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Nutritional Rickets with Normal Circulating 25-Hydroxyvitamin D: A Call for Reexamining the Role of Dietary Calcium Intake in North American Infants

Departments of Pediatrics (Endocrinology) (M.C.D., T.O.C.) and Internal Medicine (Endocrinology) (M.E.M.), Yale University School of Medicine, New Haven, Connecticut 06520-8064

Address all correspondence and requests for reprints to: Thomas O. Carpenter, M.D., Yale University School of Medicine, 333 Cedar Street, 3103 LMP, P.O. Box 208064, New Haven, Connecticut 06520-8064. E-mail: thomas.carpenter{at}yale.edu.

	Abstract

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The incidence of nutritional rickets appears to be increasing in North American infants and toddlers; it is widely assumed that this is due to vitamin D deficiency. Thus, records of 43 children with nutritional rickets from greater New Haven, Connecticut, from 1986–2002 were identified. The mean age of presentation was 20 months; 86% were of African-American, Hispanic, or Middle Eastern descent. More than 93% of children had been breastfed; however, 15% had received vitamin D supplementation. Eighty-six percent of those with food histories available were weaned to diets with minimal dairy content after nursing. Serum 25-hydroxyvitamin D was 20.9 ± 11.5 ng/ml and was less than 15 ng/ml in only 22% of patients. Three representative case histories suggest that dietary calcium intake may play a contributory role in the development of disease; 1 case documents radiographic and biochemical resolution of rachitic abnormalities after calcium treatment, but no vitamin D therapy. Clinicians should be aware that low dietary calcium intake after weaning may result in the development of nutritional rickets, and that attention to calcium intake as well as that of vitamin D is important in the establishment of optimal dietary practices for North American infants and children.

	Introduction

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NUTRITIONAL RICKETS HAS been increasingly reported in recent years, particularly among vulnerable populations of children (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Vitamin D deficiency is widely assumed to be the primary cause of this disorder. Inadequate vitamin D acquisition through either poor dietary intake or limited sunlight exposure leads to depletion of vitamin D stores, with resultant decreased calcium absorption in the small intestine, thereby decreasing the available calcium for epiphyseal cartilage and skeletal mineralization. Limited calcium availability with resultant secondary hyperparathyroidism and attendant renal phosphate losses contribute to the bone and growth plate pathophysiology that lead to the clinical manifestations of rickets.

Historical features associated with nutritional rickets include lengthy duration of breastfeeding, absence of vitamin supplementation, limited sunlight exposure, dark skin pigmentation, and limited intake of dairy products, particularly those supplemented with vitamin D. The recent increase in reported cases may reflect an increasing influence of these factors. Considerable public health efforts have resulted in an increased number of infants being breastfed (12); this expanded practice of breastfeeding may have unintentionally increased the number of infants at risk for the development of rickets, as there is minimal vitamin D present in breast milk (13). However, another potential contributor to the development of nutritional rickets is the diet to which infants are weaned after breastfeeding. Unfortified juices, which are high in carbohydrates and lacking in calcium and other key bone nutrients, have replaced milk in the diets of many children (14). As a result, appropriate dietary intake of calcium, vitamin D, protein, and other nutrients important for the maintenance of skeletal health may be lacking.

To characterize the clinical features of children presenting with rickets in the greater New Haven, Connecticut, population, we retrospectively reviewed the records of such patients as encountered at the Yale-New Haven Hospital clinics over the past several years. Data from all patients as well as three cases representing the influence of calcium therapy are presented.

	Subjects and Methods

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Chart review

The records of 134 children with the diagnostic code of rickets at our institution from 1986–2002 were reviewed. Of these, 43 children were considered to have nutritional rickets based upon characteristic clinical features, elevated serum alkaline phosphatase activity, and other typical biochemical abnormalities, and all had radiographic evidence of rickets. Children with a nutritional deficiency secondary to another disease (i.e. inherited bone disease, celiac disease, cystic fibrosis, renal disease, or hepatobiliary disorders) or rickets secondary to genetic or other nonnutritional etiologies were excluded.

Available demographic information, including age, gender, and racial/ethnic background, was identified. Information available regarding dairy intake was recorded. Details of duration of breastfeeding and vitamin supplementation were usually recorded. Physical features, as documented in the medical record, were obtained, including leg bowing, wrist/ankle splaying, rachitic rosary, and frontal bossing. Height and weight measurements were documented.

Laboratory evaluation of the children occasionally differed on a case to case basis due to delays in referral and initiation of therapy after telephone consultation with a specialty physician. Therefore, any laboratory values obtained after application of therapy were not included in the analysis. The actual number of cases in which assays were performed are described in Results for each biochemical variable. Likewise, if the onset of therapy preceded evaluation at the Yale-New Haven Hospital, clinical data for presenting signs were not analyzed, and the number of evaluated children for clinical variables is included in Results. Finally, because of differences in referred and institutional assays, PTH levels are reported as a percentage of the upper limit of normal for the assay.

All radiographs had been evaluated by a board-certified pediatric radiologist. Evidence of impaired mineralization, frayed epiphyses, and/or metaphyseal widening on radiographs were observed in all cases and were considered consistent with rickets.

These activities were approved by the human investigation committee of Yale University School of Medicine and were considered to be appropriate with respect to the treatment of human subjects.

Analytic methods

Serum and urinary biochemical determinations were performed by the Clinical Chemistry Laboratory of Yale-New Haven Hospital. Total serum calcium was determined by flame atomic absorptiometry (model 2380, PerkinElmer, Norwalk, CT). Serum magnesium, phosphorus, alkaline phosphatase, and blood urea nitrogen were measured using standard autoanalyzer technology.

Serum PTH and, in most cases (19 of 26), vitamin D metabolites were measured by the Yale Mineral Metabolism Laboratory; the serum immunoreactive PTH concentration was measured with antisera to the midregion of human PTH using the ¹²⁵I-labeled 37–84 residue fragment of bovine PTH as a radioactive trace and standards from a human PTH adenoma extract as previously described (15). The sensitivity of this assay is 1 nlEq/ml; the intra- and interassay coefficients of variation are 3.9% and 5.4%, respectively. Normal values are 10–25 nlEq/ml.

Circulating 25-hydroxyvitamin D (25-OHD) levels were measured after alcohol extraction by competitive protein binding assay, using rat plasma as the source of vitamin D-binding protein (16). The intra- and interassay coefficients of variation are 5.8% and 6.8%, respectively; the sensitivity of this assay is 0.25 ng/ml (0.6 nmol/liter); and the percent recovery is 90.8 ± 2.1%. Seven 25-OHD measurements were performed at Quest Laboratories (Norwich, NY). The intra- and interassay coefficients of variation of the Quest assay are less than 8% and less than 12%, respectively; the reported sensitivity of this assay is 1.2 ng/ml. In agreement with recent literature (17) we have interpreted values greater than 15 ng/ml (>37.5 nmol/liter) as indicative of vitamin D sufficiency. Circulating 1,25-dihydroxyvitamin D (1,25-OH₂D) values were determined by competitive protein binding assay, with calf thymus receptor used for 1,25-OH₂D, as described previously (18). The assay sensitivity is 5–6 pg/ml (12.0–14.4 nmol/liter); intra- and interassay coefficients of variation are 7% and 12%, respectively. Normal values in young children range from 30–90 ng/ml (72–216 pmol/liter).

	Results

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All children in this series demonstrated clinical, biochemical, and radiographic evidence of rickets, and all had multiple historical features associated with the development of nutritional rickets. Demographic characteristics are listed in Table 1. The average age of presentation was 20.2 ± 8.2 months (range, 4–38); boys and girls were equally affected. Four children were international adoptees (3 from Eastern Europe and 1 from China). Seventy-nine percent of the total number of cases were African-American. Among native-born children, over 87% were African-American. Assessment of breastfeeding history, dairy intake, and vitamin D supplementation was by parental report, as specifically noted in the patient’s chart by the clinician. Over 96% (32 of 33) of children with a history of breastfeeding had been breastfed for more than 6 months. The average length of breastfeeding was 13.2 ± 5.5 months (range, 3.5–31). Thirteen children were breastfeeding to some degree at the time of presentation. Of those children who were no longer breastfeeding, the average length of time since cessation of breastfeeding was 9.5 ± 6.2 months (range, 0.5–22). Eighty-three percent (30 of 36) were weaned to a diet low in dairy products. Fifteen percent (5 of 34) had received vitamin D supplementation. All but 2 infants of 35 wk gestation were born at term.

In exploration of the hypothesis that younger children may be more prone to vitamin D deficiency (during breast feeding) and older children more prone to calcium deficiency (after being weaned to low calcium diets), we examined the potential correlation between age at presentation and circulating 25-OHD level as well as time since weaning and circulating 25-OHD; neither of these correlations was significant. Furthermore, there was no difference in circulating 25-OHD between infants presenting during breast feeding (20.8 ± 2.4 ng/ml) and those presenting after weaning (21.0 ± 10.3 ng/ml), excluding any infants receiving vitamin D supplementation.

	Case Reports

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Case 1

Patient A, a 24-month-old African-American girl, presented with tibial torsion and bowing of the lower extremities. She was born after a full-term gestation, weighing 7 lb, 3 oz, to a 22-yr-old Muslim mother who wore traditional covered dress. A was breastfed until 9 months of age and had never received any vitamin supplementation. A’s mother avoided dairy products due to symptoms of lactose intolerance, including bloating and diarrhea. Similarly, A was not fed milk and only occasionally ate cheese and yogurt, as the mother considered her to be lactose intolerant. In-toeing was noted by her mother at 1 yr of age; she had had several episodes of bronchospasm, but was otherwise healthy. One month before presentation, she was evaluated for wheezing and increased work of breathing. A rachitic rosary was noted on a chest radiograph.

A’s height was less than the 5th percentile for age, and her weight was at the 90th percentile for age. Evident features of rickets included frontal bossing, rachitic rosary, bowed legs, and swelling at the wrists and ankles, with mild tenderness. Serum calcium was 7.1 mg/dl (1.77 mmol/liter), phosphate was 3 mg/dl (0.97 mmol/liter), alkaline phosphatase was 2930 U/liter, PTH was 145 nlEq/ml, 25-OHD was 28.1 ng/ml (70.1 nmol/liter), and 1,25-OH₂D was 110.5 pg/ml (265.2 pmol/liter). After establishment of the diagnosis, A was treated with vitamin D (150,000 IU, twice a day for 2 d) and 320 mg/d elemental calcium in divided doses.

Noncompliance hampered follow-up evaluation, and she was not reevaluated until 14 months later. At that time biochemical values had generally normalized: calcium, 10.5 mg/dl (2.62 mmol/liter); phosphate, 5.9 mg/dl (1.90 mmol/liter); alkaline phosphatase, 577 U/liter; PTH, 22 nlEq/ml; and 25-OHD, 29.3 ng/ml (73.1 nmol/liter). 1,25-OH₂D values remained slightly elevated at 112.1 pg/ml (269.0 pmol/liter). Height had improved to the 10–25th percentile, while weight remained stable in the 75–90th percentile. Wrist and ankle swelling had improved. Calcium supplementation had continued, but no further administration of vitamins had been implemented.

Case 2

Patient B, a 24-month-old African-American boy, was referred with severe bowing, lower extremity muscle wasting, tibial torsion, and ankle deformities, which had been evident for approximately 1 yr. B was born after a full-term gestation, weighing 6 lb, 0 oz. He was breastfed for the first 15 months of life, with very little supplemental solid food and no vitamin supplementation. He sat at 9 months and walked at 20 months with difficulty. His diet at presentation included a variety of foods, but almost no dairy products. Because of the noted lower extremity abnormalities, B was referred to the pediatric endocrinology clinic. B’s father had undergone a partial parathyroidectomy several years previously. The mother reported a history of lactose intolerance and avoided dairy products. A 4-yr-old brother and 9-month-old sister were healthy.

Height and weight were less than the fifth percentile for age. Rachitic abnormalities of the distal radius, ulna, humerus, and tibia were evident. A rachitic rosary was present, and there was severe bowing of the legs. Serum calcium was 9.2 mg/dl (2.30 mmol/liter), phosphorus was 2.8 mg/dl (0.90 mmol/liter), alkaline phosphatase was 1640 U/liter, PTH was 115 nlEq/ml, 25-OHD was 34.1 ng/ml (85.1 nmol/liter), and 1,25-OH₂D was 115.6 pg/ml (277.4 pmol/liter). The diagnosis of rickets due to nutritional deficiency was made, and he was placed on daily doses of 2000 IU vitamin D and 460 mg elemental calcium.

Within 1 month, PTH levels normalized to 19 nlEq/ml, and alkaline phosphatase levels decreased to 1440 U/liter. Height and weight percentiles increased in the subsequent 6 months, and there was radiographic improvement in bony abnormalities. Dietary intake of dairy products improved somewhat. However, 7 months after initiation of therapy, the alkaline phosphatase level had increased to 2130 U/liter. The family had recently discontinued calcium supplementation due to its expense. They had, however, continued the vitamin D supplement. Calcium therapy was resumed with a less expensive alternative preparation. Two weeks after resumption of calcium supplementation, alkaline phosphatase had fallen to 873 U/liter and eventually corrected entirely.

Case 3

Patient C, a 9-month-old African-American boy, was referred with a several-week history of poor gain in weight and height. The parents reported noticing bowing of the legs, but no aversion to weight bearing. He had been exclusively breast-fed, without any formula or vitamin supplementation, and was begun on baby food feedings approximately 1 month before the referral visit. A paternal uncle had leg bowing as a child, which was treated with orthopedic bracing. C’s length was slightly less than fifth percentile for age, and his weight was less than the fifth percentile for age. No craniotabes was evident, but widening of the wrist areas was noted. Minimal bowing of the legs was present. Radiographs were consistent with rickets (Fig. 1). Serum calcium was 8.8 mg/dl (2.20 mmol/liter), phosphorus was 2.2 mg/dl (0.71 mmol/liter), alkaline phosphatase was 1730 U/liter, PTH was 215 nlEq/ml, 25-OHD was 19.7 ng/ml (49.2 nmol/liter), and 1,25-OH₂D was 51.3 pg/ml (123.1 pmol/liter). The urinary calcium/creatinine ratio was 0.04 mg/mg (0.11 µmol/µmol). The diagnosis of nutritional rickets was made, and he was placed on 575 mg elemental calcium daily, or approximately 85 mg/kg body weight·d. No vitamin D supplement was added, and laboratory values normalized over time as shown in Table 4. Treatment with calcium alone, with no vitamin D supplementation and no substantial change in circulating 25-OHD levels, resulted in healing of the rachitic abnormalities, as evidenced by follow-up radiographs, performed 3.5 months after the initial presentation (Fig. 1).

View larger version (130K): [in this window] [in a new window]   FIG. 1. Radiographs at presentation (left panel) and after 3 months of calcium therapy, with no supplemental vitamin D (right panel). Typical rachitic features, including metaphyseal widening and fraying of the metaphyseal edge, are apparent at the time of diagnosis; these features have considerably resolved at the time of the follow-up radiograph.

	Discussion

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This report documents a population with overt clinical, biochemical, and radiological evidence of nutritional rickets. In contrast to other reports, serum 25-OHD levels were well within the normal reference range in approximately three quarters of the children for whom measurements were available. We considered that some of these children may have been exposed to vitamin D before testing, thereby increasing 25-OHD levels into the normal range after development of disease. However, most cases presented between the late fall and early spring, a period of limited sunlight in the northeastern United States. The majority of patients were of African-American background and would have likely required significantly more sunlight than lightly pigmented persons to achieve the same elevations in 25-OHD levels (19). Furthermore, most children lived in urban settings, and it is unlikely that they would have had routine access to outdoor open play areas. Thus, it is doubtful that changes in exposure to vitamin D could have caused a significant increase in stores between the onset of disease and the time of testing in the bulk of this population.

We have also considered that these findings may reflect an inadequate definition of the lower normal limit for this population. Vitamin D stores are best assessed by measurement of serum 25-OHD levels, because it is the combined measurement of both endogenously synthesized vitamin D and that obtained from the diet. However, normal reference values for serum 25-OHD levels are problematic, because they vary depending on factors such as sunlight exposure, season, latitude, skin pigmentation, age, and dietary vitamin D intake. Although the lower threshold level of serum 25-OHD associated with increased risk for the development of rickets has been reported as ranging from 5 (20) to 10 ng/ml (12.5–25 nmol/liter) (21), more than half of our rickets patients had 25-OHD levels greater than 20 ng/ml (50 nmol/liter). When using the threshold value of 15 ng/ml for establishing the diagnosis of rickets, only 22% of the affected children were considered to have biochemical evidence of vitamin D deficiency. Nevertheless, it would be useful to establish physiological correlates of circulating 25-OHD levels in this age group to better interpret such values.

In contrast, circulating PTH values were elevated in all of the affected patients. At the present time there is only limited information available in normal children concerning the level of 25-OHD that is associated with secondary hyperparathyroidism, and the available data are not for this age group. In the setting of dietary calcium sufficiency, such a value would be of use as a physiological correlate of calcium absorption. The mean level of 25-OHD at normalization of PTH in our group of patients was 33.4 ± 16.1 ng/ml (83.4 ± 40.2 nmol/liter); however, this value was obtained in the context of healing rickets, not in the setting of normal homeostasis. Thus, elevated circulating PTH values, although not a specific marker for nutritional rickets, may serve as a sensitive biochemical indicator of dietary calcium deficiency (or malabsorption) in the setting of normal circulating 25-OHD levels.

It is possible that vitamin D requirements vary in different populations. One hypothetical explanation for such variation may relate to subtle changes in the function of the vitamin D receptor (VDR) secondary to polymorphisms/mutations in this protein. In several studies the VDR genotype has been associated with fractional calcium absorption (22, 23, 24). As vitamin D status, dietary calcium, and calcium absorption are the major factors regulating calcium availability, it follows that factors that affect calcium absorption may be important in determining a susceptibility to the development of rickets. Furthermore, dietary calcium and vitamin D requirements may differ among populations, and VDR genotype could potentially play a role in this variability. Thus, it is possible that individuals with certain polymorphisms of this receptor may be more susceptible to the development of metabolic bone disease if they are consuming a low calcium diet. Indeed, a correlation between VDR genotype and the presence of rickets in the Nigerian population has been reported (25).

Nutritional rickets due to calcium deficiency has been reported in Africa (26, 27, 28, 29) and in case reports from Western Europe (30) and North America (31). For example, Pettifor et al. (26) reported nine black children (age, 4.6–13 yr; mean, 9.4 yr) with nutritional rickets in rural South Africa. Despite having spent extensive time outdoors, these children had obvious clinical features of rickets, including progressive bone deformities, decreased growth, and radiographic changes consistent with the disorder. Four children had hypocalcemia, and all nine had elevated alkaline phosphatase and 1,25-OH₂D levels, but normal 25-OHD levels. Calcium balance studies demonstrated that calcium absorption was not impaired. Treatment with calcium alone corrected the biochemical and radiographic abnormalities. In view of an environment providing plentiful vitamin D, but a diet severely lacking in calcium, the researchers concluded that calcium deficiency alone was the cause of nutritional rickets in these children.

Okonofua et al. (27) compared 10 Nigerian children with nutritional rickets and a diet low in calcium content and high in phytate content to 12 healthy age-matched controls. Serum calcium was lower, and alkaline phosphatase and PTH were elevated in the rachitic children, but 25-OHD, 1,25-OH₂D, and osteocalcin levels did not differ significantly from control values. Treatment with calcium gluconate alone resulted in healing of their rickets.

In a randomized, double-blind, controlled trial, Thacher et al. (29) compared treatment of nutritional rickets in 123 Nigerian children with calcium alone, vitamin D alone, or the combination of calcium and vitamin D. The groups treated with calcium alone or combined calcium and vitamin D demonstrated a better healing response than the group treated with vitamin D alone. Baseline dietary calcium intake was similarly low in patients and a control group. The results of this study suggest that although calcium deficiency was an important contributor to nutritional rickets in these patients, other unidentified factors may have been involved in the development of their bone disease. As in their study, we found no correlation of 25-OHD level and age of presentation of rachitic disease in our North American population.

Based on our current experience and that reported by others, it is likely that a spectrum of pathogenetic mechanisms for the development of nutritional rickets exists (32) (Fig. 2). At one end of the spectrum are patients with pure vitamin D deficiency who have a sufficient dietary intake of calcium (point A). This may include many breastfed infants who are not supplemented with vitamin D as well as other infants with inadequate dietary vitamin D intake or limited sunlight exposure. At the other end of the spectrum are patients with a pure calcium deficiency (point B) due to low dietary calcium intake, yet with normal indices of vitamin D stores. These patients are described by our case reports and in the African studies mentioned above. A third group is likely to have marginal or low vitamin D stores and a diet deficient in calcium and/or high in substances that may impair intestinal absorption of dietary calcium (point C). Nutritional rickets patients from the Asian community in Great Britain (with low vitamin D stores and a diet with a high phytate/calcium ratio) typify this category (33). The majority of patients with nutritional rickets probably fall somewhere between the two ends of the spectrum, with a deficiency in either calcium or vitamin D playing a slightly more influential etiological role. We speculate that a greater supply of vitamin D may be necessary to compensate in such children for their suboptimal dietary calcium intake, and conversely, that increased calcium intake may be required to prevent disease in the setting of low normal 25-OHD levels. Therefore, in most patients both calcium and vitamin D are important for the treatment and prevention of nutritional rickets.

View larger version (21K): [in this window] [in a new window]   FIG. 2. The spectrum of nutritional rickets. See text for details.

	Footnotes

 
Abbreviations: 25-OHD, 25-Hydroxyvitamin D; 1,25-OH₂D, 1,25-dihydroxyvitamin D; VDR, vitamin D receptor.

Received December 10, 2002.

Accepted April 10, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Case Reports Discussion References

 

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