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. 2024 Sep 23;60(11-12):1549–1560. doi: 10.1111/apt.18275

A nationwide cohort study of inflammatory bowel disease, histological activity and fracture risk

Karl Mårild 1,2,✉, Jonas Söderling 3,4, Jordan Axelrad 5, Jonas Halfvarson 6, Anders Forss 4,7; SWIBREG Study Group §, Karl Michaëlsson 8, Ola Olén 4,9,10, Jonas F Ludvigsson 3,11,12
PMCID: PMC11599792  NIHMSID: NIHMS2022869  PMID: 39308339

Summary

Background

Individuals with inflammatory bowel disease (IBD) are at increased risk of fracture. It is unclear if this risk varies by recent histological activity.

Aims

To determine the fracture risk in IBD during periods with and without histological inflammation.

Methods

We studied a nationwide cohort of 54,591 individuals diagnosed with IBD in 1990–2016 with longitudinal data on ileo‐colorectal biopsies. Fractures were identified by inpatient and hospital‐based outpatient diagnoses. We derived Cox regression estimated hazard ratios (HRs) for fracture during 12 months following a histological inflammation (vs. histological remission) record after adjusting for socio‐demographics, comorbidities, IBD duration, IBD‐related surgery and hospitalization. We adjusted sensitivity analyses for medical IBD treatment including corticosteroids.

Results

Mean age of patients was 44.0 (SD = 18.3) and 45.5 (SD = 17.1) years at biopsy with histological inflammation and remission, respectively. For histological inflammation, there were 1.37 (95% CI 1.29–1.46) fractures per 100 years' follow‐up versus 1.31 (95% CI 1.19–1.44) for remission (adjusted [a]HR 1.12; 95% CI 1.00–1.26; p = 0.04). HRs were similar with histological inflammation of Crohn's disease (1.11; 95% CI 0.91–1.36) and ulcerative colitis (1.18; 95% CI 1.02–1.36). Estimates were consistent across age groups. An overall small excess risk of any fracture remained after accounting for corticosteroids. A more prominently raised fracture risk was observed in corticosteroid‐naïve IBD patients with histological inflammation versus histological remission (aHR 1.41; 95% CI 1.07–1.85). The aHR of hip fracture following histological inflammation was 1.29 (95% CI 0.87–1.92).

Conclusions

Histological inflammation in IBD predicted a small increase in short‐term fracture risk. Measures to reduce disease activity may reduce fracture risk in IBD.

In this nationwide IBD cohort, there was a 12% increased fracture risk during 1‐year periods with versus without histological inflammation. The findings reinforce the notion that measures to reduce disease activity may prevent fracture risk in IBD.

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1. INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic and disabling immune‐mediated condition that includes Crohn's disease (CD) and ulcerative colitis (UC). Histological remission, often defined by a lack of acute or chronic inflammatory cell infiltration, is increasingly viewed as an aspirational treatment target of IBD, particularly for UC. 1 , 2 , 3

Patients with IBD have a heightened risk of fractures, 4 , 5 , 6 resulting in higher morbidity and mortality rates. 7 While the fracture risk in IBD is multifactorial, 8 corticosteroid treatment conveys particularly high risks. 4 , 9 , 10 Recent guidelines stipulate that IBD remission may mitigate fracture risk. 11 Although IBD activity is linked with corticosteroid use, most studies lack objective data on underlying IBD activity to disentangle the influence of corticosteroid use from remission status on fracture risk. Previous investigations, mostly based on small samples, have only inconsistently linked IBD symptom activity scores to reduced bone health. 12 , 13 , 14 , 15 , 16 To date, no data associate histological appearance in IBD with fracture risk. Knowledge of imminent fracture risk, noted shortly after histological examination, may influence treatment decision making in IBD.

By studying a nationwide IBD cohort with longitudinal biopsy data, 17 we examined whether histological activity was a determinant of short‐term fracture risk overall and across patient subgroups defined by corticosteroid use and other characteristics.

2. MATERIALS AND METHODS

2.1. Study sample

The nationwide ESPRESSO cohort links all computerized gastrointestinal histology reports recorded by 2016 to national health care registers in Sweden. 17 We defined IBD as having either ≥2 International Classification of Disease (ICD) codes in the Swedish National Patient Register (NPR) 18 or ≥1 ICD code and ≥1 relevant ileo‐colorectal histopathology (Systematized Nomenclature of Medicine, SNOMED) code (Table S1). This definition of IBD has demonstrated a positive predictive value of ≥93% for a clinical diagnosis of IBD. 19 , 20 Subtype‐specific ICD codes were used to classify UC, CD and IBD‐unclassified (IBD‐U). Patients were characterized according to IBD‐related surgery, 21 , 22 , 23 and the extent and location 24 of the disease at diagnosis (Tables S2 and S3).

In this study, 54,591 unique individuals diagnosed with IBD from 1990 to 2016 were included, all of whom underwent an ileo‐colorectal biopsy (Table S4). We excluded individuals who had lived outside of Sweden in the past 5 years before the index date (i.e. time of biopsy showing histological inflammation or histological remission as described below). Our primary analyses excluded individuals with any fractures before the index date, regardless of remission status, as fracture history affects the management of IBD and increases the risk of recurrent fractures.

2.2. Exposure: Histological inflammation versus histological remission

In line with earlier consensus reports, 2 , 3 and similar to our previous studies, 25 , 26 histological inflammation was defined as ≥1 histopathology (SNOMED) code for ileo‐colorectal inflammation, erosion or ulceration as detailed in Table S5. Histological remission equalled SNOMED codes for normal mucosa 17 and the absence of SNOMED codes for inflammation. Histological inflammation versus histological remission was defined by the worst histological appearance across all ileo‐colorectal segments and did not rely on laboratory markers (e.g. faecal calprotectin) or endoscopic appearance. Internationally accepted histological scoring systems of IBD 27 are not routinely used in Sweden.

Following our earlier research, 25 , 26 we hypothesized that histological inflammation and histological remission would predict histological appearance for up to 12 months (0–365 days) post‐biopsy. Therefore, our focus was analysing the fracture risk within 12‐month periods after biopsies showing histological inflammation versus histological remission. This 1‐year time window was also motivated by the annual bone remodelling during healthy and inflammatory conditions. 28 , 29 To contrast this examination of histology as a short‐term determinant for fracture risk, sensitivity analyses examined the fracture risk 1 to <10 years since biopsy. The fracture risk during this time window was assumed to be considerably less related to the histological appearance as documented at the last biopsy but related to other factors.

2.3. Outcome: Fracture

Our primary outcome was any fracture listed as a main or contributory diagnosis in the NPR between 1 January, 1990 and 31 December, 2016. Secondary analyses were limited to hip fractures. Given the age distribution of our patients (Table 1), we regarded any fracture, rather than hip fracture, as the primary outcome because hip fracture in young/middle‐aged individuals is more frequently linked to high‐energy trauma, alcohol abuse and diabetes than hip fractures in older populations. 30 , 31 The NPR captures all inpatient care diagnoses since 1987, with hospital‐based outpatient diagnoses recorded since 2001. We used the same ICD codes for fractures as Ludvigsson et al. 4 (Table S6). The accuracy of diagnosing any fracture and hip fracture is high in the Swedish NPR. 32 , 33

TABLE 1.

Characteristics of individuals during periods with histological inflammation and histological remission of inflammatory bowel disease (IBD) in 1990–2016.

Variable Biopsy in 1990–2016 a
Histological inflammation Histological remission
N patients with IBD 43,449 23,814
N patients by number of periods
1 27,834 (64.1%) 17,042 (71.6%)
2 8893 (20.5%) 4514 (19.0%)
3 3689 (8.5%) 1442 (6.1%)
≥4 3033 (7.0%) 816 (3.4%)
N exposure periods 71,444 34,192
Sex, n (%)
Males 38,094 (53.3%) 17,396 (50.9%)
Females 33,350 (46.7%) 16,796 (49.1%)
Year of biopsy, b n (%)
1990–1999 12,748 (17.8%) 2324 (6.8%)
2000–2009 31,343 (43.9%) 13,851 (40.5%)
2010–2016 27,353 (38.3%) 18,017 (52.7%)
Age (years) at biopsy b
Mean (SD) 44.0 (18.3) 45.5 (17.1)
Categories, n (%)
<18 years 4930 (6.9%) 1892 (5.5%)
18 to <40 years 26,994 (37.8%) 11,462 (33.5%)
40 to <60 years 23,817 (33.3%) 13,106 (38.3%)
≥ 60years 15,703 (22.0%) 7732 (22.6%)
Year of IBD diagnosis c , n (%)
1990–1999 26,658 (37.3%) 10,680 (31.2%)
2000–2009 32,927 (46.1%) 18,507 (54.1%)
2010–2016 11,859 (16.6%) 5005 (14.6%)
Age (years) at IBD diagnosis c
Mean (SD) 39.7 (18.2) 39.1 (16.7)
Categories, n (%)
<18 years 8219 (11.5%) 3924 (11.5%)
18 to <40 years 30,161 (42.2%) 14,272 (41.7%)
40 to <60 years 21,800 (30.5%) 11,932 (34.9%)
≥60 years 11,264 (15.8%) 4064 (11.9%)
Level of education d , n (%)
≤9 years 17,258 (24.2%) 6855 (20.0%)
10–12 years 32,968 (46.1%) 15,457 (45.2%)
≥13 years 20,996 (29.4%) 11,825 (34.6%)
Missing 222 (0.3%) 55 (0.2%)
Country of birth, n (%)
Nordic 66,657 (93.3%) 31,704 (92.7%)
Non‐Nordic 4293 (6.0%) 2231 (6.5%)
Missing 494 (0.7%) 257 (0.8%)
Disease duration (years)
Mean (SD) 4.3 (5.4) 6.4 (5.9)
Categories, n (%)
<2 years 36,115 (50.6%) 10,728 (31.4%)
≥2 years 35,329 (49.4%) 23,464 (68.6%)
IBD type, n (%)
CD 18,648 (26.1%) 10,540 (30.8%)
UC 49,481 (69.3%) 22,122 (64.7%)
IBD‐U 3315 (4.6%) 1530 (4.5%)
Montreal classification of CD, e n (%)
L1/L3/LX 12,129 (65.0%) 7457 (70.7%)
L2 4259 (22.8%) 2438 (23.1%)
L missing/ICD code before 1997 2260 (12.1%) 645 (6.1%)
Montreal classification of UC, e n (%)
E1/E2 12,474 (25.2%) 5908 (26.7%)
E3 18,999 (38.4%) 10,207 (46.1%)
EX 11,415 (23.1%) 4647 (21.0%)
E missing/ICD code before 1997 6593 (13.3%) 1360 (6.1%)
Health care and drug use
Any hospitalization from 24 to 6 months before the index date
Mean (SD) 0.6 (1.4) 0.5 (1.4)
IBD‐related hospitalization, f n (%) 43,525 (60.9%) 20,245 (59.2%)
IBD‐related surgery, f n (%) 15,135 (21.2%) 5571 (16.3%)
N periods from 2006, n (%) 41,081 (57.5%) 24,945 (73.0%)
IBD‐related drugs g (<6 months of the index date), n (%) 17,262 (42.0%) 8996 (36.1%)
Corticosteroid 11,774 (28.7%) 4551 (18.2%)
Budesonide 2036 (5.0%) 1223 (4.9%)
Immunomodulators 6582 (16.0%) 4493 (18.0%)
Targeted therapy in IBD 2248 (5.5%) 1171 (4.7%)
Other drug use, n (%)
Bisphosphonate 568 (1.4%) 317 (1.3%)
Calcium 3583 (8.7%) 2183 (8.8%)
Vitamin D supplementation 363 (0.9%) 294 (1.2%)
Cumulative corticosteroid use in the past 5 years (mg prednisolone equivalents), n (%)
N periods from July 2010, n (%) 25,311 (35.4%) 16,842 (49.3%)
0 10,668 (42.1%) 8233 (48.9%)
1–1500 5868 (23.2%) 3596 (21.4%)
1501–3000 2927 (11.6%) 1910 (11.3%)
3001–4500 1670 (6.6%) 1030 (6.1%)
4501– 4178 (16.5%) 2073 (12.3%)
Comorbidity, n (%)
Diabetes 2981 (4.2%) 1492 (4.4%)
Hypertension 5665 (7.9%) 3082 (9.0%)
Asthma 2912 (4.1%) 1687 (4.9%)
Autoimmune disease 4440 (6.2%) 2668 (7.8%)
Charlson comorbidity index h
Mean (SD) 0.7 (1.6) 0.8 (1.8)
Follow‐up time (days)
Median (IQR) 365 (365–365) 365 (365–365)
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Note: Included patients equaled 54,591 unique individuals, who contributed to periods of histological inflammation (n = 43,449) and histological remission (n = 23,814).

Abbreviations: CD, Crohn's disease; ICD, International classification of diseases; IBD‐U, inflammatory bowel disease‐unclassified; IQR, interquartile range; SD, standard deviation; UC, ulcerative colitis.

a

Histopathology reports, as recorded in the ESPRESSO cohort, 17 from the ileo‐colorectum (topography codes T65, T67 and T68) showing inflammation and normal histology, respectively, as detailed in Table S5.

b

Biopsy date equals the start of the exposure period.

c

Time of IBD diagnosis equals time of second out of ≥2 diagnostic listings for IBD or related histopathology (SNOMED) code.

d

In children with missing data on education level we used the highest attained education level of the parent.

e

Extent and location of disease at the time of diagnosis as detailed in Table S2.

f

Any time before index date. IBD‐related hospitalization equalled an inpatient visit with a main diagnosis of IBD. IBD‐related surgery was defined by relevant surgical codes listed in Table S3.

g

Medical IBD therapy is defined in Table S7.

h

The index was adapted to a Swedish setting 38 with assigned scores according to comorbidity burden up to 12 months before the index date.

2.4. Other data

Numerous comorbid conditions seem to increase fracture risk in themselves or through their management. 34 , 35 , 36 , 37 We used diagnostic data from the NPR, launched in 1964 but with nationwide coverage since 1987, 18 to create Charlson comorbidity index. 38 We assigned scores pursuant to comorbidity burden until the index date (i.e. the time of biopsy).

We used validated data from the NPR to identify any IBD‐related surgery 22 , 23 and hospitalizations for IBD as markers of disease severity (Tables S2 and S3). Because socioeconomic differences have been linked to fracture risk and IBD, 39 , 40 , 41 we retrieved data from the Longitudinal Integration Database for Health Insurance and Labor Market Studies (LISA) on the highest attained education level as a proxy for socioeconomic status and highest attained education in parents for children (<18 years) with missing education information. 42 An evaluation of the LISA database has shown that the level of education was correctly recorded in 85% of individuals. 42 Information on country of birth, age and calendar year was retrieved from the Swedish Total Population Register. 43 Data were categorized as shown in Table 1.

2.4.1. Medical therapy

In analyses with follow‐up since 2006 we examined the risk of any fracture and hip fracture after accounting for medical IBD therapy. Hence, we identified the current use of systemic corticosteroids, immunomodulators (e.g. thiopurines) or targeted therapies (Table S7). Current use was defined as dispensing/administering medical therapy <6 months before the index date. For analyses restricted to July 2010 onwards, we estimated the cumulative corticosteroid dose used in the past 5 years, converted into prednisolone equivalents. 4 Drug data were retrieved from three Swedish registers: The Swedish NPR, 18 the Swedish Prescribed Drug Register, 44 and the Swedish Quality Register for IBD (SWIBREG). 45 , 46 The Prescribed Drug Register, established in July 2005 and in this study captured since 1 January, 2006, contains prospectively recorded data on all dispensed prescriptions in Sweden. 44

At the index date, we retrieved information on the use of bisphosphonate, calcium and vitamin D (Table S8), as these drugs may be prescribed for fracture prevention in IBD. 11

We used NPR and Prescribed Drug Register data to define clinical IBD activity according to IBD‐related surgery, hospitalization, current corticosteroid use, initiation of immunomodulators or targeted therapies. 25

2.5. Statistical analyses

We used Cox regression models to estimate hazard ratios (HRs) for any fracture and hip fracture during histological inflammation (vs. histological remission) periods. Poisson regression was applied to estimate fracture incidence rate ratios (IRRs) during histological inflammation (vs. histological remission). Follow‐up periods with versus without histological inflammation started at the time of biopsy and ended at fracture diagnosis or censoring after 12 months since biopsy, emigration, death or end of data capture (31 December, 2016), whichever occurred first. In analyses of hip fractures other fractures did not result in censoring. For individuals who underwent repeated biopsies, follow‐up of histological inflammation also ended if a second biopsy showing histological remission was performed within 12 months from an earlier biopsy showing inflammation, and vice versa. Sensitivity analyses examined the fracture risk 1 to <10 years since biopsy (i.e. ignoring events outside this time window).

One individual with IBD could contribute to multiple inflammation and remission periods. Given multilevel data (i.e. one individual could contribute to repeated and even different exposures), we present results at the individual observation level (i.e. by follow‐up periods) rather than the cluster level (individual). All analyses were adjusted for sex, age, calendar year, country of birth, education level, duration since IBD diagnosis, Charlson comorbidity index and any history of IBD‐related surgery or hospitalization. Covariate values were updated at the start of each follow‐up period, except for sex and country of birth.

2.5.1. Subanalyses

We presented HRs and IRRs by IBD subtypes (UC, CD and IBD‐U) and the extent and location of the disease. Stratified analyses were performed after separating the participants by their duration of IBD diagnosis (<2, ≥2 years), age (<18, 18 to <40, 40 to <60, ≥60 years), education level (≤9, 10–12, ≥13 years), country of birth (Nordic, Other) and calendar year of index date (1990–1999, 2000–2009, 2010–2016).

2.5.2. Sensitivity analyses

Although our primary analyses focused on individuals without a prior fracture diagnosis (Table S6), we performed sensitivity analyses without applying this exclusion criterion. We also restricted the outcome to fractures listed as the main diagnoses.

When follow‐ups were restricted to 2006–2016, the risk of any fracture was adjusted for current (<6 months before the index date) use of corticosteroids, other medical IBD therapy and bisphosphonate in addition to the above‐mentioned multivariable model. For data restricted to 2010 and later, we also conducted stratified analyses by the cumulative use of corticosteroids over the past 5 years.

Finally, we estimated fracture risk during histological inflammation (vs. histological remission) in individuals with clinically quiescent IBD. We defined clinical IBD activity according to IBD‐related surgery, hospitalization, current corticosteroid use, initiation of immunomodulators or targeted therapies. 25

2.6. Ethics

This study was approved by the Stockholm Ethics Review Board.

3. RESULTS

Out of 54,591 unique individuals included in the study, 43,449 contributed to 71,444 periods with histological inflammation and 23,814 contributed to 34,192 periods with histological remission. The mean age was 44.0 (SD 18.3) years in individuals with histological inflammation and 45.5 (SD 17.1) years in individuals with histological remission. Approximately 20% of the follow‐ups occurred at or after 60 years of age (Table 1). The median number of pathology reports per individual was 1 (range 1–16, with each report representing one ileo‐colonoscopy with often multiple biopsies). Individuals with histological inflammation had more recently diagnosed IBD (mean time since diagnosis 4.3 [SD 5.4] years) than those with histological remission (6.4 [SD 5.9] years). Corticosteroid use and prior IBD‐related surgery were more common in patients with histological inflammation (Figure S1 and Table 1).

3.1. Short‐term fracture risk by histological activity

3.1.1. Any fracture

During 12‐month periods with versus without histological inflammation of IBD, we observed 1.37 (95% CI = 1.29–1.46) and 1.31 (95% CI = 1.19–1.44) fractures per 100 person‐years of follow‐up, respectively, with an adjusted HR (aHR) of 1.12 for any fracture (95% CI = 1.00–1.26; p = 0.04; Figure 1; Table S9). For individuals with clinically quiescent IBD, histological inflammation was associated with an aHR of 1.12 (95% CI = 0.94–1.33) for any fracture (Table 2).

FIGURE 1.

FIGURE 1

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Risk of fracture during 0 to <12 months of histological inflammation versus histological remission in inflammatory bowel disease (IBD). 1 *Adjusted for age at biopsy (i.e. the start of the exposure period), sex, calendar year, education level, country of birth, disease duration, hospital admission for IBD, IBD‐related surgery and the Charlson comorbidity index. Histological inflammation and histological remission as defined by biopsies originating from the ileum or colorectum (topographic codes T65, T67 and T68) with histology codes listed in Table S5. Biopsy date equals the start of the exposure period. Montreal classifications of extent and location of disease at diagnosis are detailed in Table S2. CI, confidence interval; CD, Crohn's disease; IR, incidence rate; IRR, incidence rate ratio; IBD‐U, Inflammatory bowel disease‐unclassified; PY, person‐years; UC, ulcerative colitis.

TABLE 2.

Sensitivity analyses for the risk of fracture during 0 to <12 months of histological inflammation versus histological remission in inflammatory bowel disease (IBD) a , except for sensitivity analysis of fracture risk within 1 to <10 years from biopsy.

N (% of total) N fracture (%) Follow‐up years IR (95% CI) by 100 PY IRR b (95% CI) HR b (95% CI)
Histological inflammation Histological remission Histological inflammation Histological remission Histological inflammation Histological remission Histological inflammation Histological remission
Fracture, year 1990–2016
Main analyses
IBD overall c 71,444 (100%) 34,192 (100%) 1041 (1.5%) 439 (1.3%) 75,718 33,443 1.37 (1.29–1.46) 1.31 (1.19–1.44) 1.12 (1.00–1.25) 1.12 (1.00–1.26)
CD 18,648 (26.1%) 10,540 (30.8%) 288 (1.5%) 149 (1.4%) 19,510 10,308 1.48 (1.31–1.65) 1.45 (1.21–1.68) 1.10 (0.90–1.35) 1.11 (0.91–1.36)
UC 49,481 (69.3%) 22,122 (64.7%) 706 (1.4%) 265 (1.2%) 52,757 21,649 1.34 (1.24–1.44) 1.22 (1.08–1.37) 1.18 (1.02–1.36) 1.18 (1.02–1.36)
Censoring for corticosteroid prescription c
IBD overall 71,444 (100%) 34,192 (100%) 734 (1.0%) 352 (1.0%) 59,306 28,441 1.24 (1.15–1.33) 1.24 (1.11–1.37) 1.08 (0.95–1.23) 1.09 (0.95–1.24)
CD 18,648 (26.1%) 10,540 (30.8%) 171 (0.9%) 112 (1.1%) 14,383 8174 1.19 (1.01–1.37) 1.37 (1.12–1.62) 0.96 (0.75–1.22) 0.96 (0.75–1.22)
UC 49,481 (69.3%) 22,122 (64.7%) 532 (1.1%) 222 (1.0%) 42,525 19,074 1.25 (1.14–1.36) 1.16 (1.01–1.32) 1.17 (0.99–1.38) 1.17 (1.00–1.38)
Follow‐up 1 to < 10 years after biopsy with histological inflammation versus remission
IBD overall d 43,000 (100%) 33,140 (100%) 4295 (10.0%) 2255 (6.8%) 308,117 157,021 1.39 (1.35–1.44) 1.44 (1.38–1.50) 0.99 (0.94–1.05) 0.97 (0.92–1.03)
CD 12,040 (28.0%) 10,420 (31.4%) 1176 (9.8%) 777 (7.5%) 83,658 51,441 1.41 (1.33–1.49) 1.51 (1.40–1.62) 0.97 (0.88–1.06) 0.96 (0.87–1.05)
UC 28,826 (67.0%) 21,101 (63.7%) 2929 (10.2%) 1376 (6.5%) 212,457 99,144 1.38 (1.33–1.43) 1.39 (1.31–1.46) 1.01 (0.95–1.08) 0.99 (0.92–1.05)
Fracture coded as the main diagnosis
IBD overall d 71,444 (100%) 34,192 (100%) 977 (1.4%) 415 (1.2%) 75,754 33,458 1.29 (1.21–1.37) 1.24 (1.12–1.36) 1.11 (0.99–1.25) 1.11 (0.99–1.25)
CD 18,648 (26.1%) 10,540 (30.8%) 269 (1.4%) 139 (1.3%) 19,523 10,315 1.38 (1.21–1.54) 1.35 (1.12–1.57) 1.11 (0.90–1.37) 1.12 (0.91–1.39)
UC 49,481 (69.3%) 22,122 (64.7%) 665 (1.3%) 254 (1.1%) 52,777 21,656 1.26 (1.16–1.36) 1.17 (1.03–1.32) 1.15 (0.99–1.34) 1.15 (0.99–1.34)
Not excluding individuals with prior fracture
IBD overall d 83,476 (100%) 41,087 (100%) 1620 (1.9%) 716 (1.7%) 87,959 40,026 1.84 (1.75–1.93) 1.79 (1.66–1.92) 1.09 (1.00–1.20) 1.10 (1.00–1.20)
CD 21,751 (26.1%) 12,699 (30.9%) 423 (1.9%) 248 (2.0%) 22,633 12,369 1.87 (1.69–2.05) 2.00 (1.76–2.25) 1.01 (0.86–1.18) 1.02 (0.87–1.20)
UC 57,705 (69.1%) 26,465 (64.4%) 1102 (1.9%) 422 (1.6%) 61,174 25,804 1.80 (1.70–1.91) 1.64 (1.48–1.79) 1.17 (1.04–1.32) 1.18 (1.05–1.32)
Fracture, year 2006–2016
Follow‐up ≥2006
IBD overall d 41,081 (100%) 24,945 (100%) 668 (1.6%) 345 (1.4%) 42,728 24,231 1.56 (1.44–1.68) 1.42 (1.27–1.57) 1.09 (0.96–1.25) 1.10 (0.97–1.26)
CD 10,776 (26.2%) 7642 (30.6%) 193 (1.8%) 114 (1.5%) 11,093 7413 1.74 (1.49–1.99) 1.54 (1.26–1.82) 1.12 (0.89–1.42) 1.14 (0.90–1.45)
UC 27,911 (67.9%) 16,070 (64.4%) 439 (1.6%) 210 (1.3%) 29,189 15,625 1.50 (1.36–1.64) 1.34 (1.16–1.53) 1.14 (0.96–1.35) 1.14 (0.96–1.35)
Adjusting for IBD medical treatment e
IBD overall d 41,081 (100%) 24,945 (100%) 668 (1.6%) 345 (1.4%) 42,728 24,231 1.56 (1.44–1.68) 1.42 (1.27–1.57) 1.09 (0.95–1.25) 1.10 (0.96–1.26)
CD 10,776 (26.2%) 7642 (30.6%) 193 (1.8%) 114 (1.5%) 11,093 7413 1.74 (1.49–1.99) 1.54 (1.26–1.82) 1.14 (0.90–1.44) 1.15 (0.91–1.46)
UC 27,911 (67.9%) 16,070 (64.4%) 439 (1.6%) 210 (1.3%) 29,189 15,625 1.50 (1.36–1.64) 1.34 (1.16–1.53) 1.12 (0.94–1.33) 1.12 (0.94–1.33)
Adjusting for IBD medical treatment and bisphosphonate f
IBD overall c 41,081 (100%) 24,945 (100%) 668 (1.6%) 345 (1.4%) 42,728 24,231 1.56 (1.44–1.68) 1.42 (1.27–1.57) 1.09 (0.95–1.25) 1.10 (0.96–1.26)
CD 10,776 (26.2%) 7642 (30.6%) 193 (1.8%) 114 (1.5%) 11,093 7413 1.74 (1.49–1.99) 1.54 (1.26–1.82) 1.13 (0.90–1.44) 1.15 (0.91–1.46)
UC 27,911 (67.9%) 16,070 (64.4%) 439 (1.6%) 210 (1.3%) 29,189 15,625 1.50 (1.36–1.64) 1.34 (1.16–1.53) 1.12 (0.94–1.33) 1.12 (0.94–1.33)
Restricted to patients with clinically quiescent IBD e , g
IBD overall c 36,234 (100%) 22,307 (100%) 361 (1.0%) 222 (1.0%) 24,629 16,733 1.47 (1.31–1.62) 1.33 (1.15–1.50) 1.12 (0.94–1.33) 1.12 (0.94–1.33)
CD 8310 (22.9%) 6376 (28.6%) 74 (0.9%) 55 (0.9%) 4880 4310 1.52 (1.17–1.86) 1.28 (0.94–1.61) 1.20 (0.84–1.71) 1.19 (0.84–1.70)
UC 25,879 (71.4%) 14,828 (66.5%) 265 (1.0%) 152 (1.0%) 18,378 11,614 1.44 (1.27–1.62) 1.31 (1.10–1.52) 1.12 (0.91–1.38) 1.12 (0.91–1.38)
Fracture, July 2010–2016
Cumulative corticosteroid use within 5 years from the index date [mg prednisolone equivalents]
IBD overall d
0 10,668 (42.1%) 8233 (48.9%) 162 (1.5%) 88 (1.1%) 10,768 7888 1.50 (1.27–1.74) 1.12 (0.88–1.35) 1.41 (1.07–1.85) 1.41 (1.07–1.85)
1–1500 5868 (23.2%) 3596 (21.4%) 98 (1.7%) 52 (1.4%) 5974 3433 1.64 (1.32–1.96) 1.51 (1.10–1.93) 1.06 (0.75–1.50) 1.07 (0.75–1.51)
1501–3000 2927 (11.6%) 1910 (11.3%) 36 (1.2%) 26 (1.4%) 2998 1836 1.20 (0.81–1.59) 1.42 (0.87–1.96) 0.87 (0.52–1.45) 0.85 (0.51–1.43)
3001–4500 1670 (6.6%) 1030 (6.1%) 24 (1.4%) 17 (1.7%) 1744 988 1.38 (0.83–1.93) 1.72 (0.90–2.54) 0.74 (0.40–1.39) 0.78 (0.42–1.47)
4501– 4178 (16.5%) 2073 (12.3%) 91 (2.2%) 36 (1.7%) 4436 1969 2.05 (1.63–2.47) 1.83 (1.23–2.43) 1.18 (0.80–1.74) 1.19 (0.80–1.76)
CD
0 2363 (9.3%) 2087 (12.4%) 44 (1.9%) 21 (1.0%) 2363 1991 1.86 (1.31–2.41) 1.05 (0.60–1.51) 1.90 (1.10–3.26) 1.90 (1.10–3.26)
1–1500 1633 (6.5%) 1235 (7.3%) 27 (1.7%) 13 (1.1%) 1654 1179 1.63 (1.02–2.25) 1.10 (0.50–1.70) 1.39 (0.70–2.75) 1.40 (0.71–2.78)
1501–3000 937 (3.7%) 655 (3.9%) 10 (1.1%) 11 (1.7%) 939 623 1.06 (0.40–1.72) 1.76 (0.72–2.81) 0.59 (0.25–1.40) 0.57 (0.24–1.36)
3001–4500 522 (2.1%) 381 (2.3%) 7 (1.3%) 9 (2.4%) 544 361 1.29 (0.33–2.24) 2.49 (0.86–4.11) 0.48 (0.18–1.32) 0.50 (0.19–1.37)
4501– 1267 (5.0%) 777 (4.6%) 27 (2.1%) 13 (1.7%) 1317 733 2.05 (1.28–2.82) 1.77 (0.81–2.74) 1.18 (0.60–2.31) 1.24 (0.64–2.44)
UC
0 7549 (29.8%) 5750 (34.1%) 108 (1.4%) 63 (1.1%) 7646 5513 1.41 (1.15–1.68) 1.14 (0.86–1.42) 1.31 (0.94–1.81) 1.30 (0.94–1.81)
1–1500 3821 (15.1%) 2157 (12.8%) 63 (1.6%) 35 (1.6%) 3905 2059 1.61 (1.21–2.01) 1.70 (1.14–2.26) 0.94 (0.61–1.44) 0.94 (0.61–1.44)
1501–3000 1818 (7.2%) 1154 (6.9%) 25 (1.4%) 14 (1.2%) 1891 1118 1.32 (0.80–1.84) 1.25 (0.60–1.91) 0.99 (0.51–1.94) 0.98 (0.50–1.93)
3001–4500 1061 (4.2%) 602 (3.6%) 16 (1.5%) 8 (1.3%) 1112 580 1.44 (0.73–2.14) 1.38 (0.42–2.33) 1.11 (0.47–2.63) 1.16 (0.49–2.74)
4501– 2659 (10.5%) 1149 (6.8%) 58 (2.2%) 20 (1.7%) 2857 1097 2.03 (1.51–2.55) 1.82 (1.02–2.62) 1.20 (0.71–2.01) 1.17 (0.70–1.98)
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Abbreviations: CI, confidence interval; CD, Crohn's disease; IR, incidence rate; IRR, incidence rate ratio; PY, person‐years; UC, ulcerative colitis.

a

Histological inflammation and histological remission are defined by biopsies originating from the ileum or colorectum (topographic codes T65, T67 and T68) using histology codes listed in Table S5.

b

Adjusted for age at index date (i.e. the start of the exposure period), sex, calendar year, education level, country of birth, disease duration, any history of inpatient IBD care, IBD‐related surgery and the Charlson comorbidity index.

c

Analyses censored for corticosteroid use.

d

Any IBD subtype, including IBD‐unclassified (IBD‐U), which, due to few events, was not separately examined in these sensitivity analyses.

e

Follow‐up since 2006, allowing for additional adjustment for current use of medical IBD therapy as detailed in Table S7.

f

Additional adjustments for current use of medical IBD therapy and bisphosphonate (Table S8).

g

Clinical disease activity as in a recent paper from our group, 25 and based on IBD‐related surgery, hospitalization, budesonide or corticosteroid dispensing, initiation of immunomodulators or targeted therapies.

We found a modestly increased fracture risk with histological inflammation in male IBD patients (aHR = 1.21; 95% CI = 1.02–1.44) and patients with more recent IBD diagnoses (<2 years, aHR = 1.33; 95% CI = 1.09–1.62). The aHRs of any fracture were relatively consistent across age groups, including older adults with IBD (≥60 years, aHR = 1.08; 95% CI = 0.89–1.31), education levels and IBD subtypes (Figure 1).

The aHRs for any fracture were similar in CD (1.11; 95% CI = 0.91–1.36) and UC (1.18; 95% CI = 1.02–1.36). Figure S2 depicts the time to any fracture in the 12 months following a record of histological inflammation versus histological remission of IBD, CD and UC.

3.1.2. Hip fracture

There were 123 hip fractures during 76,235 follow‐up years with histological inflammation and 34 hip fractures during 33,651 follow‐up years with histological remission (0.16 [95% CI = 0.13–0.19] and 0.10 [95% CI = 0.07–0.13] per 100 person‐years, respectively). This corresponded to an aHR of 1.29 (95% CI = 0.87–1.92) for hip fracture in the 12 months following a record of histological inflammation versus histological remission (Figure 2; Table S10). Subgroup data are presented in Figure 2, and Kaplan–Meier curves for hip fracture are shown in Figure S3.

FIGURE 2.

FIGURE 2

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Risk of hip fracture during 0 to <12 months of histological inflammation versus histological remission in inflammatory bowel disease (IBD). 1 *Adjusted for age at biopsy (i.e. the start of the exposure period), sex, calendar year, education level, country of birth, disease duration, any history of inpatient IBD care, IBD‐related surgery and the Charlson comorbidity index. Histological inflammation and histological remission are defined by biopsies originating from the ileum or colorectum (topographic codes T65, T67 and T68) with histology codes listed in Table S5. Biopsy date equals the start of the exposure period. Montreal classifications of extent and location of disease at diagnosis are detailed in Table S2. CI, confidence interval; CD, Crohn's disease; IR, incidence rate; IRR, incidence rate ratio; IBD‐U, inflammatory bowel disease‐unclassified; PY, person‐years; UC, ulcerative colitis.

3.2. Sensitivity analyses for the risk of any fracture

Independent of remission status, we expectedly observed higher fracture rates in patients with long‐term corticosteroid use versus no use (Table 2). However, additional adjustments for current use (<6 months before the index date) of corticosteroids, other medical IBD therapy and bisphosphonate had no major impact on our aHRs (aHR for any fracture = 1.10 [95% CI = 0.96–1.26]). Also, analyses censored for corticosteroid use 0 to <12 months after biopsy revealed largely unchanged fracture risk with histological inflammation (Table 2). On the other hand, in analyses stratified by cumulative dose of corticosteroid use, the increased fracture risk after histological inflammation (vs. histological remission) was most clearly observed in corticosteroid‐naïve IBD patients (aHR = 1.41 [95% CI = 1.07–1.85]; Table 2).

Sensitivity analysis not excluding IBD patients with prior fracture, showed an aHR of 1.10 (95% CI = 1.00–1.20) for any fracture with histological inflammation (vs. remission; Table 2).

Histological inflammation was not associated with an increased fracture risk 1 to <10 years after biopsy (aHR = 0.97; 95% CI = 0.92–1.03; Table 2).

4. DISCUSSION

This nationwide cohort study may be the first to examine fracture risk in IBD according to an objective marker of disease activity. We revealed a small (+12%) overall increased fracture risk within a year after a record of histological inflammation versus histological remission of IBD. While the overall small fracture risk following histological inflammation remained after accounting for corticosteroid use, the most prominently raised fracture risk (+41%) was observed in corticosteroid‐naïve patients with histological inflammation versus histological remission. In current study population of primarily young and middle‐aged patients, histological inflammation was associated with a non‐significantly increased risk of hip fracture (aHR = 1.29; 95% CI = 0.87–1.92).

4.1. Previous literature

Previous literature has consistently found an increased risk of fractures in IBD, 5 , 6 even in IBD populations exposed to modern IBD care with a HR of any fracture of 1.18 (95% CI = 1.15–1.20) in IBD patients versus matched general population comparators. 4 These earlier studies also found that fracture risk increases for both IBD patients and non‐IBD comparators with increasing cumulative doses of steroids. 10 In contrast, IBD patients not exposed to steroids still had a small but statistically significantly increased risk of fractures compared to reference individuals not yet exposed to steroids. 4 The relationship between IBD inflammation and fracture risk, independent of steroid use, has yet to be investigated. Inflammatory mediators play a pivotal role in inflammatory osteolysis. 47 In CD, T‐cells have been shown to influence bone resorption by triggering osteoclasts. 48 Inflammation also has wide‐ranging deleterious effects on bone formation. 49 Our study reveals a newfound connection between inflammation in IBD and increased fracture risk, with an aHR of 1.12 (95% CI = 1.00–1.26; p = 0.04) for any fracture during 12‐month periods of histological inflammation (vs. histological remission) of IBD. Importantly, a similar, albeit not significantly increased fracture risk was observed among individuals in the clinically quiescent phase of IBD but persistent histological inflammation (aHR = 1.12; 95% CI = 0.94–1.33). Our findings reinforce the impact of inflammation on fracture risk in IBD. We found that the association between histological inflammation and fractures was most clearly observed in corticosteroid‐naive IBD patients, demonstrating intestinal inflammation's role in the absence of dominating risk factors. However, our findings may also be mediated by other factors tied to the inflammatory activity of IBD, such as sarcopenia, low body mass index and gut dysbiosis, all of which contribute to fracture risk. 11 , 50 , 51 Furthermore, often secondary to inflammation, 52 , 53 malabsorption and malnutrition can lower vitamin D levels essential for bone mineralization. 54 , 55 , 56 , 57 , 58

Most, but not all, 6 large‐scale studies have reported increased risks for hip fracture in IBD, with HRs ranging from 1.4 to 1.6. 4 , 5 , 59 We found a 29% increased risk of hip fractures during periods of histological inflammation. Although this HR did not reach statistical significance (aHR = 1.29; 95% CI = 0.87–1.92), it is consistent with a modest excess risk of any fractures. Only 20% of follow‐up time pertained to ages ≥60, where osteoporosis is most common, even though other factors (such as disability, frailty and falls) can impact hip fracture risk.

4.2. Strengths and limitations

A major strength of this study is the use of population‐based histopathology data as an objective measure of IBD activity. Our nationwide approach minimized selection bias, and our prospectively collected data reduced the risk of information bias. Our IBD definition has shown a positive predictive value of ≥93% for a clinical diagnosis of IBD. 19 , 20 , 60 Diagnostic codes to identify fractures in the NPR have also demonstrated high validity. 32 , 33 Multiple register linkages allowed us to adjust for sociodemographic characteristics and comorbidities, as well as medical, surgical 22 and inpatient care of IBD.

This study also has some limitations. We lacked data on whether the histological appearance changed over the 12 months since the last biopsy, which probably has attenuated the difference between histological inflammation and histological remission. Also, some subanalyses lacked sufficient sample sizes to determine definitive conclusions on whether fracture risk varies across patient subgroups.

As in any observational study, non‐causal explanations of our findings cannot be ruled out. For instance, residual confounding from missing data on smoking, dietary habits and physical activity may have influenced our findings. The lack of data on body mass index is particularly relevant given the substantial fracture risk associated with lower levels. 61 This study examined fractures requiring hospital care. Consequently, how our findings relate to fractures that may not come to clinical attention (e.g. vertebral fractures) is still being determined. 62 While we adjusted for bisphosphonate use to indicate pre‐existing fracture risk, we lacked information on bone densitometry.

We also had no endoscopic or biochemical remission data or symptoms to define clinical activity. A related limitation is the absence of data on clinical indications that prompted the histological assessment of IBD, which may have varied across patients with histological inflammation versus remission. Furthermore, this study included histological assessments collected in routine clinical practice and may not capture the entire burden of IBD activity, especially in intramural, stricturing or segmentally distributed intestinal inflammation of CD. Histological assessments are subject to inter‐individual variation. Because our histology data relied on SNOMED criteria, and we could not examine whether the degree of histological inflammation affects fracture risk.

Within these limitations, our data support recent IBD recommendations 11 for managing IBD activity while avoiding prolonged corticosteroid use. From our findings, it is unlikely that fracture preventive treatments would provide important therapeutic value following histological inflammation of IBD alone. However, histological activity may prompt such treatment considerations in other fracture risk factors.

In conclusion, in this nationwide IBD cohort, 12‐month periods of histological inflammation (vs. histological remission) pose a small, albeit statistically significant, incremental fracture risk. The increased fracture risk relative to histological inflammation was most prominent in corticosteroid‐naive IBD patients, demonstrating intestinal inflammation's role in the absence of dominating risk factors. Our findings support recommendations for careful management of disease activity while avoiding corticosteroid use to prevent fracture risk in IBD. Further research is needed to investigate the relationship between persistent histological inflammation and long‐term fracture risk.

AUTHOR CONTRIBUTIONS

Karl Mårild: Conceptualization; investigation; funding acquisition; writing – original draft; methodology; writing – review and editing; project administration. Jonas Söderling: Conceptualization; methodology; data curation; investigation; formal analysis; visualization; writing – review and editing. Jordan Axelrad: Conceptualization; methodology; investigation; writing – review and editing. Jonas Halfvarson: Conceptualization; methodology; investigation; writing – review and editing. Anders Forss: Conceptualization; methodology; investigation; writing – review and editing. Karl Michaëlsson: Conceptualization; methodology; investigation; writing – review and editing. Ola Olén: Conceptualization; methodology; investigation; writing – review and editing; supervision; funding acquisition; resources. Jonas F. Ludvigsson: Conceptualization; methodology; investigation; funding acquisition; writing – original draft; writing – review and editing; supervision; resources.

FUNDING INFORMATION

This work was supported by the University of Gothenburg (KM), ALF‐funding from Region Västra Götaland (KM), The Swedish Research Council (Dnr 2020‐01980 to KM; Dnr: 2020‐02002 to OO), The Swedish Society of Medicine (SLS‐935346/935415/935418 to KM), Karolinska Institutet (JFL), Region Stockholm (Dnr: RS2021‐0855 to OO), Crohn's and Colitis Foundation (JA), the Judith Stewart Colton Center for Autoimmunity (JA) and the NIH NIDDK Diseases (K23DK124570 to JA). The funding sources did not influence any aspect of the study (its design, the collection, analysis and interpretation of data) or approval of the manuscript and the decision to submit it for publication.

AUTHORSHIP

Guarantor of the article: JFL and KM.

Supporting information

Data S1.

APT-60-1549-s001.docx (534.2KB, docx)

Data S2.

APT-60-1549-s002.docx (18.8KB, docx)

ACKNOWLEDGMENTS

Thank you to Leslie Shaps, at Proofreading, Editing & Translation Global Services for language editing.

Declaration of personal interests: Dr. Mårild is a sub‐investigator at a clinical trial financed by Pfizer. Dr. Ludvigsson has coordinated an unrelated study on behalf of the Swedish Quality Register for IBD (SWIBREG). That study received funding from the Janssen Corporation. Dr. Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. Dr. Ludvigsson has also received funding from Takeda for celiac disease research. Dr. Olén has been PI for projects (unrelated to the current paper) at Karolinska Institutet financed by Janssen, Takeda, AbbVie, Ferring, Galapagos, Bristol Myers Squibb and Pfizer grants. Karolinska Institutet has received fees for lectures (OO) and participation on advisory boards (OO) from Janssen, Ferring, Bristol Myers Squibb, Galapagos and Takeda. Dr. Halfvarson has served as a speaker or advisory board member for AbbVie, BMS, Celgene, Celltrion, Dr. Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, Medtronic, MSD, Novartis, Olink Proteomics, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, ThermoFisher Scientific, Tillotts Pharma, Vifor Pharma and UCB. He has also received grant support from Janssen, MSD and Takeda. Dr. Axelrad has received research grants from BioFire Diagnostics and Genentech; consultancy fees, advisory board member or honorarium from BioFire Diagnostics, Adiso, Bristol‐Myers Squibb, Abbvie, Pfizer, Fresnius and Janssen; and holds U.S. patent 2012/0052124A1. Dr. Forss has served as a speaker and advisory board member for Janssen and Tillotts Pharma. The other authors report no conflicts of interest.

Mårild K, Söderling J, Axelrad J, Halfvarson J, Forss A, Michaëlsson K, et al. A nationwide cohort study of inflammatory bowel disease, histological activity and fracture risk. Aliment Pharmacol Ther. 2024;60:1549–1560. 10.1111/apt.18275

The Handling Editor for this article was Dr Sreedhar Subramanian, and it was accepted for publication after full peer‐review.

Contributor Information

Karl Mårild, Email: karlmarild@gmail.com.

SWIBREG Study Group:

Malin Olsson, Pär Myrelid, Henrik Hjortswang, Jonas Bengtsson, Hans Strid, Marie Andersson, Susanna Jäghult, Michael Eberhardson, Caroline Nordenvall, Jan Björk, Martin Rejler, Olof Grip, Ulrika L. Fagerberg, and Pontus Karling

DATA AVAILABILITY STATEMENT

No additional data are available because of Swedish regulations.

REFERENCES

  • 1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, et al. STRIDE‐II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat‐to‐target strategies in IBD. Gastroenterology. 2021;160(5):1570–1583. [DOI] [PubMed] [Google Scholar]
  • 2. Magro F, Doherty G, Peyrin‐Biroulet L, Svrcek M, Borralho P, Walsh A, et al. ECCO position paper: harmonization of the approach to ulcerative colitis histopathology. J Crohns Colitis. 2020;14(11):1503–1511. [DOI] [PubMed] [Google Scholar]
  • 3. Magro F, Sabino J, Rosini F, Tripathi M, Borralho P, Baldin P, et al. ECCO position on harmonisation of Crohn's disease mucosal histopathology. J Crohns Colitis. 2022;16(6):876–883. [DOI] [PubMed] [Google Scholar]
  • 4. Ludvigsson JF, Mahl M, Sachs MC, Björk J, Michaelsson K, Ekbom A, et al. Fracture risk in patients with inflammatory bowel disease: a Nationwide population‐based cohort study from 1964 to 2014. Am J Gastroenterol. 2019;114(2):291–304. [DOI] [PubMed] [Google Scholar]
  • 5. Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population‐based cohort study. Ann Intern Med. 2000;133(10):795–799. [DOI] [PubMed] [Google Scholar]
  • 6. Vestergaard P, Mosekilde L. Fracture risk in patients with celiac disease, Crohn's disease, and ulcerative colitis: a nationwide follow‐up study of 16,416 patients in Denmark. Am J Epidemiol. 2002;156(1):1–10. [DOI] [PubMed] [Google Scholar]
  • 7. Olen O, Askling J, Sachs MC, Neovius M, Smedby KE, Ekbom A, et al. Mortality in adult‐onset and elderly‐onset IBD: a nationwide register‐based cohort study 1964‐2014. Gut. 2020;69(3):453–461. [DOI] [PubMed] [Google Scholar]
  • 8. Karnsund S, Lo B, Bendtsen F, Holm J, Burisch J. Systematic review of the prevalence and development of osteoporosis or low bone mineral density and its risk factors in patients with inflammatory bowel disease. World J Gastroenterol. 2020;26(35):5362–5374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Weinstein RS. Clinical practice. Glucocorticoid‐induced bone disease. N Engl J Med. 2011;365(1):62–70. [DOI] [PubMed] [Google Scholar]
  • 10. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton LJ III, et al. A meta‐analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004;19(6):893–899. [DOI] [PubMed] [Google Scholar]
  • 11. Harbord M, Annese V, Vavricka SR, Allez M, Barreiro‐de Acosta M, Boberg KM, et al. The first European evidence‐based consensus on extra‐intestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2016;10(3):239–254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Schule S, Rossel JB, Frey D, Biedermann L, Scharl M, Zeitz J, et al. Prediction of low bone mineral density in patients with inflammatory bowel diseases. United European Gastroenterol J. 2016;4(5):669–676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Reffitt DM, Meenan J, Sanderson JD, Jugdaohsingh R, Powell JJ, Thompson RP. Bone density improves with disease remission in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2003;15(12):1267–1273. [DOI] [PubMed] [Google Scholar]
  • 14. Targownik LE, Leslie WD, Carr R, Clara I, Miller N, Rogala L, et al. Longitudinal change in bone mineral density in a population‐based cohort of patients with inflammatory bowel disease. Calcif Tissue Int. 2012;91(5):356–363. [DOI] [PubMed] [Google Scholar]
  • 15. Soare I, Sirbu A, Martin S, Diculescu M, Mateescu B, Tieranu C, et al. Assessment of bone quality with trabecular bone score in patients with inflammatory bowel disease. Sci Rep. 2021;11(1):20345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Bakker SF, Dik VK, Witte BI, Lips P, Roos JC, Van Bodegraven AA. Increase in bone mineral density in strictly treated Crohn's disease patients with concomitant calcium and vitamin D supplementation. J Crohns Colitis. 2013;7(5):377–384. [DOI] [PubMed] [Google Scholar]
  • 17. Ludvigsson JF, Lashkariani M. Cohort profile: ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden). Clin Epidemiol. 2019;11:101–114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Nguyen LH, Ortqvist AK, Cao Y, Simon TG, Roelstraete B, Song M, et al. Antibiotic use and the development of inflammatory bowel disease: a national case‐control study in Sweden. Lancet Gastroenterol Hepatol. 2020;5(11):986–995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Jakobsson GL, Sternegard E, Olen O, Myrelid P, Ljung R, Strid H, et al. Validating inflammatory bowel disease (IBD) in the Swedish National Patient Register and the Swedish Quality Register for IBD (SWIBREG). Scand J Gastroenterol. 2017;52(2):216–221. [DOI] [PubMed] [Google Scholar]
  • 21. Shrestha S, Olen O, Eriksson C, Everhov ÅH, Myrelid P, Visuri I, et al. The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register. Scand J Gastroenterol. 2020;55(4):430–435. [DOI] [PubMed] [Google Scholar]
  • 22. Forss A, Myrelid P, Olen O, Everhov ÅH, Nordenvall C, Halfvarson J, et al. Validating surgical procedure codes for inflammatory bowel disease in the Swedish National Patient Register. BMC Med Inform Decis Mak. 2019;19(1):217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Olen O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population‐based cohort study. Lancet. 2020;395(10218):123–131. [DOI] [PubMed] [Google Scholar]
  • 24. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55(6):749–753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Mårild K, Söderling J, Stephansson O, Axelrad J, Halfvarson J, SWIBREG Study Group , et al. Histological remission in inflammatory bowel disease and risk of adverse pregnancy outcomes: a nationwide study. EClinicalMedicine. 2022;53:101722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Marild K, Soderling J, Axelrad J, Halfvarson J, Forss A, SWIBREG Study Group , et al. Histological activity in inflammatory bowel disease and risk of serious infections: a nationwide study. Clin Gastroenterol Hepatol. 2023;22(4):831–846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Vespa E, D'Amico F, Sollai M, Allocca M, Furfaro F, Zilli A, et al. Histological scores in patients with inflammatory bowel diseases: the state of the art. J Clin Med. 2022;11(4):939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133–143. [DOI] [PubMed] [Google Scholar]
  • 29. Guder C, Gravius S, Burger C, Wirtz DC, Schildberg FA. Osteoimmunology: a current update of the interplay between bone and the immune system. Front Immunol. 2020;11:58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Holmberg AH, Johnell O, Nilsson PM, Nilsson JA, Berglund G, Akesson K. Risk factors for hip fractures in a middle‐aged population: a study of 33,000 men and women. Osteoporos Int. 2005;16(12):2185–2194. [DOI] [PubMed] [Google Scholar]
  • 31. Robinson CM, Court‐Brown CM, McQueen MM, Christie J. Hip fractures in adults younger than 50 years of age. Epidemiology and results. Clin Orthop Relat Res. 1995;312:238–246. [PubMed] [Google Scholar]
  • 32. Bergstrom MF, Byberg L, Melhus H, Michaelsson K, Gedeborg R. Extent and consequences of misclassified injury diagnoses in a national hospital discharge registry. Inj Prev. 2011;17(2):108–113. [DOI] [PubMed] [Google Scholar]
  • 33. Michaelsson K, Melhus H, Ferm H, Ahlbom A, Pedersen NL. Genetic liability to fractures in the elderly. Arch Intern Med. 2005;165(16):1825–1830. [DOI] [PubMed] [Google Scholar]
  • 34. Chalitsios CV, Shaw DE, McKeever TM. Corticosteroids and bone health in people with asthma: a systematic review and meta‐analysis. Respir Med. 2021;181:106374. [DOI] [PubMed] [Google Scholar]
  • 35. Ludvigsson JF, Michaelsson K, Ekbom A, Montgomery SM. Coeliac disease and the risk of fractures—a general population‐based cohort study. Aliment Pharmacol Ther. 2007;25(3):273–285. [DOI] [PubMed] [Google Scholar]
  • 36. Van Hulten V, Rasmussen N, Driessen JHM, Burden AM, Kvist A, van den Bergh JP. Fracture patterns in type 1 and type 2 diabetes mellitus: a narrative review of recent literature. Curr Osteoporos Rep. 2021;19(6):644–655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Li C, Zeng Y, Tao L, Liu S, Ni Z, Huang Q, et al. Meta‐analysis of hypertension and osteoporotic fracture risk in women and men. Osteoporos Int. 2017;28(8):2309–2318. [DOI] [PubMed] [Google Scholar]
  • 38. Ludvigsson JF, Appelros P, Askling J, Byberg L, Carrero JJ, Ekström AM, et al. Adaptation of the Charlson Comorbidity Index for Register‐Based Research in Sweden. Clin Epidemiol. 2021;13:21–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Montgomery SM, Pounder RE, Wakefield AJ. Infant mortality and the incidence of inflammatory bowel disease. Lancet. 1997;349(9050):472–473. [DOI] [PubMed] [Google Scholar]
  • 40. Shivananda S, Lennard‐Jones J, Logan R, Fear N, Price A, Carpenter L, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC‐IBD). Gut. 1996;39(5):690–697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Hvidberg MF, Frolich A, Lundstrom SL. Catalogue of socioeconomic disparities and characteristics of 199+ chronic conditions—a nationwide register‐based population study. PLoS One. 2022;17(12):e0278380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Ludvigsson JF, Svedberg P, Olen O, Bruze G, Neovius M. The longitudinal integrated database for health insurance and labour market studies (LISA) and its use in medical research. Eur J Epidemiol. 2019;34(4):423–437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Ludvigsson JF, Almqvist C, Bonamy AK, et al. Registers of the Swedish total population and their use in medical research. Eur J Epidemiol. 2016;31(2):125–136. [DOI] [PubMed] [Google Scholar]
  • 44. Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish prescribed drug register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007;16(7):726–735. [DOI] [PubMed] [Google Scholar]
  • 45. Ludvigsson JF, Andersson M, Bengtsson J, Eberhardson M, Fagerberg UL, Grip O, et al. Swedish inflammatory bowel disease register (SWIBREG)—a nationwide quality register. Scand J Gastroenterol. 2019;54(9):1089–1101. [DOI] [PubMed] [Google Scholar]
  • 46. Broms G, Soderling J, Sachs MC, Halfvarson J, SWIBREG Study Group , Myrelid P, et al. Capturing biologic treatment for IBD in the Swedish prescribed drug register and the Swedish National Patient Register—a validation study. Scand J Gastroenterol. 2021;56(4):410–421. [DOI] [PubMed] [Google Scholar]
  • 47. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF‐alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106(12):1481–1488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Oostlander AE, Everts V, Schoenmaker T, Bravenboer N, van Vliet SJ, van Bodegraven AA, et al. T cell‐mediated increased osteoclast formation from peripheral blood as a mechanism for Crohn's disease‐associated bone loss. J Cell Biochem. 2012;113(1):260–268. [DOI] [PubMed] [Google Scholar]
  • 49. Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos Int. 2017;28(12):3301–3314. [DOI] [PubMed] [Google Scholar]
  • 50. Steihaug OM, Gjesdal CG, Bogen B, Kristoffersen MH, Lien G, Ranhoff AH. Sarcopenia in patients with hip fracture: a multicenter cross‐sectional study. PLoS One. 2017;12(9):e0184780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Hernandez CJ, Guss JD, Luna M, Goldring SR. Links between the microbiome and bone. J Bone Miner Res. 2016;31(9):1638–1646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281. [DOI] [PubMed] [Google Scholar]
  • 53. Del Pinto R, Pietropaoli D, Chandar AK, Ferri C, Cominelli F. Association between inflammatory bowel disease and vitamin D deficiency: a systematic review and meta‐analysis. Inflamm Bowel Dis. 2015;21(11):2708–2717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Fletcher J, Cooper SC, Ghosh S, Hewison M. The role of vitamin D in inflammatory bowel disease: mechanism to management. Nutrients. 2019;11(5):1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Neale RE, Baxter C, Romero BD, McLeod DSA, English DR, Armstrong BK, et al. The D‐health trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol. 2022;10(2):120–128. [DOI] [PubMed] [Google Scholar]
  • 56. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta‐analyses of observational studies and randomised trials. BMJ. 2014;348:g2035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Michaelsson K. The puzzling world of vitamin D insufficiency. Lancet Diabetes Endocrinol. 2014;2(4):269–270. [DOI] [PubMed] [Google Scholar]
  • 59. Card T, West J, Hubbard R, Logan RF. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251–255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Mouratidou N, Malmborg P, Jaras J, Sigurdsson V, Sandström O, Fagerberg UL, et al. Identification of childhood‐onset inflammatory bowel disease in Swedish healthcare registers: a validation study. Clin Epidemiol. 2022;14:591–600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. De Laet C, Kanis JA, Oden A, Kanis JA, Odén A, Johanson H, et al. Body mass index as a predictor of fracture risk: a meta‐analysis. Osteoporos Int. 2005;16(11):1330–1338. [DOI] [PubMed] [Google Scholar]
  • 62. Cooper C, O'Neill T, Silman A. The epidemiology of vertebral fractures. European Vertebral Osteoporosis Study Group. Bone. 1993;14(Suppl 1):S89–S97. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1.

APT-60-1549-s001.docx (534.2KB, docx)

Data S2.

APT-60-1549-s002.docx (18.8KB, docx)

Data Availability Statement

No additional data are available because of Swedish regulations.

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