Evaluation and Management of Skeletal Health in Celiac Disease: Position Statement
MA Fouda, AA Khan, M Sultan, et al. Evaluation and management
of skeletal health in celiac disease: Position statement. Can J
Gastroenterol
evaluation and management of skeletal health in celiac disease: Position statement
Mona A Fouda FRCPEdin
Aliya A Khan FRCPC
Muhammad Sultan BHSc
Lorena P Rios
Karen McAssey FRCPC
David Armstrong MA MB BChir FRCPC
ObJECtivE: To review the evaluation and management of skeletal health in patients with celiac disease (CD), and to make recommendations on screening, diagnosis, treatment and follow-up of low bone mineral density (BMD) in CD patients. MEthOdS: A multidisciplinary team developed clinically relevant questions for review. An electronic search of the literature was conducted using the MEDLINE and EMBASE databases from 1996 to 2010. All original studies, reviews and guidelines, both pediatric and adult, were included. A document summarizing the results of the review and proposed recommendations was prepared and underwent multiple revisions until consensus was reached. RESult S: At diagnosis, approximately one-third of adult CD patients have osteoporosis, one-third have osteopenia and one-third have normal BMD. Children with CD have low bone mass at diagnosis. Adult and pediatric CD patients are at increased risk of fractures. di SCu SSiOn: For adults, serum calcium, albumin, 25(OH) vitamin D3, parathyroid hormone and 24 h urine calcium testing should be performed at diagnosis; patients with 'classic' CD and those at risk for osteoporosis should undergo a dual x-ray absorptiometry scan. An abnormal baseline dual x-ray absorptiometry scan should be repeated one to two years after initiation of a gluten-free diet (GFD). For children, BMD should be assessed one year after diagnosis if GFD adherence is not strict. A GFD is the most important treatment for bone loss. Supplemental antiresorptives may be justified in those who remain at high fracture risk (eg, postmenopausal women, older men) after implementation of a GFD. COnCluSiOn: Current evidence does not support the screening of all CD patients for low BMD at diagnosis. Follow-up BMD assessment should be performed one to two years after initiation of a GFD.
Bone; Celiac disease; Osteoporosis
-
Cgenetically susceptible individuals (human leukocyte antigen
eliac disease (CD) is an autoimmune enteropathy that occurs in
[HLA]-DQ2 and HLA-DQ8) as a result of an immune response to
gluten (
1
).
The clinical presentation of CD is heterogenous, ranging from the
classic features of malabsorption, weight loss and steatorrhea, to
clinically asymptomatic forms that probably represent two-thirds of CD
patients today (
2,3
).
More than 10 years ago, Ferguson et al (
3
) likened the CD
population to an iceberg, with only the tip visible over the waterline (the
classically symptomatic patients), and the main body remaining
underwater (the asymptomatic patients). Among the asymptomatic
patients, silent cases are defined as those with abnormal mucosal
changes on biopsy that return to normal on a gluten-free diet (GFD).
Latent CD patients are defined as those with a normal jejunal biopsy
but test positive for immunoglobulin (Ig) A endomysial antibody
(EMA) and/or IgA-tissue transglutaminase (tTG) (
4
).
l ’évaluation et la prise en charge de la santé
squelettique en cas de maladie coeliaque :
un document de principes
ObJECtiF : Analyser l’évaluation et la prise en charge de la santé
squelettique des patients ayant une maladie coeliaque (MC) et faire des
recommandations sur le dépistage, le diagnostic, le traitement et le suivi d’une faible
densité minérale osseuse (DMO) chez des patients ayant une MC.
MÉthOdOl OGi E : Une équipe multidisciplinaire a préparé des
questions pertinentes sur le plan médical à analyser. Elle a procédé à une
recherche électronique des publications de 1996 à 2010, dans les bases de
données MEDLINE et EMBASE. Toutes les études originales, les analyses
et les lignes directrices, pour les groupes pédiatriques et adultes, en
faisaient partie. Un document résumant l’information et proposant des
recommandations a été préparé et modifié à de multiples reprises jusqu’à
l’atteinte d’un consensus.
RÉSult AtS : Au diagnostic, environ le tiers des patients adultes ayant
une MC présente une ostéoporose, un tiers, de l’ostéopénie et un tiers, une
DMO normale. Les enfants ayant une MC ont une faible masse osseuse au
diagnostic. Les patients des groupes pédiatriques et adultes ayant une MC
sont plus vulnérables aux fractures.
EXPOSÉ : Au diagnostic des adultes, il faudrait vérifier le calcium
sérique, l’albumine, la 25(OH) vitamine D3, la parathyroïde et la calciurie
des 24 heures; les patients ayant une MC « classique » et ceux qui sont
vulnérables à l’ostéoporose devraient subir une absorptiométrie
biénergétique à rayons X. Lorsque les résultats de départ sont anormaux, il faudrait
reprendre cette absorptiométrie de un à deux ans après le début d’un régime
sans gluten (RSG). Chez les enfants, la DMO devrait être évaluée un an
après le diagnostic si la compliance au RSG n’est pas rigoureuse. Le RSG est
le principal traitement de perte de densité osseuse. Des inhibiteurs de la
résorption osseuse d’appoint peuvent être justifiés chez les personnes qui
présentent un risque élevé de fracture (p. ex., femmes post-ménopausées,
homme âgés) après la mise en oeuvre du RSG.
COnC luSiOn : Les données probantes actuelles n’étayent pas le
dépistage de tous les patients ayant une MC afin de diagnostiquer une faible
DMO. Une évaluation de suivi de la DMO devrait être effectuée de un à
deux ans après le début du RSG.
The reported prevalence of CD has increased over the past 10 years;
recent systematic reviews report a CD prevalence, measured by
screening unselected populations of European ancestry, of nearly 1% (
5
),
with similar figures reported in North America (
6
).
Fifty per cent of adults are diagnosed after 50 years of age (
7
), and
population-based studies suggest that 50% to 90% of people with CD
remain undiagnosed (
8,9
). Metabolic bone disease in CD patients has
been reported in the literature for more than 70 years (
10-12
), with
greater malabsorption leading to greater bone loss. Even subclinical or
silent cases have lower bone mineral density (BMD) than healthy
controls (
13,14
).
Many longitudinal studies have confirmed that BMD improves in
adult patients who adhere to a GFD (
13,15-19
).
Given this information, the need for an evidence-based approach
to the management of bone disease in patients with CD was
recognized. Our objective is to provide recommendations on which CD
patients should be screened for low BMD, the extent of biochemical
1College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Department of Medicine; 3Michael G DeGroote School of Medicine;
4Department of Pediatrics; 5Division of Gastroenterology, McMaster University, Hamilton, Ontario
Correspondence: Dr Aliya A Khan, 331-209 Sheddon Avenue, Oakville, Ontario L6J 1X8. Telephone 905-844-5677, fax 905-844-8966,
e-mail
Received for publication January 1, 2012. Accepted January 10, 2012
Glucocorticoids PTH
Calcitriol
PGE2
IL-11
IL-6
IL-1
PTHrP
data sources
An electronic search of the medical literature relevant to the key
clinical questions was conducted using the MEDLINE and EMBASE
databases from 1996 to 2010 without language restriction. The search
strategy included the following terms: “celiac disease”, “osteoporosis”,
“osteopenia”, “low bone mineral density (low BMD)”, “vitamin D”,
“fractures”, “parathormone (PTH)”, “metabolic bone diseases”,
“serological markers for celiac disease” and “bone markers”. References
from relevant articles and clinical guidelines were also reviewed.
Study selection
All original studies, reviews and clinical guidelines potentially relating
to skeletal complications of CD, and with the association between the
severity of CD and biochemical and serological markers in both
pediatric and adult populations, were considered for inclusion. If
nonEnglish language articles were selected, only the abstracts in English
were reviewed; no studies were excluded based on design or
methodological quality.
data extraction
Fifty studies on BMD and fractures in CD patients were retrieved and
summarized by the first author (MF) in the form of evidence tables, which
were circulated to all of the team members. An additional 60 articles were
reviewed, and a manuscript was drafted by the first author (MF) based
on the information gathered and recommendations were proposed.
The recommendations were graded according to the levels of evidence
adopted from the Canadian Task Force on Preventive Healthcare (
20
)
(Appendix 1). The draft was revised by each team member until
consensus was reached.
RESult S
What causes bone loss in Cd?
Pathophysiological aspects: The main mechanisms underlying low
BMD in adult CD are secondary hyperparathyroidism and
osteomalacia due to calcium and vitamin D malabsorption (
21
). Markers of
bone resorption, such as telopeptides of type I collagen, urinary collagen
cross links and urinary hydroxyproline, are increased in the presence of
secondary hyperparathyroidism. The resulting effect is net bone loss
(
13,17,22,23
).
Bone health in youth with CD is determined by factors that
influence both bone mineral accrual and bone loss. At the conclusion of
puberty, growth of the skeleton and bone mass reaches its peak.
Studies on bone metabolism in youth with CD indicate that the
PTHvitamin D levels are not affected (
24,25
). Similarly, serum levels of
calcium and phosphate, when compared with laboratory reference
ranges, are reported to be within normal limits (
24,26
). There are few
pediatric studies that have measured markers of bone formation and
bone resorption. Limited data indicate that depressed bone formation
rates and enhanced bone resorption may contribute to reduced bone
mass in children with CD (
26,27
).
Immunological and inflammatory changes also contribute to bone
mass reduction (Figure 1). Production of proinflammatory cytokines,
such as interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha, has
been detected in the intestinal mucosa of adult CD patients (
28
), and
increased serum levels of IL-1 and IL-6 have also been observed
(
29,30
). In untreated adult CD patients, serum IL-6 levels correlate
inversely with lumbar BMD (29) and directly with serum PTH and
N-telopeptide of type I collagen levels (
30
). Along with decreased
levels of the inhibitory cytokines IL-12 and IL-18, these cytokine
imbalances cause bone loss by virtue of direct effects on
osteoclastogenesis and osteoblast activity (
31-33
).
Untreated adult CD patients have been found to have an increased
receptor activator of nuclear factor kappa-B ligand/osteoprotegrin ratio,
leading to enhanced bone resorption secondary to increased
formation, function and survival of osteoclasts (
31
). Clinical and subclinical
hypogonadism in women can also contribute to bone loss (
34,35
).
Similar findings have not been confirmed in men (
30
).
bone mineralization and serological markers in Cd: PTH levels
z-score
significantly
lower in
untreated
and lower in
treated
compared
with control
–2.5
–1.85
(women),
–0.95 (men)
–0.89
(women),
–0.95 (men)
–1.3, –2.6
–0.76
50
70
bone mineral density (bMD) in untreated celiac disease (CD) in published studies
Study type
Participants, n DXa site Outcomes
Argentina Longitudinal 25 CD, 151 control, mean age 45 years
Retrospective 41 CD, cohort mean age 34.3 years
Prospective 20 CD,
case control 15 control
Case control
Argentina Longitudinal 16
Lumbar LS
–1.6
44
author
(reference), year Country
Sategna- Italy
Guidetti et al
(
57
), 2000
Valdimarsson Sweden et al (37), 2000
Study type
Longitudinal
Prospective cohort
Vazquez et al
(
62
), 2000
Kalayci et al (79), 2001
Meyer et al (44), 2001
Mora et al (80), 2001
Carvalho et al (81), 2003
Kavak et al (47), 2003
Barera et al (82), 2004 Argentina Turkey
↑ Increase; BMC Bone mineral content; BMI Body mass index; DXA Dual x-ray absorptiometry; F Femur; FN Femoral neck; GFD Gluten-free diet; LS Lumbar spine;
PTH Parathyroid hormone; vs Versus
at CD diagnosis are predictive of bone mineralization status in adult
patients. Patients with higher PTH levels are more likely to have lower
BMD (
36-39
) and less likely to normalize their BMD after three years
on a GFD (37). These data suggest that PTH levels at CD diagnosis
may be a useful prognostic factor for bone disease in CD patients.
Several studies also indicate that serum osteocalcin and
bonespecific alkaline phosphatase levels correlate negatively with BMD
(
18,37,38
), while in adults, 25(OH)D3 levels correlate positively with
BMD (
18,36,37
).
Adults who respond to a GFD have lower levels of bone-specific
alkaline phosphatase and osteocalcin, and higher levels of 25(OH)D3
than patients with refractory disease or persistent villous atrophy
(
17,39
). Baseline levels of carboxy-terminal propeptide of type I
collagen have been reported to correlate best with an increase in BMD
following a GFD (18).
Based on these studies, it appears reasonable to measure 25(OH)D3,
calcium corrected for albumin and PTH levels in newly diagnosed
adult CD patients, to assess the extent of bone loss at diagnosis and to
estimate the likely effect of a GFD in restoring bone density.
Other serological markers that correlate with BMD include tTG
antibodies and IgA EMA. A study by Agardh et al (
40
) showed
that in women 50 to 64 years of age, high tTG antibody levels
(>17 U/mL) were correlated with lower BMD (0.41±0.08 g/cm2
versus 0.44±0.08 g/cm2; P=0.001), a higher prevalence of osteoporosis
(13.4% versus 6.5%; P=0.008) and a higher fracture frequency (32.2%
versus 18.8%; P=0.009). A study by Duerksen et al (
41
) confirmed
that women who were seropositive for tTG and/or EMA had lower
BMD at all measured sites than the seronegative control group. The
prevalence of osteoporosis among seropositive patients was 67.7%
versus 44.8% for seronegative patients. Recommended cut-off values
for commercial tTG kits are <20 U/mL (normal), 20 U/mL to 100 U/mL
(mid-range), and >100 U/mL (high). Using these cut-offs and a known
IgA status, the sensitivity and specificity of tTG as a screening test has
been shown to be 0.980 and 0.972, respectively (
42
).
A study by Blazina et al (
43
) compared BMD in children and
adolescents who were on a strict GFD with patients who had occasional
gluten intake. Compliance with a GFD was monitored by EMA status.
Patients who were EMA positive at any time during the study were
classified as not strictly compliant, whereas those who were EMA
negative throughout the study were classified as strictly compliant.
The results showed that 71% of patients who were EMA positive had
total body BMD Z-scores below −1.0 compared with 38% in the
strictly compliant group (P=0.03). However, it is important to note
that calcium intake and vitamin D levels were below
recommendations within both groups. The authors proposed that because BMD is
affected both by impaired absorption of calcium and vitamin D in the
bowel, as well as by the presence of inflammatory cytokines and
autoantibodies, patients with occasional gluten ingestion remain
seropositive and are thus at an increased risk of reduced BMD even if intestinal
absorption is not significantly affected.
how common is skeletal disease in Cd patients?
bMd : BMD at diagnosis of CD: Studies evaluating the mean BMD at
the time of CD diagnosis are summarized in Table 2. The absolute
prevalence of osteoporosis/osteopenia in CD patients is unclear due to the
small numbers of patients studied and the varied study populations.
However, data from two studies involving adult CD patients suggest that
approximately one-third have osteoporosis, one-third have osteopenia
and one-third have a normal BMD at presentation (
36,44
).
Low BMD is detected in children and adolescents with newly
diagnosed CD (
45-47
). One study conducted in Edmonton, Alberta, observed
lumbar spine BMD Z-scores ≤−2 SDs in 16% of pediatric CD patients,
Z-scores below −1 SD but above −2 SDs in 19%, and a Z-score ≥−1 SD
in 65% (
48
). In another study that assessed bone mineral content (BMC)
in children with CD (
26
), whole body and lumbar spine BMC were
identified to be lower in children with CD than in healthy controls by 1.0 g
(lumbar spine) and 38.7 g (whole body). In 24 children ranging in age
from one to 11 years at diagnosis, lumbar spine BMD measurements
expressed as Z-scores were reported to be low (−1.36±1.20) and 17% had
Z-scores that were >2 SDs below the population mean (
25
).
The risk of low BMD among newly diagnosed adult CD patients is
higher with increased age, lower body mass index and years after
menopause (
16,36,44, 49-52
).
Effect of GFD on BMD: Studies evaluating the BMD response to a
GFD are summarized in Table 3.
In 2003, the American Gastroenterological Association (
53
)
concluded that, among newly-diagnosed CD patients, osteoporosis was
found in 28% when mesuring the lumbar spine and 15% when
measuring the hip. Adults and children had a similar prevalence of low BMD
at diagnosis, but children normalized their BMD after initiation of a
GFD (
45,54,55
). Adults had the greatest increase in BMD
(approximately 5%) in their first year on a GFD, but remained below average
thereafter (
15,56,57
). Children diagnosed with CD before two years of
age, who were on a GFD for at least 24 months, tended to attain
greater bone mass than older patients (
46
). Patients having persistent
abnormal small bowel morphology have the lowest BMD (
55
).
The American Gastroenterological Association proposed broader
screening of family members of patients with CD and those with type 1
diabetes mellitus, Addison disease and other polyglandular diseases
because low BMD does not seem to be fully reversible in adults, and
because early diagnosis and treatment for asymptomatic CD patients
may optimize skeletal health and prevent fracture development.
Fracture risk
BMD is only one of the factors associated with increased fracture rates
in CD patients. Bone quality, microarchitecture, geometry, bone cell
function, mineralization and collagen fibre strength, as well as
neuromuscular function, all determine the risk of fracture and bone strength.
This was best highlighted in a study by Moreno et al (
58
), who did not
find a significant difference between T-scores and Z-scores of CD
patients with or without fractures. The study found that patients with
a classical presentation of CD had a higher fracture risk (47%)
compared with controls (15%) (OR 5.2 [95% CI 2.8 to 9.8];
P<0.0001). Fractures in subclinical/silent cases were not different from
their controls (20% versus 14%; OR 1.7 [95% CI 0.7 to 4.4]; P not
significant). Multivariate analyses did not show any one single
characteristic to be highly predictive of fracture risk.
Studies evaluating the risk of fracture in CD patients are
conflicting, with some showing no significant increase in fractures (
59,60
),
and others reporting a higher risk (
27,61,62
). RRs for fractures of any
type range from 0.94 (95% CI −0.71 to 1.24) (46) to 7.0 (
63
), and for
hip fractures, range from 0.66 (95% CI −0.05 to 9.50)(
64
) to 1.9 (95%
CI −1.2-3.02) (
65
).
In the largest study to date on the incidence of fractures in CD
population, Ludvigsson et al (
63
) used a Swedish National Registry to
estimate the risk of hip fractures and fractures of any type in a large
general population cohort study. The hazard ratio (HR) for a hip
fracture was 2.1 (95% CI 1.8 to 2.4) in adults, and 2.6 (95% CI 1.1 to 6.2)
in children. It is important to note that hip fractures are rare in
children; the increased HR was based on six hip fractures per 100,000
patient years for pediatric CD patients compared with two per 100,000
patient years among reference individuals. The HR for fractures of any
type for all ages was 1.4 (95% CI 1.3 to 1.5), with a marginal statistical
significance of P=0.052. Although a GFD allows for improvement in
BMD, adult patients do not regain their peak bone mass and their
BMD remains lower than in healthy controls (
70
). As a result, CD
patients remain at an increased risk of fractures 20 years after diagnosis
even if they adhere to a GFD (
63
).
The studies above conclude that both adult and pediatric CD
patients have a significant increase in the risk of hip fractures and
fractures of any other type, regardless of whether the fracture occurred
before or after the diagnosis of CD. The duration after diagnosis of CD
did not notably influence the risk of hip fractures and, therefore, no
evidence was found in the study by Ludvigsson et al (
63
) that a GFD
lowers the risk of hip fractures. The positive association between CD
and hip fractures was independent of sex and age (
63
). The study also
showed increased risk of subsequent hip fractures in individuals with
CD diagnosed in childhood (HR 2.6 [95% CI −1.1 to 6.2]).
Moreno et al (
58
) showed that peripheral fractures are more
common in adult CD patients than in age- and sex-matched controls. CD
patients with a classic clinical course (eg, chronic diarrhea and
malabsorption) had a significantly higher prevalence of fractures in the
peripheral skeleton (OR −5.2 [95% CI −2.8 to 9.8) compared with patients
with subclinical or silent CD, and to age- and sex-matched controls.
Vazquez et al (
62
) also showed that adult CD patients had a higher
prevalence of peripheral fractures (25%) compared with sex- and
agematched controls (8%). Other studies (
64,67,68
) reported trends toward
an increased fracture risk that were not statistically significant.
A recent systematic review of case control and cohort studies (
64
)
reported that the fracture risk was 43% greater in adult CD patients than
in controls (OR 1.43 [95% CI −1.15 to 1.78]), although there was
significant, unexplained, quantitative and qualitative heterogeneity among
the studies, possibly attributable to differences in subject selection, small
sample sizes and differences in methodologies used to assess and define
fractures, and lack of information on disease duration and therapeutic
interventions. Nonetheless, the results of the systematic review,
supplemented by the results of two case control studies (Table 4) confirm that
adult CD patients have a significantly increased risk of fracture.
Additional research is needed to identify which CD patients are at a
higher risk of fracture so that clinicians can implement screening, risk
stratification and treatment strategies more effectively.
Who should undergo bMd testing?
Based on the available data, there is no indication to perform a BMD test
in the pediatric age group if they are compliant with a GFD because data
confirm full recovery. The International Society for Clinical Densitometry
guidelines do not include CD as an indication to perform a DXA scan on
children and adolescents (
69
). On the other hand, symptomatic adults
with classic malabsorption (weight loss, diarrhea, etc) should have their
BMD tested at diagnosis and ensure that malabsorption of calcium,
phosphate and vitamin D are corrected. The asymptomatic/silent group
represent a ‘grey zone’ with conflicting data and no consensus, but it
would seem prudent to treat them with a GFD and perform a DXA scan
one year later when the need for further management can be assessed.
The recent British guidelines (
70
) recommend that BMD testing
be completed in all patients at the time of diagnosis in recognition of
the potential impact of chronic malabsorption.
Compston et al (
67
) suggest BMD assessment be restricted to the
minority of individuals in whom short-term fracture risk (five to 10 years)
is probably high. In adult CD patients, risk factors may include
nonadherence to a GFD, failure to respond to a GFD, corticosteroid
treatment, untreated hypogonadism, old age, low body mass index and
previous fragility fractures, as well as menstrual irregularity and
subclinical hypogonadism in premenopausal women, unexplained iron
deficiency anemia and low vitamin D status (indicated by low vitamin D
levels and/or low 24 h urinary calcium). Based on this, Corrazza et al
(
71
) proposed DXA assessment in peri- and postmenopausal women
with CD and male CD patients >50 years of age.
A repeat DXA scan after one year on a GFD is recommended in the
presence of osteoporosis/osteopenia at diagnosis (
13,15,16,57
). In the
presence of normal BMD at diagnosis, follow-up may be after two to three years
on a GFD, based on other clinical risk factors and response to therapy.
The WHO has developed an absolute fracture risk assessment tool
(‘FRAX’) to estimate the 10-year fracture risk in all adults, which is based
on the integration of femoral neck bone density, age and other important
clinical risk factors (
66
). Given that one of the risk factors is chronic
malabsorption, use of the FRAX tool would be reasonable for CD patients.
Gaps and limitations with future directions
In summary, although there is agreement that adult CD patients have
an increased fracture risk, there are important knowledge gaps
regarding the prevalence of fragility fracture and relevant risk factors.
Prospective population-based fracture data with small bowel biopsy
follow-up to clinical presentation and GFD compliance will be very
informative. Prevention of osteoporotic fractures should be the main
aim when addressing bone health in the adult CD population;
restoration of normal bone metabolism, to achieve optimal peak bone mass at
the end of puberty, should be the main aim for pediatric CD patients.
Data on management options, other than GFD, for low BMD in
CD patients are limited. Supplementation of calcium and vitamin D
has been recommended in some studies but not others, and the role of
antiresorptive medications on BMD and fracture risk in CD patients
is not known (
70,71
). There is also no agreement regarding the BMD
threshold for treatment in CD patients or whether a T-score or Z-score
should be used in adult CD patients (70); in this context, the FRAX
tool may be more useful for determining the fracture risk and
appropriate management. In pediatric CD patients, the only meaningful
value is a BMD Z-score to compare unaffected age- and sex-matched
populations.
RECOMMEndAtiOnS FOR diAGnOSiS, FOllOW-uP
And tREAtMEnt OF P AtiEntS With Cd With
REGARd tO SKElEtAl hEAlth
indications for bMd testing
1. In adults with classic CD, BMD should be evaluated following the
diagnosis of CD. (Level I)
2. In adults with asymptomatic or silent CD, BMD should be
evaluated after one year on a GFD. (Level I)
In the absence of other risk factors, the fracture risk is probably less
than in patients with classic CD, and it may not be significantly higher
than in the general population.
3. In adults with asymptomatic or silent CD, early BMD testing
<1 year after diagnosis, may be considered if there are other risk
factors for low BMD such as the following:
a) Peri- or postmenopausal women. (Level I)
b) Men older than 50 years of age. (Level I)
c) History of fragility fracture. (Level I)
Davie et al (
87
), United Case control, CD, n=383 Any fracture
2005 Kingdom questionnaire-based 90.3% biopsy proven Any fracture after 50 yrs
fractures by recall Control, n=445 Any wrist fracture
postmenopausal Any wrist fracture after 50 yrs
women Any nonwrist fracture
Any nonwrist fracture after 50 yrs
More than one fracture
Ludvigsson et al Sweden Population-based CD, n=13,724 First hip fracture
(
63
), 2007 cohort Control, n=65,627 *First year excluded
Any CD HR 2.1 (1.8–2.4)
0–15 yrs HR 2.6 (1.1–6.2)
≥16 yrs HR 2.1 (1.8–2.4)
Males HR 2.2 (1.7–2.9)
Females HR 2.0 (1.7–2.4)
* First year included HR 2.2 (2.0–2.5)
Any fracture
*First year excluded
Any CD HR 1.4 (1.3–1.5)
0–15 yrs HR 1.1 (1.0–1.2)
≥16 yrs HR 1.8 (1.6–2.0)
Males HR 1.4 (1.2–1.5)
Females HR 1.4 (1.3–1.6)
*First year included HR 1.5 (1.4–1.6)
Jafri et al (
88
), United Population-based CD, n=83 Any fracture OR 2.0 (1.0–3.9)
2007 States cohort, Control, n=166 Peripheral OR 2.0 (1.0–3.8)
administrative Axial OR 1.7 (0.7–4.1)
databases Osteoporotic OR 8.0 (0.9–72)
Data analysis showing fracture risk in CD. The analysis in this table was first performed in 2008, before the systematic review and meta-analysis by Olmos et al (
65
)
was published. Thus, much of the analysis in this table is similar to the analysis in that study. However, this table has been re-updated to include new data that
became available after the Olmos et al (
65
) systematic review. The Olmos et al (
65
) article, which includes the first eight studies in this table, showed that fracture
risk was 43% greater in adult CD patients than in controls (OR 1.43 [95% CI 1.15 to 1.78]), with significant, unexplained, quantitative and qualitative heterogeneity
among the studies, possibly attributable to differences in subject selection, small sample sizes, differences in methodologies used to assess and define fractures,
and lack of information on disease duration and therapeutic interventions. ref Reference; vs Versus; yrs Years of age
d) Unexplained iron deficiency anemia. (Level III)
e) Vitamin D deficiency/insufficiency. (Level II)
f) High titres for CD serological markers. (Level I)
g) In pediatric CD patients, BMD testing should be offered one
year after diagnosis if patients do not self-report strict
adherence to a GFD. (Level I)
4. In adult CD patients, repeat DXA (or first time DXA) testing
should be offered to all groups at menopause and men after
50 years of age. (Level II)
5. The FRAX tool will be useful to estimate fracture risk and plan
management accordingly. (Level II)
indications for bMd follow-up in adults
1. In the presence of osteopenia/osteoporosis at diagnosis, follow-up
BMD should be offered after one year on a GFD. (Level I)
2. In the presence of a normal BMD at diagnosis, follow-up should
be after two years on a GFD, particularly if the patient remains
symptomatic or is nonadherent to the diet. (Level III)
indications for biochemical assessment and follow-up
1. In adult CD patients, biochemical profile for the assessment of
skeletal mineralization should be offered at the time of CD
diagnosis in adults, including serum calcium, albumin,
25(OH)D3 and PTH levels. (Level II)
2. In adult CD patients, routine 24 h urine calcium testing is not
recommended. (Level III)
Comment: Urinary calcium testing may be helpful to assess calcium
absorption; however, there are few data to support this
recommendation and there other factors, including renal function, that will affect
urinary calcium excretion.
3. Biochemical profile could be repeated every six months until
normalization. (Level III)
4. Biochemical markers of bone turnover (eg, osteocalcin,
procollagen type 1 N-terminal propeptide, urinary collagen
crosslinks [NTx]) should be reserved for research studies. (Level
III)
5. Serological CD markers (IgA, tTGA, IgA EMA) can be used as
indicators of the severity of CD-related mucosal damage. (Level I).
Comment: The severity of mucosal damage appears to be a predictor
of malabsorption and, hence, of the risk of low bone density. Cytokine
excess associated with mucosal damage (increased IL-6, decreased
IL-12 and IL-18 levels) also contributes to bone loss through increased
osteoclast formation, function and survival.
6. Serological CD markers may be used as a screening tool in
asymptomatic/silent CD patients to identify those who may
benefit from an early DXA to diagnose low bone mass. (Level II)
treatment
1. GFD adherence is the treatment of choice for normalization of
BMD in CD patients. (Level I)
2. Pharmacological intervention with antiresorptive medications
can be used to treat osteoporosis in postmenopausal adult CD
patients after ensuring that adequate calcium and vitamin D
supplementation has been provided. (Level III)
Comment: Other strategies used in the management of
postmenopausal osteoporosis may be considered but there are no longitudinal
data to support this practice in CD patients.
APPEndiX 1: lEvElS OF EvidEnCE AdAPtEd FROM
thE CAnAdiAn tASK FORCE On PREvEntivE
hEAlth CARE (
20
)
levels of evidence
level i:
level ii:
At least one properly conducted randomized controlled
trial, systematic review, or meta-analysis.
Other comparison trials, non-randomized, cohort,
casecontrol, or epidemiologic studies, and preferably more than
one study.
level iii: Expert opinion or consensus statement.
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