Tom D. Thacher

Vitamin D Insufficiency

Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials.

Nutritional rickets around the world: causes and future directions

Abstract Introduction: Nutritional rickets has been described from at least 59 countries in the last 20 years. Its spectrum of causes differs in different regions of the world. Methods: We conducted a systematic review of articles on nutritional rickets from various geographical regions published in the last 20 years. We extracted information about the prevalence and causes of rickets. Results: Calcium deficiency is the major cause of rickets in Africa and some parts of tropical Asia, but is being recognised increasingly in other parts of the world. A resurgence of vitamin D deficiency has been observed in North America and Europe. Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas calcium deficiency typically presents after weaning and often after the 2nd year. Few studies of rickets in developing countries report values of 25(OH)D to permit distinguishing vitamin D from calcium deficiency. Conclusions: Rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Vitamin D supplementation alone might not prevent or treat rickets in populations with limited calcium intake.

Consensus Statement: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

BACKGROUND Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Radiographic scoring method for the assessment of the severity of nutritional rickets.

Radiographic changes of rickets are well characterized, but no method of grading the severity of these changes has been in general use. Consequently, it is difficult to compare objectively or follow radiographic improvement. We prospectively evaluated the utility and reproducibility of a scoring method for measuring the severity of rickets. A 10-point score for radiographs of wrists and knees was devised to assess the degree of metaphyseal fraying and cupping and the proportion of the growth plate affected. The score progresses in half point increments from zero (normal) to 10 points (severe). Four trained physicians independently scored radiographs on two separate occasions from 67 children with active rickets. A broad representation of mean radiographic scores was moderately correlated with alkaline phosphatase (r = 0.58). Interobserver correlation of radiographic scores was 0.84 or greater for all observer pairs and intraobserver correlation was 0.89 or greater for each observer. Researchers and clinicians should find the score useful to assess objectively the severity of rickets.

Absence of vitamin D deficiency in young Nigerian children

OBJECTIVE To determine the prevalence of vitamin D deficiency in young Nigerian children residing in an area where nutritional rickets is common. STUDY DESIGN A randomized cluster sample of children aged 6 to 35 months in Jos, Nigeria. RESULTS Of 218 children evaluated, no child in the study had a 25-hydroxyvitamin D (25-OHD) concentration <10 ng/mL (the generally held definition of vitamin D deficiency). Children spent an average of 8.3 hours per day outside of the home. Twenty children (9.2%) had clinical findings of rickets. Children with clinical signs of rickets were more likely to be not currently breast fed and have significantly lower serum calcium concentrations than those without signs of rickets (9.1 vs 9.4 mg/dL, respectively, P =.01). Yet, 25-OHD levels were not significantly different between those children with clinical signs of rickets and those without such clinical signs. CONCLUSION Vitamin D deficiency was not found in this population of young children in whom clinical rickets is common. This is consistent with the hypothesis that dietary calcium insufficiency, without preexisting vitamin D deficiency, accounts for the development of clinical rickets in Nigerian children.

The Effect of Vitamin D2 and Vitamin D3 on Intestinal Calcium Absorption in Nigerian Children with Rickets

CONTEXT Children with calcium-deficiency rickets have high 1,25-dihydroxyvitamin D values. OBJECTIVE The objective of the study was to determine whether vitamin D increased calcium absorption. DESIGN This was an experimental study. SETTING The study was conducted at a teaching hospital. PARTICIPANTS Participants included 17 children with nutritional rickets. INTERVENTION The participants were randomized to 1.25 mg oral vitamin D(3) (n = 8) or vitamin D(2) (n = 9). MAIN OUTCOME MEASURE Fractional calcium absorption 3 da after vitamin D administration was measured. RESULTS Mean baseline 25-hydroxyvitamin D concentrations were 20 ng/ml (range 5-31 ng/ml). The increase in 25-hydroxyvitamin D was equivalent after vitamin D(3) (29 +/- 10 ng/ml) or vitamin D(2) (29 +/- 17 ng/ml). Mean 1,25-dihydroxyvitamin D values increased from 143 +/- 76 pg/ml to 243 +/- 102 pg/ml (P = 0.001), and the increase in 1,25-dihydroxyvitamin D did not differ between vitamin D(2) and vitamin D(3) (107 +/- 110 and 91 +/- 102 ng/ml, respectively). The increment in 1,25-dihydroxyvitamin D was explained almost entirely by the baseline 25-hydroxyvitamin D concentration (r(2) = 0.72; P < 0.001). Mean fractional calcium absorption did not differ before (52.6 +/- 21.4%) or after (53.2 +/- 23.5%) vitamin D, and effects of vitamin D(2) and vitamin D(3) on calcium absorption were not significantly different. Fractional calcium absorption was not closely related to concentrations of 25-hydroxyvitamin D (r = 0.01, P = 0.93) or 1,25-dihydroxyvitamin D (r = 0.21, P = 0.24). The effect of vitamin D on calcium absorption did not vary with baseline 25-hydroxyvitamin D values or with the absolute increase in 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D values. CONCLUSIONS Despite similar increases in 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with vitamin D(2) or vitamin D(3), fractional calcium absorption did not increase, indicating that rickets in Nigerian children is not primarily due to vitamin D-deficient calcium malabsorption.

Increasing Incidence of Nutritional Rickets: A Population-Based Study in Olmsted County, Minnesota

OBJECTIVE To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population. PATIENTS AND METHODS Rochester Epidemiology Project data were used to identify all children (aged <18 years) residing in Olmsted County, Minnesota, between January 1, 1970, and December 31, 2009, with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select individuals with radiographic confirmation of rickets. Age- and sex-matched controls were identified for the evaluation of risk factors. The main outcome measure was radiographic evidence of rickets without identifiable inherited, genetic, or nonnutritional causes. Incidence rates were calculated using Rochester Epidemiology Project census data. RESULTS Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All 17 children were younger than 3 years, and 13 (76%) were of nonwhite race/ethnicity. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children younger than 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively (P=.003 for incidence trend). Nutritional rickets was associated with black race, breast-feeding, low birth weight, and stunted growth (P<.05 for all). Four of 13 patients (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL. CONCLUSION Nutritional rickets remains rare, but its incidence has dramatically increased since 2000. Not all cases of rickets can be attributed to vitamin D deficiency.

Maternal vitamin D supplementation to improve the vitamin D status of breast-fed infants: A randomized controlled trial

OBJECTIVE To determine whether a single monthly supplement is as effective as a daily maternal supplement in increasing breast milk vitamin D to achieve vitamin D sufficiency in their infants. PATIENTS AND METHODS Forty mothers with exclusively breast-fed infants were randomized to receive oral cholecalciferol (vitamin D3) 5000 IU/d for 28 days or 150,000 IU once. Maternal serum, breast milk, and urine were collected on days 0, 1, 3, 7, 14, and 28; infant serum was obtained on days 0 and 28. Enrollment occurred between January 7, 2011, and July 29, 2011. RESULTS In mothers given daily cholecalciferol, concentrations of serum and breast milk cholecalciferol attained steady levels of 18 and 8 ng/mL, respectively, from day 3 through 28. In mothers given the single dose, serum and breast milk cholecalciferol peaked at 160 and 40 ng/mL, respectively, at day 1 before rapidly declining. Maternal milk and serum cholecalciferol concentrations were related (r=0.87). Infant mean serum 25-hydroxyvitamin D concentration increased from 17±13 to 39±6 ng/mL in the single-dose group and from 16±12 to 39±12 ng/mL in the daily-dose group (P=.88). All infants achieved serum 25-hydroxyvitamin D concentrations of more than 20 ng/mL. CONCLUSION Either single-dose or daily-dose cholecalciferol supplementation of mothers provided breast milk concentrations that result in vitamin D sufficiency in breast-fed infants. CLINICAL TRIAL REGISTRATION clinicaltrials.gov NCT01240265.

The usefulness of clinical features to identify active rickets

Abstract To develop a clinical prediction rule that could accurately identify children with active rickets in countries where nutritional rickets is common, we prospectively recorded clinical features in 736 Nigerian children aged 18 months and older presenting with leg deformities or inability to walk. We scored radiographs of the wrists and knees for active rickets of the growth plates. Sensitivities and specificities of clinical variables for radiographically active rickets were calculated and, using logistic regression, we derived a clinical prediction rule. The prediction rule was tested in a validation set of 89 children. Wrists and costochondral enlargement were the clinical signs with the best combination of sensitivity (72% and 76%, respectively) and specificity (81% and 64%, respectively) for active rickets. Age <5 years, height-for-age Z-score <-2, leg pain during walking, wrist enlargement and costochondral enlargement were independently predictive of active rickets (p<0.01 for each in multivariate model). In the validation set, any three of these clinical features accurately identified 87% of children with active rickets, whereas only 24% of those without active rickets had three or more features. We conclude that clinical features can be used to identify children with active rickets.