Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease

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1 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 Written and approved by the British Society of Gastroenterology June

2 NR Lewis, BB Scott CONTENTS 1.0 The Problem 2.0 Risk factors for fracture in general 2.1 Reduced bone mineral density The importance of low BMD Measurement of BMD 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 Reduced BMD Factors affecting BMD in IBD Age and age at diagnosis Gender Weight, height and body mass index Duration of disease Disease site, activity, severity and previous surgery Corticosteroid use Reduced physical activity Smoking Other risk factors for fracture independent of low BMD Age Gender 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 Reduced BMD Factors affecting low BMD in coeliac disease Years exposed to gluten Gender Body mass index (BMI) Degree of villous atrophy Symptomatic disease 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 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

3 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 Osteoporosis 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 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 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] 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 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) Women Men 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 ( 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 June 2007 BSG Guidelines in Gastroenterology

4 2 NR Lewis, BB Scott Box 1: Risk factors for fracture related to low BMD High risk (RR>2) Non-modifiable Older age (> 70 years) Prior 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 Moderate risk (RR 1-2) Non-modifiable Female Untreated early menopause (<45) Late menarche (>15) Short fertile period (<30 years) Family history of osteoporotic fracture Modifiable Smoking Low calcium intake 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 3.2 RISK FACTORS FOR FRACTURE IN IBD 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 Factors affecting BMD in IBD 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 ] v 40.9 [95% CI ] 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 v 0.12, p= ) and total body (Z-score v 0.20, p= 0.018) in comparison to those diagnosed over 18 BSG Guidelines in Gastroenterology June 2007

5 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease 3 Table 2: Occurrence of osteoporotic fractures in IBD Authors Study population Fracture Fracture risk in Crohn s disease [95% CI] Fracture risk in ulcerative colitis [95% CI] Vestergaard et al [27] Vestergaard et al [28] Population-based survey of Danish Crohn s (n=383) Colitis (n=434) Association members Danish in-patient registry of Crohn s disease (n=7072) and ulcerative colitis (n=8323) All Forearm All Colles RR 1.7 [ ] Women RR 2.5 [ ] Postmenopausal RR 1.8 [ ] Family history RR 2.4 [ ] Current smoking RR RR 1.3 [ ] RR 6.7 [ ] RR 2.0 [ ] RR 1.5 [ ] IRR 1.19 [ ] IRR 1.87 [ ] IRR 1.04 [ ] IRR 1.10 [ ] RR 1.1 [ ] Women RR 1.1 [ ] Postmenopausal RR 0.6 [ ] Family history RR 1.9 [ ] Current smoking RR 3.8 [ ] RR 2.4 [ ] RR 1.2 [ ] RR 0.6 [ ] IRR 1.08 [ ] IRR 1.04 [ ] IRR 1.02 [ ] IRR 1.08 [ ] Bernstein et al [29] Canadian population-based cohort study (n=6027) All Forearm Hip IRR 1.36 [ ] IRR 1.54 [ ] IRR 1.30 [ ] IRR 1.47 [ ] IRR 1.45 [ ] IRR 1.90 [ ] IRR 1.36 [ ] IRR 1.69 [ ] Loftus et al [30] American population-based cohort study (n=238) All Forearm RR 0.9 [ ] RR 2.2 [ ] RR 1.8 [ ] RR 0.2 [ ] Van Staa et al [31] UK population-based cohort study using GPRD (n=725 Crohn s disease; n=1305 ulcerative colitis) All Radius Hip OR 1.4 [ ] OR 1.9 [ ] OR 1.45 [ ] OR 1.86 [ ] OR 1.2 [ ] OR 1.4 [ ] OR 1.2 [ ] OR 1.40 [ ] Card et al [32] UK population-based cohort study using GPRD (n=5960 Crohn s disease; n=8301 ulcerative colitis; indeterminate n=2289) Hip HR 2.08 [ ] Adjusted HR 1.68 [ ] HR 1.49 [ ] Adjusted HR 1.41 [ ] Klaus et al [33] Stockbrugger et al [34] Hospital-based case series in Germany of patients with T score <-1.0 (n=156) Multicentre European/Israeli hospital based study (n=271) Prevalence 21.8% (n=34) among those with T score <-1.0 Prevalence overall 14% 25/179 steroid-free (14%) 13/89 steroid dependent (14.6%) RR = relative risk; IRR = incidence rate ratio; OR = odds ratio; HR = hazard ratio June 2007 BSG Guidelines in Gastroenterology

6 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 Number DEXA site Mean age Mean disease Mean Mean % osteoporosipenia % osteo- of (years) duration Z-score T-score patients +/- SD (years) +/- SD Pigot et al [35] France / / Ghosh et al [36] Scotland Forearm -1.1 Bernstein et al [37] USA Total hip -1.5 Roux et al [38] France Silvennoinen et al [39] Finland Staun et al [40] Denmark Jahnsen et al [41] Norway Robinson et al [42] England 117 Trochanter Schulte et al [43] Germany 104 Schulte et al [44] Germany 61 Pollak et al [45] Israel / / / / / / / Patients with a preserved colon; 2 Patients with a resected colon; 3 did not receive steroids; 4 received steroids; 5 p < 0.05 on comparison of z-score with controls; 6 control , , , , / / / / / Dinca et al [46] Italy / / Lee et al [47] Korea / Ardizzone et al [48] Italy / / / Schoon et al [49] Netherlands 24 Total body / Schoon et al [50] Netherlands 119 Total body Haugeberg et al [51] Norway 55 Total hip Schoon et al [452] Netherlands 26 Total body De Jong et al [53] Netherlands 91 Jahnsen et al [54] Norway 60 Total body Habtezion et al [55] Canada 168 Total hip De Jong et al [56] Netherlands 29 Tobias et al [57] England 15 Siffledeen et al [58] Canada 242 Wrist Total hip Jahnsen et al [59] Norway 60 Total body Van Hogezand et al [60] Netherlands / / / / / / / / / / / / / / BSG Guidelines in Gastroenterology June 2007

7 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease 5 Table 4: Cross-sectional survey of the prevalence of reduced BMD in ulcerative colitis using DEXA Study and year Country Number of DEXA site Mean patients T-score Mean age (years) +/- SD Mean disease Mean duration Z-score (years) +/- SD % osteoporosis Dinca et al [46] Italy /-2 8 +/ Ghosh et al [36] Scotland 15 Forearm Bernstein et al [37] USA 23 Total hip Roux et al [38] France 9 Silvennoinen et al [39] Finland Jahnsen et al [41] Norway Pollak et al [45] Israel 26 Lee et al [47] Korea 25 Ardizzone et al [48] Italy 40 Schoon et al [49] Netherlands 44 Total body Jahnsen et al [54] Norway 60 Total body Kuisma et al [62] Finland 20 ileostomy Lumbar 14 IPAA 1 47 IPAA 2 27 IPAA 3 Ileostomy IPAA 1 IPAA 2 IPAA / / / , , , , / / / / / / / / / / / % osteopenia Schulte et al [43] Germany 45 Ulivieri et al [61] Italy control Total body male female male female IPAA Ileal pouch anal anastomosis with 1 normal 2 partial 3 severe pouch mucosal inflammation; 4 BMD values not statistically different from controls; 5 control; 6 did not receive steroids; 7 received steroids; 8 p < 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) Gender 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] Weight, height and body mass index 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 Duration of disease 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 June 2007 BSG Guidelines in Gastroenterology

8 6 NR Lewis, BB Scott Table 5: Pooled analysis of BMD in inflammatory bowel disease Analysis Weighted Number of Mean Mean mean studies age disease value (number of duration patients) Crohn s disease 36 years 10 years Z-score (1283) Hip Z-score (1209) T-score (685) Hip T-score (413) Osteoporosis spine (%) (1169) Osteoporosis hip (%) 13 9 (1002) Osteopenia spine (%) (1114) Osteopenia hip (%) 44 7 (843) Ulcerative colitis 40 years 12 years Z-score (542) Hip Z-score (435) T-score (140) Hip T-score (91) Osteoporosis spine (%) 15 4 (145) Osteoporosis hip (%) 11 2 (85) Osteopenia spine (%) 36 3 (100) Osteopenia hip (%) 67 1 (40) and a control group, though sample size and selection bias may have affected the results 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 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] 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 Smoking No relationship between smoking and BMD was observed where it was studied [36, 42, 58-60] 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: Age As expected, fracture rates in patients with Crohn s disease and ulcerative colitis increase with advancing age [29, 30, 32-34] 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 Fracture Fracture risk (95% CI) Vasquez et al [74] Hospital-based case series in Argentina Peripheral skeleton OR 3.5 ( ) (n=165 with 165 subjects with functional OR 2.8 ( ) gastrointestinal disorder used as controls) Fickling et al [75] Hospital-based case series survey in England Any X 2 = 10.7 p= (n=75 with 75 age- and sex-matched controls) Thomason et al [76] Population-based survey in England Any OR 1.05 ( ) (n=244 with 161 age- and Forearm OR 1.21 ( ) sex-matched controls) West et al [77] Population-based cohort study using GPRD Any HR 1.30 ( ) (n=4732 with age- and Hip HR 1.90 ( ) sex-matched controls) Ulna, radius HR 1.77 ( ) Moreno et al [78] Hospital-based case series in Argentina Any OR 5.2 ( ) classic CD (n=148 with 292 age- an sex-matched controls OR 1.7 ( ) silent CD with functional gastrointestinal disorders) Vestergaard et al [79] Hospital-based in-patient registry in Denmark Any IRR 0.70 ( ) (n=1021 with 3063 age- and IRR 2.14 ( ) sex-matched controls) Colles IRR 2.00 ( ) IRR 0.71 ( ) Davie et al [80] Female patients aged > 50 (n=383) and Any OR 1.51 ( ) controls (n=445) Ludvigsson et al [81] Population-based cohort study in Sweden Any HR 1.4 ( ) (n=13,000 with 65,000 age- and Hip HR 2.1 ( ) sex-matched controls) RR = relative risk; IRR = incidence rate ratio; OR = odds ratio; HR = hazard ratio BSG Guidelines in Gastroenterology June 2007

9 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease 7 Table 7: BMD in untreated coeliac disease in published studies Study Country Number of patients DEXA site Mean Z-score Mazure et al [82] Argentina 28 Lumbar All Asymptomatic Symptomatic Total skeleton All Asymptomatic Symptomatic Gonzalez et al Argentina [83] Total skeleton -2.9 Mautalen et al Argentina [84] Total skeleton -1.5 Bai et al [85] Argentina Total skeleton -2.2 Fornari et al [86] Argentina 16 Total skeleton Vasquez et al [75] Argentina Total skeleton -2.0 Corazza et al [87] Italy 14 silent classic -2.6 Corazza et al [88] Italy 20 Di Stefano et al Italy [89] Di Stefano et al Italy 21 silent -2.5 classic [90] 18 classic -1.1 silent -2.5 classic -1.2 silent Sategna-Guidetti Italy et al [91] -1.8 Walters et al [92] England women men women men Lewis et al [93] England 43 Valdimarsson et al [94] Valdimarsson et al [95] Valdimarsson et al [96] Kemppainen et al [97] Sweden 63 Sweden 29 Total hip Sweden 105 Total hip Forearm Finland 28 Meyer et al [98] USA 31 Radius women men classic 0.13 silent women men 0 classic 0.15 silent Median Z-score women men women men Mean %osteoporosis T-score % osteopenia Corticosteroid use and disease activity 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 ) [31]. 4.0 OSTEOPOROSIS IN COELIAC DISEASE 4.1 ARE FRACTURES A PROBLEM IN COELIAC DISEASE? 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 ) compared with controls. There was also an increase in fractures of the spine but that was not significant (odds ratio June 2007 BSG Guidelines in Gastroenterology

10 8 NR Lewis, BB Scott Table 8: Pooled analysis of BMD in untreated coeliac disease Analysis Weighted Number of mean value studies (number of patients) Untreated coeliac disease Z-score (490) Hip Z-score (329) T-score (86) Hip T-score (86) Osteoporosis spine (%) 26 6 (212) Osteoporosis hip (%) 11 3 (102) Osteopenia spine (%) 41 4 (188) Osteopenia hip (%) 43 3 (102) 2.8; 95% CI ). 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 ). 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 ) or after diagnosis (incidence rate ratio for all fractures 0.94; 95%CI ) [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 ) [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 ) for hip fracture and 1.4 (95% CI ) 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 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 score 2 on DEXA and risk factors, or if prior fragility fracture: Oral bisphosphonate long term 3 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 2 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 BSG Guidelines in Gastroenterology June 2007

11 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease 9 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-score 2 on DEXA and risk factors, or if prior fragility fracture: Oral bisphosphonate long term 3 (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: 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 2 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 Factors affecting low BMD in coeliac disease Years exposed to gluten BMD has not been observed to be related to years exposed to gluten [82, 84, 89, 93, 98] 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 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 Body Mass Index (BMI) Low weight [97] and low BMI [90, 93] have both been associated with reduced BMD 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] Symptomatic disease Classic symptoms were associated with lower BMD in some studies [82, 87,90] but not all [84, 93, 94, 98] 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 mg 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 [ ], 1000 mg daily seems a reasonable aim although, for post-menopausal women and elderly men, a higher intake of 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]. June 2007 BSG Guidelines in Gastroenterology

12 10 NR Lewis, BB Scott 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 ( 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 [ ] 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 [ ] of nine studies [ ] 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 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 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 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 BSG Guidelines in Gastroenterology June 2007

13 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease 11 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 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 [ ] 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 [ ]. 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, which is licensed and can be given as a push injection over 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 [ ] 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 [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 [ ] with an NNT for vertebral fractures during 21 months of treatment of 10 (95% CI ) and an NNT for non-vertebral fractures during 19 months of treatment of 27 (95% CI ) [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 ] for a high-risk pop- June 2007 BSG Guidelines in Gastroenterology

14 12 NR Lewis, BB Scott 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 ]) 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 ]) 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 [ ]. 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. 7.8 FLUORIDE Fluoride treatment leads to a dramatic increase in vertebral BMD but in higher doses caused an increased incidence of hip fracture [171]. It is not recommended. 8.0 SUMMARY OF RECOMMENDATIONS The main recommendations for preventing fracture are summarised in Box 3 for IBD and Box 4 for coeliac disease. 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 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). REFERENCES 1. National Institutes of Health. 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17 Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease Molteni N, Bardella MT, Vezzoli G, et al. Intestinal calcium absorption as shown by stable strontium test in celiac disease before and after gluten-free diet. Am J Gastroenterol 1995;90: Palomba S, Orio F, Manguso F, et al. Eficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease. Osteoporos Int 2005;16: Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343: Ringe JD, Dorst A, Faber H, et al. Alendronate treatment of established primary osteoporosis in men; 3-year results of a prospective, comparative, two arm study. Rheumatol Int 2004;24: Haderslev KV, Tjellesen L, Sorensen HA, et al. Alendronate increases lumbar spine bone mineral density in patients with Crohn s disease. Gastroenterology 2000;119: Bartram SA, Peaston RT, Rawlings DJ, et al. 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Scottish Medicines Consortium issues advice on strontium ranelate (Protelos) for the treatment of brittle bone disease following the menopause. August Riggs BL, Hodgson SF, O Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322: Scott EM, Gaywood I, Scott BB for the British Society of Gastroenterology. Guidelines for osteoporosis in coeliac disease and inflammatory bowel disease. Gut 2000;46(Suppl I):i1-8. June 2007 BSG Guidelines in Gastroenterology

18 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 Oxford Centre for Evidence-based Medicine: levels of evidence Level Therapy/prevention/ aetiology/harm Prognosis Diagnosis Differential diagnosis/ symptom prevalence study Economic and decision analyses 1a 1b SR (with homogeneity*) of RCTs Individual RCT (with narrow confidence interval) SR (with homogeneity*) of inception cohort studies; CDRÀ validated in different populations Individual inception cohort study with >80% follow up; CDRÀ validated in a single population SR (with homogeneity*) of level 1 diagnostic studies; CDRÀ with 1b studies from different clinical centres Validatingô cohort study with good1 reference standards; or CDRÀ tested within 1 clinical centre 1c All or none` All or none case series Absolute SpPins and SnNouts`` 2a SR (with homogeneity*) SR (with homogeneity*) of SR (with homogeneity*) of of cohort studies either retrospective cohort level.2 diagnostic studies studies or untreated control groups in RCTs 2b 2c 3a 3b Individual cohort study (including low quality RCT (,80% follow up) Outcomes research, ecological studies SR (with homogeneity*) of case control studies Individual case control study 4 Case series (and poor quality cohort and case-control studies**) 5 Expert opinion without explicit critical appraisal or based on physiology, bench research or first principles Retrospective cohort study of follow up of untreated controls in an RCT; Derivation of CDRÀ or validation on split samplesôô only Exploratoryô cohort study with good1 reference standards; CDRÀ after derivation; or validated only on split samplesôô or databases SR (with homogeneity*) of prospective cohort studies Prospective cohort study with good follow up11 All or none case series SR (with homogeneity*) of level 2b and better studies Retrospective cohort study, or poor follow-up SR (with homogeneity*) of level 1 economic studies 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 Analysis based on clinically sensible costs or alternatives; limited reviews of the evidence, or single study; and including multi-way sensitivity analysis Outcomes research Ecological studies Audit or outcomes research SR (with homogeneity*) of SR (with homogeneity*) of SR (with homogeneity*) of3b 3b and better studies 3b and better studies and better studies Non-consecutive study, or Non-consecutive study, or Analysis based on limited without consistently applied very limited population alternatives or costs, poor reference standards quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations Case series (and poor quality prognostic cohort studiesàà) Expert opinion without explicit critical appraisal or based on physiology, bench research, or first principles Case control study, poor or non-dependent reference standards Expert opinion without explicit critical appraisal or based on physiology, bench research or first principles Case series or supervised reference standards Expert opinion without explicit critical appraisal or based on physiology, bench research or first principles Analysis with no sensitivity analysis Expert opinion without explicit critical appraisal or based on physiology, bench 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. ÀClinical 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. ôvalidating 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. ÀÀPoor 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. ôôsplit 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. BSG Guidelines in Gastroenterology June 2007