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Prevalence of Vitamin D Deficiency and Insufficiency in Children With Osteopenia or Osteoporosis Referred to a Pediatric Metabolic Bone Clinic

^a Divisions of Endocrinology
^b Nephrology, Department of Pediatrics, Columbus Children's Hospital/Ohio State University College of Medicine, Columbus, Ohio

	ABSTRACT

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OBJECTIVES. The purpose of this work was to determine the prevalence of vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis and to evaluate the relationship between serum 25-hydroxyvitamin D levels and bone parameters, including bone mineral density.

MATERIALS AND METHODS. Serum 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, parathyroid hormone, and other bone markers, as well as bone mineral density, were obtained for 85 pediatric patients with primary osteoporosis (caused by osteogenesis imperfecta or juvenile idiopathic osteoporosis) and secondary osteopenia or osteoporosis caused by various underlying chronic illnesses. Pearson's correlation was used to assess the relationship between vitamin D levels and different bone parameters.

RESULTS. Vitamin D insufficiency (defined as serum 25-hydroxyvitamin D <30 ng/mL) was observed in 80.0% of patients. Overt vitamin D deficiency (defined as serum 25-hydroxyvitamin D <10 ng/mL) was present in 3.5% of patients. Using a more recent definition for vitamin D deficiency in adults (defined as serum 25-hydroxyvitamin D <20 ng/mL), 21.1% of the patients had vitamin D deficiency. There was a significant inverse correlation between 25-hydroxyvitamin D and parathyroid hormone levels. There was a positive correlation between 1,25 dihydroxyvitamin D and parathyroid hormone, alkaline phosphatase, and urine markers for bone turnover.

CONCLUSIONS. Vitamin D insufficiency was remarkably common in pediatric patients with primary and secondary osteopenia or osteoporosis. The inverse relationship between 25-hydroxyvitamin D and parathyroid hormone levels suggests a physiologic impact of insufficient vitamin D levels that may contribute to low bone mass or worsen the primary bone disease. We suggest that monitoring and supplementation of vitamin D should be a priority in the management of pediatric patients with osteopenia or osteoporosis.

Key Words: vitamin D deficiency • vitamin D insufficiency • pediatric osteopenia • pediatric osteoporosis • low bone density in children

Abbreviations: 25-OHD—25-hydroxyvitamin D • PTH—parathyroid hormone • BMD—bone mineral density • 1,25-OHD—1,25-dihydroxyvitamin D • CV—coefficient of variation

Vitamin D is essential for bone growth and mineralization in children and adults. Severe vitamin D deficiency causes rickets in children and osteomalacia in adults.¹ It has been recognized recently in adult studies that less severe vitamin D deficiency (otherwise called "vitamin D insufficiency") can lead to alterations in bone metabolism, secondary hyperparathyroidism, bone loss, osteoporosis, and increased risk of fracture.^2–7 The effects of vitamin D insufficiency on bone metabolism during skeletal growth in children have not been established.

Redefining normal levels or, more particularly, desirable levels of vitamin D for healthy children and adults has been a subject of debate in recent years. The "normal" laboratory reference range of 25-hydroxyvitamin D (25-OHD; ie, 10–55 ng/mL for the reference range given by the laboratory used in this study) may not truly represent "desirable" vitamin D status for children, because this range is defined in subjects without taking into the account sunlight exposure or nutritional vitamin D intake.⁸ In fact, individuals with an ample amount of sunlight exposure have circulating 25-OHD ranging from 54 to 90 ng/mL.⁸ Many studies have demonstrated significant negative biological consequences on calcium homeostasis and bone with lower "normal" levels of 25-OHD, including alterations in parathyroid hormone (PTH), calcium absorption, and bone mineral density (BMD).^9–11 Adequate circulating 25-OHD levels, as defined by the absence of negative biological consequences, have now been defined in adults.^9–12

Diminished vitamin D supply by a lack of dietary vitamin D or decreased sunlight exposure can result in lowered levels of plasma 25-OHD and 1,25-dihydroxyvitamin D (1,25-OHD). These lower levels can then lead to decreased intestinal absorption of calcium, which subsequently results in increased PTH secretion. Secondary hyperparathyroidism is the key hallmark of poor nutritional vitamin D status in adults, especially in the elderly, because the inverse relationship between 25-OHD and PTH levels is more pronounced with increasing age.⁹ In large adult studies, circulating 25-OHD levels well above 32 ng/mL (80 nmol/L) effectively suppress PTH, and mean serum PTH concentrations begin to rise when the serum 25-OHD concentrations fall below 31 to 32 ng/mL (77–80 nmol/L).^9,13 Recently, Hollis⁸ recommended using 25-OHD <80 nmol or 32 ng/mL as the cutoff for nutritional vitamin D deficiency. In some studies, different stages of vitamin D status have been used: hypovitaminosis D has been defined by serum 25-OHD <30 ng/mL (75 nmol/L); vitamin D insufficiency by <20 ng/mL (50 nmol/L); and vitamin D deficiency by <10 ng/mL (25 nmol/L).^14,15 Most recently, Holick¹⁶ defined vitamin D deficiency as 25-OHD <20 ng/mL (50 nmol/L) and vitamin D insufficiency as 25-OHD at 21 to 29 ng/mL (52–72 nmol/L) in adults. For the pediatric population, optimal 25-OHD levels for good bone health have not yet been established.

Vitamin D insufficiency is very common in adults, particularly in the elderly, and is present in as many as 50% of individuals, depending on the characteristics of the study population.^5–7,17,18 Little is known about the prevalence of vitamin D insufficiency in children in the United States. Four studies in Europe (Spain, France, and Finland) found that 80% of children and adolescents had insufficient vitamin D levels (25-OHD levels <20 ng/mL) in winter.^19–22 A study in a sunny country, Lebanon, found that 52% of healthy school children had 25-OHD at <20 ng/mL (50 nmol/L).²³ A recent study in Boston, Massachusetts, observed that 36% of young adults (aged 18–29 years) had vitamin D insufficiency (25-OHD <20 ng/mL or 50 nmol/L) at the end of winter.²⁴ All of the pediatric studies stated above were done in healthy subjects, and there are no published reports on vitamin D status and relationship with bone markers in pediatric patients with low bone density or metabolic bone disease. The aim of this study was to determine the prevalence of vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis seen in our pediatric metabolic bone clinic. We also examined the relationship between vitamin D levels and biochemical markers for bone turnover, as well as the BMD.

	METHODS

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Subjects and Protocols
Eight-five pediatric patients were referred by primary care physicians or other subspecialists to our pediatric metabolic bone clinic at Columbus Children's Hospital from 2001 to 2004 for evaluation of multiple fractures or possible metabolic bone disorder. This retrospective study was approved by the committee for the protection of human subjects internal review board at Columbus Children's Hospital. Data at the first clinic visit were collected, including demographic data, detailed medical history, concurrent drug therapy, fracture rate, and biochemical laboratory studies (serum calcium, phosphorus, alkaline phosphatase, 25-OHD, 1,25-OHD, PTH, osteocalcin, urine pyridinoline, and deoxypyridinoline). BMD was performed in all of the patients suspected of having osteopenia or osteoporosis. All of the patients had a BMD test performed and were included in the study, regardless of BMD test results.

Laboratory Studies
Serum 25-OHD was measured by a competitive protein-binding assay with an interassay coefficient of variation (CV) between 8.5% and 12.4%. The sensitivity of the method is 5 ng/mL. The laboratory reference range is 10 to 55 ng/mL (or 25–137 nmol/L [the conversion factor from ng/mL to nmol/L is 1 ng/mL x 2.496). Serum 1,25-OHD was measured by radioreceptor assay with interassay CV between 5.6% and 17.0%. The PTH was measured by a 2-site immunochemiluminometric method, with interassay CV between 9.9% and 19.0%. The laboratory reference range is 10 to 65 pg/mL. All of these were performed at Esoterix Laboratory (Calabasas Hills, CA). Routine chemistries were measured by a Hitachi multichannel analyzer (Boehringer Mannheim Diagnostics, Indianapolis, IN). Urine pyridinoline and deoxypyridinoline were measured by high-performance liquid chromatography at the Mayo Clinic (Rochester, MN).

BMD and total body bone mineral content were measured by dual-energy radiograph absorptiometry (Hologic Delphi, Waltham, MA). The z score of the lumbar spine BMD was determined by using our institution's normative data based on the report by Southard et al²⁵ from our institution that studied 218 healthy children aged 1 to 19 years. The lumbar BMD was adjusted for weight and pubertal status, because the results of multiple regression analyses in this study showed that Tanner stage and weight were the best predictive indicators of bone mass and BMD.²⁵

With regard to the terminology of osteopenia or osteoporosis used in this study, we recognize that there is no consensus criteria of BMD for osteopenia or osteoporosis in the pediatric population. We use these terms in this study based on the definition of osteoporosis, described as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, typically associated with a consequent increase in bone fragility and susceptibility to fractures. Osteopenia was used to describe a less severe degree of diminished bone mass. Osteopenia was defined as lumbar vertebral BMD between –1.0 and –2.0 and osteoporosis as lumbar vertebral BMD less than –2.0. All of the patients in this study had clinical suspicion for osteoporosis.

Definition of Vitamin D Insufficiency
For purposes of analysis, various cut points of serum 25-OHD were used to define vitamin D deficiency and insufficiency (<10, <15, <20, <25, or <30 ng/mL) in the absence of a consensus value in pediatrics. Based on the suggested cutoffs for adults, serum 25-OHD concentrations <10 ng/mL have been used to define overt vitamin D deficiency,¹⁴ <20 ng/mL as vitamin D deficiency,¹⁶ and <30 ng/mL as vitamin D insufficiency.⁸ The 30-ng/mL cutoff was used based on the fact that, in healthy adults, serum PTH concentrations begin to rise when serum 25-OHD concentrations fall below 30 ng/mL.^9,13

Statistical Analysis
Pearson's correlation and regression were used to assess the relationship between vitamin D levels and different bone parameters. Analysis of variance was used to test the effect of season. Demographic data were tested with ². Data were reported as means and SDs. A P value of <.05 was considered to be statistically significant. All of the statistical analyses were conducted by using SPSS 14.0 for Windows (SPSS Inc, Chicago, IL).

	RESULTS

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Clinical Characteristics of the Study Groups
Eighty-five patients were studied. The mean age was 9.7 ± 4.5 years, with a range of 1.5 to 19 years. Fifty-three patients (62%) were boys. Seventy-four patients (87%) were white, 9 (10.6%) were black, and 2 (2.4%) were Hispanic. All of the patients had a history of bone fragility or underlying chronic medical conditions that put them at risks for osteoporosis. Patients were categorized into different groups according to their underlying diseases (Table 1). All of the patients with osteogenesis imperfecta were diagnosed clinically, and some were confirmed by fibroblast collagen study. The group of immobilization patients consisted of children with cerebral palsy or spinal muscular dystrophy. The group with steroid-induced osteoporosis was mostly children with juvenile rheumatoid arthritis or acute lymphoblastic leukemia who had been on chronic high-dose corticosteroids. Idiopathic osteoporosis was diagnosed in 4 patients with severe osteoporosis and clinical bone fragility with no identified cause. The group of other patients had a variety of medical disorders, such as cystic fibrosis, celiac disease, inflammatory bowel disease, and genetic syndromes not known to directly affect bone. Fourteen patients (16%) patients reported use of anticonvulsant agents, medications known to affect vitamin D metabolism. Fifteen patients (17.6%) reported taking multivitamins, whereas 9 patients (10.5%) were taking a calcium supplement. Only 5 patients (6%) were taking both calcium and vitamin D supplements. Lumbar BMD z scores were undetermined in 8 patients because of the presence of metal hardwares in the spine or other artifacts in the abdomen, such as gastrostomy tubes. Four patients with osteogenesis imperfecta had lumbar BMD z score above –1.0 (0.12, 0.3, –0.7, and –0.8). All of the other patients had low bone density (defined by a z score less than –1.0).

Prevalence of Vitamin D Deficiency and Insufficiency
The prevalence of vitamin D insufficiency (25-OHD <30 ng/mL) was remarkably high, at 80% (68 patients) of all of the patients studied (Fig 1). Even with the more conservative 25-OHD level cutoff proposed by El-Hajj Fuleihan²³ of 20 ng/mL, 21.1% of the patients had values below this cutoff point. Three patients (3.5% of all of the patients) had overt vitamin D deficiency (25-OHD <10 ng/mL). The mean 25-OHD levels in each group of patients classified by various bone disorders were similar. When using the cutoff value of 25-OHD <20 ng/mL, the prevalence of vitamin D insufficiency in each group was between 21% and 27%, with the group with steroid-induced osteoporosis having the highest prevalence of 27%. When using the cutoff value of 25-OHD <30 ng/mL, nearly all of the children with steroid-induced osteoporosis (90%) had vitamin D insufficiency, whereas, in the other groups, the prevalence was also markedly high, ranging from 72% to 83%.

View larger version (16K): [in this window] [in a new window]   FIGURE 1 Prevalence of vitamin D insufficiency in all of the subjects. Data show the percentage of patients with serum 25-OHD concentrations below the various cutoffs of <10, <15, <20, <25, and <30 ng/mL.

View larger version (11K): [in this window] [in a new window]   FIGURE 2 Inverse relationship between serum 25-OHD and intact PTH levels (P < .01).

View larger version (10K): [in this window] [in a new window]   FIGURE 3 Serum PTH (pg/mL) according to serum 1,25-OHD levels.

	DISCUSSION

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A high prevalence of vitamin D insufficiency was found in this study of children with osteopenia or osteoporosis referred to our pediatric metabolic bone clinic. To our knowledge, we are the first to report the prevalence of vitamin D insufficiency in pediatric patients with primary and secondary osteopenia or osteoporosis. Serum concentrations of 25-OHD are the best indicators of total body stores of vitamin D.⁸ The prevalence of vitamin D deficiency using the newly accepted cutoff of 25-OHD <20 ng/mL was 21.1% in all of the subjects. The prevalence of vitamin D insufficiency (25-OHD <30 ng/mL) was remarkably high at 80% of all of the subjects.

Regardless of the etiology of the bone disorder, the prevalence of vitamin D insufficiency with different cutoffs was similar in each group of patients classified as having osteogenesis imperfecta, immobilization, idiopathic juvenile osteoporosis, steroid-induced osteoporosis, and other types of chronic medical conditions that were associated with metabolic bone disease. A recent study reported that 90% of patients (aged 4–22 years) with steroid-sensitive nephrotic syndrome in remission had vitamin D insufficiency.²⁶ This prevalence is similar to our finding of 80% of children with metabolic bone disease displaying a 25-OHD level <30 ng/mL. The factors that may account for vitamin D insufficiency in various chronic medical conditions include low vitamin D intake and decreased sun exposure. This demonstration of such a high prevalence of vitamin D insufficiency in our pediatric patients with primary and secondary osteopenia or osteoporosis supports our present approach to assess vitamin D status in all children with any type of metabolic bone disease, regardless of suspected etiology, with subsequent supplementation with extra vitamin D to optimize vitamin D levels in these children.

The significant negative correlation between 25-OHD levels and PTH levels found in our patients supports the biological relevance of hypovitaminosis D in these children. The magnitude of serum 25-OHD reduction that results in increased PTH levels in healthy children is still a matter of debate. The study of healthy children in Lebanon by El-Hajj Fuleihan et al²³ showed that, similar to adults, 25-OHD levels >20 ng/dL, and even more so >30 ng/dL, are desirable to keep PTH less than the upper limit of normal. In our study, although no obvious threshold effect between 25-OHD and PTH was found, we were able to demonstrate a continuous inverse relationship between 25-OHD and PTH, with a similar trend of secondary hyperparathyroidism with lower vitamin D levels. The increased PTH levels in the presence of vitamin D insufficiency suggest a physiologic effect of the insufficient vitamin D level in children with osteopenia or osteoporosis.

In these children, there was also a significant positive correlation between 1,25-OHD levels and PTH and alkaline phosphatase levels, as well as the urine markers for bone resorption. These data suggest that the presence of subtle secondary hyperparathyroidism in these subjects may be the cause of compensatory elevated 1,25-OHD levels and increased bone turnover. This may be in response to vitamin D insufficiency and suggests that vitamin D insufficiency may be more deleterious to skeletal health in children and adolescents with underlying metabolic bone disorders than we had suspected previously.

We found no effect of seasonality on vitamin D insufficiency in our study population, which could be because of the fact that this group of patients generally had decreased sunlight exposure and/or more abnormal vitamin D intake and metabolism because of their medical conditions.

It has been shown in adult studies that high-dose vitamin D replacement rapidly reestablishes vitamin D stores and can lead to significant improvements in BMD.²⁷ The effect of vitamin D supplementation on BMD in children with osteopenia or osteoporosis has not been investigated to date. These observations in adults suggest that studies should be performed to determine whether there are similar benefits in a pediatric population.

We did not find a direct correlation between low vitamin D and fracture rate in this study. Our ability to detect a relationship may have been limited by the fact that all of the children in this referral group had previous fractures. It is possible that a study that includes children without fractures may demonstrate a positive correlation. Based on the recent report of evidence for fracture prevention with oral vitamin D supplementation in adults,²⁸ we believe that this issue deserves additional study in children, and we emphasize vitamin D supplementation in our pediatric patients with metabolic bone disorders to optimize their bone health and to potentially prevent fractures.

	CONCLUSIONS

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In this study we demonstrate that vitamin D insufficiency is common even in children with recognized osteopenia and osteoporosis caused by primary metabolic bone disease or secondary to chronic illnesses and could be one of the risk factors for low bone density. This study emphasizes the importance of assessing vitamin D status in children with low bone density and/or multiple fractures. Additional research is needed to determine whether vitamin D insufficiency represents a correctable risk factor for fragility fractures in pediatric osteopenia or osteoporosis resulting from primary and secondary causes. In addition, additional investigation of the dose of vitamin D and level of 25-OHD required to obtain better bone health may prove very useful in the care of these children. Only in such a manner can we determine whether supplemental vitamin D can significantly improve bone density and reduce the fracture rate in children with osteopenia or osteoporosis.

	ACKNOWLEDGMENTS

 
We especially thank John Hayes, PhD, for advice and assistance with statistical analysis, and we thank Naomi Tokar for excellent administrative support.

	FOOTNOTES

 
Accepted Nov 26, 2007.

Address correspondence to Sasigarn A. Bowden, MD, Columbus Children's Hospital, Division of Endocrinology, 700 Children's Dr, Columbus, OH 43205. E-mail: bowdens{at}pediatrics.ohio-state.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

What's Known on This Subject To our knowledge, there has not been a report on the prevalence of vitamin D deficiency or vitamin D insufficiency in pediatric patients with primary or secondary osteopenia or osteoporosis.

 

What This Study Adds This study is the first to report the prevalence of vitamin D deficiency and vitamin D insufficiency in pediatric patients with primary and secondary osteopenia or osteoporosis. We also found biological consequences of hypovitaminosis D.

 

	REFERENCES

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Bowden, S. A. Articles by Mahan, J. D. PubMed Articles by Bowden, S. A. Articles by Mahan, J. D. Related Collections Nutrition & Metabolism

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