PEDIATRICS Vol. 121 No. 5 May 2008, pp. 890-897 (doi:10.1542/peds.2007-2079)
ARTICLE |
Healthy Children With Frequent Fractures: How Much Evaluation Is Needed?
a Division of Endocrinology
b Department of Orthopedics, Nemours Children's Clinic, Jacksonville, Florida
c Nemours Clinical Management Program, Nemours Children's Clinic, Orlando, Florida
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ABSTRACT |
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OBJECTIVE. We performed a case-control study to determine whether occult bone disease is associated with a history of frequent fractures in children.
METHODS. Healthy children with 
2 incidences of low-energy fractures were recruited (n = 68). Children with no history of fractures served as control subjects (n = 57). Food logs, activity surveys, physical examinations, laboratory tests, and dual-energy radiographic absorptiometry were used.
RESULTS. Bone mineral density z scores were significantly reduced in case subjects, compared with control subjects. Three case subjects (4.3%) and 1 control subject (1.8%) had bone mineral density z scores below the expected range. Of those 4 subjects, 2 had dairy avoidance and 2 had delayed puberty. An additional case subject had evidence of vitamin D deficiency. A significant number of subjects (20% of case subjects and 23% of control subjects) had idiopathic hypercalcuria, based on 24-hour urine collections. Among the case subjects, bone mineral density z scores were significantly lower for those with idiopathic hypercalcuria. Among the control subjects, the presence of idiopathic hypercalcuria did not affect bone mineral density. The case subjects with idiopathic hypercalcuria accounted for virtually all of the differences in bone mineral density between the case and control groups. Analysis of parathyroid hormone and 1,25-dihydroxy-vitamin D levels showed that children with frequent fractures and hypercalcuria had renal hypercalcuria, whereas children with no fractures and hypercalcuria had absorptive hypercalcuria.
CONCLUSIONS. We identified a significant association between a history of frequent fractures and hypercalcuria in children. We propose that the appropriate screening evaluation for children who present with a history of frequent fractures consists of a dietary history targeted at calcium and vitamin D intakes, a physical examination to assess for pubertal delay, and urinary calcium concentration/creatinine ratio determination to assess for hypercalcuria. Children with abnormalities in this screening should undergo dual-energy radiographic absorptiometry and appropriate evaluation.
Key Words: fractures • bone density • laboratory techniques • hypercalcuria • vitamin D deficiency
Abbreviations: AI—adequate intake • BMD—bone mineral density • DXA—dual-energy radiographic absorptiometry • IH—idiopathic hypercalcuria • PTH—parathyroid hormone
Bone fractures are not uncommon in childhood, and there has been a steady increase in the incidence of fractures in children over the past 30 years.1 Less frequently, children have >1 fracture. Children presenting with a history of multiple fractures most commonly have normal skeletal health but are prone to fracture because of high levels of exposure to trauma (such as contact sports) or are just unlucky. However, such a history might also be a sign of underlying bone fragility attributable to undiagnosed metabolic bone disease. Therefore, these children present a dilemma for their pediatricians and orthopedic surgeons; how much evaluation is needed for a child with a history of multiple fractures? This study was designed to address this question.
It is well documented that low bone mineral density (BMD) and a history of a previous fracture are risk factors for future fractures in adults.2,3 However, only a few investigators have studied the association of decreased BMD and fractures in children. Goulding et al4 reported that girls with a history of a fracture had an average BMD z score of –0.5. Of those girls, 34% had lumbar spine BMD z scores lower than –1.0, more than twice the rate expected if there was no association. Similar results were reported for boys.5 The same group reevaluated the girls 4 years later for subsequent fractures.6 They found that a history of a previous fracture increased the risk for a subsequent fracture 3.3-fold and a total-body BMD z score lower than –1.0 increased the risk 1.9-fold. A history of both increased the risk of a subsequent fracture 9.4-fold. A recent meta-analysis of case-control studies confirmed a standardized mean difference in BMD z scores of –0.32 between children with and without fractures.7 A large, prospective study (the Avon Longitudinal Study of Parents and Children) recently reported on 6213 children who had dual-energy radiographic absorptiometry (DXA) performed at 9.9 years of age.8 Of those children, 550 had 1 fracture within 2 years after DXA. Again, the children with fractures had reduced BMD (standardized mean difference: –0.26). The authors determined that the odds ratio for risk of fracture was 1.12 per 1-SD decrease in BMD. These data suggest that, like adults, children with a history of fractures or abnormal BMD are at risk for future fractures and that risk is increased substantially if both factors are present. The implication of these studies is that DXA for children with a history of fractures might allow clinicians to identify a group of children at high risk for subsequent fractures. Other risk factors for childhood fractures, such as increased weight5 and milk avoidance,9 have been identified. However, none of those studies included a biochemical analysis to assess for other potential causes of low BMD or increased fracture risk.
Besides prediction of future fractures, BMD determination also serves as a screen for metabolic bone disease. A substantial number of conditions have been shown to be associated with low BMD10 and fractures11 in children. Most of these conditions affect BMD because of disturbances in growth and puberty, disturbances in calcium or phosphorous metabolism, chronic inflammation, or medications. Many of these conditions can be present with few symptoms and may escape prompt diagnosis. Tannenbaum et al12 reported on secondary contributors to osteoporosis in otherwise healthy, postmenopausal woman. Those authors found that 32% of subjects had evidence of undiagnosed disorders of bone and mineral metabolism, including primary hyperparathyroidism, vitamin D deficiency, renal calcium wasting, calcium malabsorption, hyperthyroidism, and Cushing syndrome. A similar study has not been performed for children.
We studied otherwise healthy children who had multiple fractures associated with low-energy trauma, to determine the incidence of undiagnosed bone disease. We then used these data to recommend appropriate evaluation of children presenting with this history.
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METHODS |
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Study Subjects
Case subjects were identified from the patients of the orthopedic clinic at Nemours Children's Clinic-Jacksonville. Included were healthy children, 3 to <18 years of age, with a history of
2 instances of fractures associated with low-energy trauma. For this study, a "low-energy fracture" excluded accidents involving motor vehicles, bicycles, skateboards, monkey bars, and falls from more than standing height. Control subjects were healthy siblings of the case patients (n = 32; 56%) and unrelated healthy children (n = 25; 44%) with no history of fractures. The control subjects who were not related to case subjects were drawn from the same northeast Florida population. Specifically excluded from the study were children with a history of any disease or syndrome associated with low BMD or fractures, a history of corticosteroid or antiepileptic medication use, a history of prolonged immobilization, spina bifida, or a history of spinal surgery. This study was approved by the local internal review board, and all subjects had parental permission forms signed before any study procedures.
DXA Studies
DXA was performed by using a Discovery A system (Hologic, Bedford, MA). Scans were obtained after all casts were removed. The median time from the last fracture to the DXA scan was 24 weeks, with a range of 6 to 83 weeks. Lumbar spine scans were obtained by using the "fast array" mode. Whole-body scans were obtained by using the "auto whole body" mode, which also provided data on body composition. Image analysis was performed with QDR for Windows XP 12.4 software (Hologic), by a single technician. BMD z scores were determined with the same software, by using the Hologic-specific pediatric reference range.13
Anthropometric Measurements
Heights were determined by using a wall-mounted Harpendon stadiometer and weights by using a digital scale. Height, weight, and BMI SD scores were calculated by using National Health and Nutrition Examination Survey normal population data.14 Physical examinations, including Tanner staging, were performed by a single observer (Dr Olney).
Activity Scores
Weight-bearing activity scores were determined by using an interview-driven questionnaire (the Weight-Bearing Activity Questionnaire for Kids).15 This validated instrument estimates the minutes per week spent in specific weight-bearing activities. Each activity was previously assigned an empirically determined weighting factor for the intensity of activity. Score were calculated by multiplying the weekly time spent in each activity by the weighting factor for that activity and summing the results for all activities.
Nutritional Intakes
Nutritional intake was assessed with 3-day food logs. Subjects were asked to record all food and beverage intake for 2 weekdays and 1 weekend day. The logs were analyzed for total energy, protein, calcium, phosphorous, magnesium, vitamin D, sodium, and potassium intakes by a clinical dietician, using Nutritionist IV 3.5.2 diet analysis software (First DataBank, San Bruno, CA). Daily intakes for these nutrients were estimated by averaging the results over the 3 days. Dietary reference intakes for elements and vitamins from the Food and Nutrition Board of the Institute of Medicine of the National Academies were used to calculate percentages of the recommended dietary allowance or adequate intake (AI) for these nutrients.
Biochemical Analyses
Fasting blood samples were drawn for complete blood count, erythrocyte sedimentation rate, comprehensive chemistry panel, phosphorous, magnesium, intact parathyroid hormone (PTH), and thyrotropin analyses, which were performed by the local clinical laboratory. 25-Hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and anti-tissue transglutaminase antibody levels were assessed by Quest Diagnostics (Madison, NJ). Twenty-four-hour urine collections for calcium, phosphorous, and creatinine measurements and spot urine samples for urinalysis were obtained on an outpatient basis and were analyzed by the local laboratory. Renal calcium excretion was calculated by using the following equation: urinary calcium concentration x 24-hour urine volume/body weight. Renal tubular phosphate reabsorption per glomerular filtration rate was calculated by using the following equation: serum phosphate concentration – (urinary phosphate concentration x serum creatinine concentration/urinary creatinine concentration).16
Statistical Analyses
Interval data that were found to be normally distributed were compared by using Student's t tests. For the BMD z score data, our hypothesis was that children with a history of frequent fractures would have BMD z scores lower than those for control subjects. For this reason, 1-tailed tests were used. Two-tailed tests were used for all other analyses. Subgroup analysis comparing subjects with hypercalcuria was performed through analysis of variance, with Holm's pairwise, posthoc comparisons. Data that were not normally distributed were weight-bearing activity scores and dietary intakes. Mann-Whitney rank-sum tests were used for these analyses. Subgroup analyses of these data were performed with Kruskal-Wallis tests. Nominal data were analyzed through 
2 analysis. Linear correlations were determined by fitting a line to the data using least-squares methods and performing linear regression analysis. The software used for these analyses was Primer of Biostatistics 5.0 (McGraw-Hill Professional, New York, NY). Significance was assumed at P < .05.
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RESULTS |
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Study Subjects
Sixty-eight healthy children with a history of frequent fractures and 57 healthy control subjects were studied. The study groups were reasonably well matched, with no differences in the age, gender, race distribution, height SD score, or BMI SD score (Table 1). The control group showed a nonsignificant trend of being younger and having a larger proportion of prepubertal subjects. Table 2 shows the sites of the fractures experienced by the case group. The most common injuries were fractures of the distal radius and of the bones in the hand. Most of the case subjects had had only 2 fractures, whereas 1 subject had had 7 fractures (Table 3). The number of fractures was positively correlated with age (r2 = 0.165; P = .006).
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BMD Values
BMD values were lower for the case subjects, compared with the control subjects (Fig 1). Lumbar spine BMD z scores were –0.2 ± 1.1 (mean ± SD) for the case subjects and 0.2 ± 1.0 for the control subjects (P = .03). Whole-body BMD z scores were –0.4 ± 1.1 for the case subjects and 0.0 ± 0.9 for the control subjects (P = .006). Among the case subjects, 3 had BMD values below the expected range (defined as any BMD z score lower than –2).17 This proportion (4.4%) was not statistically different from that of the control subjects (1.8%; P = .8) or from that expected in a healthy population (2.3%; P = .8). This analysis had a power of 93%.
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Two of the case subjects with low BMD values were girls avoiding dairy, 1 because of a milk allergy and 1 because of a perceived association with migraine headaches. Calcium intakes were 65% and 66% of AI and vitamin D intakes were 30% and 20% of AI, respectively. One of those girls also had a weight-bearing activity score of 0. The other case subject with a low BMD value was a 16-year-old boy with short stature (relative to the range predicted by his midparental height), a history of delayed puberty, and a bone age SD score of –2.6. He was diagnosed as having constitutional delay of growth and maturation. Among the case subjects, there was no correlation between the numbers of fractures and BMD z scores (lumbar spine: r2 = 0.001; P = .8; whole body: r2 = 0.003; P = .7).
Weight-Bearing Activity Scores
The weight-bearing activity scores (determined with the Weight-Bearing Activity Questionnaire for Kids) were identical for the case and control subjects (Table 4). There were no correlations between weight-bearing activity scores and either fracture numbers (case subjects only) or BMD z scores (case subjects or control subjects) (r2 < 0.07 for all; P = not significant).
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Dietary Nutrient Intakes
There were no significant differences between the groups in dietary intake of calcium, phosphate, magnesium, or vitamin D (Table 4). Intake levels for the case subjects trended somewhat higher, probably because of a number of subjects who had been advised to increase their calcium and vitamin D intakes because of their fracture histories. For the combined groups, only 31% were meeting the AI for calcium and only 41% were meeting the AI for vitamin D.
For the case subjects, there were no correlations between any nutrient intake levels and fracture numbers (r2 < 0.07 for all; P = not significant). For both groups, there were no correlations between any nutrient intake levels and BMD z scores (r2 < 0.06 for all; P = not significant).
General Laboratory Results
For all of the components of complete blood counts, erythrocyte sedimentation rate, components of the comprehensive chemistry panel, and components of the urinalysis, there were no differences between the case and control groups (data not shown). There were no instances of abnormal erythrocyte sedimentation rate, thyrotropin levels, or anti-tissue transglutaminase antibody levels. Serum calcium, phosphate, magnesium, alkaline phosphatase, PTH, 25-hydroxy-vitamin D, and 1,25-dihydroxy-vitamin D levels were comparable between the case and control groups. With a 25-hydroxy-vitamin D cutoff value of <20 ng/mL for vitamin D insufficiency, 21% of case subjects and 18% of control subjects (P = not significant, 2 analysis) had vitamin D insufficiency. There were no instances of vitamin D deficiency (25-hydroxy-vitamin D level of <10 ng/mL).
For 1 case subject (and no control subjects), the 25-hydroxy-vitamin D level was in the insufficient range (15.5 ng/mL) and the PTH level was elevated (77 pg/mL; reference range: 9–52 pg/mL), which suggested functional vitamin D deficiency and secondary hyperparathyroidism. Serum calcium, phosphorous, and alkaline phosphatase levels were normal for that subject. Lumbar spine and whole-body BMD z scores (0.5 and 0.2, respectively) also were normal for that subject.
Renal Calcium Excretion
Daily renal calcium excretion, determined with 24-hour urine collections, did not differ between the groups. In both groups, however, we found large numbers of subjects with hypercalcuria (defined as daily urinary calcium excretion of >4 mg/kg per day).18,19 Thirteen (20%) of 66 case subjects and 13 (23%) of 57 control subjects had hypercalcuria. None of the subjects had a history of kidney stones. All other renal test results were normal, including serum creatinine levels and renal tubular phosphate reabsorption per glomerular filtration rate. Posthoc subgroup analyses were performed to identify other differences between the subjects with and without hypercalcuria (Table 5). 25-Hydroxy-vitamin D levels were higher for control subjects with hypercalcuria than for control subjects without hypercalcuria or case subjects with or without hypercalcuria (P = .007, analysis of variance; P = .001, Holm's pairwise comparisons). However, none of these levels was in the range suggesting vitamin D intoxication. Similarly, PTH levels were lower for control subjects with hypercalcuria than for control subjects without hypercalcuria or case subjects with or without hypercalcuria (P = .009, analysis of variance; P = .007, Holm's pairwise comparisons).
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Other comparisons included anthropometric measures, weight-bearing activity scores, dietary intakes, and laboratory values. There were no differences in dietary calcium, phosphate, magnesium, potassium, or protein intakes between the subgroups. Sodium intake trended higher for the case subjects with hypercalcuria (Table 5), but the difference did not reach significance. This analysis was underpowered for detection of this level of difference. 1,25-Dihydroxy-vitamin D levels were not different between the groups. However, the relationship between PTH and 1,25-dihydroxy-vitamin D levels differed between the groups (Fig 2). PTH and 1,25-dihydroxy-vitamin D levels had a positive linear correlation for the case subjects (r = 0.78, n = 12; P = .003) but a nonsignificant negative correlation for the control subjects (r = –0.40, n = 13; P = .2). A comparison of the 2 regressions showed that they were significantly different (F = 3.8; P = .04) and the slopes were significantly different (mean ± SE: 1.29 ± 0.33 vs –1.26 ± 0.87; P = .01).
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DXA information was then reexamined by segregating the subjects with hypercalcuria (Table 5 and Fig 3). Case subjects with hypercalcuria had substantially lower BMD z scores, compared with the other case subjects and with the control subjects with or without hypercalcuria. Furthermore, the reduced BMD for the case subjects with hypercalcuria accounted for virtually all of the reduced BMD found in the case group as a whole.
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DISCUSSION |
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The purpose of this study was to determine the extent to which otherwise healthy children with a history of multiple fractures should be evaluated for occult metabolic bone disease. We performed a comprehensive evaluation of bone health in a group of such children and a comparable group of children with no history of fractures. Among 68 children with fractures, we found 3 instances (4%) of (probable) calcium/vitamin D insufficiency and 1 case (1%) of constitutional delay in growth and maturation. We also identified 13 instances (20%) of hypercalcuria. Therefore, 25% of children presenting with frequent fractures were found to have an underlying abnormality that could potentially affect their bone health.
Our data confirm previous reports in several respects. Children with a history of fractures have lower BMD values than do those with no history of fractures,4,20 and children with milk avoidance are at risk for low BMD values and fractures.21 The majority of children and adolescents in our study were not meeting guidelines for calcium and vitamin D intakes, which is now a common finding. Unlike other studies,20 however, we failed to show that these dietary deficiencies had an impact on BMD values, and they were not associated with a history of multiple fractures. Similarly, we did not show an association between weight-bearing activity and BMD values, as shown previously.15 This may be the result of our relatively small sample size and the use of siblings in the control group.
The use of DXA for children involves continuing controversies. Although there is agreement that age, gender, race/ethnicity, height, weight, bone size, and sexual development should all be taken into account when DXA is used, there is no consensus on the best way to achieve this.22 For this study, we used reference data based on age and gender, which is the protocol most widely available to clinicians.
In this study, 21% of the children had hypercalcuria. The urinary calcium levels found in our study are likely to be somewhat underestimated, because of incomplete urine collections. None of the subjects reported a family history of kidney stones, and there were no history findings or laboratory results suggesting known causes of hypercalcuria, such as hyperthyroidism, glucocorticoid use, prolonged immobilization, vitamin D intoxication, hypercalcemia, primary hyperparathyroidism, hyperphosphaturia, or renal tubular acidosis. In addition, none of the subjects had hypercalcemia or hypocalcemia. Therefore, these children would be diagnosed as having idiopathic hypercalcuria (IH).23 None of the subjects had a history of urolithiasis, but the majority of children with IH do not. Our data suggest that higher sodium intake, which is a known risk factor for IH, might have been a contributing factor in these cases.
IH can be divided into 3 types on the basis of pathogenesis.24 Absorptive hypercalcuria is the result of excessive calcium absorption from the gastrointestinal tract, either through a direct increase in calcium absorption (eg, excessive calcium intake) or through excess 1,25-dihydroxy-vitamin D-mediated absorption. In such cases, the hypercalcuria is a physiologic response to prevent hypercalcemia. Feedback mechanisms result in (among other things) reduced PTH levels to limit further vitamin D activation. Renal hypercalcuria is the result of reduced calcium reabsorption in the kidney, either through a primary renal defect or through other factors, such as excessive sodium delivery to the kidneys. The resulting calcium loss results in higher PTH levels to draw calcium from bone and to increase vitamin D activation to prevent hypocalcemia. The third category is resorptive hypercalcuria, which results from excessive resorption of bone. This is the least common cause of IH. The incidence of IH has been increasing in industrialized countries, presumably because of changes in diet.25 Reduced BMD has been associated with IH in children,26–28 although there are no literature reports showing an association with increased fracture risk. Borghi et al29 showed that, in adults with urolithiasis, BMD was reduced in subjects with "diet-independent" hypercalcuria (generally renal hypercalcuria; mean lumbar spine BMD z score: –1.3) but not subjects with "diet-dependent" hypercalcuria (generally absorptive hypercalcuria; mean lumbar spine BMD z score: –0.3).
We compared children with and without IH and with and without a history of frequent fractures to identify other differences between these groups. For children with fractures and IH, there was a strong positive correlation between PTH and 1,25-dihydroxy-vitamin D levels, characteristic of renal IH.24 These children also had substantially reduced BMD. PTH was the primary driver of 1
-hydroxylation of 25-hydroxy-vitamin D in these children, and they had relative hyperparathyroidism, secondary to calcium loss from primary hypercalcuria. These problems then combined to reduce BMD and to increase the risk for fractures. In contrast, for the children with IH without a history of fractures, but 25-hydroxy-vitamin D levels were higher, PTH levels were lower, and there was no correlation between PTH and 1,25-dihydroxy-vitamin levels, all suggesting absorptive IH. In these children, PTH levels were reduced through excessive calcium absorption and were not the primary driver of vitamin D activation. In these children, BMD was not affected and there was no increased risk of bone fracture.
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CONCLUSIONS |
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We conclude that, although the incidences of IH were similar between the case and control groups, the causes of the IH were different. In the control subjects, the IH was primarily absorptive in nature and hence not associated with low BMD and subjects were not at increased risk for fracture. In the case subjects, the IH was primarily of renal pathogenesis, was associated with reduced BMD, and was a potential cause of increased risk for fractures. It is important to note that the urinary calcium findings in this study were identified posthoc and were not predicted a priori. Therefore, there is increased possibility that these associations occurred in our study through random chance. Furthermore, this was an observational case-control study. Imperfectly matched control subjects and unintentional selection bias might have played a significant role in our findings. Prospective studies are required for confirmation. Tannenbaum et al12 similarly found undiagnosed IH as a secondary contributor to osteoporosis in 9.8% of 173 postmenopausal women.
The recommended treatment for IH consists of a stepped regimen.23 Initially, children are placed on a diet limiting sodium to 2.0 to 2.4 g/day and adding fruits and vegetable to increase potassium intake to 3.0 to 3.5 g/day. If the hypercalcuria persists after 4 to 6 weeks, then potassium citrate is added at 1 to 1.5 mEq/kg per day. If hypercalcuria still persists (or the child does not tolerate the potassium citrate), then a thiazide diuretic is recommended. Limiting calcium in the diet of children with IH is not recommended, because it may place the child in negative calcium balance and increase the risk for reduced bone mineralization. Evaluation and management of hypercalcuria is best left in the hands of a physician experienced with the condition.
We found that, in children with a history of multiple fractures, hypercalcuria was associated with reduced BMD. We also identified 3 children with multiple fractures who had evidence of calcium and/or vitamin D insufficiency and a single child with delayed puberty. We conclude from these findings that, for children presenting with a history of multiple fractures, the appropriate evaluation might consist of 3 steps. The first step is a dietary history targeted at calcium and vitamin D intakes. For a child with a history suggesting insufficiency, 25-hydroxy-vitamin D and PTH levels and DXA would be appropriate. The second screening step is a physical examination to assess for pubertal delay. If suspected, DXA and referral to an endocrinologist for further evaluation would be appropriate. The third step is screening for hypercalcuria. This can be performed easily with evaluation of a random urine sample for calcium/creatinine ratio. If the ratio is elevated (ratio of >0.2),30 then DXA and in-depth evaluation for hypercalcuria are indicated. For children found to have reduced BMD, families should be counseled about a possible increased risk for future fractures until the underlying problem is adequately addressed.
In the absence of such findings on screening, DXA for children with a history of multiple fractures may not be needed. It should be noted that this proposed algorithm would not detect mild primary bone disorders (such as osteogenesis imperfecta type I) in children who present with fractures but show no other symptoms and have no family history. This situation is rare but must be considered by clinicians.
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ACKNOWLEDGMENTS |
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This study was funded by the Nemours Clinical Management Program.
We are grateful to the families that participated in this study, to Kristen Farnham for assistance with the nutritional assessments, and to Yvette Lui-Hing for her excellent administrative assistance.
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FOOTNOTES |
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Accepted Sep 20, 2007.
Address correspondence to Robert C. Olney, MD, Division of Pediatric Endocrinology, Nemours Children's Clinic-Jacksonville, Jacksonville, FL 32207. E-mail: rolney{at}nemours.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Children with frequent fractures are known to have lower BMD, and low BMD is associated with increased fracture risk in children. Previous studies have not examined the cause of low BMD in otherwise healthy children who have had multiple fractures.
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| What This Study Adds This study describes a previously unknown association between idiopathic hypercalcuria and low BMD in children with a history of frequent fractures. We also propose an approach for evaluating children with such a history.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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