weight which is not relevant for this review)
[n] of screened participants (I1/ I2 / C1 / total)????
[n] of randomised/included participants (for primary endpoint)I1: 302
C1: 374
I1: 238
I2: 260
C1: 259
I1: 32
C1: 34
Total: 259
[n] of participants finishing the studyI1: 293
C1: 369
I1: 209
I2: 242
C1: 247
I1: 32
C1: 31
Total: 245
[n] of patients analysed (for primary endpoint)no summary statistic providedno summary statistic for rickets providedno summary statistic for rickets providedI1: 183
C1: 46
Total: 229
Description of discontinuing participantsNYNN
Drop-outs (reasons explained)NYNN
Withdrawals (reasons explained)NYNN
Losses-to-follow-up (reasons explained)NYNN
[n] of participants who discontinued1459314
[%] discontinuation rate2855
Discontinuation rate similar between groupsYYYY
Differences [n] calculated to analysed patientsN/AN/AN/AN/A
Adjustment for multiple outcomes / repeated measurementsN/A
no summary statistic provided
Y
no summary statistic for rickets provided
N/A
no summary statistic provided
Y
Baseline characteristics: clinically relevant differences???Y
(more preterm born children in intervention group)
Treatment identical (apart from intervention)????
Compliance measured?YYY
Other important covariates measured (specify)????
Co-morbidities measured????
Co-medications measured????
Different length of follow-up (taken into account) (*)N/AN/AN/AN/A
Loss of study patients taken into accountYYYY
Specific doubts about study qualityNNNN
Funding: commercial?N?N
Funding: non-commercial?Y?Y
Publication status: peer review journalYYYY
Publication status: journal supplementNNNN
Publication status: abstractNNNN
Publication status: otherNNNN
Symbols & abbreviations: Y = yes; N = no; ? = unclear; N/A = not applicable; I = intervention; C = control
(*) for prospective cohort studies only
    
     
     

Assessment of risk of bias in included studies

Both authors independently assessed the methodological quality of each included study, differences were resolved by discussion. For randomised controlled trials we used quality criteria specified by Schulz 1995 and by Jadad 1996, for other prospective comparative studies quality criteria specified by Downs 1998 and by Deeks 2003. We planned to explore the influence of individual quality criteria in a sensitivity analysis (see under 'sensitivity analyses'). Inter-rater agreement was calculated using the kappa statistic (Cohen 1960).

Measures of treatment effect

We decided to base the analysis on dichotomous data (here, rickets yes/no) expressed as relative risks (RR) with 95% confidence intervals (CI).

Unit of analysis issues

We planned to address cluster-randomised studies or studies with multiple interventions for meta-analyses specifically.

Dealing with missing data

Relevant missing data were obtained or tried to obtain from authors. Evaluation of important numerical data such as screened, eligible and randomised children as well as intention-to-treat and per-protocol population was carefully performed. Drop-outs, misses to follow up and withdrawn study participants were investigated.

Dealing with duplicate publications

In the case of duplicate publications and companion papers of a primary study, we planned to maximise yield of information by simultaneous evaluation of all available data. In cases of doubt, the original publication (usually the oldest version) was planned to obtain priority.

Assessment of heterogeneity

In case of relevant heterogeneity due to clinical, methodological or statistical issues, study result were not planned to be combined in a meta-analysis. Heterogeneity was planned to be identified and quantified using the χ²-test with significance being set α = 0.1 and the I2 statistic (Higgins 2002; Higgins 2003), the latter describing the percentage of total variation across studies that is due to heterogeneity rather than chance. I2-values of 50% or more indicate relevant heterogeneity. We planned to identify possible sources of heterogeneity by evaluating individual study characteristics and subgroup and sensitivity analyses.

Assessment of reporting biases

We planned to use funnel plots to assess small study bias.

Data synthesis

Data were planned to be summarised statistically if they were available, sufficiently similar and of sufficient quality. Statistical analysis was planned to be performed according to the statistical guidelines referenced in the newest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006). Pooled results were planned to be analysed using primarily the DerSimonian and Laird random-effects method (DerSimonian 1986). For preventive measures, the relative risk of adverse outcome, here occurrence of rickets, is the appropriate summary statistic (Deeks 2002).

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were planned to be only performed if one of the primary outcome parameters demonstrated statistically significant differences between treatment groups.
The following subgroup analyses were planned:

  • using the three groups described in the section 'Description of the disease';

  • breast milk nutrition during infancy;

  • veiling of the mother during pregnancy or nursing;

  • mode of administration of the intervention.

Subgroup analyses were planned to be mainly used to explore heterogeneity due to clinical, methodological or statistical issues and as a hypothesis generating exercise.

Sensitivity analysis

We planned to perform sensitivity analyses in order to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies;

  • repeating the analysis taking account of study quality, as specified above;

  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results;

  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country, no primary consensus regarding study selection.

The robustness of the results was planned to be tested by repeating the analysis using different measures of effects size (risk difference, odds ratio etc.) and different statistic models (fixed- and random-effects models).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search
The initial search identified 7542 records, from these, 221 full papers were identified for further examination. The other studies were excluded on the basis of their abstracts because they were not relevant to the question under study (see Figure 1 for details of the amended QUOROM (quality of reporting of meta-analyses) statement). After screening the full text of the selected papers, four studies finally met the inclusion criteria.

Assessment of inter-rater agreement
Inter-rater agreement for study selection, that is qualifying a study as 'potentially relevant' was 74%.

Missing data
We contacted or tried to contact all authors of included studies:
Beser 1994 was contacted for clarification of the mode of group allocation. We received no response.
Du 2004 was contacted for clarification if there was a thorough clinical examination regarding the clinical signs of rickets and if participants with rickets were discovered. Authors provided additional data.
Duhamel 2000 was contacted for clarification if the two participants who showed radiological signs of rickets at the beginning of the study were the same as the two participants showed radiological signs of rickets at the end of the study. We received no response.
Strand 2002/2003 was contacted for providing the number of participants in each group and the number of participants with rickets in each group. Authors provided additional data. Specific data for participants who were compliant with vitamin D and calcium supplementation were not available.

Excluded studies
Two studies had to be excluded after careful evaluation of the full publication. Reasons for exclusion was high risk for bias due to high or marked different attrition rates (for details see table Characteristics of excluded studies).

Characteristics of included studies
For details see Table 1 and Appendix 2, Appendix 3, Appendix 4.

Interventions
Comparisons

Beser 1994 investigated vitamin D versus no intervention. Du 2004 studied milk fortified with calcium versus milk fortified with calcium and cholecalciferol versus no intervention. Duhamel 2000 investigated vitamin D versus placebo. Strand 2002/2003 studied a combined intervention of supplementation of vitamin D and calcium plus parents' nutritional counselling.

Number of study centres
Three of the four included studies had one study centre only, Duhamel 2000 reported four study centres.

Country and location
Du 2004 and Strand 2002/2003 were performed in China, Beser 1994 in Turkey and Duhamel 2000 in France.

Setting
Beser 1994 recruited children from the community. Du 2004 was a cluster study with recruitment from schools. Duhamel 2000 recruited from hospital patients. Strand 2002/2003 was also a cluster study, recruiting from different villages.

Treatment before study
No publication informed about treatment before the intervention.

Methods
Duration of the intervention

Included studies had a treatment duration ranging from six months to two years.

Duration of follow up
The follow up in Strand 2002/2003 lasted 6 to 30 months, including a post-intervention follow up up to 6 months. In the remaining studies duration of treatment and follow up was identical, there was no post-intervention follow up.

Language of publication
Three of the four included studies were published in English, Duhamel 2000 in French.

Participants
Who participated

Study participants were aged from one months to 15 years, Du 2004 recruited only girls.

Inclusion and exclusion criteria
In three of four included studies, participants were described as 'healthy'. Duhamel 2000 recruited from hospital patients, but excluded patients with gastrointestinal or nephrological diseases or other conditions involved in the metabolism of vitamin D or phosphorus. Beser 1994 excluded all children with clinical signs of nutritional rickets, Strand 2002/2003 excluded children with heart malformations.

Relevant diagnostic criteria
Beser 1994 used a stepwise approach with clinical signs leading to radiological and biochemical assessment. Duhamel 2000 used radiological criteria. Du 2004 and Strand 2002/2003 used clinical signs only.

Co-morbidities
No study described co-morbidities, although Duhamel 2000 recruited hospital patients.

Co-medications
No study described co-medications.

Outcomes
Primary, secondary and additional outcomes

Beser 1994 and Strand 2002/2003 used the occurrence of rickets as the only outcome parameter. Duhamel 2000 measured calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone and alkaline phosphatases in blood and radiographed wrists without distinction of primary or secondary outcomes. Du 2004 investigated bone mineral content, bone area, bone mineral density, total body composition, plasma 25-hydroxyvitamin D, intact parathyroid hormone, blood calcium, calcium/creatinine ratio in urine, weight, length, sitting height, clinical signs of rickets without distinction of primary or secondary outcomes.

Risk of bias in included studies

For details on methodological quality of included studies see Table 1.

Overview
All included studies were of parallel design.
Interrater agreement for the key quality indicators was 100%.

Randomisation and allocation concealment
Beser 1994 was probably as a controlled clinical trial with researcher determined group assignment. The other three studies were randomised controlled clinical trials, two of which used a cluster randomisation design (Du 2004; Strand 2002/2003). None of the randomised controlled clinical trials provided details about the method of randomisation or the concealment of allocation.

Blinding
Beser 1994 and Strand 2002/2003 used no placebo, so participants were not blinded. Duhamel 2000 was described as 'double-blind' without further details. Du 2004 gave no details regarding blinding. No publications reported checking of blinding.

Definition of primary endpoint and secondary endpoints
No study provided an explicit definition of the primary endpoint. However, Beser 1994 and Strand 2002/2003 investigated one endpoint only .

Power calculation
None of the included studies reported power calculation.

Intention-to-treat and per-protocol analyses, missing data
Beser 1994 did not report summary statistics, therefore we calculated relative risks on an intention-to-treat basis. Strand 2002/2003 provided count data, relative risk was based on analysed patients. In the remaining studies, there were no quantitative data for rickets in both, intervention and control groups.
For missing data, imputation was not used for relevant outcomes in any of the included studies.

Screened and randomised patients
None of the included studies reported number of screened patients.

Discontinuing participants and attrition rates
All included studies reported the number of discontinuing participants, only Du 2004 provided details of the reasons for discontinuation.

Compliance measures
Du 2004 and Duhamel 2000 controlled adherence by direct observation of intake of the interventional medication.

Funding
Two of the four studies reported funding. Strand 2002/2003 was funded by an non-governmental organisation, Du 2004 was funded by an organisation which receives money from diary levies and the Australian government.

Publication status
All included studies were published in regular issues of journal with a peer review system.

Effects of interventions

Baseline characteristics
For details of baseline characteristics see Appendix 2.

Primary outcomes

For details of primary outcomes see Appendix 3.

Occurrence of rickets
In two of the four included studies, rickets neither occurred in the intervention nor the control group (Du 2004; Duhamel 2000).
Beser 1994 recruited children aged 3 to 36 months at inclusion in a rural community in Turkey aiming for a complete survey. After exclusion of children with clinical signs of rickets, the remaining children were divided in two groups with similar socio-economic and cultural background and nourishment levels. The intervention group received oral vitamin D 400 IU per day for 12 months, the control group received no intervention. At the end of the study a stepwise approach was used for the diagnosis of nutritional rickets: clinical signs led to biochemical and radiological assessment. In the intervention group rickets was not observed in any of the 302 children. In the control group 14 children out of 374 developed rickets. The relative risk (RR) was 0.04 (95% confidence interval (CI) 0 to 0.71).
Strand 2002/2003 was a cluster-randomised study in rural China. The intervention consisted of the promotion of exclusive breastfeeding from birth, supplementation of solid foods at the age of five months, weaning at 12 to 18 months, oral vitamin D 300 IU/day during the first 12 months, oral calcium 378 mg/day from age five months to 24 months. At the timing of outcome assessment, children were aged 6 to 30 months meaning that some children still received the intervention. Outcome assessment used clinical parameters. In the intervention group 100 out of 183 children showed clinical signs of nutritional rickets, in the control group 13 out of 46 children. The RR was 0.76 (95% CI 0.61 to 0.95). There was a pronounced non-compliance to the recommended supplementation of vitamin D and calcium.

Adverse effects of the interventions
Duhamel 2000 stated, that no hypercalcaemia was observed. The remaining studies did not investigate adverse effects.

Secondary outcomes
For details of secondary outcomes see Appendix 4.

Mortality
No study investigated mortality.

Quality of life
No study investigated health-related quality of life.

Costs
No study investigated costs.

Heterogeneity
Due to obvious clinical heterogeneity and only a few included studies, we did not perform a meta-analysis.

Subgroup analyses
Not performed due to lack of data.

Sensitivity analyses
Not performed due to lack of data.

Publication and small study bias
Not performed due to insufficient amount of data.

Discussion

Summary of the main findings
This systematic review shows that there are only few studies on the prevention of clinical or radiological diagnosed nutritional rickets in term born children. Because of the clinical heterogeneity in nutritional rickets itself as well as between the included studies neither a quantitative nor a qualitative data synthesis is reasonable. Vitamin D prevented rickets in children up to three years of age in Turkey. In China, a combined intervention of vitamin D, calcium and nutritional counselling led to a decreased risk of rickets in children up to three years of age, although there was a marked non-compliance. In a study conducted in prepubertal girls in China rickets did not occur in both control or intervention groups who received calcium or calcium plus vitamin D. In France, rickets were not observed in children of about twelve years of age who received vitamin D or placebo.
Adverse effects were only addressed in one study, in which no hypercalcaemia was observed after administration of vitamin D. No study investigated health-related quality of life or economic costs of the interventions.

Limitations of the review
We focused on a minimum duration of intervention of three months for children under twelve months of age and of six months for children over twelve months of age. Theoretically, studies of a shorter duration could demonstrate a significant impact, but this is thought to be highly unlikely.
Although the prevention of nutritional rickets has a long history and was studied many years ago, we decided to include studies conducted in the last 50 years only because of the substantial changes of life circumstances like nutritional issues, sun exposure or environmental factors such as air pollution.
Since preventive measures were introduced to prevent nutritional rickets with its 'classical' clinical and radiological features we used this definition for our review. We did not include rickets diagnosed solely on biochemical data.

Authors' conclusions

Implications for practice

We discovered only a few published studies of interventions for the prevention of nutritional rickets in term born children. Considering pathophysiological aspects, the high frequency of nutritional rickets and the favourable risk-benefit ratio we conclude that it is reasonable to offer preventive measures (vitamin D or calcium) to all children up to two years of age. Further groups of high risk are children living in Africa, Asia or the Middle East and migrants from these regions into areas where rickets is not frequent.

Implications for research

Due to a marked clinical heterogeneity and scarcity of data, the current indication for prevention of nutritional rickets should be investigated in different countries, different age groups and in children of different ethnic origin. Besides patient-oriented outcomes on efficacy, adverse effects of the chosen intervention should be studied. Especially with reference to vitamin D, controlled prospective studies should investigate both short-time effects on occurrence of nutritional rickets and long-term effects on occurrence of autoimmune diseases or cancer.

Acknowledgements

We thank the Department of General Pediatrics, University Children's Hospital, Moorenstr. 5, 40225 Duesseldorf, GERMANY (Dr Thomas Meissner) for its support to finish this review.

For help with translations we thank (in alphabetical order) Markéta Benesová, Daniel Bereczki, Barbara and Frank Brüderle, Monica Durosca, Hanna Kauffmann, Marta Kollenda, Morgane Legendre, Regina Miltner, Andrey Solodarenko, translation bureau Semantik and Maria Zangmeister.
We thank the following experts and authors of studies for their responses to our enquiries (in alphabetical order): Uri Alon, Annie Anderson, Christopher Bates, Abdullah Bereket, Xueqin Du, Ghada El-Hajj Fuleihan, Philip Fischer, Catherine Gordon, Frank Greer, Zeev Hochberg, Marjo Lehtonen-Veromaa, Michael Levine, John Pettifor, Willem Proesmans, Frank Rauch, Eckhard Schönau, Nicolas Shaw, Mark Strand, Tom Thacher, Jan-Maarten Wit, Zvi Zadik and Kathy Zu.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Search strategy

Search strategy
Unless otherwise stated, search terms were free text terms; exp = exploded MeSH: Medical Subject Heading (Medline medical index term); the dollar sign ($) stands for any character(s); the question mark (?) = substitute for one or no characters; tw = text word; pt = publication type; sh = MeSH: Medical subject heading (MEDLINE medical index term); adj = adjacency.

The following MEDLINE search strategy using the OVID database will be adapted for use with the other databases.

(1) exp RICKETS/
(2) rickets.tw.
(3) rachiti$.tw.
(4) exp OSTEOMALACIA/
(5) osteomalac$.tw.
(6) exp VITAMIN D Deficiency/
(7) (vitamin$-D adj defic$).tw.
(8) (defic$ adj vitamin$-D).tw.
(9) or/1-8

(10) exp CALCIUM/
(11) exp Vitamin D/
(12) exp Ergocalciferols/
(13) exp CHOLECALCIFEROL/
(14) (calcium or vitamin$ D).tw.
(15) sunlight$.tw.
(16) exp SUNLIGHT/
(17) or/10-16

(18) exp Dietary Supplements/
(19) supplement$.tw.
(20) (defic$ or poor$ or poverty or lack$ or limit$).tw.
(21) 18 or 19 or 20
(22) 17 and 21
(23) 22 or 9

(24) exp Infant, Newborn/
(25) exp INFANT/
(26) exp CHILD/
(27) (infant$ or newborn$ or child$).tw.
(28) or/24-27
(29) 23 and 28

(30) exp Infant, Premature/
(31) preterm$ or prematur$) adj infant$).tw.
(32) 30 or 31
(33) 29 not 32
(34) limit 33 to human

Appendix 2. Baseline characteristics

CharacteristicBeser 1994Du 2004Duhamel 2000Strand 2002/2003
Intervention 1 (I1) / intervention 2 (I2) / control 1 (C1)I1: vitamin D 400 IU/day per os
C1: no placebo or other intervention
I1: fortified milk, averaged calcium 245 mg/day per os
I2: fortified milk, averaged calcium 245 mg/day per os, vitamin D3 133 IU/day per so
C1: no placebo or other intervention
I1: vitamin D3 100,000 IU every three months per os
C1: placebo
I1: promoting of exclusive breastfeeding from birth, supplementation of solid foods at age 5 months, weaning at 12 to 18 months, vitamin D 300 IU/day per os during the first 12 months, calcium 378 mg/day per os from age 5 months to 24 months
C1: no placebo or other intervention
[n] (I1/ I2 / C1 / total)I1: 302
I2: 374
Total: 676
I1: 238
I2: 260
C1: 259
Total: 757
I1: 32
C1: 34
Total: 66
I1: 183
C1: 46
Total: 229
Age at inclusion [mean (SD)]Total: 3 months to 36 months (range)Total: 10 yearsTotal: 12.5 years (1.5)Total: approximately 1 month
Sex [n,%]?female: 100male: 51
female: 49
I1: male 50
female 50
C1: male 63
female 37
Ethnic groups [%]????
Socioeconomic status????
LocationTurkey, villages around AkcaabatChina, BeijingFrance, northern LoireChina, Shanxi Province
Start of study [year]1990199919961997
Length of follow-up12 months24 months9 months6 to 30 months

(mean age at outcome assessment:
I1: 18.2 months
C1: 15.6 months)
Outcome assessmentfirst clinical, than biochemical and radiological assessmentclinical assessmentradiological assessmentclinical assessment
Notes  Number of participants: Two children who showed radiological changes at the beginning of the study and at the end of the study were excluded for this review. Thus, number of participants was corrected.Participants:
included a small amount of preterm born children (which is assumed as a risk factor for rickets), proportion in intervention group higher than on control group (8.2% vs. 4.3%)
Number of participants: based on analysed participants, total of enrolled 259, total of study completed 245
Symbols & abbreviations: ? = unclear
I = intervention; C = control
    

Appendix 3. Primary outcome data

StudyOccurence of ricketsAdverse effects
Beser 1994

I1: vitamin D 400 IU/day per os
C1: no placebo or other intervention
I1: 0/302
C1: 14/374
not investigated
Du 2004

I1: fortified milk, averaged calcium 245 mg/day per os
I2: fortified milk, averaged calcium 245 mg/day per os, vitamin D3 133 IU/day per so
C1: no placebo or other intervention
I1: 0/238
I2: 0/260
C1: 0/259
not investigated
Duhamel 2000

I1: vitamin D3 100,000 IU every 3 months per os
C1: placebo
I1: 0/32
C1: 0/34
hypercalcaemia:
I1: 0/32
C1: 0/34
Strand 2002/2003

I1: promoting of exclusive breastfeeding from birth, supplementation of solid foods at age 5 months, weaning at 12 to 18 months, vitamin D 300 IU/day per os during the first 12 months, calcium 378 mg/day per os from age 5 months to 24 months
C1: no placebo or other intervention
I1: 100/183
C1: 33/46

based on analysed patients
not investigated
Symbols & abbreviations: I = intervention; C = control  

Appendix 4. Secondary outcome data

CharacteristicMortalityQuality of lifeCosts
Beser 1994

I1: vitamin D 400 IU/day per os
C1: no placebo or other intervention
not investigatednot investigatednot investigated
Du 2004

I1: fortified milk, averaged calcium 245 mg/day per os
I2: fortified milk, averaged calcium 245 mg/day per os, vitamin D3 133 IU/day per so
C1: no placebo or other intervention
not investigatednot investigatednot investigated
Duhamel 2000

I1: vitamin D3 100,000 IU every 3 months per os
C1: placebo
not investigatednot investigatednot investigated
Strand 2002/2003

I1: promoting of exclusive breastfeeding from birth, supplementation of solid foods at age 5 months, weaning at 12 to 18 months, vitamin D 300 IU/day per os during the first 12 months, calcium 378 mg/day per os from age 5 months to 24 months
C1: no placebo or other intervention
not investigatednot investigatednot investigated
Abbreviations: I = intervention; C = control   

What's new

DateEventDescription
22 October 2008AmendedConverted to new review format.

History

Protocol first published: Issue 3, 2006
Review first published: Issue 4, 2007

Contributions of authors

CHRISTIAN LERCH: protocol development, searching for trials, quality assessment of trials, data extraction, data analysis, review development
THOMAS MEISSNER: protocol development, quality assessment of trials, data extraction, review development

Declarations of interest

None known.

Sources of support

Internal sources

  • Heinrich-Heine University, Germany.

External sources

  • No sources of support supplied

Differences between protocol and review

Backgrounddetails added, arrangement changed  
Types of studiesprospective cohort studies, controlled clinical trials, randomised controlled clinical trialsrandomised controlled trials preferred, if not identified also controlled clinical trials, cohort studies, case-control studiesto minimise bias
Time of outcome assessmentintervention or follow-up for children under 12 months of age three months at least, for children over 12 months of age six months at leastminimum duration of prospective studies three yearswe did not identify studies lasting three years
Selection of studiesin the first step, only one author (CL) checked title, abstract or both to determine publications dealing with nutritional rickets and obviously not reporting non-comparative dataevery step of studies selection was planned to be done by two authorsapproximately 8000 records retrieved, efforts to reduce work load

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Beser 1994

MethodsDURATION OF INTERVENTION:
12 months
DURATION OF FOLLOW-UP:
12 months
LANGUAGE OF PUBLICATION:
English
ParticipantsWHO PARTICIPATED:
Turkish children, aged 3 to 36 months at inclusion
INCLUSION CRITERIA:
prior exclusion of rickets
EXCLUSION CRITERIA:
see above
DIAGNOSTIC CRITERIA:
stepwise approach: clinical signs led to radiological and biochemical assessment
CO-MORBIDITIES:
not stated
CO-MEDICATIONS:
not stated
InterventionsNUMBER OF STUDY CENTRES:
1
COUNTRY/ LOCATION:
Turkey, rural
SETTING:
community
INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
Vitamin D 400 IU/day per os
CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
none
TREATMENT BEFORE STUDY:
not stated
TITRATION PERIOD:
not stated
OutcomesPRIMARY OUTCOME(S):
occurrence of rickets
SECONDARY OUTCOMES:
none
NotesSTATED AIM OF STUDY:
to assess primary prevention of rickets
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearD - Not used

Du 2004

MethodsDURATION OF INTERVENTION:
2 years
DURATION OF FOLLOW-UP:
2 years
LANGUAGE OF PUBLICATION:
English
ParticipantsWHO PARTICIPATED:
Chinese girls, aged 10 years at inclusion
INCLUSION CRITERIA:
free of any disease that might affect bone development
EXCLUSION CRITERIA:
see above
DIAGNOSTIC CRITERIA:
clinical assessment
CO-MORBIDITIES:
not stated
CO-MEDICATIONS:
not stated
InterventionsNUMBER OF STUDY CENTRES:
1
COUNTRY/ LOCATION:
China, urban
SETTING:
cluster study with primary schools as cluster
INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
I1: fortified milk with calcium 560 mg/school day, averaged 245 mg/day
I2: fortified milk with calcium 560 mg plus vitamin D3 200 (during first third of study) or 320 (during second and third third of study) IU/school day, averaged calcium 245 mg plus vitamin D3 133 IU/day
CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
none
TREATMENT BEFORE STUDY:
not stated
OutcomesPRIMARY OUTCOME(S):
bone mineral content, bone area, bone mineral density, total body composition, 25-hydroxyvitamin D in blood, intact parathyroid hormone in blood, blood calcium in blood, calcium/creatinine ratio in urine, weight, length, sitting height, clinical signs of rickets
SECONDARY OUTCOMES:
no distinction made between primary and secondary outcomes
NotesSTATED AIM OF STUDY:
to examine the effects of providing a dietary supplement of a small volume of milk to Chinese pre-pubertal girls in Beijing
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Duhamel 2000

MethodsDURATION OF INTERVENTION:
9 months
DURATION OF FOLLOW-UP:
9 months
LANGUAGE OF PUBLICATION:
French
ParticipantsWHO PARTICIPATED:
French children, aged 10 to 15 years
INCLUSION CRITERIA:
hospital admission
EXCLUSION CRITERIA:
gastrointestinal or nephrological diseases or other conditions involved in the metabolism of vitamin D or phosphate
DIAGNOSTIC CRITERIA:
clinical, radiological and biochemical assessment
CO-MORBIDITIES:
not stated
CO-MEDICATIONS:
not stated
InterventionsNUMBER OF STUDY CENTRES:
4
COUNTRY/ LOCATION:
France, urban
SETTING:
hospital based
INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
vitamin D3 100,000 IU at beginning, after 3 and after 6 month, per os
CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
placebo
TREATMENT BEFORE STUDY:
not stated
OutcomesPRIMARY OUTCOME(S):
calcium in blood and urine, phosphorus in blood and urine, alkaline phosphatases in blood, intact parathyroid hormone in blood, 25-hydroxyvitamin D in blood, radiographs of the wrist
SECONDARY OUTCOMES:
no distinction made between primary and secondary outcomes
NotesSTATED AIM OF STUDY:
to follow the changes in calcium status and 25-hydroxyvitamin D and parathyroid hormone levels under repeated dosis of vitamin D in winter
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Strand 2002/2003

MethodsDURATION OF INTERVENTION:
2 years
DURATION OF FOLLOW-UP:
up to 2.5 years
LANGUAGE OF PUBLICATION:
English
ParticipantsWHO PARTICIPATED:
Chinese children, age at inclusion approximately 1 month
INCLUSION CRITERIA:
not stated
EXCLUSION CRITERIA:
not stated (however, children with congenital heart defects were excluded)
DIAGNOSTIC CRITERIA:
clinical assessment
CO-MORBIDITIES:
not stated
CO-MEDICATIONS:
not stated
InterventionsNUMBER OF STUDY CENTRES:
1
COUNTRY/ LOCATION:
China, rural
SETTING:
cluster study with villages as clusters
INTERVENTION (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
promoting of exclusive breastfeeding from birth, supplementation of solid foods at age 5 months, weaning at 12 to 18 months, vitamin D 300 IU/day per os during the first 12 months, calcium 378 mg/day per os from age 5 months to 24 months
CONTROL (ROUTE, TOTAL DOSE/DAY, FREQUENCY):
none
TREATMENT BEFORE STUDY:
not stated
OutcomesPRIMARY OUTCOME(S):
occurrence of rickets
SECONDARY OUTCOMES:
none stated
NotesSTATED AIM OF STUDY:
to determine the effectiveness of this rickets prevention programme
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Nguema-Asseko 2005high risk for bias due to marked differences in discontinuation rates between groups after three months (intervention 9%, comparison 29%, overall 19%), after six months discontinuation rate 34%
Thacherhigh risk for bias due to discontinuation 40%

Ancillary