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 D
Exogenous sources of vitamin D provide vitamin D
Vitamin D, which denotes both 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 17
In the 20
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.
To assess the effects of various interventions on the prevention of nutritional rickets in term born children.
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
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.
Placebo or no intervention.
Types of outcome measures
- occurrence of rickets;
- adverse effects.
- all-cause mortality;
- quality of life (ideally measured by a validated instrument);
Covariates, effect modifiers and confounders
- different groups of children (mentioned under 'Frequency of nutritional rickets');
- nutrition (for example phytate or oxalate intake);
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
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.
We tried to identify additional studies by searching the reference lists of included trials and reviews identified.
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.
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 I
Assessment of reporting biases
We planned to use funnel plots to assess small study bias.
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.
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).
Description of 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%.
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.
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).
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.
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.
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.
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.
No study described co-morbidities, although Duhamel 2000 recruited hospital patients.
No study described co-medications.
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.
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.
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.
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.
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.
All included studies were published in regular issues of journal with a peer review system.
Effects of interventions
For details of baseline characteristics see Appendix 2.
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.
For details of secondary outcomes see Appendix 4.
No study investigated mortality.
Quality of life
No study investigated health-related quality of life.
No study investigated costs.
Due to obvious clinical heterogeneity and only a few included studies, we did not perform a meta-analysis.
Not performed due to lack of data.
Not performed due to lack of data.
Publication and small study bias
Not performed due to insufficient amount of data.
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.
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.
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
This review has no analyses.
Appendix 1. Search strategy
Appendix 2. Baseline characteristics
Appendix 3. Primary outcome data
Appendix 4. Secondary outcome data
Last assessed as up-to-date: 21 August 2007.
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
Sources of support
- Heinrich-Heine University, Germany.
- No sources of support supplied
Differences between protocol and review
Medical Subject Headings (MeSH)
MeSH check words
Child, Preschool; Humans; Infant