John M. Pettifor

A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children.

BACKGROUND Nutritional rickets remains prevalent in many tropical countries despite the fact that such countries have ample sunlight. Some postulate that a deficiency of dietary calcium, rather than vitamin D, is often responsible for rickets after infancy. METHODS We enrolled 123 Nigerian children (median age, 46 months) with rickets in a randomized, double-blind, controlled trial of 24 weeks of treatment with vitamin D (600,000 U intramuscularly at enrollment and at 12 weeks), calcium (1000 mg daily), or a combination of vitamin D and calcium. We compared the calcium intake of the children at enrollment with that of control children without rickets who were matched for sex, age, and weight. We measured serum calcium and alkaline phosphatase and used a 10-point radiographic score to assess the response to treatment at 24 weeks. RESULTS The daily dietary calcium intake was low in the children with rickets and the control children (median, 203 mg and 196 mg, respectively; P=0.64). Treatment produced a smaller increase in the mean (+/-SD) serum calcium concentration in the vitamin D group (from 7.8+/-0.8 mg per deciliter [2.0+/-0.2 mmol per liter] at base line to 8.3+/-0.7 mg per deciliter [2.1+/-0.2 mmol per liter] at 24 weeks) than in the calcium group (from 7.5+/-0.8 [1.9+/-0.2 mmol per liter] to 9.0+/-0.6 mg per deciliter [2.2+/-0.2 mmol per liter], P<0.001) or the combination-therapy group (from 7.7+/-1.0 [1.9+/-0.25 mmol per liter] to 9.1+/-0.6 mg per deciliter [2.3+/-0.2 mmol per liter], P<0.001). A greater proportion of children in the calcium and combination-therapy groups than in the vitamin D group reached the combined end point of a serum alkaline phosphatase concentration of 350 U per liter or less and radiographic evidence of nearly complete healing of rickets (61 percent, 58 percent, and 19 percent, respectively; P<0.001). CONCLUSIONS Nigerian children with rickets have a low intake of calcium and have a better response to treatment with calcium alone or in combination with vitamin D than to treatment with vitamin D alone.

Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets.

We treated 11 children with vitamin D-resistant rickets with a phosphate mixture either alone (1.2 to 3.6 g per day) or combined with ergocalciferol (vitamin D2, to 50 x 103 IU per day) or with calcitriol (1,25-dihydroxyvitamin D3, 0.25 to 1 microgram per day). Serum calcitriol concentrations were normal in all patients. Calcitriol therapy circulating levels of the hormone to values above normal and increased intestinal phosphate absorption. In some patients this regimen decreased the need for phosphate supplements. None of the treatment regimens corrected the renal phosphate leak. Radiologic studies and bone histomorphometric analyses showed that phosphate (alone or with ergocalciferol) induced the mineralization of the growth plate but not of the endosteal bone surface. Combined calcitriol and phosphate therapy for a total of 2850 patient-days greatly improved the mineralization of trabecular bone. Short-term episodes of hypercalcemia were easily controlled by changes in calcitriol dosage. The data indicate that the combined calcitriol and phosphate regimen is useful in the treatment of vitamin D-resistent rickets.

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.

The prevalence of stunting, overweight and obesity, and metabolic disease risk in rural South African children

BackgroundLow- to middle-income countries are undergoing a health transition with non-communicable diseases contributing substantially to disease burden, despite persistence of undernutrition and infectious diseases. This study aimed to investigate the prevalence and patterns of stunting and overweight/obesity, and hence risk for metabolic disease, in a group of children and adolescents in rural South Africa.MethodsA cross-sectional growth survey was conducted involving 3511 children and adolescents 1-20 years, selected through stratified random sampling from a previously enumerated population living in Agincourt sub-district, Mpumalanga Province, South Africa. Anthropometric measurements including height, weight and waist circumference were taken using standard procedures. Tanner pubertal assessment was conducted among adolescents 9-20 years. Growth z-scores were generated using 2006 WHO standards for children up to five years and 1977 NCHS/WHO reference for older children. Overweight and obesity for those <18 years were determined using International Obesity Task Force BMI cut-offs, while adult cut-offs of BMI ≥ 25 and ≥ 30 kg/m2 for overweight and obesity respectively were used for those ≥ 18 years. Waist circumference cut-offs of ≥ 94 cm for males and ≥ 80 cm for females and waist-to-height ratio of 0.5 for both sexes were used to determine metabolic disease risk in adolescents.ResultsAbout one in five children aged 1-4 years was stunted; one in three of those aged one year. Concurrently, the prevalence of combined overweight and obesity, almost non-existent in boys, was substantial among adolescent girls, increasing with age and reaching approximately 20-25% in late adolescence. Central obesity was prevalent among adolescent girls, increasing with sexual maturation and reaching a peak of 35% at Tanner Stage 5, indicating increased risk for metabolic disease.ConclusionsThe study highlights that in transitional societies, early stunting and adolescent obesity may co-exist in the same socio-geographic population. It is likely that this profile relates to changes in nutrition and diet, but variation in factors such as infectious disease burden and physical activity patterns, as well as social influences, need to be investigated. As obesity and adult short stature are risk factors for metabolic syndrome and Type 2 diabetes, this combination of early stunting and adolescent obesity may be an explosive combination.

Congenital malformations associated with the administration of oral anticoagulants during pregnancy

Three small infants whose mothers had received oral anticoagulant therapy during the first trimester of pregnancy are described. These infants all had hypoplasia of the nasal bones, and two had stippling of epiphyses and bones and deformities of the bones of the hand. One child is mentally retarded. It is suggested that these abnormalities may be related to maternal oral anticoagulant therapy during the first trimester.

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.

Rickets in children of rural origin in South Africa: is low dietary calcium a factor?

Studies of nine children 4 7/12 to 13 years of age who had rickets are presented. No evidence of renal abnormalities, vitamin D deficiency, or of the inherited varieties of rickets was found. The salient features were their rural origins, mild hypocalcemia with evidence of secondary hyperparathyroidism, and improvement with a normal diet that contained an average of 944 mg calcium/24 hours. It is proposed that the etiology of the rickets is related to low calcium intake with or without a high oxalate concentration in the diet.

Serum Levels of Free 1,25-Dihydroxyvitamin D in Vitamin D Toxicity

Vitamin D toxicity in humans is characterized by markedly elevated serum levels of 25-hydroxyvitamin D (25-OHD) [1-5]. However, levels of the active metabolite 1,25-dihydroxyvitamin D (1,25-[OH]2D) have been reported to be either normal to decreased [4, 5] or elevated [1, 2, 6]. In rats, experimentally induced vitamin D toxicity leads to a more than 10-fold increase in circulating 25-OHD levels but to a 37% decrease in 1,25-(OH)2D levels [7]. The absence of consistently elevated levels of 1,25-(OH)2D in vitamin D toxicity has led to the suggestion that metabolites other than 1,25-(OH)2D might be responsible for the hypercalcemia and hypercalciuria [8, 9]. The high 25-OHD levels might directly interact with the vitamin D receptor in the intestine and bone [7]. Vieth [8] has suggested that the high levels of 25-OHD could cause an increase in free levels of 1,25-(OH)2D (despite normal total levels), which might be responsible for the changes in calcium homeostasis. We recently tested this hypothesis by measuring the free levels of 1,25-(OH)2D in patients who were evaluated for vitamin D toxicity after inadvertently using a vitamin D concentrate as a cooking oil. We also did in vitro studies using mixtures of various vitamin D metabolites to simulate the vitamin D toxic state so that we could assess their effect on the percentage of free 1,25-(OH)2D in normal serum. Methods Patients Ten members of a family and their domestic maid (age range, 8 to 69 years) were hospitalized during a 10-day period after unintentionally using a veterinary vitamin D concentrate (cholecalciferol in peanut oil; 2 million U/g) as a cooking oil. All patients presented with abdominal cramps, vomiting, and neurologic symptoms and were found to have severe hypercalcemia (Table 1). Although they were treated with a combination of intravenous fluids, diuretics, corticosteroids, and calcitonin, four patients died from related complications. Table 1. Serum Biochemical Values in the 11 Patients Hospitalized with Vitamin D Toxicity* Laboratory Evaluation Blood samples for the estimation of vitamin D metabolite concentrations were obtained between 10 and 40 days after admission while the patients were receiving therapy for hypercalcemia. Free levels of 1,25-(OH)2D were not measured in two patients because of insufficient serum volumes. Serum total 25-OHD and 1,25-(OH)2D levels were measured by the kidney cytosol [10] and calf thymus receptor [11] assays, respectively. All the specimens were measured in one assay. The intra-assay coefficients of variation were 1.1% for 25-OHD and 16.0% for 1,25-(OH)2D. The percentage of free 1,25-(OH)2D was measured using centrifugal ultrafiltration isodialysis [12, 13]. The intra-assay variation was 13%. We calculated the free levels of 1,25-(OH)2D using the following formula: Free 1,25-(OH)2D (fmol/L) = percentage of free 1,25-(OH)2D x total 1,25-(OH)2D level (pmol/L) 10. We measured serum levels of vitamin D-binding protein (DBP) by radial immunodiffusion [14] and used a rabbit antihuman DBP antibody and purified human DBP as the standard. In the in vitro studies, we determined the ability of exogenously added vitamin D metabolites to alter the percentage of free 1,25-(OH)2D by adding the desired amount of metabolites with the tracers Hydrogen-3-1,25-(OH)2D and Carbon-14-glucose to the incubation tube, removing the vehicle by drying it under a nitrogen stream, and then adding serum (0.45 mL) for a 45-minute incubation period at 37 C. Duplicate 0.2-mL aliquots from each incubate were then subjected to centrifugal ultrafiltration as previously described [12, 13]. Each incubation was done in duplicate, and the results are reported as the mean range. The serum sample used in the in vitro study was obtained from a normal control; it contained 100 nM of 25-OHD and 85 pM of 1,25-(OH)2D. The 25-OHD3-26,23 lactone was provided by Dr. Ronald Horst (Ames, Iowa); the other vitamin D metabolites were provided by Dr. Milan Uskokovic (Hoffman-LaRoche, Nutley, New Jersey). Results The results of the relevant investigations are shown in Table 1. At hospital admission, all patients had markedly elevated serum calcium values. In keeping with the typical presentation of vitamin D toxicity, most patients also had increased serum inorganic phosphate levels and urea concentrations. Levels of 25-OHD ranged from 847 to 1652 nmol/L, which are 8 to 15 times greater than the upper limit of normal. Total 1,25-(OH)2D levels were elevated in 3 of the 11 patients, and the percentages of free 1,25-(OH)2D were more than two standard deviations above the reference mean in all 9 patients in whom it was measured. The free levels of 1,25-(OH) (2D) were also more than two standard deviations above the reference mean in 6 of the 9 patients. The free levels of 1,25-(OH)2D correlated with the total 1,25-(OH)2D levels (r = 0.957; P < 0.001), which in turn correlated with 25-OHD levels (r = 0.660; P = 0.027). However, neither the free levels of 1,25-(OH)2D nor the percentage of free 1,25-(OH)2D were correlated with DBP or albumin concentrations. Serum calcium values measured when blood samples were obtained for vitamin D metabolites did not correlate with the free 1,25-(OH)2D; total 1,25-(OH)2D; or 25-OHD levels. The results of the in vitro studies on the effect of adding various metabolites to a control serum sample on the percentage of free 1,25-(OH)2D are shown in Table 2. When 25-OHD was added in concentrations similar to those found in the patients, the percentage of free 1,25-(OH)2D increased from 0.312% to 0.557%. A smaller but consistent increase in the percentage of free 1,25-(OH)2D was noted when 24(R),25-(OH)2D was added to the serum sample. No effect was noted when 25-OHD-26,23 lactone or 25(R),26-(OH)2D was added. The addition of a combination of 25-OHD; 25-OHD-26,23 lactone; 24(R),25-(OH)2D; and 25,26-(OH)2D in concentrations that might be found in vitamin D toxicity did not increase the percentage of free 1,25-(OH)2D more than did the addition of 25-OHD alone. Table 2. Effect of Adding Various Concentrations of Vitamin D Metabolites on the Percentage of Free 1,25-(OH)2D* Discussion As in previous studies [1-4, 6], 25-OHD levels were consistently and markedly elevated in the patients with vitamin D toxicity. In our study, most total 1,25-(OH)2D levels were within the normal range. Elevated values were only marginally increased, particularly if the ages of the patients are considered. These findings are in agreement with those of several studies [2, 4, 5, 7] in which vitamin D toxicity was associated with a normal or low 1,25-(OH)2D level, but they do not support the findings of Mawer and colleagues [1], who reported elevated 1,25-(OH) (2D) levels. The inability to document elevated 1,25-(OH)2D levels in most patients with vitamin D toxicity has led to many hypotheses about the cause of the hypercalcemia, such as a direct action of 25-OHD on the 1,25-(OH)2D receptor [1, 7] and an increase in free levels of 1,25-(OH)2D caused by the displacement of 1,25-(OH)2D from DBP by the high 25-OHD levels [8]. The elevated free 1,25-(OH)2D levels in most patients in our study might support the latter hypothesis. The presence of elevated free 1,25-(OH)2D levels despite normal total 1,25-(OH)2D levels suggests that 1,25-(OH)2D is displaced from DBP by the micromolar concentrations of 25-OHD and other unmeasured metabolites (such as 25-OHD-26,23 lactone; 24,25-[OH]2D; and 25,26-[OH]2D) [7]. Concentrations of DBP are approximately 5 10 (6) M, and the vitamin D metabolites appear to bind to DBP in a 1:1 molar ratio and to compete for the same site. However, this hypothesis has not been rigorously tested. Thus, as the vitamin D metabolite concentrations approach those of DBP, the level of saturation of DBP binding reaches a point where the percentage of bound metabolites decreases in a clinically significant manner [13, 15]. The above hypothesis is supported in part by our in vitro studies. When 25-OHD was added to normal serum in the same concentrations (800 nM) as those recorded in the patients, the percentage of free 1,25-(OH) (2D) increased by 78%. Surprisingly, doubling the concentration of added 25-OHD did not further increase the percentage of free 1,25-(OH)2D. The addition of 24,25-(OH)2D also increased the percentage in a dose-dependent manner, but the percentage was not affected when we added 25-OHD-26,23 lactone or 25,26-(OH)2D in the concentrations reported by Horst and colleagues [16, 17] to occur in pigs given large doses of vitamin D. In our in vitro experiments, a combination of various metabolites did not increase the percentage of free 1,25-(OH)2D more than did the addition of 25-OHD alone, and it did not increase the percentage to the levels found in the patients. An explanation for these discrepancies is unclear, although it is possible that in vitamin D toxicity, other metabolites such as vitamin D itself might influence the binding of 1,25-(OH)2D to DBP. In conclusion, we found that patients with vitamin D toxicity had elevated free 1,25-(OH)2D levels despite normal or only marginally elevated total 1,25-(OH)2D levels. The increased free levels of 1,25-(OH)2D might contribute to the pathogenesis of hypercalcemia in vitamin D toxicity.

Histomorphometry of iliac crest bone in 346 normal black and white South African adults

We examined undecalcified transiliac bone samples from 346 normal black and white South African adults (age range 21-83 years) by routine histomorphometry. The results were analysed for race-, age- and sex-dependent characteristics of trabecular microstructure (bone volume, trabecular thickness, trabecular number, trabecular separation) and static bone turnover variables (osteoid surface, osteoid volume, osteoid thickness, erosion surface). Trabecular thickness was greater in blacks than in whites, and bone volume was greater in black males, but not in black females, than in their white counterparts. Values for osteoid surface, volume and thickness, and for erosion surface were greater in blacks than in whites. Age-related changes were: a decline in bone volume in all race/sex groups; a decline in trabecular thickness in all groups except black males; a decline in trabecular number in all groups except black females; and a rise in trabecular separation in all groups except black females. There was an increase with age in osteoid surface in all groups except white males, in osteoid volume in all groups, and in erosion surface in blacks only. When correcting for age there were no sex-dependent differences in microstructure but values of some osteoid variables were greater in males than in females. If the greater osteoid and erosion values in blacks reflect greater bone turnover, then trabecular bone in blacks would be renewed more frequently, be subjected to fewer loading cycles and be less prone to fatigue failure. Blacks may thus have trabecular bone of better quality and sturdier microarchitecture. These features could contribute to the lower spontaneous fracture rate in blacks.