Guidelines for osteoporosis in inflammatory bowel disease and

Transcription

14
BRITISH SOCIETY
OF GASTROENTEROLOGY
Guidelines for osteoporosis
in inflammatory bowel
disease and coeliac disease
Designed, Typeset and Printed by
Q3 Digital/Litho
Loughborough, Leicestershire
01509 213456
Written and approved by the British Society of Gastroenterology
June 2007
http://www.bsg.org.uk
NR Lewis, BB Scott
CONTENTS
1.0 The Problem
2.0 Risk factors for fracture in general
2.1 Reduced bone mineral density
2.1.1 The importance of low BMD
2.1.2 Measurement of BMD
2.1.3 Risk factors for low BMD and fracture
2.2 Other risk factors for fracture independent of low
BMD
3.0 Osteoporosis in IBD
3.1 Are fractures a problem in IBD?
3.2 Risk factors for fracture in IBD
3.2.1 Reduced BMD
3.2.2 Factors affecting BMD in IBD
3.2.2.1 Age and age at diagnosis
3.2.2.2 Gender
3.2.2.3 Weight, height and body mass
index3.2.2.4 Duration of disease
3.2.2.5 Disease site, activity, severity and
previous surgery
3.2.2.6 Corticosteroid use
3.2.2.7 Reduced physical activity
3.2.2.8 Smoking
3.2.3 Other risk factors for fracture independent of low BMD
3.2.3.1 Age
3.2.3.2 Gender
3.2.3.3 Corticosteroid use and disease activity
4.0 Osteoporosis in coeliac disease
4.1 Are fractures a problem in coeliac disease?
4.2 Risk factors for fracture in coeliac disease
4.2.1 Reduced BMD
4.2.2 Factors affecting low BMD in coeliac disease
4.2.2.1 Years exposed to gluten
4.2.2.2 Gender
4.2.2.3 Body mass index (BMI)
4.2.2.4 Degree of villous atrophy
4.2.2.5 Symptomatic disease
4.2.2.6 Adherence to a gluten-free diet
5.0 Prevention of osteoporosis in IBD and coeliac disease
5.1 General measures
5.2 Calcium
5.3 Vitamin D
5.4 Steroid avoidance in IBD
5.5 Bone-protective measures during steroid use in IBD
6.0 Detection of osteoporosis in IBD and coeliac disease
6.1 Indications for DEXA
6.2 Special considerations in IBD
6.2.1 DEXA in steroid treated patients
6.3 Special considerations in coeliac disease
7.0 Treatment of osteoporosis
7.1 Bisphosphonates
7.2 Teriparatide
7.3 Raloxifene
7.4 Calcitonin
7.5 Calcium and vitamin D
7.6 Strontium
7.7 Sex hormone replacement therapy (HRT)
7.8 Fluoride
8.0 Summary of recommendations
9.0 The process of guideline formulation
10.0 Targets for audit
References
BSG Guidelines in Gastroenterology
June 2007
Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease
1
Guidelines for osteoporosis in inflammatory bowel
disease and coeliac disease
NR Lewis, BB Scott
1.0 THE PROBLEM
O
steoporosis is a major public health problem because
of its potentially severe consequences for both the
patient and the health care system if it leads to fracture. It has been estimated that one in two women and one in
five men older than 50 years will develop an osteoporotic fracture during the course of their remaining lifetime in the
United States [1] and that in the United Kingdom (UK)
osteoporosis causes more than 200,000 fractures per year [2,
3]. Osteoporotic fractures are associated with pain, disability
and up to 30% mortality at 1 year in addition to an estimated
monetary cost in the UK of more than £1 billion yearly [3–5].
Osteoporosis is likely to become even more common and
costly because of the ageing population. Gastroenterologists
care for groups of patients at increased risk of osteoporotic
fracture, such as those with inflammatory bowel disease
(IBD) and coeliac disease. These guidelines review the risks of
osteoporosis and fracture in these conditions with a view to
identifying subgroups of patients that would benefit from
screening and interventions to prevent fractures.
2.0 RISK FACTORS FOR FRACTURE IN GENERAL
Before considering IBD and coeliac disease in particular it is
important to consider the risk factors for fracture in general
since they are likely to operate also in those conditions.
2.1 REDUCED BONE MINERAL DENSITY
2.1.1 The importance of low BMD
Although osteoporosis is just one of many factors predisposing to fracture, it is one of the most important and can be
reliably assessed by measurement of bone mineral density
(BMD). BMD can be expressed as the number of standard
deviations (SD) above or below either the mean BMD for
young adults (T-score) or the mean BMD for age-matched
controls (Z-score).Cross-sectional and prospective population
studies suggest that the risk of fracture increases by a factor
of 1.4 – 2.6 for each SD decrease in bone mineral density [6].
Osteoporosis is defined as a T-score <-2.5 [3]. The significance
of a given T-score in terms of absolute fracture risk will differ
according to age (table 1). For example, a T-score of –2 is associated with a 9.2% probability of an osteoporotic fracture in
the next ten years in non-steroid treated women aged 50
years but at 70 years this probability is twice as high [7].
2.1.2 Measurement of BMD
BMD is usually measured using dual energy x-ray absorptiometry (DEXA) which is relatively simple and non-invasive
and has accuracy and precision (measurement error of 5–6%)
[8–10]. Although DEXA instruments are calibrated against
excised bone samples, methodological differences in how this
calibration is performed have led to large discrepancies in
patient measurements when using different machines, making comparison difficult [11]. For this reason, whenever
possible, follow-up examinations should be done using the
June 2007
Table 1: 10-year probability (%) of hip, spine, proximal
humerus or distal forearm fracture in non-steroid treated
individuals according to T-score at femoral neck [7].
T-score
Age (years) +1
0
-1
-2
-3
-4
Women
50
2.4
3.8
5.9
9.2
14.1
21.3
60
3.2
5.1
8.2
13.0 20.2
30.6
70
4.3
7.1
11.5
18.3 28.4
42.3
80
4.6
7.7
12.7
20.5 31.8
46.4
Men
50
60
70
80
1.2
1.6
2.3
3.6
2.0
2.7
3.8
5.8
3.4
4.5
6.2
9.3
5.8
7.3
10.0
14.7
9.6
11.8
16.0
22.6
15.9
18.7
25.0
33.3
same instrument. The use of BMD measurement alone as a
prognostic tool in a population-screening programme is limited by both its poor discriminatory power to detect those who
will fracture from those that will not and its cost if used indiscriminately [6, 12–14].
Quantitative ultrasound might be considered where DEXA
is not readily available. However, it doesn’t measure BMD
directly and cannot be used to diagnose osteoporosis using
current definitions based on BMD. Thus the T-score thresholds used in these guidelines cannot be applied using results
from quantitative ultrasound. Nevertheless, a low quantitative ultrasound measurement is an independent predictor of
osteoporotic fracture in post-menopausal women and may be
used as such. It is not suitable for monitoring treatment. A
code of practice for the use of quantitative ultrasound can be
obtained from the National Osteoporosis Society
(www.nos.org.uk).
2.1.3 Risk factors for low BMD and fracture
There are many predisposing factors for low BMD and fracture. Some are modifiable; others are not. A systematic review
[15] of those risk factors for fracture which are probably
related to a low BMD identified high risk factors (relative risk
or odds ratio of >2) and moderate risk factors (relative risk
1–2) and they are shown in Box 1. Factors which are modifiable are indicated. There is emerging evidence that proton
pump inhibitors used long term [16] and thiazolidinedones
such as rosiglitazone [17] also predispose to fractures.
2.2 OTHER RISK FACTORS FOR FRACTURE INDEPENDENT
OF LOW BMD
There are many other factors which predispose to fracture
independently, at least partly, of any effect on BMD [18,19] as
shown in Box 2. Some, such as increasing age, previous
fragility fracture, low body weight, poor visual acuity and
neuromuscular disorders, presumably act by predisposing to
or showing a predisposition to falls. Alcohol excess is another
2
NR Lewis, BB Scott
Box 1: Risk factors for fracture related to low BMD
High risk (RR>2)
Moderate risk (RR 1-2)
Non-modifiable
• Older age (> 70 years)
• Prior osteoporotic fracture
Non-modifiable
• Female
• Untreated early menopause (<45)
• Late menarche (>15)
• Short fertile period (<30 years)
• Family history of osteoporotic fracture
Modifiable
• Low body weight (BMI <20 – 25 kg/m2 or
weight <40 kg)
• Weight loss (greater than 10%)
• Physical inactivity
• Use of corticosteroids
• Use of anticonvulsants
factor [20] which may also be partly related to falls.
Corticosteroid use may also predispose to fracture independent of any effect on the BMD [21–23]. This may be related to
higher daily dose rather than cumulative dose [24] and a
rapid decrease in fracture risk towards baseline has been
shown to occur shortly after stopping steroids [25, 26].
3.0 OSTEOPOROSIS IN IBD
3.1 ARE FRACTURES A PROBLEM IN IBD?
Since fracture is the only clinically important outcome of
osteoporosis, it is important to determine the impact of IBD
on the risk of fracture. The results of eight studies are shown
in Table 2 [27–34]. They demonstrate a modest increase in
fracture risk. For all fractures the relative risk is approximately 1.3 for Crohn’s disease and 1.2 for UC. The risk is
slightly greater for hip fractures – 1.5 for Crohn’s disease and
1.4 for UC. Since most of the studies rely on reports of fracture, the prevalence of spinal fracture (and therefore all
fractures) is likely to be underestimated. The only two studies
to use quantitative morphometry of spinal x-rays revealed a
very high prevalence of vertebral fractures. In one, the
researchers selected for study just over half their Crohn’s disease patients by excluding those with a lumbar T-score >-1
and found a fracture prevalence of 22% [33]. The other found
lumbar spine fractures in 14% of 271 patients with ileo-caecal
Crohn’s disease [34]. Several risk factors for osteoporotic fracture specific for IBD have been identified which may be then
used to target diagnostic and therapeutic interventions most
appropriately.
Box 2: Risk factors for fracture at least partly
independent of low BMD
Non-modifiable
• Older age
• Prior osteoporotic fracture
• Family history of hip fracture
• Poor visual acuity*
• Neuromuscular disorders*
Modifiable
• Low body weight
• Use of corticosteroids
• Cigarette smoking
• Alcohol excess
* Modifiable in some cases
Modifiable
• Smoking
• Low calcium intake
3.2 RISK FACTORS FOR FRACTURE IN IBD
3.2.1 Reduced BMD
As explained above, low BMD is an important predictor for
fracture risk, although one study of Crohn’s disease patients
[34] found that the vertebral fracture rate did not correlate
with the BMD. The prevalence of low BMD in Crohn’s disease
and ulcerative colitis observed in cross-sectional studies is
summarised in tables 3 and 4, respectively [35–62]. Pooling of
the results (table 5) suggests that BMD is modestly reduced in
both Crohn’s and UC with mean Z-scores being approximately
-0.5 and -0.7 at the spine and hip respectively in Crohn’s disease and -0.1 and -0.3 at those sites in UC. When using
T-scores, pooled bone mineral density in both patients with
Crohn’s disease and ulcerative colitis is within the osteopenic
or osteoporotic range in over half of patients. However there
are limitations with these studies. Many of the studies are
small with only 8 of the 40 studies having sample sizes above
100 patients with IBD. The majority of the studies are based on
observations from specialist IBD clinics and not populationbased and thus the findings may not reflect the true risk. Only
7 of the studies included a control group. Overall, longitudinal
changes in BMD in patients with IBD were similar to those in
the general population [36, 38, 40, 44, 46, 55, 56]. Pooling of
these results demonstrates -0.50% change per year in spine
BMD and -1.09% change per year in femoral neck BMD in
patients with Crohn’s disease. In comparison, -1.33% change
per year in spine BMD and +0.26% change per year in femoral
neck BMD was observed in patients with ulcerative colitis.
3.2.2 Factors affecting BMD in IBD
3.2.2.1 Age and age at diagnosis
As expected, advancing age was associated with reduced
BMD in most studies. However, Haugeberg et al [51] observed
that Crohn’s disease patients with reduced BMD were
younger than those without reduced BMD (33.6 v 41.1 years
at lumbar spine, p= 0.02; 34.7 v 41.5 years at femoral neck,
p= 0.04 respectively) though the patients with reduced BMD
had a significantly higher cumulative steroid dose. Kuisma et
al [62] also observed that patients with Crohn’s disease and
osteopenia were significantly younger than those with normal
BMD (33.5 years [95%CI 29.4–37.6] v 40.9 [95% CI 38.3–43.5]
years, respectively) and though there were no differences in
cumulative steroid doses, patients with osteopenia had suffered more exacerbations of their Crohn’s disease.
The age at diagnosis also may also be important. Though
based on small numbers, Schoon et al [50] observed a greater
risk of reduced BMD in patients with Crohn’s disease aged
under 18 years at diagnosis (n=12) at the lumbar spine
(Z-score -1.07 v 0.12, p= 0.0001) and total body (Z-score -0.86
v –0.20, p= 0.018) in comparison to those diagnosed over 18
June 2007
June 2007
Study population
American population-based cohort study (n=238)
Loftus et al
[30]
Spine
Multicentre European/Israeli hospital based study
(n=271)
Stockbrugger
et al [34]
RR = relative risk; IRR = incidence rate ratio; OR = odds ratio; HR = hazard ratio
Prevalence 21.8% (n=34) among those
with T score <-1.0
Spine
Hospital-based case series in Germany of patients
with T score <-1.0 (n=156)
Klaus et al
[33]
Prevalence overall 14%
25/179 steroid-free (14%)
13/89 steroid dependent (14.6%)
HR 2.08 [1.36 – 3.18]
Adjusted HR 1.68 [1.01 – 2.78]
OR 1.4 [1.2 – 1.6]
OR 1.9 [1.1 – 3.2]
OR 1.45 [1.0 – 2.0]
OR 1.86 [1.08 – 1.21]
UK population-based cohort study using GPRD
Hip
(n=5960 Crohn’s disease; n=8301 ulcerative colitis;
indeterminate n=2289)
All
Spine
Radius
Hip
RR 0.9 [0.6 – 1.4]
RR 2.2 [0.9 – 5.5]
RR 1.8 [0.5 – 6.1]
RR 0.2 [0.03 – 2.2]
IRR 1.36 [1.17 – 1.59]
IRR 1.54 [1.04 – 2.30]
IRR 1.30 [1.01 – 1.66]
IRR 1.47 [1.03 – 2.10]
IRR 1.19 [1.06 – 1.33]
IRR 1.87 [1.24 – 2.82]
IRR 1.04 [0.76 – 1.43]
IRR 1.10 [0.87 – 1.38]
RR 1.7 [1.2 – 2.3]
Women RR 2.5 [1.7 – 3.6]
Postmenopausal RR 1.8 [1.0 – 3.3]
Family history RR 2.4 [1.4 – 4.1]
Current smoking RR RR 1.3 [0.6 – 2.8]
RR 6.7 [2.1 – 21.7]
RR 2.0 [0.8 – 5.1]
RR 1.5 [0.2 – 11.7]
Fracture risk in Crohn’s disease [95% CI]
Card et al
[32]
Van Staa et al UK population-based cohort study using GPRD
(n=725 Crohn’s disease; n=1305 ulcerative colitis)
[31]
All
Spine
Forearm
Hip
Canadian population-based cohort study (n=6027)
Bernstein et
al [29]
All
Spine
Forearm
Femur
All
Spine
Colles
Femur
Spine
Forearm
Femur
All
Fracture
Vestergaard et Danish in-patient registry of Crohn’s disease
al [28]
(n=7072) and ulcerative colitis (n=8323)
Vestergaard et Population-based survey of Danish Crohn’s
al [27]
(n=383) Colitis (n=434) Association members
Authors
Table 2: Occurrence of osteoporotic fractures in IBD
HR 1.49 [1.04 – 2.15]
Adjusted HR 1.41 [0.94 – 2.11]
OR 1.2 [1.05 – 1.3]
OR 1.4 [0.9 – 2.2]
OR 1.2 [0.9 – 1.5]
OR 1.40 [0.92 – 2.13]
IRR 1.45 [1.26 – 1.67]
IRR 1.90 [1.36 – 2.65]
IRR 1.36 [1.06 – 1.73]
IRR 1.69 [1.26 – 2.28]
IRR 1.08 [0.97 – 1.20]
IRR 1.04 [0.67 – 1.62]
IRR 1.02 [0.76 – 1.37]
IRR 1.08 [0.88 – 1.32]
RR 1.1 [0.8 – 1.6]
Women RR 1.1 [0.7 – 1.8]
Postmenopausal RR 0.6 [0.3 – 1.6]
Family history RR 1.9 [1.0 – 3.5]
Current smoking RR 3.8 [1.9 – 7.8]
RR 2.4 [0.5 – 11.9]
RR 1.2 [0.1 – 13.8]
RR 0.6 [0.1 – 4.9]
Fracture risk in ulcerative colitis [95% CI]
3
4
NR Lewis, BB Scott
Table 3: Cross-sectional survey of the prevalence of reduced BMD in Crohn’s disease patients using DEXA
Authors
Country
Pigot et al [35]
France
Ghosh et al [36]
Scotland
Bernstein et al [37] USA
Number DEXA site
of
patients
27
Spine
Femoral neck
15
Spine
Forearm
26
Spine
Total hip
14
Spine
Femoral neck
78
Spine
73 6
Femoral neck
Mean age
(years)
+/- SD
34 +/-13
Mean disease
duration
(years) +/- SD
5.3 +/-6.3
24
0.36
38.6 +/-8.7
40.8 +/-9.3
11.5 +/-6.0
13 +/-8.4
11.8+/-7.2
Roux et al [38]
France
Silvennoinen et al
[39]
Finland
Staun et al [40]
Denmark
40 1
68 2
Spine
Femoral neck
40.1 +/-13.2
36.5 +/-12.3
Jahnsen et al [41]
Norway
60
60 6
Spine
Femoral neck
36
36 6
Robinson et al [42] England
117
40.6 +/-13
9.6
Schulte et al [43]
Germany
104
38 +/-15
11.5 +/-8
Schulte et al [44]
Germany
61
Pollak et al [45]
Israel
33
Dinca et al [46]
Italy
54
Spine
Femoral neck
Trochanter
Spine
Femoral neck
Spine
Femoral neck
Spine
Femoral neck
Spine
Lee et al [47]
Korea
14
Spine
Femoral neck
Spine
Femur
Total body
Spine
Femoral neck
Spine
Femoral neck
Total body
Spine
Femoral neck
Total hip
Spine
Femoral neck
Total body
Spine
Femoral neck
Spine
Femoral neck
Total body
Spine
Total hip
Spine
Femur
Spine
Femoral neck
Wrist
Spine
Femoral neck
Total hip
Spine
Femoral neck
Total body
Femoral neck
Spine
2.17 +/-0.25
Ardizzone et al [48] Italy
51
Schoon et al [49]
Netherlands
24
Schoon et al [50]
Netherlands
119
Haugeberg et al
[51]
Norway
55
Schoon et al [452]
Netherlands
26
De Jong et al [53]
Netherlands
91
Jahnsen et al [54]
Norway
60
Habtezion et al [55] Canada
168
De Jong et al [56]
Netherlands
29
Tobias et al [57]
England
15
Siffledeen et al [58] Canada
242
Jahnsen et al [59]
60
Norway
Van Hogezand et al Netherlands
[60]
146
37.4 +/- 4.9
8.4 +/-8.1
39 +/-2
6.6 +/-0.7
38.7 +/-13.2
39.4 +/-11.6
29.7 +/-10.4
7.0 +/-5.6
42 +/-14
10.5 +/-8.8
38.5 +/-12.7
9.1 +/-7.4
38 +/12
16 +/-8
41.3 +/-13.3
11.6 +/-8.5
36
10
33
8
40.8 +/-12
11.3 +/-8.3
35.1 +/-14.5
7.1 +/-5.8
3.7 /-12.3
11.1 /-.7
36
10
43.5
20
0.41
Mean
Z-score
Mean
T-score
% osteoporosis
% osteopenia
12
29
15
12
36
-2.26
-2.49
-1.16
57.6
36.4
5.5
42.5
-0.96
-0.07
-1.49
-1.80
0
50
37
55
-0.42
-0.96
-0.50
7
11
6
5.5
9.1
5.5
15
4
8
20
25
22
41
27
10
11
45
40
-1.29
-1.07
-1.06
-0.67
9.5
7.9
5.9
3
44. 8
38.3
46
27.8
-1.43
-0.95
19
15
45
33
-1.11
-0. 83
-1.1
-1.1
-1.1
-1.5
-1.12
-1.01
-0.18
0.406
-0.43
0.12 6
-0.51
-0.80
-1.24
-1.23
-0.07 3,5
-0.52 4,5
-0.17 3,5
-0.97 4,5
-0.09
-0.20
-0.30
-0.70
-0.55
-1.4
-1.8
-0.90
-0.61
0.03
-1.24
-1.24
0.5
0.13
0.0
0.00
-0.52
-0.27
-0.51
-0.58
-0.23
-0.43
-0.90
-0.38
-1.1
-1.1
0.05
-0.61
-0.68
-0.71
-1.03
-0.67
23
31
27
40
47
-1.6
-1.4
-0.38
-0.55
-0.34
-0.61
-0.68
-0.58
-0.44
Patients with a preserved colon; 2Patients with a resected colon; 3did not receive steroids; 4received steroids; 5p < 0.05 on comparison of z-score with controls; 6control
1
June 2007
5
Table 4: Cross-sectional survey of the prevalence of reduced BMD in ulcerative colitis using DEXA
Study and year
Country
Number of
patients
DEXA site
Mean age
(years)
+/- SD
Mean disease Mean
duration
Z-score
(years) +/- SD
Mean
T-score
% osteo- % osteoporosis penia
Dinca et al [46]
Italy
49
Spine
38 +/-2
8 +/-1
-0.63
-0.75
6
32
Ghosh et al [36]
Scotland
15
Spine
Forearm
28
0.24
-0.03
0.03
Bernstein et al
[37]
USA
23
Spine
Total hip
-1.0
-1.1
Roux et al [38]
France
9
Spine
Femoral neck
-0.37
-0.28
67
73 5
Spine
Silvennoinen et al Finland
[39]
42.0 +/-9.6
40.8 +/-9.3
11.5 +/-6
Femoral neck
Jahnsen et al [41] Norway
60
60 5
Spine
0.36
0.40 5
-0.38
0.12 5
0.06 6,8
0.29 7,8
0.09 6,8
0.16 7,8
38
36 5
Femoral neck
Pollak et al [45]
Israel
26
Spine
Femoral neck
37.8 +/-14.2
10.4 +/-8.2
-0.48
-1.26
-1.6
-2.09
50
34.6
Lee et al [47]
Korea
25
Spine
Femoral neck
36 +/-10
1.3 +/-0.8
-0.58
0.14
-0.70
-0.12
8
44
Ardizzone et al
[48]
Italy
40
Spine
Femur
34.4 +/-12.5
70.9 +/-44
-1.44
-1.20
-1.67
-1.60
18
67
Schoon et al [49] Netherlands 44
Total body
Spine
Femoral neck
38.4 +/- 14.4 0.28
-0.25
0.13
0.25
Jahnsen et al [54] Norway
60
Spine
Femoral neck
Total body
38
7
0.53
0.08
0.03
Kuisma et al [62] Finland
20 ileostomy Lumbar
14 IPAA 1
47 IPAA 2
27 IPAA 3
Ileostomy
Femoral neck
IPAA 1
IPAA 2
IPAA 3
52.6
47.1
46.3
44.7
4 +/-1.3
8.6 +/-1.5
7.6 +/-0.8
5.2 +/-1.1
0.2
0.7
-0.03
-0.3
0.4
0.2
-0.1
-0.1
Schulte et al [43] Germany
45
Spine
Femoral neck
Ulivieri et al [61] Italy
43
121 control
Spine
9
4
35.9
Total body
8
-0.59 male 4
-0.05 female 4
-0.93 male 4
-1.23 female 4
IPAA Ileal pouch anal anastomosis with 1normal 2partial 3severe pouch mucosal inflammation; 4BMD values not statistically different from controls;
5
control; 6did not receive steroids; 7received steroids; 8p < 0.05 on comparison of z-score with controls
years of age (n=107). These findings are supported by
Haugeberg et al [51] who found the mean age at diagnosis in
patients with reduced BMD in Crohn’s disease was 24.3 years
in comparison to 32.4 years in those with normal BMD
(p=0.02).
3.2.2.3 Weight, height and body mass index
3.2.2.2 Gender
BMD was inversely related to duration of disease in most of
the studies [45, 48, 56, 60] but not in all [44, 63]. There are
few studies that have assessed bone mineral density at diagnosis of IBD. One small study observed that 2 of 15 and 1 of
12 patients with Crohn’s disease at diagnosis had a Z-score
<-2.0 at the spine and forearm respectively, though the sample size is probably too small to make any meaningful
conclusions [36]. Schoon et al [49] evaluated 24 patients with
Crohn’s disease and 44 patients with ulcerative colitis within
6 months of diagnosis and observed no significant difference
between the patients with Crohn’s disease, ulcerative colitis
The majority of studies observed that BMD was reduced
significantly more in males with Crohn’s disease in comparison to females [41, 42, 48, 50, 58]; similar observations were
found in ulcerative colitis [41, 48]. Although previously undiagnosed hypogonadism is an uncommon cause of low BMD in
men with Crohn’s disease, one study found 6% had secondary
hypogonadism who might benefit from replacement therapy
[65]. Testicular function may also be impaired by steroids [66,
67].
June 2007
Lower body mass index [36, 49, 53, 58, 59, 64, 68], lower
height [57, 64] and lower body weight [42, 51, 57, 63, 64]
have been shown to be associated with reduced BMD.
3.2.2.4 Duration of disease
6
NR Lewis, BB Scott
Table 5: Pooled analysis of BMD in inflammatory
bowel disease
Analysis
Weighted Number of
mean
studies
value
(number of
patients)
Crohn’s disease
Spine Z-score
Hip Z-score
Spine T-score
Hip T-score
Osteoporosis spine (%)
Osteoporosis hip (%)
Osteopenia spine (%)
Osteopenia hip (%)
-0.5
-0.7
-1.1
-1.3
12
13
36
44
23 (1283)
21 (1209)
8 (685)
7 (413)
12 (1169)
9 (1002)
11 (1114)
7 (843)
Ulcerative colitis
Spine Z-score
Hip Z-score
Spine T-score
Hip T-score
Osteopenia hip (%)
-0.1
-0.3
-1.2
-1.3
15
11
36
67
13 (542)
10 (435)
4 (140)
3 (91)
4 (145)
2 (85)
3 (100)
1 (40)
Mean
age
Mean
disease
duration
36 years
10 years
40 years
12 years
and a control group, though sample size and selection bias
may have affected the results.
3.2.2.5 Disease site, activity, severity and previous surgery
Disease site (small bowel, ileal, colonic) had no effect on BMD
[36, 42, 59, 60, 69]. However, a higher prevalence of osteoporosis
was observed in patients with Crohn’s disease who had undergone
an ileal resection with or without a concomitant colon resection
[60]. Patients with previous bowel resection were observed to have
reduced BMD in some [42, 51, 56, 62] but not all studies [35, 41,
48, 59, 63]. Other markers of disease activity such as reduced albumin [51, 64], higher white cell counts [58], higher platelet counts
[58], higher bowel movements [70], higher IL-6 levels [45] and
higher CRP [59] were associated with reduced BMD. Furthermore,
in patients with an ileal pouch-anal anastomosis after proctocolectomy for UC, BMD was significantly reduced in those with
compared with those without pouchitis [62], suggesting that
inflammation adversely affects bone health.
3.2.2.6 Corticosteroid use
Cumulative corticosteroid dose is usually associated with
reduced BMD in Crohn’s disease and ulcerative colitis [34, 35,
39, 42, 44, 46, 48, 51, 58, 59, 60, 63, 64, 68, 71], although de Jong
et al [53] found no correlation in Crohn’s disease after adjusting
for BMI and history of bowel resections. Since corticosteroids
are more likely to be given to patients with increased disease
activity, the role of corticosteroids, disease activity and disease
severity are difficult to separate as independent factors associated with reduced BMD. Treatment with budesonide was
associated with significantly higher BMD compared with prednisolone, though of equal clinical efficacy, in corticosteroid-naïve
patients with active ileocaecal Crohn’s disease [72].
3.2.2.7 Reduced physical activity
Physical activity is an important determinant of bone
health [73]. This is often reduced in IBD, perhaps because of
weakness, fatigue, pain, diarrhoea or nausea.
3.2.2.8 Smoking
No relationship between smoking and BMD was observed
where it was studied [36, 42, 58-60].
3.2.3 Other risk factors for fracture independent of low BMD
Although BMD is an important and measurable predictor of
fracture, it is clear that other risk factors for osteoporotic fracture are involved in IBD:
3.2.3.1 Age
As expected, fracture rates in patients with Crohn’s disease
and ulcerative colitis increase with advancing age [29, 30, 32-34].
3.2.3.2 Gender
The majority of the studies observed similar risks of fracture in
men and women with IBD [29–33] whereas one [27] observed
an increased risk in women with Crohn’s disease but not in men.
Table 6: Occurrence of fractures in coeliac disease
Authors
Study population
Vasquez et al [74]
Hospital-based case series in Argentina
(n=165 with 165 subjects with functional
gastrointestinal disorder used as controls)
Fickling et al [75]
Hospital-based case series survey in England
(n=75 with 75 age- and sex-matched controls)
Thomason et al [76]
Population-based survey in England
(n=244 with 161 age- and
sex-matched controls)
West et al [77]
Population-based cohort study using GPRD
Moreno et al [78]
Hospital-based case series in Argentina
(n=148 with 292 age- an sex-matched controls
with functional gastrointestinal disorders)
Vestergaard et al [79] Hospital-based in-patient registry in Denmark
Davie et al [80]
Ludvigsson et al [81]
Female patients aged > 50 (n=383) and
controls (n=445)
Population-based cohort study in Sweden
(n=13,000 with 65,000 age- and
Fracture
Peripheral skeleton
Spine
Fracture risk (95% CI)
OR 3.5 (1.8 – 7.2)
OR 2.8 (0.7 – 11.5)
Any
X2 = 10.7 p=0.0004
Any
Forearm
OR 1.05 (0.68 – 1.62)
OR 1.21 (0.66 – 2.25)
Any
Hip
Ulna, radius
Any
HR 1.30 (1.16 – 1.46)
HR 1.90 (1.20 – 3.02)
HR 1.77 (1.35 – 2.34)
OR 5.2 (2.8 – 9.8) classic CD
OR 1.7 (0.7 – 4.4) silent CD
Any
Spine
Colles
Femoral neck
Any
IRR 0.70 (0.45 – 1.09)
IRR 2.14 (0.70 – 6.57)
IRR 2.00 (0.58 – 6.91)
IRR 0.71 (0.27 – 1.89)
OR 1.51 (1.13-2.02)
Any
Hip
HR 1.4 (1.3 – 1.5)
HR 2.1 (1.8 – 2.4)
RR = relative risk; IRR = incidence rate ratio; OR = odds ratio; HR = hazard ratio
June 2007
7
Table 7: BMD in untreated coeliac disease in published studies
Study
Country
Mazure et al [82] Argentina
Number of DEXA site
patients
28
Lumbar
Total skeleton
Gonzalez et al
[83]
Mautalen et al
[84]
Bai et al [85]
Argentina
20
Argentina
14
Argentina
25
Fornari et al [86]
Argentina
16
Vasquez et al [75] Argentina
51
Corazza et al [87] Italy
14 silent
10 classic
20
Corazza et al [88] Italy
Di Stefano et al
[89]
Di Stefano et al
[90]
Italy
16
Italy
21 silent
18 classic
Spine
Total skeleton
Spine
Total skeleton
Spine
Total skeleton
Spine
Total skeleton
Spine
Total skeleton
Spine
Spine
Spine
Femur
Spine
Femur
Spine
Femur
Sategna-Guidetti Italy
et al [91]
Walters et al [92] England
86
10
Spine
Femur
Spine
Femur
Lewis et al [93]
England
43
Spine
Femur
Valdimarsson et al Sweden
[94]
63
Mean
Z-score
All -1.98
Asymptomatic -1.05
Symptomatic -2.37
All -2.16
Asymptomatic -1.54
Symptomatic -2.41
-2.5
-2.9
-1.3
-1.5
-1.9
-2.2
29
-1.3
-2.0
-1.3
-2.6
Kemppainen et al Finland
[97]
Meyer et al [98] USA
28
105
31
% osteopenia
0
80
-2.0
-2.0
-1.70
-1.93
-2.5 classic
-1.1 silent
-2.5 classic
-1.2 silent
-1.5
-1.8
-1.85 women
-0.95 men
-0.89 women
-0.95 men
-0.26
0.22 women
-1.16 men
-0.36 classic
0.13 silent
0.04
0.22 women
-1.04 men
0 classic
0.15 silent
Spine
Spine
Total hip
Spine
Total hip
Forearm
Spine
Femur
Spine
Femoral neck
Radius
Mean %osteoT-score porosis
-1.6
-2.4
-1.7
-1.4
26
40
14
40
7
36
33
0
34
27
36
49
54
38
44
32
-0.63
-0.57 women
-0.78 men
-0.54
-0.48 women
-0.95 men
Femur
[95]
[96]
Median
Z-score
-1.12
-1.23
-0.72
-0.79
-0.88
3.2.3.3 Corticosteroid use and disease activity
4.0 OSTEOPOROSIS IN COELIAC DISEASE
An increased risk of osteoporotic fracture has been observed
with steroid use in patients with Crohn’s disease and ulcerative colitis [27, 29, 31, 32]. However, neither Loftus et al [30]
nor Stockbrugger et al [34] found that the use of steroids predicted fracture risk. Disease severity, assessed by the presence
of symptoms for IBD, predicted fracture even after adjusting
for corticosteroid use (OR 1.46; 95% CI 1.04 – 2.04) [31].
4.1 ARE FRACTURES A PROBLEM IN COELIAC DISEASE?
June 2007
There are eight studies of fracture prevalence/incidence in
coeliac disease (Table 6) [74 – 81]. A study of 165 coeliac
patients in Argentina [74] found an increased prevalence of
fractures of the peripheral skeleton (odds ratio 3.5; 95%CI 1.87.2) compared with controls. There was also an increase in
fractures of the spine but that was not significant (odds ratio
8
NR Lewis, BB Scott
Table 8: Pooled analysis of BMD in untreated coeliac
disease
Analysis
Untreated coeliac disease
Spine Z-score
Hip Z-score
Spine T-score
Hip T-score
Osteopenia hip (%)
Weighted
mean value
-1.3
-1.1
-1.7
-1.4
26
11
41
43
Number of
studies
(number of patients)
14 (490)
7 (329)
1 (86)
1 (86)
6 (212)
3 (102)
4 (188)
3 (102)
2.8; 95% CI 0.7-11.5). A further study by the same group
showed that the increased fracture prevalence was only found
in those with classical as opposed to subclinical/silent disease
[78]. A study of 75 coeliac patients in England showed 21%
had a history of fracture compared with 3% of controls
(p=0.0004; relative risk 7.0) [75]. A larger study from
England of 244 coeliac patients and 161 controls found no significant difference in the prevalence of fracture (35% v 33%)
[76]. Another study from England [80] of 383 female coeliac
patients aged >50 and 445 controls found a modest increased
prevalence of fracture (Odds ratio 1.51; 95%CI 1.13-2.02). A
whole nation population study from Denmark of 1,021 coeliac
patients and three age and gender matched controls for each
patient demonstrated no increased fracture risk before diagnosis (incidence rate ratio for all fractures 0.7; 95%CI
0.45-1.09) or after diagnosis (incidence rate ratio for all fractures 0.94; 95%CI 0.71-1.24) [79]. A second population-based
study from England, of 4732 coeliac patients and 23,620 controls showed just a small increase in fracture risk (hazard
ratio for any fracture = 1.3; 95%CI 1.16-1.46) [77]. A population-based study from Sweden of 13,000 coeliac patients and
65,000 controls gave a hazard ratio of 2.1 (95% CI 1.8 – 2.4)
for hip fracture and 1.4 (95% CI 1.3 – 1.5) for any fracture
[81]. Spinal fractures (and therefore all fractures) are likely to
be underestimated because all except one study [74] relied on
reports of fracture rather than quantitative morphometry of
spinal x-rays.
We conclude from these studies that there is a definite but
modest increased risk of fracture in coeliac disease, most probably with a relative risk of approximately 1.4 for all fractures.
4.2 RISK FACTORS FOR FRACTURE IN COELIAC DISEASE
4.2.1. Reduced BMD
The prevalence of reduced BMD in untreated patients with
coeliac disease observed in published studies [82-98] is summarised in table 7; pooled results are given in table 8.
However there are limitations with these studies. Many of the
studies are small with only 1 of the 18 studies having a sample size above 100 patients with untreated coeliac disease.
Most of the studies are based on observations from specialist
coeliac disease clinics and may not reflect the true risk. Only
4 of the studies included a control group. However, they do
suggest that there is a moderate reduction of BMD in
untreated coeliac disease with mean Z-scores at the lumbar
spine and hip of -1.3 and -1.2 respectively. Since BMD has
been shown to increase significantly on a gluten-free diet the
mean Z-score of treated patients is likely to be significantly
higher.
Box 3: Summary of recommendations for
preventing fracture in adults with IBD
General advice
• Encourage frequent weight bearing exercise (including
walking, using stairs, gardening and housework) (B)
• Ensure nutritious diet (C)
• Ensure adequate dietary calcium; add calcium
tablets (e.g. Adcal chewable tablet and Sandocal-400
effervescent tablet which provide 600mg and 400mg
calcium respectively) if necessary to ensure daily intake
of 1000mg (1200mg for postmenopausal women and
men>55) (B)
• Seek (check calcium, ALP and then consider PTH) and
treat vitamin D deficiency (B)
• No smoking (B)
• Avoid alcohol excess (C)
Treat IBD energetically to achieve/maintain
remission (C for BMD)
Steroid avoidance:
• Early use of azathioprine/mercaptopurine
• Use steroids sparingly; consider budesonide instead
of prednisolone for small bowel and caecal Crohn’s
• Consider elemental or polymeric diet before steroids
in Crohn’s disease
• Consider biologic therapy or surgery if steroid-free
remission not achieved
For those on steroids:
• All >65: consider bisphosphonate at commencement
of steroids (A)
• <65 at high risk and requiring steroids >3 months:
DEXA and consider bisphosphonate if T-score<-1.5 (D)
• Give vitamin D and calcium (e.g. Adcal D3 or
Calcichew D3 Forte I bd) whilst on steroids (D)
DEXA for those at higher risk of osteoporosis e.g.
1
2 or more of (but also refer to Boxes 1&2):
• Continuing active disease
• Weight loss >10%
• BMI < 20
• Age >70
Treatment of osteoporosis if low-T score2 on DEXA
and risk factors, or if prior fragility fracture:
• Oral bisphosphonate long term3 e.g. weekly
risedronate or alendronic acid (B)
• Intolerance of oral bisphosphonate: consider
3-monthly iv ibandronic acid or an alternative class
of drug (see below)
• Intolerance or failure of bisphosphonate in
postmenopausal women or men aged >55 consider:
• Raloxifene (for postmenopausal women long
term) (B)
• Teriparatide (by daily injection for 18 months)
(B)
• Calcitonin by intranasal spray(B)
• Men with low BMD: check blood testosterone and
replace if low (C)
Grade of recommendation A,B,C or D according to
Oxford Centre for Evidence-based Medicine
1
This is a suggestion in the absence of firm evidence
There is no single T-score threshold below which treatment must be
given. If risk factors are substantial, T-score of <-1.5 might be
appropriate; if risk factors are slight, T-score of <-3.0 might be
appropriate. Age particularly should be taken into account
3
But see text for duration of treatment, especially in younger patients
2
June 2007
Box 4: Summary of recommendations for
preventing fracture in adults with coeliac disease
General advice
• Encourage frequent weight bearing exercise
(including walking, using stairs, gardening and
housework) (B)
• Ensure nutritious diet (C)
• Ensure adequate dietary calcium; add calcium
tablets (e.g. Adcal chewable tablet or Sandocal-400
effervescent tablet which provide 600mg and 400mg
calcium respectively) if necessary to ensure daily intake
of 1000mg (1200mg for postmenopausal women and
men>55)(B)
• Seek (check calcium, ALP and then consider PTH) and
treat vitamin D deficiency (B)
• No smoking (B)
• Avoid alcohol excess (C)
Strict gluten-free diet (B for BMD)
DEXA for those at higher risk of osteoporosis
e.g. 1 2 or more of (but also refer to Boxes 1&2):
• Persisting symptoms on gluten-free diet for 1 year
or poor adherence to gluten-free diet
• Weight loss >10%
• BMI < 20
• Age >70
Treatment of osteoporosis if low T-score2 on DEXA
and risk factors, or if prior fragility fracture:
• Oral bisphosphonate long term3 (e.g. weekly
risedronate or alendronic acid) (B)
• Intolerance of oral bisphosphonate: consider 3monthly iv ibandronic acid or an alternative class of
drug (see below)
• Intolerance or failure of bisphosphonate in
postmenopausal women or men aged >55 consider:
• Raloxifene (for postmenopausal women long
term) (B)
• Teriparatide (by daily injection for 18 months)
(B)
• Calcitonin by intranasal spray (B)
• Men with low BMD: consider hypogonadism–check
blood testosterone and replace if low (N.B. a normal
level does not exclude hypogonadism because there appears
to be androgen resistance, especially before treatment with a
GFD) (C)
Grade of recommendation A,B,C or D according to
Oxford Centre for Evidence-based Medicine
1
This is a suggestion in the absence of firm evidence
There is no single T-score threshold below which treatment must be
given. If risk factors are substantial a T-score of <-1.5 might be
appropriate; if risk factors are slight a T-score of <-3.0 might be
appropriate. Age in particular should be taken into account.
3
But see text for duration of treatment, especially in younger patients.
2
4.2.2 Factors affecting low BMD in coeliac disease
4.2.2.1 Years exposed to gluten
BMD has not been observed to be related to years exposed
to gluten [82, 84, 89, 93, 98].
4.2.2.2 Gender
BMD was significantly lower in men with coeliac disease
than in females in one study [93] whereas the converse was
found in another [90]. No difference between genders was
seen in most studies [91, 94, 97, 98, 102]. Hypogonadism may
June 2007
9
be a factor in men, as in postmenopausal women. However, in
untreated men with coeliac disease serum testosterone may
be high due to androgen resistance [100] and therefore a normal value cannot exclude hypogonadism. This may be due to
impairment of peripheral reduction of testosterone to the
active dihydrotestosterone.
4.2.2.3 Body Mass Index (BMI)
Low weight [97] and low BMI [90, 93] have both been
associated with reduced BMD.
4.2.2.4 Degree of villous atrophy
BMD did not differ according to the degree of villous atrophy in one study [93] but BMD was observed to be more
reduced in severe compared with mild villous atrophy in
another [89].
4.2.2.5 Symptomatic disease
Classic symptoms were associated with lower BMD in some
studies [82, 87,90] but not all [84, 93, 94, 98].
4.2.2.6 Adherence to a gluten-free diet
There is a significant improvement in BMD after introduction of a gluten-free diet [85, 91, 94, 99, 101, 102].
5.0 PREVENTION OF OSTEOPOROSIS IN IBD AND
COELIAC DISEASE
5.1 GENERAL MEASURES
Education on the importance of lifestyle changes such as
avoiding alcohol excess, smoking cessation and taking regular
weight-bearing exercise should be given [103]. It is difficult to
make precise recommendations for exercise but at the very
least patients should be encouraged to walk and use stairs
more and to undertake mundane tasks such as housework
and gardening. Dancing, participation in active sports and
attending keep-fit classes are other activities which should
give additional benefit. However, no large study has established whether such interventions reduce fracture risk [104].
Risk assessment should be made in those at increased risk of
falling and appropriate measures introduced. The other main
risk factors for fracture (and low BMD) which are particularly
operative in IBD and coeliac disease and which can be corrected include poor nutrition, low BMI and, in IBD, steroid
use. Thus the main thrust of management to prevent osteoporosis is effective management of the underlying disease,
ensuring good nutrition (particularly with regard to calcium
and vitamin D) and remission of disease, and, in IBD, the
avoidance of steroids as far as possible. In coeliac disease the
importance of a strict gluten-free diet should be stressed.
5.2 CALCIUM
Calcium supplements of 500-2000mg daily have been shown
to have small beneficial effects on bone mineral density in
postmenopausal women in general and a trend towards
reduction in vertebral fractures [105]. There are grounds for
ensuring adequate calcium intake particularly in coeliac disease and Crohn’s disease since anorexia may lead to poor
dietary intake and small bowel disease may lead to malabsorption. A dietary assessment may help to ensure an
adequate daily intake. Although there is controversy over
exact requirements [106–109], 1000 mg daily seems a reasonable aim although, for post-menopausal women and elderly
men, a higher intake of 1200 -1500 mg daily has been recommended [110, 111]. Since milk and milk products provide
most dietary calcium, supplements should be considered
where these are avoided, especially in those with symptomatic
lactose intolerance [112].
10
5.3 VITAMIN D
Vitamin D deficiency causing osteomalacia should be sought
and treated if found. Clinicians usually rely on serum calcium,
phosphate and alkaline phosphatase (ALP) measurements
but osteomalacia may still exist even if these tests are normal.
When these tests are normal and osteomalacia is still suspected serum 25-hydroxy vitamin D is usually measured but
the assay is poorly standardised and is expensive. An alternative, and an approach which is useful in the commoner
situation of vitamin D insufficiency (where secondary hyperparathyroidism is needed to maintain calcium homeostasis in
the presence of an inadequate vitamin D intake), is to measure serum calcium and parathormone (PTH). This is cheap
and reliable and the combination of a normal calcium and an
elevated parathormone indicates secondary hyperparathyroidism, and treatment with vitamin D (800–1000 units daily)
together with 1G calcium daily should be given (e.g. using
Adcal D3 or Calcichew D3 Forte which provide 400 units of
vitamin D per tablet and 600 mg and 500 mg of calcium per
tablet respectively).
5.4 STEROID AVOIDANCE IN IBD
With a view to avoiding or reducing steroid use, azathioprine/mercaptopurine should be considered at an early stage.
Dietary treatment [113] including elemental, half elemental
and polymeric diets [114–116] should be considered in
Crohn’s disease. Where appropriate, budesonide should be
used before prednisolone [72]. Any steroid should be used in
the lowest effective dose for as short a time as possible.
Biologic therapy and surgery should be considered for
patients who cannot achieve steroid-free remission.
5.5 BONE-PROTECTIVE MEASURES DURING STEROID USE
IN IBD
During steroid use, we recommend that the Royal College of
Physicians guidelines should be followed [117]. These recommend that treatment with a bisphosphonate should be
considered when commencing steroids for all aged over 65
and all who have had a fragility fracture. In those under 65,
who are likely to need steroids for more than three months, a
risk assessment incorporating age should be made and, in
those at higher risk, DEXA should be done and a bisphosphonate considered if the T-score is <-1.5. We recommend
(without evidence) that the bisphosphonate is only given
whilst the patient is on steroids, unless the bisphosphonate is
advised on other grounds.
Although the evidence is not strong, we recommend the use
of calcium and vitamin D (e.g. Adcal D3 1 bd or Calcichew D3
Forte 1 bd) during steroid use. Four [118–121] of nine studies
[118–126] showed a beneficial effect on BMD but no study
has looked at fracture reduction. However, at the dose recommended, they are unlikely to do harm and they may correct
unsuspected calcium and vitamin D deficiency which are not
unusual in Crohn’s disease.
6.0 DETECTION OF OSTEOPOROSIS IN IBD AND COELIAC
DISEASE
6.1 INDICATIONS FOR DEXA
The modest increased risk of fracture and reduced BMD in
IBD and coeliac disease cannot justify routine DEXA in all
patients. Since the main reason for assessing BMD is to plan
specific treatment for osteoporosis and so to prevent fracture,
it is more appropriate to select those patients for scanning
who are most at risk of fracture. Although many risk factors
are known, it is difficult to assess their relative importance
and thereby to produce a reliable scoring system to select
those most at risk. There is clearly a need to develop and validate such a scoring system. (It is expected that WHO will
NR Lewis, BB Scott
make a 10-year fracture risk calculator available in 2007.)
Reduced BMD, as explained earlier, is just one risk factor for
fracture and there is no particular threshold BMD below
which treatment must be given. Although not designed to be
used as a treatment threshold, a T-score <-2.5 is often used as
such. However, the BMD should probably be considered
together with other risk factors before deciding on treatment.
Treatment might therefore be offered to one patient with a
slightly reduced BMD (e.g. T = -1.5) if there are many other
risk factors and another might be treated if the BMD is very
low (e.g. T = -3.0) with few other risk factors. As illustrated
in Table 1, the significance of any T-score for predicting fracture is very much dependent on the age, which should always
be taken into account. All patients who have sustained a
fragility fracture should be considered for treatment even
without DEXA, if waiting for that would delay treatment
6.2 SPECIAL CONSIDERATIONS IN IBD
Without a reliable scoring system, common sense suggests
that patients with the features shown in Boxes 1 and 2, such
as age over 70, together with those with very active disease,
those with disease responding poorly to treatment, and those
with poor nutrition should be considered for DEXA. Those
requiring steroids need special consideration.
6.2.1 DEXA in steroid treated patients
Not all corticosteroid-treated patients develop osteoporosis
[40, 43, 46, 127] though the dose dependence of corticosteroid-induced fractures and the increased risk of vertebral
fractures even for prednisolone doses between 2.5 – 7.5
mg/day suggests that there is no safe dose of oral corticosteroids [25] emphasising the importance of evaluating
fracture risk in all individuals using oral corticosteroids. Since
rates of bone loss are greatest in the first few months of corticosteroid administration and bone loss is related to
cumulative dose and duration of corticosteroids [24, 128],
prevention of bone loss and fractures should be carefully evaluated at corticosteroid introduction.
Guidelines already exist for DEXA in patients on steroids in
general. The UK Consensus Group recommended DEXA in all
patients taking 7.5mg or more of prednisolone daily for 6
months or more with a view to giving a bisphosphonate if the
T-score <-1.5 [129]. The later Royal College of Physicians
guidelines [117] recommend that treatment with a bisphosphonate should be considered for all aged over 65 years on
commencing steroids (or those under 65 who have had a
fragility fracture), thus restricting DEXA to those under 65 at
higher risk who require steroids in any dose for at least three
months.
Because of the unpredictability of steroid requirements in
IBD and because bone loss from steroids may occur early, we
recommend DEXA in all those aged <65 who are at higher
risk of osteoporosis (i.e. by virtue of greater age, severity of
disease, low body weight etc.) when they are prescribed
steroids which are likely to be continued for three months, to
help decide whether they would benefit from a concurrent
bisphosphonate. Corticosteroid-induced bone loss continues,
albeit at a slower rate, after the first year of therapy [130,
131]. We therefore recommend that in those at high risk,
especially if the dose of steroid is high and the initial T-score
approaches the threshold, a DEXA is repeated in each subsequent year of corticosteroid use or until the intervention
threshold (e.g. T-score <-1.5) is reached.
6.3 SPECIAL CONSIDERATIONS IN COELIAC DISEASE
Since there is only a small increase in fracture risk and since
prospective studies have demonstrated a significant improvement in BMD and calcium absorption after introduction of a
gluten-free diet [85, 91, 94, 97, 99, 101, 102, 132], DEXA
should only be done after introduction of a gluten-free diet on
June 2007
the subgroups of patients in whom the risk of osteoporotic
fracture is high. As with IBD, although many risk factors are
known, it is difficult to assess their relative importance and
thereby to produce a reliable scoring system to select those
most at risk. Without a reliable scoring system common sense
suggests that patients with the features shown in Boxes 1 and
2 such as age over 70 years, together with those with symptoms responding poorly to a gluten-free diet or not adhering
to a gluten-free diet, especially those with a low BMI, should
be considered for DEXA.
7.0 TREATMENT OF OSTEOPOROSIS
Treatment should be offered if there is a reduced BMD
together with other risk factors for fracture. The more the risk
factors and the greater their degree, the higher the BMD
threshold for treatment.
There are many specific treatments for osteoporosis. Their
effectiveness has largely been established in postmenopausal
women and, in the UK, most treatments are licensed only for
postmenopausal osteoporosis. The spectrum of anti-fracture
efficacy differs between drugs, with only alendronic acid, risedronate and strontium ranelate having been shown to reduce
hip fractures. None has been studied looking for fracture
reduction in coeliac disease, but one study [133] has looked at
fracture reduction (with the bisphosphonate, risedronate, in
postmenopausal osteoporosis) in IBD. Thus it has been necessary to extrapolate from the published studies. There is no
theoretical reason why these treatments would not be as
effective in older men (e.g. over 55 years) as in postmenopausal women. Furthermore, there is no reason to
suspect that IBD and coeliac patients would benefit less than
patients with osteoporosis from other causes.
It is more difficult to make recommendation in premenopausal women and men under 55 years. There are
acceptable guidelines for younger patients on steroids.
Caution is urged in other situations until appropriate trials
have been done. In the meantime, treatment should be considered and discussed with younger adult patients if the risk
profile, including a T-score <-2.5, is very bad, especially if they
have already experienced a fragility fracture.
Support for this policy, with regards to bisphosphonates
only, comes from recent studies of the bisphosphonate, alendronic acid, in men. Orwoll et al in a two-year double blind
trial of alendronic acid or placebo, studied 241 men with
osteoporosis aged 31 to 87 years (mean 63) [134]. They found
that alendronic acid significantly increased BMD and helped
prevent vertebral fractures. As a consequence of this, alendronic acid was approved in the USA for the treatment of
osteoporosis in men in 2000. Ringe et al, comparing alendronic acid with alfacalcidol in an open-label prospective
study over three years in 134 men with a mean age of 53
years, showed a significantly greater increase in BMD and significantly fewer patients with new vertebral fractures in those
patients on alendronic acid [135].
Further support for use of bisphosphonates in younger
patients and in men comes from the studies of bisphosphonates in IBD [136 – 140] which showed significant increases
in BMD with bisphosphonates and in which there were usually more men than women and the mean ages ranged from
35 to 50 years.
7.1 BISPHOSPHONATES
Bisphosphonates are the first choice treatment. They inhibit
the enzyme in osteoclasts which induce apoptosis and thus
reduce bone resorption. They reduce the risks of both vertebral and non-vertebral fractures [141 – 147]. There are oral
preparations which can be taken daily (cyclical etidronate,
alendronic acid and risedronate), weekly (alendronic acid and
risedronate), or monthly (ibandronic acid), and intravenous
preparations which are given three monthly (ibandronic acid,
June 2007
11
which is licensed and can be given as a push injection over 1530 secs, and pamidronate, which needs to be given over at
least 2 hours). Oral preparations may not be tolerated – often
because of oesophagitis, and they are not well absorbed.
However, one study of absorption in 19 patients with severe
Crohn’s disease [148] found adequate absorption. Five of six
studies have shown significant increases in BMD, three in
Crohn’s disease [136 – 138] and two in mixed IBD [139, 140].
One study of Crohn’s disease [146] found no significant benefit by the addition of etidronate to calcium and vitamin D
supplements. Although no study has looked at fracture reduction in coeliac disease, one study [133] of risedronate in
postmenopausal IBD patients with osteoporosis found a significant reduction in the incidence of vertebral fractures
during one year’s treatment. In high-risk populations of postmenopausal women using an oral bisphosphonate the NNT
for vertebral fracture over a period of two years is 72–96 [144].
Bisphosphonates appear safe, at least during the first ten
years of treatment [150]. There is concern about osteonecrosis of the jaw [151] although this has mainly been reported
with high dose intravenous bisphosphonates for malignancy.
To reduce the risk of osteonecrosis the importance of good
dental hygiene should be emphasised. There is also concern
about possible fractures following the accumulation of
fatigue-induced damage predisposed by prolonged suppression of bone turnover [152]. They should be avoided in
women who could become pregnant because they can cross
the placenta. If tolerated, they are usually given indefinitely.
However, because of uncertainty about side effects in the
longer term (>10 years), especially in younger patients, it
would seem sensible, especially in younger patients (e.g. <65
years), to reassess fracture risk after, say, two years of clinical
remission without steroids and with satisfactory weight gain.
In these circumstances, a T-score on DEXA of >-2.5 would
give reassurance for the discontinuation of treatment, especially since increase in BMD accounts for only a small fraction
of the antifracture efficacy [153]. Biochemical markers of
bone remodelling such as aminoterminal propeptide of type 1
collagen (P1NP) may prove useful in practice to assess the
efficacy of treatment and the need to change to another agent
[154].
7.2 TERIPARATIDE
Teriparatide, a human recombinant parathyroid hormone
given by once daily subcutaneous injection, stimulates both
trabecular and cortical bone formation resulting in improvements in bone microarchitecture. It has been shown to
increase BMD and decrease vertebral and non-vertebral fractures in post-menopausal osteoporosis [155 – 157] with an
NNT for vertebral fractures during 21 months of treatment of
10 (95% CI 7.5–16) and an NNT for non-vertebral fractures
during 19 months of treatment of 27 (95% CI 15-101) [157].
There is concern that teriparatide effects could be reduced by
recent treatment with bisphosphonate [158, 159] making its
use as a second-line agent problematic. It has not been tested
in IBD. It is recommended by NICE for postmenopausal
women >65 years who have had both an unsatisfactory
response to a bisphosphonate and either a T-score <-4 or a T
score <-3 if there are more than two fractures and any additional age-independent risk factor. It is licensed for treatment
for 18 months only. Another recombinant parathyroid hormone preparation (Preotact) has recently been licensed [160].
7.3 RALOXIFENE
Raloxifene is a selective oestrogen receptor modulator. Such
nonhormonal agents bind with high affinity to oestrogen
receptors and exhibit oestrogen-agonist effects on bone and
oestrogen-antagonist effects on endometrium and breast.
Raloxifene increases BMD and reduces vertebral fractures
(NNT over two years = 99 [95%CI 79-145] for a high-risk pop-
12
ulation) [144]. Little effect has been shown on nonvertebral
fractures. There is an increased risk of venous thromboembolism but it does not increase the risk of coronary heart
disease and it reduces the risk of invasive breast cancer [161].
The risk-benefit profiles have been discussed [162]. It has not
been tested in IBD. It is recommended by NICE that raloxifene
should be considered in postmenopausal osteoporosis when
an oral bisphosphonate is contraindicted or if the patient is
unable to physically comply with such treatment.
7.4 CALCITONIN
Calcitonin is a naturally occurring hormone which inhibits
bone resorption by osteoclasts. A meta-analysis [163, 164]
concluded that it likely increases BMD in postmenopausal
women predominantly at the lumbar spine and forearm for
weekly doses greater than 250IU. It also reduces the risk of
vertebral fracture (NNT over 2 years for a high risk population = 99 [95%CI 79-145]) but its effect on non-vertebral
fracture is uncertain. Until recently, in the UK, the more
attractive presentation of intranasal spray (rather than injection) was unavailable and the drug has not proved popular.
7.5 CALCIUM AND VITAMIN D
Calcium supplementation may prevent bone loss in older men
and women [165] but there is no convincing evidence that it
decreases the risk of fracture in patients with osteoporosis.
Vitamin D decreases vertebral fractures in postmenopausal
women (NNT over two years in a high risk population = 94
[95% CI 63-289]) and may also decrease nonvertebral fractures [144, 166].
7.6 STRONTIUM RANELATE
Strontium ranelate seems to have a unique effect in that it
inhibits bone resorption as well as stimulating bone formation. It prevents both vertebral and nonvertebral fractures,
including hip fractures in older women [167 – 169]. It also
causes an impressive increase in BMD but much of this effect
is due to the higher atomic number of the strontium incorporated into bone compared with calcium. Its use is associated
with a small increase in the likelihood of venous thromboembolism. The Scottish Medicines Consortium has advised [170]
that it should be restricted to use when bisphosphonates are
contra-indicated or not tolerated and then only in women
aged over 75 years with a previous fracture and low bone mineral density or in other women at equivalent risk It is licensed
for the treatment of postmenopausal osteoporosis.
7.7 SEX HORMONE REPLACEMENT THERAPY (HRT)
HRT is no longer recommended for osteoporosis in women
because of cardiovascular and breast cancer risks. However,
testosterone treatment should be considered in men with low
blood levels. A daily skin patch is convenient and the dose is
adjusted according to the plasma testosterone. Although previously undiagnosed hypogonadism is an uncommon cause of
low BMD in men with Crohn’s disease, one study found 6%
had secondary hypogonadism who might benefit from testosterone [65]. Detection in untreated coeliac disease is more
difficult because of high testosterone levels due to androgen
resistance [100]. Thus a normal level will not exclude hypogonadism. It is preferable to measure plasma testosterone after
treatment and consider testosterone treatment if low.
NR Lewis, BB Scott
Although there is much repetition between the two summaries, we felt it useful to keep the recommendations for the
two conditions separate so that they can each be copied and
used in the appropriate out-patient clinics.
The recommendations are graded A-D based on the levels of
evidence on which they are made according to the scheme
devised by the Oxford Centre for Evidence-Based Medicine.
Since there is minimal evidence for or against the use of any
treatment in IBD and none in coeliac disease for the prevention of fracture, it has been necessary to extrapolate from the
results of treatments in non G-I patients and from the effects
of treatment on BMD.
9.0 THE PROCESS OF GUIDELINE FORMULATION
The previous guidelines, prepared in 1999 [172] comprehensively reviewed the literature up to that time. We have kept
details of relevant publications since then. In addition, a literature search was conducted using PubMed, Medline and
Ovid databases in 2006 to identify relevant articles in
English. The search terms used were: osteoporosis, osteopenia, fracture, coeliac disease, ulcerative colitis, and Crohn’s
disease. The reference lists of selected articles were also used
to identify other relevant articles. The guidelines have been
formulated for use by all doctors responsible for the management of patients with coeliac disease or inflammatory bowel
disease, whether in primary or secondary care.
10.0 TARGETS FOR AUDIT
• All those over 65 on steroids should either be prescribed a
bisphosphonate or have an adequate explanation in the
case notes why not.
• All patients with coeliac disease should have their serum
calcium and alkaline phosphatase recorded in the notes
and, where the calcium is low and/or the alkaline
phosphatase raised, either serum 25-hydroxy vitamin D or
parathormone should have been measured and an
abnormal result acted upon appropriately.
• All patients with a history of fragility fracture should have
been considered for treatment with a bisphosphonate.
AUTHORS’ AFFILIATIONS
Nina R Lewis, Specialist Registrar in General Medicine and
Gastroenterology, Mid-Trent rotation, Queen’s Medical
Centre, Nottingham NG7 2UH
Brian B Scott, Honorary Consultant Physician, Lincoln
County Hospital, Lincoln LN2 4BJ
Conflict of interest: None
ACKNOWLEDGEMENTS
We thank Professor David Hosking of Nottingham University
Hospitals for advice on the section on vitamin D and osteomalacia (Section 5.3).
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7.8 FLUORIDE
Fluoride treatment leads to a dramatic increase in vertebral
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8.0 SUMMARY OF RECOMMENDATIONS
The main recommendations for preventing fracture are summarised in Box 3 for IBD and Box 4 for coeliac disease.
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16
NR Lewis, BB Scott
APPENDIX 1
Table A1 summarises the levels of evidence according to the Oxford Centre for Evidence-based Medicine.
Table A1
Level
Oxford Centre for Evidence-based Medicine: levels of evidence
Therapy/prevention/
aetiology/harm
Prospective cohort study
with good follow up11
Analysis based on clinically
sensible costs or alternative
systematic reviews of the
evidence and including multiway sensitivity analyses
Absolute better value or
worse value analysis***
SR (with homogeneity*) of
level .2 economic studies
Absolute SpPins and
SnNouts``
level .2 diagnostic studies
All or none case series
Exploratory cohort study
with good1 reference
standards; CDR after
derivation; or validated
only on split samples
or databases
Retrospective cohort study,
or poor follow-up
Individual RCT (with
narrow confidence
interval)
1c
All or none`
All or none case series
2a
SR (with homogeneity*)
of cohort studies
2b
Individual cohort study
(including low quality
RCT (,80% follow up)
either retrospective cohort
studies or untreated control
groups in RCTs
Retrospective cohort study
of follow up of untreated
controls in an RCT; Derivation
of CDR or validation on split
samples only
2c
‘‘Outcomes’’ research,
ecological studies
of case control studies
Individual case control
study
‘‘Outcomes’’ research
Case series (and poor
quality cohort and
case-control studies**)
Expert opinion without
explicit critical appraisal
or based on physiology,
bench research or ‘‘first
principles’’
Case series (and poor quality
prognostic cohort studies)
5
level 1 economic studies
level 1 diagnostic studies;
CDR with 1b studies from
different clinical centres
Validating cohort study
with good1 reference
standards; or CDR tested
within 1 clinical centre
1b
4
prospective cohort studies
inception cohort studies;
CDR validated in different
populations
Individual inception cohort
study with >80% follow up;
CDR validated in a single
population
of RCTs
3b
Economic and decision
analyses
Diagnosis
1a
3a
Differential diagnosis/
symptom prevalence study
Prognosis
explicit critical appraisal or
based on physiology, bench
research, or ‘‘first principles’’
level 2b and better studies
Ecological studies
3b and better studies
Non-consecutive study, or
without consistently applied
reference standards
3b and better studies
Non-consecutive study, or
very limited population
Case control study, poor or
non-dependent reference
standards
research or ‘‘first principles’’
Case series or supervised
reference standards
explicit critical appraisal
or based on physiology,
bench research or ‘‘first
principles’’
Analysis based on clinically
sensible costs or alternatives;
limited reviews of the
evidence, or single study;
and including multi-way
sensitivity analysis
Audit or ‘‘outcomes’’
research
SR (with homogeneity*) of 3b
and better studies
Analysis based on limited
alternatives or costs, poor
quality estimates of data, but
including sensitivity analyses
incorporating clinically
sensible variations
Analysis with no sensitivity
analysis
research or ‘‘first principles’’
SR, Systematic review; RCT, randomised controlled trial.
*Homogeneity means a systematic review that is free from worrisome variations (heterogeneity) in the results between individual studies.
Clinical decision rules are algorithms or scoring systems leading to a diagnostic category or prognostic estimation.
`All patients died before the therapy became available, but some survive now on it, or some died before therapy became available, but none now die on it.
Validating studies test the quality of a diagnostic test, based on prior evidence. An exploratory study collects information and (for example, using a regression
analysis) identifies which factors are significant
1Good, better, bad, and worse refer to the comparison between treatments in terms of their clinical benefit and risks.
**Poor quality cohort study is one that failed to define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded)
objective way in both exposed and non-exposed individuals, and/or failed to identify and control for confounders and/or to complete long follow up. Poor quality
case control study is one that failed to define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way
in both cases and controls, and/or failed to identify and control for confounders.
Poor quality prognostic cohort study is one with biased sampling in favour of patients who already had the target outcome, or outcomes were measured in
,80%, or outcomes were determined in an unblended non-objective way, or there was no correction for the confounders.
``An ‘‘absolute SpPin’’ is a diagnostic finding whose specificity is so high that a positive result confirms the diagnosis. ‘‘Absolute SnNout’’ is a diagnostic finding
whose sensitivity is so high that negative results rule out the diagnosis.
Split sample validation is achieved by collecting all the information in a single tranche and then dividing this into ‘‘derivation’’ and ‘‘validation’’ samples.
11Good follow up is .80%, with adequate time for alternative diagnosis to emerge (for example, 1–8 months acute, 1–5 years chronic).
***Better value treatments are clearly as good, but cheaper or better at the same or reduced cost. Worse value treatments are as good and more expensive, or
worse and equally/more expensive
These guidelines have been prepared by the British Society of Gastroenterology. They
represent a consensus of best practice based on the available evidence at the time of
preparation. They may not apply in all situations and should be interpreted in the light
of specific clinical situations and resource availability.
June 2007

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