Abstract
Background:
Longitudinal changes in bone health in children with intestinal failure (IF) are unclear. We aimed to better understand the trajectory of bone mineral status over time in children with IF and identify clinical factors that influence the trajectory.
Methods:
Clinical records of patients attending the Intestinal Rehabilitation Center of Cincinnati Children's Hospital Medical Center between 2012 and 2021 were reviewed. Children diagnosed with IF before age 3 years with at least two lumbar spine dual-energy x-ray absorptiometry scans were included. We abstracted information on medical history, parenteral nutrition, bone density, and growth. We calculated bone density z scores with and without adjustment for height z scores.
Results:
Thirty-four children with IF met inclusion criteria. Children were shorter than average with a mean height z score of −1.5 ± 1.3. The mean bone density z score was −1.5 ± 1.3 with 25 of the cohort having a z score < −2.0. After height adjustment, the mean bone density z score was −0.42 ± 1.4 with 11% below −2.0. Most dual-energy x-ray absorptiometry scans (60%) had a feeding tube artifact. Bone density z scores increased slightly with age and lower parenteral nutrition dependency and were higher in scans without an artifact. Etiologies of IF, line infections, prematurity, and vitamin D status were not associated with height-adjusted bone density z scores.
Conclusion:
Children with IF were shorter than expected for age. Deficits in bone mineral status were less common when adjusting for short stature. Etiologies of IF, prematurity, and vitamin D deficiency were not associated with bone density.
Keywords: dual energy x-ray absorptiometry (DXA), metabolic bone disease, pediatric intestinal failure, short bowel syndrome
INTRODUCTION
Pediatric intestinal failure is defined as the reduction of intestinal mass below that which can sustain life, resulting in dependence on parenteral support for a minimum of 60 days within a 74 consecutive day interval.1,2 Many pathologies may result in children developing intestinal failure, including short bowel syndrome, dysmotility disorders, and mucosal diseases/enteropathies affecting absorption. The majority of those with pediatric intestinal failure experience onset in early infancy, the most common cause being short bowel syndrome arising from necrotizing enterocolitis, gastroschisis, intestinal atresia, and volvulus.3 The duration of parenteral nutrition use among children with intestinal failure ranges from months to years. The goals of parenteral nutrition are to provide adequate nutrition while promoting the restoration of bowel function and gradually weaning parenteral nutrition support as able.3,4
The management of intestinal failure presents challenges, with morbidity arising from central line–associated bloodstream infections, thromboses, intestinal failure–associated liver disease, and metabolic bone disease.5 In adults receiving long-term parenteral nutrition, metabolic bone disease manifests as decreased bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry (DXA), and histologic features of incomplete osteoid mineralization on bone biopsies.6 Bone health in pediatric patients with intestinal failure is less clear; some studies found a deficit in BMD among patients with intestinal failure compared with reference populations7–12 whereas others did not.10,13,14 The etiology of intestinal failure may confer different risks for metabolic bone disease. Patients with congenital motility or enteropathy disorders have been found to have lower BMD z scores than patients with short bowel syndrome7 in some but not all studies.9,11,12 Inconsistency in findings may be related to different definitions of intestinal failure and “low BMD,” age of BMD measurement, receipt of parenteral nutrition at BMD measurement, and small sample sizes.
The interpretation of BMD results in children requires consideration of age, sex, and African ancestry.15 BMD increases with age, and the age-related BMD trajectories differ between boys and girls and between children with and without African ancestry.16 In addition, growth status must be considered, as DXA is a two-dimentional imaging technique and is subject to size-related artifacts where smaller bones appear to have lower BMD than larger bones. Failure to account for short stature for age results in an overestimation of bone mineral deficits.15 A large multicenter study of pediatric intestinal patients receiving parenteral nutrition found that about a third had short stature, defined as a height-for-age z score (HAZ) < −2.17 Some,7,11,13,18,19 but not all8–10,20,21 studies accounted for short stature when interpreting BMD measures in children with intestinal failure.
There is sparse information on longitudinal changes in BMD over time in children with intestinal failure. The effects of parenteral nutrition duration and nutrition intake, including vitamin D supplementation or status, have been conflicting,8,9,11,12,18 whereas improvements in growth were positively associated with BMD.11,12,18
There is a need to better understand the trajectory of bone mineral status over time in children with intestinal failure and to identify clinical factors that influence the trajectory to inform bone health monitoring strategies. Our objectives were (1) to assess the longitudinal changes in BMD z scores in young children with intestinal failure when adjusting for height z score and (2) to identify clinical factors that impact the trajectory of BMD z scores with age. Clinical variables of interest were intestinal failure etiology (necrotizing enterocolitis, gastroschisis, or atresia), prematurity, small bowel transplant, presence of comorbidities (central line–associated bloodstream infections or cholestasis), parenteral nutrition dependency, and vitamin D status.
MATERIALS AND METHODS
Study design and participants
We performed a longitudinal retrospective cohort study. We systematically reviewed the electronic health record of patients seen in the Intestinal Rehabilitation Center at Cincinnati Children's Hospital Medical Center between January 2012 and December 2021 with a history of intestinal failure. We identified children that had lumbar spine DXA scans performed at two or more time points from our Intestinal Rehabilitation Center registry. We included children whose diagnosis of intestinal failure was the result of intestinal dysfunction or disease that occurred prior to age 3 years. Children were excluded if they were older than age 10 years at their first DXA scan to minimize the influence of pubertal changes in bone mineral accrual. Other exclusions were diagnosis of medical conditions known to affect bone density or if there was insufficient information in the medical record regarding intestinal failure history. The Cincinnati Children's Hospital Medical Center Institutional Review Board classified this protocol (#2021-0832) as exempt and waived the need for participant consent.
Data collection
We abstracted information on demographics, medical history, diagnoses, and intestinal anatomy for characterization of our sample. For patients who underwent bowel surgery, we collected information on the total length of residual small bowel, small bowel continuity with the colon, degree of colon remaining, and presence of the ileocecal valve.
Between 2012 and 2021, the standard practice in the Intestinal Rehabilitation Center was to obtain a lumbar spine DXA scan using a Hologic, Inc, densitometer after age 3 years. The acquisition of follow-up scans was at the discretion of the clinical provider. Our primary outcome was BMD z scores adjusted for the HAZ. BMD z scores account for expected differences in BMD according to age, sex, and African ancestry with use of reference data from healthy samples of children ages 1 to <5 years16 and children ages ≥5 to 20 years.22 We corrected BMD z scores for the HAZ using published equations.16,22 All DXA scans were visually reviewed, and the location of artifacts, such as feeding tubes, was noted as overlying bone, soft tissue, or both. BMD z scores of ≤−2.0 were considered “low BMD” and BMD z scores >−2.0 were considered to be within the expected range for age.15
We abstracted information within 3 months of each DXA scan on factors that might affect BMD. Growth status measures included weight, height, body mass index (BMI), and respective z scores based on the Centers for Disease Control growth reference. Nutrition intake included enteral nutrition (energy from tube feeds) and parenteral nutrition (macronutrients and frequency). For those receiving parenteral nutrition, we calculated the level of parenteral nutrition dependency using the ratio of nonprotein energy intake to resting energy expenditure derived using Schofield equations.23 The parenteral nutrition dependency index was classified as mild, high, and very high for nonprotein energy intake/resting energy expenditure ratios of <80%, 80%–120%, and >120%, respectively.23 Laboratory measures included serum calcium, serum phosphorus, serum albumin, total and direct bilirubin, gamma-glutamyl transferase, alkaline phosphatase, and serum 25-hydroxy vitamin D concentrations. Cholestasis was defined as a direct bilirubin value >2.0 mg/dl. If a direct bilirubin value was not present but the total bilirubin was <1.2 mg/dl, then they were deemed to not have cholestasis. Vitamin D levels were classified as deficient (<20 ng/ml), insufficient (20–30 ng/ml), or sufficient (>30 ng/ml). We collected information on the number of central line–associated bloodstream infections and the use of supplements (yes/no) containing calcium, phosphorous, sodium, or vitamin D.
Statistical analysis
Data were analyzed using SAS, version 9.4 (SAS Institute). Continuous data were expressed as median, 25th and 75th percentiles and range, or mean ± SD. Categorical data were expressed as counts and percentages. We compared BMD between those with two vs those with three to four DXA scans with Mann-Whitney U tests. We compared study proportions with 2.5%, the expected value associated with −2 SDs, with binomial proportion tests. We used multivariable generalized linear mixed effects models to determine the trajectory of BMD z scores with age and to identify clinical factors associated with BMD z scores. Clinical variables considered were intestinal failure etiology (necrotizing enterocolitis, atresia, or gastroschisis), preterm status, receipt of a small bowel transplant, comorbidities (line infections or cholestasis), parenteral nutrition dependency index, and vitamin D status and supplement intake. Variables were tested using forwards and backwards elimination and were kept in the model if P < 0.10 given the exploratory nature and small sample size of this study. We repeated analyses, including a variable for feeding tube artifacts. Because it is unclear whether a feeding tube was a marker of sicker children and on the causal pathway for low bone density, we report results both ways.
RESULTS
In total, 1495 children were managed by the Intestinal Rehabilitation Center between January 2012 and December 2021, and 132 had a history of intestinal failure. Eighty-one patients with intestinal failure had two or more DXA scans within the study period. Of these, we excluded 47 children: those with an intestinal failure etiology because of a nongastrointestinal disorder (eg, metabolic disorders, immune dysregulation syndromes, or bone marrow or solid organ transplants; n = 21); those with an age at intestinal failure diagnosis >3 years (n = 17); those with an age >10 years at the first DXA scan (n = 3); those with an underlying primary bone disorder (n = 1); those with insufficient data in the medical record (n = 3); and those with different DXA scan types (not lumbar spine scan) (n = 2). The final sample included 34 children.
The study sample was half female and majority non-Hispanic White. On average, children were diagnosed with intestinal failure at age 2 months, and most were born prematurely (<37 week gestation) (Table 1). The most common cause of intestinal failure was gastroschisis, followed by intestinal atresia and necrotizing enterocolitis. Most participants (28/33) had some degree of small bowel resection, and most (31/34) had achieved continuity of their gastrointestinal tract (reconnection of the small bowel to colon) by the time of the first DXA scan. About half of the children had a fully intact colon. Seven children had a small bowel transplant.
TABLE 1.
Characteristics of study participants with intestinal failure.
| Characteristic | N = 34 |
|---|---|
| Age at intestinal failure diagnosis, months | 2 (2–3); [2, 35] |
| Female sex | 17 (50%) |
| Race | |
| White | 25 (74%) |
| Black/African American | 5 (15%) |
| Other | 4 (12%) |
| Ethnicity (non-Hispanic/non-Latino) | 33 (97%) |
| Gestational age, weeks | 35 (34–36); [26, 41] |
| Preterm <37 weeks (n = 33) | 25 (76%) |
| History of any small bowel resection (n = 33) | 28 (85%) |
| Gastrointestinal tract in continuity | 31 (91%) |
| Presence of ileocecal valve | 10 (29%) |
| History of any colon resection | 15/33 (45%) |
| Amount of colon remaining | |
| All | 19 (56%) |
| Partial | 12 (35%) |
| None | 3 (9%) |
| Amount of small bowel remaining, cm (n = 25) | 59.0 (38.0–90.0); [12.5, 235.0] |
| History of small bowel transplant | 7 (21%) |
| Medical diagnoses associated with intestinal failurea | |
| Gastroschisis | 17 (50%) |
| Atresia | 11 (32%) |
| Necrotizing enterocolitis | 8 (24%) |
| Volvulus | 6 (18%) |
| Hirschsprung | 4 (12%) |
| Pseudo-obstruction | 4 (12%) |
| Other | 3 (9%) |
| History of fracture | 1 (3%) |
Note: Data are presented as median (25th–75th percentiles), [minimum, maximum], or n (%).
The sum exceeds 100%, as some children may have had more than one diagnosis.
By design, all 34 children included had at least two lumbar spine DXA scans; of those, 21 children had three scans and 11 had four scans. The median age was 3.4 years (range, 3.0–8.4 years) at the first DXA scan and 5.4 years (range, 3.8–11.8 years) at the second scan. The median duration between the first and second scans was 1.5 years (range, 0.7–8.6 years).
We tabulated growth status, nutrition intake, and laboratory characteristics according to age categories (Table 2). Some children had two observations within an age category, and these were treated as independent observations for descriptive purposes. The median weight-for-age z score for each age interval ranged from −1.4 to −0.5, and the median BMI z score ranged from −0.3 to 0.8. Children were uniformly short at all ages, with a mean overall HAZ of −1.5 ± 1.3, and 25% (25 of 100) of measurements had an HAZ < −2. About half the children ages 3–5 years were receiving parenteral nutrition at the time of their DXA scan; the percentage at older ages varied. Among those receiving parenteral nutrition, the median parenteral nutrition dependency index was in the mild dependency range (score < 80%) with little variation in parenteral nutrition dependency index with age (Table 2). The prevalence of vitamin D deficiency ranged from 0% (0/15) to 19% (4/21) across age groups, and almost half of the children consumed vitamin D supplements.
TABLE 2.
Growth status, nutrition intake, and laboratory characteristics by age category.
| Age 3 to <4 y | Age 4 to <5 y | Age 5 to <7 y | Age 7 to <9 y | Age >9 y | |
|---|---|---|---|---|---|
| n = 23 | n = 22 | n = 27 | n = 17 | n = 11 | |
| Age at DXA, y | 3.1 (3.1–3.5) | 4.5 (4.2–4.8) | 5.8 (5.4–6.5) | 7.9 (7.7–8.4) | 10.3 (9.7–11.1) |
| [3.0, 3.8] | [4.1, 5.0] | [5.1, 7.0] | [7.1, 9.0] | [9.3, 14.2] | |
| Weight‐for‐age z score | −0.5 (−1.1 to 0.0) | −0.6 (−1.4 to −0.2) | −0.6 (−1.1 to −0.3) | −0.7 (−1.4 to −0.4) | −1.4 (−1.9 to −0.3) |
| [−1.8, 0.3] | [−2.6, 2.3] | [−2.7, 1.6] | [−2.2, 1.1] | [−2.3, 1.0] | |
| Height‐for‐age z score | −1.3 (−2.6 to −0.6) | −1.5 (−2.1 to −0.7) | −1.4 (−1.9 to −0.6) | −1.8 (−2.4 to −1.3) | −1.6 (−2.5 to −1.5) |
| [−2.8, 0.3] | [−4.1, 1.3] | [−4.8, 2.1] | [−4.5, 1.9] | [−3.8, −0.5] | |
| Body mass index z score | 0.8 (−0.2, 1.1) | 0.6 (0.0, 1.6) | 0.8 (−0.4, 1.1) | 0.4 (−0.1, 1.3) | −0.3 (−1.1, 0.6) |
| [−2.5, 1.9] | [−1.4, 2.3] | [−2.5, 2.0] | [−1.6, 2.0] | [−1.3, 1.9] | |
| Body mass index z score category | |||||
| Mild (−1 to >-2) | 0 (0%) | 1 (4.5%) | 3 (11.1%) | 2 (11.8%) | 4 (36.4%) |
| Moderate (−2 to >-3) | 1 (4.3%) | 0 (0%) | 1 (3.7%) | 0 (0%) | 0 (0%) |
| Ambulatory | 21/22 (95%) | 21 (95%) | 27 (100%) | 16/16 (100%) | 11 (100%) |
| Receiving enteral tube feeds | 19 (83%) | 18 (82%) | 20 (74%) | 12 (71%) | 5 (45%) |
| Receiving parenteral nutrition | 12 (52%) | 11 (50%) | 11 (41%) | 5 (29%) | 5 (45%) |
| Parenteral nutrition frequency, days/week | 7 (7–7) | 7 (7–7) | 7 (7–7) | 7 (7–7) | 7 (7–7) |
| [7, 7] | [4.7, 7] | [5, 7] | [7, 7] | [7, 7] | |
| Receiving lipid in parenteral nutrition | 9/12 (75%) | 7/11 (64%) | 8/11 (73%) | 3/5 (60%) | 5/5 (100%) |
| Lipid frequency, days/week | 7 (4–7) | 7 (7–7) | 4 (3–7) | 4.7 (1.3–7) | 3 (3–7) |
| [1.3, 7] | [4.7, 7] | [1.2, 7] | [1.3, 7] | [2.3, 7] | |
| Lipid type | |||||
| Intralipid only | 9/9 (100%) | 6/7 (86%) | 6/8 (75%) | 3/3 (100%) | 4/5 (80%) |
| SMOF only | 0/9 (0%) | 0/7 (0%) | 0/8 (0%) | 0/3 (0%) | 1/5 (20%) |
| Omegaven only | 0/9 (0%) | 0/7 (0%) | 1/8 (12.5%) | 0/3 (0%) | 0/5 (0%) |
| SMOF + Omegaven | 0/9 (0%) | 1/7 (14%) | 0/8 (0%) | 0/3 (0%) | 0/5 (0%) |
| Intralipid + SMOF | 0/9 (0%) | 0/7 (0%) | 1/8 (12.5%) | 0/3 (0%) | 0/5 (0%) |
| Parenteral nutrition dependency index, % | 75 (37–108) | 60 (39–72) | 68 (38–87) | 68 (35–74) | 68 (57–87) |
| [14, 122] | [9, 115] | [9, 122] | [16, 141] | [49, 112] | |
| <80% (mild) | 6/12 (50%) | 10/11 (91%) | 8/11 (73%) | 4/5 (80%) | 3/5 (60%) |
| 80%–120% (high) | 5/12 (42%) | 1/11 (9%) | 2/11 (18%) | 0/5 (0%) | 2/5 (40%) |
| >120% (very high) | 1/12 (8%) | 0/11 (0%) | 1/11 (9%) | 1/5 (20%) | 0/5 (0%) |
| Energy from dextrose, % of total kcal | 69 (64–79) | 75 (60–100) | 71 (56–77) | 60 (57–84) | 56 (46–63) |
| [61, 100] | [39, 100] | [39, 100] | [45, 87] | [36, 72] | |
| n = 12 | n = 11 | n = 11 | n = 5 | n = 5 | |
| Energy from protein, % of total kcal | 13 (12–16) | 12 (0–16) | 14 (10–16) | 16 (13–17) | 16 (12–16) |
| [0, 19] | [0, 18] | [0, 23] | [9, 21] | [10, 18] | |
| n = 12 | n = 11 | n = 11 | n = 5 | n = 5 | |
| Energy from lipid, % of total kcal | 14 (5–23) | 14 (0–26) | 17 (0–28) | 26 (0–31) | 26 (25–38) |
| [0–27] | [0–43] | [0–46] | [0–34] | [12–54] | |
| n = 12 | n = 11 | n = 11 | n = 5 | n = 5 | |
| Serum 25‐hydroxy vitamin D, ng/ml | 30.5 (25.3–44.4) | 33.7 (27.6–42.6) | 33.8 (25.7–43.2) | 33.8 (24.9–41.0) | 31.4 (22.0–39.7) |
| [7.3, 60.3] | [13.5, 71.0] | [18.8, 131.0] | [21.8, 55.6] | [10.0, 83.4] | |
| Vitamin D statusa | |||||
| Deficient | 2/22 (9%) | 4/21 (19%) | 2/24 (8%) | 0/15 (0%) | 2 (18%) |
| Insufficient | 8/22 (36%) | 5/21 (24%) | 8/24 (33%) | 5/15 (33%) | 3 (27%) |
| Sufficient | 12/22 (55%) | 12/21 (57%) | 14/24 (58%) | 10/15 (67%) | 6 (55%) |
| Using vitamin D supplement | 9 (39%) | 11 (50%) | 13 (48%) | 7 (41%) | 5 (45%) |
| Serum calcium level, mg/dl | 8.9 (8.6–9.4) | 9.2 (8.5–9.5) | 8.9 (8.4–9.1) | 9.1 (8.6–9.6) | 9.1 (8.7–9.8) |
| [8.0, 9.9] | [8.2, 9.9] | [7.4, 10.1] | [8.2, 10.5] | [8.2, 11.1] | |
| n = 24 | n = 14 | ||||
| Corrected serum calcium level, mg/dl | 9.4 (9.1–9.6) | 9.3 (9.0–9.7) | 9.2 (9.0–9.6) | 9.4 (9.3–9.6) | 9.1 (9.0–9.7) |
| [8.4, 10.4] | [8.4, 10.2] | [7.6, 10.5] | [8.7, 10.2] | [8.4, 10.6] | |
| n = 21 | n = 24 | n = 14 | |||
| Low serum calcium levelb | 3 (13%) | 2 (9%) | 4/24 (17%) | 1/14 (7%) | 1 (9%) |
| Low corrected serum calcium level | 0 (0%) | 0/21 (0%) | 1/24 (4%) | 0/14 (0%) | 0 (0%) |
| Using calcium supplement | 3 (13%) | 4 (18%) | 9 (33%) | 4 (24%) | 0 (0%) |
| Serum albumin level, g/dl | 3.5 (3.1–3.9) | 3.6 (3.3–3.9) | 3.5 (2.9–3.8) | 3.7 (3.1–4.2) | 3.7 (3.5–4.6) |
| [2.3, 4.3] | [2.2, 4.6] | [1.7, 4.4] | [2.5, 4.6] | [3.0, 4.9] | |
| Low serum albumin levelc | 10 (43%) | 10/21 (48%) | 12/25 (48%) | 6/16 (38%) | 2 (18%) |
| Serum phosphorus level, mg/dl | 4.8 (4.2–5.3) | 4.7 (4.2–4.9) | 4.3 (3.9–4.6) | 4.7 (4.3–5.3) | 4.9 (4.3–5.8) |
| [2.1, 6.7] | [3.6, 6.8] | [1.3, 6.0] | [4.0, 5.6] | [2.9, 6.8] | |
| n = 21 | n = 25 | n = 16 | |||
| Low serum phosphorus leveld | 3 (13%) | 3/21 (14%) | 7/25 (28%) | 0/16 (0%) | 1 (9%) |
| Alkaline phosphatase, unit/L | 281 (161–359) | 214 (183–237) | 235 (152–292) | 221 (118–288) | 198 (155–253) |
| [101, 618] | [99, 801] | [104, 842] | [95, 339] | [136, 356] | |
| Low alkaline phosphatasee | 1 (4%) | 1 (5%) | 1/25 (4%) | 3/16 (19%) | 0 (0%) |
| Total bilirubin, mg/dl | 0.2 (0.2–0.3) | 0.3 (0.2–0.4) | 0.3 (0.2–0.5) | 0.3 (0.2–0.4) | 0.4 (0.3–0.4) |
| [0.0, 5.7] | [0.1, 5.2] | [0.1, 10.6] | [0.1, 0.5] | [0.2, 0.5] | |
| n = 25 | n = 16 | ||||
| Gamma‐glutamyl transferase, unit/L | 23 (14–66) | 16 (10–32) | 13 (9–34) | 12 (7–26) | 15 (13–18) |
| [7, 228] | [5, 287] | [3, 259] | [5, 77] | [6, 33] | |
| n = 21 | n = 17 | n = 22 | n = 14 | n = 9 | |
| Concurrent cholestasisf | 1 (4%) | 1 (5%) | 2 (7%) | 0 (0%) | 0 (0%) |
| Patients with line infections | 7 (30%) | 2 (9%) | 5 (19%) | 2 (12%) | 3 (27%) |
| Number of line infections | |||||
| 1 | 6/7 (86%) | 1/2 (50%) | 5/5 (100%) | 2/2 (100%) | 3/3 (100%) |
| 2 | 1/7 (14%) | 1/2 (50%) | 0/5 (0%) | 0/2 (0%) | 0/3 (0%) |
| Using sodium supplement | 4 (17%) | 3 (14%) | 2 (7%) | 2 (12%) | 0 (0%) |
| Corticosteroid use (hydrocortisone 10 mg or prednisone 2.5 mg daily for >30 days) | 0 (0%) | 1 (5%) | 2 (7%) | 2 (12%) | 0 (0%) |
| Protein pump inhibitor use >1 year | 1 (4%) | 3 (14%) | 2 (7%) | 2 (12%) | 0 (0%) |
Note: Data are presented as n (%), median (25th-75th percentiles), or [minimum, maximum].
Abbreviations: DXA, dual‐energy x‐ray absorptiometry; SMOF, soy oil, medium‐chain triglycerides, olive oil, and fish oil fat emulsion.
Deficient is defined as <20 ng/ml, insufficient as 20–30 ng/ml, and sufficient as >20 ng/ml.
A low serum calcium level was <8.3 mg/dl.
A low serum albumin level was <3.5 g/dl.
A low serum phosphorus level was <4.0 mg/dl.
A low alkaline phosphatase value was <111 units/L.
Cholestasis and direct bilirubin were >2.0 mg/d.
BMD results by age group are shown in Table 3. There was a visible artifact (feeding tube or central line tubing) on 60 out of 100 DXA scans, and the percentage affected was lowest in the oldest age group. Artifacts were mostly in the soft tissue. BMD z scores (not adjusted for height) had an overall mean of −1.12 ± 1.57. HAZ-adjusted BMD z scores were higher, and the overall mean was −0.43 ± 1.45 (n = 100). Overall, 25 out of 100 (95% CI, 16.5%–33.5%) scans had a BMD z score ≤−2.0 (not adjusted for height), whereas only 11 out of 100 (95% CI, 4.9%–17.1%) had a low HAZ-adjusted BMD z score. Both proportions for low BMD z score were significantly >2.5% (P < 0.05), which is the expected percentage of z scores < −2 in a normal distribution. The median (25th, 75th percentiles) HAZ-adjusted BMD z score at the second DXA scan did not significantly differ (P = 0.75) between children with three or four scans (−0.62 [−1.9, 0.73]) vs just two scans (−0.12 [−0.81, 0.21]).
TABLE 3.
Lumbar spine bone mineral density by age category.
| Age 3 to <4 y | Age 4 to <5 y | Age 5 to <7 y | Age 7 to <9 y | Age >9 y | |
|---|---|---|---|---|---|
| n = 23 | n = 22 | n = 27 | n = 17 | n = 11 | |
| Artifact on DXA | 14 (61%) | 14 (64%) | 18 (67%) | 10 (59%) | 4 (36%) |
| Location of artifact | |||||
| Bone | 2/14 (14%) | 1/14 (7%) | 2/18 (11%) | 0/10 (0%) | 0/4 (0%) |
| Soft tissue | 11/14 (79%) | 12/14 (86%) | 16/18 (89%) | 9/10 (90%) | 4/4 (100%) |
| Bone and soft tissue | 1/14 (7%) | 1/14 (7%) | 0/18 (0%) | 1/10 (10%) | 0/4 (0%) |
| BMD z score | −0.97 (−2.03 to −0.32) | −1.37 (−2.45 to 0.06) | −1.12 (−2.48 to 0.22) | −0.78 (−1.46 to −0.35) | −0.93 (−1.67 to 0.78) |
| [−4.25, 1.71] | [−4.83, 1.19] | [−4.08, 1.65] | [−3.31, 1.60] | [−3.70, 2.10] | |
| Low BMDa | 6 (26%) | 8 (36%) | 7 (26%) | 2 (12%) | 2 (18%) |
| HAZ‐adjusted BMD z score | −0.62 (−1.61 to 0.39) | −0.91 (−1.92 to 0.54) | −0.67 (−1.39 to 0.25) | −0.21 (−0.55 to 0.65) | 0.27 (−0.84 to 1.33) |
| [−3.52, 2.68] | [−4.27, 1.90] | [−2.52, 2.56] | [−2.32, 2.49] | [−2.84, 2.90] | |
| Low HAZ‐adjusted BMD z scorea | 3 (13%) | 5 (23%) | 1 (4%) | 1 (6%) | 1 (9%) |
Note: Data are presented as median (25th–75th percentiles), [minimum, maximum], or n (%).
Abbreviations: BMD, bone mineral density; DXA, dual‐energy x‐ray absorptiometry; HAZ, height‐for‐age z score.
Low BMD defined as a BMD z score ≤ −2.0.
Trends in HAZ-adjusted BMD z scores by age (ie, over time) are illustrated using spaghetti plots (Figure 1), with panels illustrating the trajectories for (A) the presence of a soft tissue artifact in the scan, (B) necrotizing enterocolitis diagnosis, (C) preterm status, and (D) small bowel transplant. In mixed effects regression analyses, we found evidence that HAZ-adjusted BMD z scores improved slightly (β = 0.16/month, P = 0.001) as children aged (ie, over time). Children who had an artifact in the soft tissue region of the DXA scan had lower BMD z scores (β = −0.44, P = 0.052) than children without an artifact when adjusting for the child's age. We found no statistical association between the etiology of intestinal failure (necrotizing enterocolitis diagnosis, atresia, or gastroschisis), prematurity, or receipt of a small bowel transplant and HAZ-adjusted BMD z scores (all P > 0.20) controlling for the child's age, with or without controlling for soft tissue artifacts. Similarly, central line–associated bloodstream infections were not associated with HAZ-adjusted BMD z scores (P > 0.20); there were too few cases of cholestasis (n = 4) for meaningful analyses. A higher parenteral nutrition dependency index category was potentially associated with lower BMD z scores (β = −0.24/category, P = 0.11) when the variable for soft tissue artifact was not included in the regression model; it was not significant (P > 0.20) when soft tissue artifact was in the model. Vitamin D status and vitamin D supplement intake were not associated with BMD z scores (P > 0.20), with or without controlling for soft tissue artifacts.
FIGURE 1.
Spaghetti plot trajectories of HAZ-adjusted BMDZs with age. Each line represents one child with intestinal failure. (A) This panel distinguishes those with a soft tissue artifact. (B) This panel distinguishes those who had NEC. (C) This panel distinguishes those born preterm. (D) This panel distinguishes those who had a small bowel transplant. BMDZ, bone mineral density z score; HAZ, height-for-age z score; NEC, necrotizing enterocolitis.
DISCUSSION
In our longitudinal study of 34 children with a history of intestinal failure diagnosed during infancy, we found that the children were adequately nourished based on weight and BMI z scores; mild malnutrition based on BMI z score was observed in only 10 out of the 100 observations, with moderate malnutrition even more uncommon (2 out of 100 observations). However, children were of short stature that persisted over time. The overall mean BMD at all time points was lower than expected for age, and 25% (25/100) of observations had low BMD z scores. Importantly however, HAZ-adjusted BMD z scores were higher, and only 11% (11/100) had low HAZ-adjusted BMD z scores. These findings illustrate the importance of accounting for the HAZ when interpreting BMD to not falsely raise the prevalence of low bone density, particularly in populations who are at risk for short stature. Although deficits in BMD were evident, bone health morbidity was not widespread. BMD z scores improved slightly with age but remained lower than expected by midchildhood, underscoring the need for additional research to identify interventions to optimize bone density in these patients.
Our finding of a higher-than-expected prevalence of short stature in pediatric patients with intestinal failure has been found by others.10,11,13,24 In a multicenter study of pediatric patients with intestinal failure receiving parenteral nutrition (n = 558), about one-third had short stature (HAZ < −2), and the HAZ was negatively associated with the time receiving parenteral nutrition and degree of parenteral nutrition dependency.17 The causes of short stature in these patients warrants investigation, especially the role of chronic malnutrition, persistent inflammation, and micronutrient deficiencies.
We aimed to identify clinical predictors of BMD that may inform bone health screening strategies. However, there were no significant differences in BMD z scores according to prematurity status, diagnosis of necrotizing enterocolitis, atresia, gastroschisis, or receipt of a small bowel transplant. This may, in part, be explained by standardized care plans based on monitoring micronutrient status, stool output, and weight gain to promote optimal long-term outcomes. The small sample size of subgroups, however, limited our power to detect differences among groups.
Central line–associated bloodstream infections and cholestasis, known morbidities in pediatric intestinal failure, were infrequent in our sample. Likewise, vitamin D deficiency was not common with the median serum 25-hydroxy vitamin D concentration around 30.0 ng/ml. The low frequency of comorbidities and the good vitamin D status likely reflect family education in line care, structured medical response for suspected infections, active weaning of parenteral nutrition with enteral advancements, and careful monitoring of micronutrient imbalances.19 Central line–associated bloodstream infections and vitamin D status were not associated with HAZ-adjusted BMD z scores in our sample.
HAZ-adjusted BMD z scores were lower in children with a feeding tube artifact in the soft tissue of the DXA field compared with children without an artifact. It is unclear if the lower BMD was related to the changes in attenuation between soft tissue and bone that are inherently altered with the presence of any artifact,25 or if the lower BMD z scores reflect a sicker population still requiring a feeding tube for nutrition support. A lower parenteral nutrition dependency index would indirectly inform us that a child was making more progress in enteral autonomy. We found suggestive evidence that lower parenteral nutrition dependency was associated with higher HAZ-adjusted BMD z scores when not adjusting for a feeding tube artifact.
Our study is limited by its small sample size and statistical power to detect differences. Given the small number of pediatric patients with intestinal failure at individual centers, future studies may require multiple centers to yield a larger sample size. Most children in our sample were reported as White and non-Hispanic. Thus, our results may not be translatable to all children, especially those experiencing different social, cultural, and economic environments or genetic endowments. DXA scans were not obtained at standard intervals, and it is unknown whether the study sample is reflective of all patients with intestinal failure. Because of our sample selection process, we do not know if those who did not have two DXA scans differed from those who had at least two scans. Because the frequency of follow-up scans was at the discretion of the clinical provider, it is possible that DXA scans were obtained more often for those who were perceived as being at greater risk of bone deficits. Indeed, the HAZ-adjusted BMD z score at the second DXA scan was slightly lower in patients with three to four DXA scans compared with those with only two scans, although the difference was not statistically significant. As additional scans generally correspond to older ages, this potential bias could have resulted in underestimating improvements in bone health with age. A standardized bone health assessment regimen in future studies would address this concern. As many patients were not receiving parenteral nutrition at the time of their DXA scan, and those still receiving parenteral nutrition had a low dependency index, we cannot assess the extent to which parenteral nutrition dependency and composition affected bone health.
Unfortunately, we did not have information on bone loading physical activity or lean body mass, both of which are positively associated with BMD in children.26 Children with intestinal failure receiving parenteral nutrition have been reported to have reduced physical activity27,28 and lower lean mass despite similar body weight compared with their peers.21,28–30 Additional research in this area is needed to optimize the bone health of children with intestinal failure. Other factors that may increase the risk of metabolic bone disease in children with intestinal failure include chronic malnutrition, insufficient calcium intake, challenges in providing optimum nutrition support because of parenteral nutrition shortages, aluminum toxicity, and excess sodium delivery leading to calcinuria. We were unable to investigate these in this retrospective study.
Despite these limitations, our findings provide reassurance that bone health is not uniformly compromised in children with intestinal failure receiving current clinical management practices, though the prevalence of low BMD remains higher than expected in a healthy cohort. Given the short stature of children with intestinal failure, it is critical that BMD z scores account for height status so that bone deficits are not overstated. The effects of feeding tubes on BMD interpretation are important to consider, as they can affect the BMD value. Alternatives include removing the feeding tube, if feasible, just before obtaining a scan or obtaining a whole-body DXA scan instead, as feeding tube artifacts have less impact on the results of whole-body scans as a feeding tube affects a much smaller portion of the region scanned. Whole-body scans may also provide insight into the accretion of fat-free mass.
CLINICAL RELEVANCY STATEMENT.
Parenteral nutrition has allowed life-sustaining advantages for children with intestinal failure yet raises new challenges in morbidity. In adults, prolonged parental nutrition is associated with metabolic bone disease. In pediatrics, the long-term impact of chronic parenteral nutrition and intestinal failure on bone is less clear. Our study suggests that children with intestinal failure have short stature and only a slight deficit in bone mineral density over time after correcting for short stature. This reassuring clinical outcome may reflect receiving current standards in medical management with active weaning from parenteral support.
Footnotes
CONFLICT OF INTEREST STATEMENT
None declared.
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