Should Pediatric Patients with Celiac Disease Be Screened for Low Bone Mineral Density?

A recent retrospective study (J Webster et al. Clin Gastroenterol Hepatol 2019; 17: 1509-14) with 673 children with newly diagnosed (biopsy-proven) celiac disease (CD) (median age 10.6 y) evaluated DXA studies at time of diagnosis.

Key findings:

  • Approximately 7% (n=46) had a low lumbar spine areal bone mineral density (aBMD) z-score (less than -2)
  • Of those with abnormal aBMDs, 18 had repeat studies.  11 of 18 normalized after institution of dietary management. Mean time for repeat DXA was 2.3 years
  • Of note, mean BMI z-score at time of repeat DXA was 0.005 (this includes 90 who had followup studies after a normal baseline DXA).
  • Low body mass index (BMI) with z-score of -0.4 identified a >10% risk of an abnormal aBMD

The authors acknowledge than DXA screening is controversial.  The current study’s strength is its large size.  Limitations include the inability to correlate with clinical factors including adherence to a gluten-free diet.

My take:

  1. Based on this study, it is likely that only 2-3% of pediatric patients with celiac disease will have a persistently abnormal DXA after institution of a gluten free diet for 2 years; it is likely that even more will improve with time if receiving appropriate dietary treatment.
  2. I am not likely to recommend obtaining a baseline DXA study in pediatric patients with newly diagnosed celiac disease; the treatment for low bone mineral density in the setting of celiac disease is the same as for all children with celiac disease.  If one were inclined to look for low BMD, optimal timing would likely be AFTER being adherent on a gluten free diet for at least two years particularly in those who had low BMI at presentation.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

 

Celiac Studies

Three reports on celiac disease:

  • KM Simmons et al. J Pediatr 2016; 169: 44-8.
  • NR Reilly et al. J Pediatr 2016; 169: 40-54
  • MMS Wessels et al. J Pediatr 2016; 169: 55-60.

In the first study, the authors examined bone mineral density (BMD), glycemic control with hemoglobin A1c, and celiac autoimmunity in children with type 1 diabetes (T1D).  This was a cross-sectional study of 252 children with T1D; 123 had positive serology were anti-tissue transglutaminase (tTG) antibody.  In addition, another cohort (n=141) of children without T1D were examined who carried HLD-DR, DQ genotypes with (n=71) and without (n=70) tTG.  Key findings:

  • Children with T1D: those positive for tTG had significantly worse BMD L1-L4 (-0.45 ± 1.22 vs 0.09 ± 1.10, P= .0003).  Higher tTG and higher HgbA1c were independent predictors of lower BMI.
  • In children without T1D: no differences in BMD were found based on tTG status.
  • The authors concluded that celiac autoimmunity and hyperglycemia had synergistic effects on low BMD.

In the second study, the researchers used a population-based cohort study and compared 958 individuals with both T1D and celiac disease (CD) to 4598 similar individuals with T1D alone. Key finding: Over a 13 year period, 12 patients with both T1D and CD had a fracture (1 osteoporotic fracture). CD did not influence the risk of any fracture (aHR 0.77) in patients with T1D.  The researches concluded: “CD does not seem to influence fracture risk in young patients with T1D.”

My take: Looking at these studies in juxtaposition shows how important it is to consider multiple studies and how frequent discrepant results occur.  While the second study does not show a significant fracture risk, the preponderance of evidence does show an association between celiac disease and low BMD particularly in adults. In addition, a gluten free diet has been shown to reverse low BMD in those with CD.

Relevant studies:

  1. Gastroenterology 2010; 139: 763.
  2. Aliment Pharmacol Ther 2000; 14: 35-43.
  3. JPGN 2003; 37: 434-6.
  4. Gut 1996; 38: 322-7.

In the third study, the investigators looked at “complementary” investigation in children with CD.  These included tests like hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D, and thyroid assays.  Between 2009-2014, 182 children were evaluated included 119 with new diagnosis. Key findings:

  • At time of diagnosis: Iron deficiency (28%), iron deficiency anemia (9%), folate deficiency (14%), vitamin B12 (1%), and vitamin D deficiency (27%) were identified. No hypocalcemia or thyroid dysfunction was found.
  • At followup: iron deficiency (8%), iron deficiency anemia (2%), folate (3%), vitamin D (25%) were identified and no other abnormalities were evident.
  • The investigators concluded that these complementary tests “are relevant at the time of diagnosis of CD but have little diagnostic yield during followup-visits” after institution of gluten-free diet.

My take: Particularly at followup, identification of nutrient deficiencies is typically similar to the general population.

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Generation R Study: Insights into the Effects of Anti-Tissue Transglutaminase Antibody Positivity

In a study from Rotterdam (Jansen MAE, et al. Clin Gastroenterol Hepatol 2015; 13: 913-20), the authors show that positivity for anti-tissue transglutaminase IgA antibodies (TTG) is associated with lower growth trajectories and bone mineral density.

This was a population-based prospective cohort study which examined children born from 2002-2006 (median age 6 years).  4249 children with TTG <7 U/mL were compared with 57 children with TTG >7 U/mL.  The authors specifically looked at those >70 U/mL as well. Children with a previous diagnosis of celiac disease were excluded.

Key findings:

  • Positive TTG serology was associated with reduced weight gain 0.05 standard deviation score (SDS) per year and less linear growth 0.02 SDS/year.
  • Children with positive TTG were shorter 0.29 SDS and weighed less 0.38 SDS.
  • Children with positive TTG had lower bone mineral density (BMD) 0.26 SDS less.
  • Children with positive TTG did not have increased gastrointestinal symptoms compared with control children.

The authors note that the majority of these effects (poor growth, shortness, lower BMD) were mostly present in children with TTG >10 times upper limit of normal.

Bottomline: Subclinical or potential celiac disease is associated with reduced growth and bone mineral density.

Briefly noted:  Emilsson L, et al. Clin Gastroenterol Hepatol 2015; 13: 921-27.  Using a Norwegian cohort study with 95,200 women and 114,500 children (199-2008), the authors showed that development of celiac disease was associated with maternal celiac disease and type 1 diabetes.  There was no significant association noted with intrauterine growth, or mode of delivery.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

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Explaining the Vitamin D Paradox

For a long time, there has not been a satisfying explanation for the fact that blacks have higher bone mineral density but lower 25-hydroxy-vitamin D levels than whites.  New research (NEJM 2013; 369: 1991-2000, editorial 22047-48) helps explain this paradox.

This study examined a community cohort of 2085 individuals in the “Healthy Aging in Neighborhoods of Diversity across the Life Span” study.

Key Findings:

  • Blacks had higher bone mineral density and lower 25-hydroxy-vitamin D levels than whites
  • The calculated bioavailable levels of 25-hydroxy-vitamin D were similar to whites.

The editorial notes that the similar bioavailability is due to differences in the vitamin D-binding protein (aka GC-globulin).  “GC1F is the most abundant form in persons of African ancestry whereas GC1S is most abundant in European populations.”  Thus, it has been hypothesized that the vitamin D-binding protein in blacks has “increased affinity for vitamin D3, and thus able to transport vitamin D3 more efficiently from the skin to the liver for its metabolism to 25-hydroxy-vitamin D.”

Bottomline: This research in vitamin D metabolism may impact on how we determine vitamin D deficiency.  The measurement of vitamin D-binding protein may need to be incorporated into the assessment.

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Does bone density improve with IBD therapy?

Long term followup is needed to determine the significance of low bone mineral density (BMD) in children and adolescence with IBD; data with 2 year followup is available (JPGN 2012; 55: 511-18).

In this study from Sweden, 144 patients with IBD were enrolled and 126 were available at 2-year followup (2003-2005).  Among the 144 patients, there were 93 males and 83 with UC. Low BMD was noted in children with both UC and CD for the lumbar spine at baseline and no improvement was noted at 2 years.  Only boys had lower BMD z scores for the lumbar spine (LS) (-1.1); girls had normal LS z scores (0).

While the investigators could not demonstrate catch up in bone mineral density, they note that gains in BMD may accrue beyond late adolescence into early adulthood; this takes place after completion of linear growth.  In the subgroup of subjects in early adulthood, there was improvement in BMD:

  • For boys: from -1.7 at baseline (age 17.9) to -0.5 at followup (age 20.0)
  • For girls: from -0.4 at baseline (age 17.1) to 0.4 at followup (age 19.2)

With greater use of biologic therapy, these data are likely to change.  Among medical treatments, only biologic therapies have been shown to improve bone formation and improve catchup growth.

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Additional references:

  • -JPGN 2011;53: 361. Similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for low bone mineral density in IBD.
  • -JPGN 2009; 48: 538. Need to adjust bone density for bone age.
  • -Gastroenterol 2009; 136: 123. Longitudinal bone health study. Steroids did NOT adversely affect bones. n=78.
  • -Clin Gastro & Hep 2008; 6: 1378. IFX improves biomarkers of bone formation.
  • -J Pediatr 2008; 153: 454, 484. Use of biomarkers of bone turnover in Crohn dz; even when controlling for other factors like delayed bone age, delayed puberty, etc, still evidence of decrease bone formation and increased resorption.
  • -JPGN 2007; 45: 538. Ca/Vit D supplements -no change in BMD in IBD patients over 12 months.
  • -Clin Gastro & Hep 2007; 5: 721. DXA may not predict risk well.
  • -IBD 2007; 4: 416. Inflammation, not steroids, is key factor in bone mineral density.
  • -IBD 2006; 13: 42. Natural hx of bone mineral density in IBD; steroid dose did not correlate with BMD. Children did not have “catch up” bone density.
  • -JPGN 2006; 43: 597. Crohn’s patients had similar rate of fractures as siblings w/o IBD.
  • -Clin Gastro & Hep 2006; 4: 152. Osteoporosis in IBD.
  • -IBD 2006; 12: 797. Review of bone mineral density with IBD
  • -Clin Gastro & Hepatol 2005; 3: 113-121, 122-132 & editorial 110. In 1st article, budesonide better for bones than other steroids. In 2nd article, unable to show benefit of addition of etidronate to Ca++/Vit D.
  • -NEJM 2002; 351: 868. Intermittent steroids in nephrotic syndrome did NOT change bone mineral density.
  • -Gastro 2001; 121: 1485-88. Tanning bed Rx of vitamin D deficiency.
  • -Gastro 2000; 119: 639-46. Alendronate increases BMD in pts c Crohn’s
  • -NEJM 1998; 339: 292-9/ J Bone Miner Res 2000; 15: 1006-13. Bisphosphonates effective in steroid-induced bone disease