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Open Access

Peer-reviewed

Research Article

The risk of revision following total hip arthroplasty in patients with inflammatory bowel disease, a registry based study

  • Meghan M. Moran ,

    Contributed equally to this work with: Meghan M. Moran, Peter Wessman, Ola Rolfson

    Roles Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

    meghan_moran@rush.edu

    Affiliation Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, IL, United States of America

    ⨯
  • Peter Wessman ,

    Contributed equally to this work with: Meghan M. Moran, Peter Wessman, Ola Rolfson

    Roles Data curation, Formal analysis, Methodology, Software, Writing – review & editing

    Affiliation Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    ⨯
  • Ola Rolfson ,

    Contributed equally to this work with: Meghan M. Moran, Peter Wessman, Ola Rolfson

    Roles Conceptualization, Data curation, Methodology, Resources, Supervision, Writing – review & editing

    Affiliation Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    ⨯
  • Daniel D. Bohl ,

    Roles Conceptualization, Methodology, Writing – original draft

    ‡ These authors also contributed equally to this work.

    Affiliation Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, United States of America

    ⨯
  • Johan Kärrholm ,

    Roles Conceptualization, Formal analysis, Methodology, Supervision, Writing – review & editing

    ‡ These authors also contributed equally to this work.

    Affiliation Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    ⨯
  • Ali Keshavarzian ,

    Roles Conceptualization, Investigation, Resources, Supervision, Writing – review & editing

    ‡ These authors also contributed equally to this work.

    Affiliation Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush Medical College, Chicago, IL, United States of America

    ⨯
  • D. Rick Sumner

    Roles Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing

    Affiliations Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, IL, United States of America, Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, United States of America

    ⨯

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract and is associated with decreased bone mineral density. IBD patients are at higher risk of osteopenia, osteoporosis and fracture compared to non-IBD patients. The impact of IBD on the performance of orthopedic implants has not been well studied. We hypothesized that a history of IBD at the time of primary total hip arthroplasty (THA) would increase the risk of subsequent failure as assessed by revision surgery. A retrospective implant survival analysis was completed using the Swedish Hip Arthroplasty Registry and the Sweden National Patient Register. A total of 150,073 patients undergoing THA for osteoarthritis within an 18-year period were included in the study. THA patients with (n = 2,604) and without (n = 147,469) a history of IBD at the time of THA were compared with primary revision as the main endpoint and adjusted using sex, age category and comorbidity (Elixhauser scores) as covariates. We found that patients with a history of IBD had a relatively higher risk of revision surgery for septic causes while the non-IBD patients had a relatively higher risk of revision for aseptic causes (p = 0.004). Our findings suggest there may be an association between gut health and THA performance.

Citation: Moran MM, Wessman P, Rolfson O, Bohl DD, Kärrholm J, Keshavarzian A, et al. (2021) The risk of revision following total hip arthroplasty in patients with inflammatory bowel disease, a registry based study. PLoS ONE 16(11): e0257310. https://doi.org/10.1371/journal.pone.0257310

Editor: Valérie Pittet, Center for Primary Care and Public Health, SWITZERLAND

Received: January 30, 2021; Accepted: August 30, 2021; Published: November 4, 2021

Copyright: © 2021 Moran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Due to legal restrictions, the dataset cannot be uploaded and remains available upon request. This study is based on data from the Swedish National Patient Register governed by the National Board of Health, and data from the Swedish Hip Arthroplasty Register governed by Centre of Registers in Västra Götaland. These data contain sensitive information and are not possible to fully anonymize. The merged data used in the present study are located in a security server at Centre of Registers Västra Götaland with restricted access. For researchers interested in the data, these will be made available upon request to registercentrum@vgregion.se, given that the interested party can provide approval from the data owners, the National Board of Health and Welfare (http://www.socialstyrelsen.se/english) and Registercentrum Västra Götaland (http://www.registercentrum.se) along with ethical approval from the Swedish Ethical Review Authority.

Funding: Research reported in this manuscript was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers R01AR066562.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases that attack the intestinal tract, including Crohn’s disease (CD) and ulcerative colitis (UC) [1, 2]. IBD as a diagnosis is increasing world-wide [3]. IBD patients are most commonly diagnosed between 20 and 40 years of age [4], but a second peak of IBD diagnoses has presented in patients >60 years of age [4–6]. Older IBD patients account for ~10% of first-flare patients [7] and comprise 10–30% of the IBD population [8]. IBD-related intestinal symptoms can flare regularly and repeatedly throughout a patient’s life [4]. While CD can attack any region of the digestive track from the mouth to the anus, UC targets only the colon [9]. Location of disease within the intestinal track impacts local intestinal physiology including barrier function [10], and has downstream implications in remote organs including bone and joint in humans [11, 12] and in rats [13].

IBD patients are more susceptible to adverse effects in the skeleton compared to the non-IBD population. IBD patients have been shown to have low bone mineral density (BMD) due to increased bone resorption [14] and increased collagen breakdown [15], which is consistent with higher incidences of osteoporosis and fracture [1, 12, 16–21]. In fact, CD patients have a 60% higher risk of hip fracture [16, 22] and more generally, IBD patients have a 40% higher risk of other types of fractures, including spine and rib [23] compared to the general population. Further contributing to low BMD, an IBD diagnosis is associated with decreased bone formation serum markers (osteocalcin, bone alkaline phosphatase and C-terminal collagen propeptide) [20], decreased longitudinal bone growth in childhood and failure to attain normal peak bone mass [20, 24]. It has been shown that there is already significant reduction in trabecular bone by the time of CD diagnosis, suggesting bone is affected by IBD early in disease progression [25]. Drugs commonly prescribed for IBD have been shown to have mixed effects on the skeleton. Tumor necrosis factor-alpha (TNFα) targeting therapeutics lead to diminished bone quantity and quality [26] while corticosteroids have been associated with increased fracture risk in some [16] but not all [22, 27] studies.

Skeletal effects are exacerbated by CD-related nutritional deficiencies [21, 28, 29] and surgical and drug interventions. For example, ileal resection surgery can lead to malabsorption of vitamin D and calcium, which contributes to metabolic bone disease [30, 31]. IBD has also been associated with peripheral joint arthritis, which is present in 4.5% of IBD patients at the time of diagnosis and increases to 30% by the 20 year follow up [32]. Aging exacerbates these negative effects of IBD on the musculoskeletal system [27]. Thus, as patients with a history of IBD age, joint replacement surgery will likely become more prevalent in this population.

There has been limited study of orthopedic implant performance in IBD patients. Post-operative complications and revision rates following total hip arthroplasty (THA) are higher in some IBD patients [33]. Vitamin D deficiency, associated with CD, has also been linked to poor outcomes after total joint replacement [34, 35]. These studies indicate that there may be a link between IBD diagnosis and orthopedic implant outcomes.

The incidence of primary total hip and knee arthroplasty is expected to at least double in the next 30 years [36–40]. The impact of IBD on the lifespan of orthopedic implants is unknown. This study tested the hypothesis that the diagnosis of IBD is associated with decreased implant survivorship following THA.

Materials and methods

Ethical considerations

This study is part of a multidimensional research project based within the Swedish Hip Arthroplasty Register investigating factors associated with outcomes following hip replacement. Patients scheduled for THA are informed about the data collection in national registers in a written document that does not require a signature. Patients can, at any time, withdraw their consent actively, which means that all data about them, their surgery and follow-up information are deleted from the register. The ethical review board in Gothenburg approved the study and waived informed consent. The informed consent waiver is regulated within the Patient Data Act (2008:355) and the Act Concerning the Ethical Review of Research Involving Humans (2003:460).

Study inclusion and exclusion criteria

We used the Swedish Hip Arthroplasty Registry and the Sweden National Patient Register to identify patients for this study, starting with 226,270 patients who had a primary THA within the 18 year period from January 1, 1999 to December 31, 2017 (Fig 1). Patients were excluded if they met one or more of the following criteria: 1) not the patient’s first THA (47,091), 2) THA for reasons other than primary OA (27,214), 3) double-sided THA (1,519), 4) patients who had resurfacing arthroplasties (2,816). Thus, a total of 150,073 patients who had a primary THA for osteoarthritis were included in the study (Fig 1).

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Fig 1. Flow diagram illustrating patient inclusion and exclusion criteria.

The number of patients is described per inclusion and exclusion criteria throughout this figure. Patients were selected from the Swedish Hip Arthroplasty Register and the Sweden National Patient Register. THA- total hip arthroplasty.

https://doi.org/10.1371/journal.pone.0257310.g001

Classification of patients

The patients were identified as IBD (n = 2,604) based on having a history of ICD-10-SE (Swedish ICD-10) codes for CD (K50), UC (K51) or unspecified colitis (K52) at the time of their primary THA. For patient identification prior to 2015, ICD-9-SE codes were used CD (555), UC (556) or unspecified colitis (558). The remaining patients were classified as non-IBD (n = 147,469).

Statistical analysis

The included patients were followed until December 31, 2017 (107,828) or death prior to December 31, 2017 (42,245). Data were summarized using absolute numbers and proportions for categorical variables and means and standard deviations (SD) for continuous variables. Pearson’s Chi-squared test was used to compare groups with regards to categorical variables. Time to all-cause mortality and time to revision were analysed using the Kaplan-Meier method. Cox proportional hazards models with IBD diagnose at index arthroplasty surgery were used to adjust for sex, age category, and comorbidity (Elixhauser scores) as covariates. Hazard ratios (HR) are presented with unadjusted 95% confidence intervals, Cox proportional hazard (PH) model assumption was assessed using stratified Kaplan-Meier and diagnostic plots. A competing risk analysis was performed for time to first revision with septic cause for revision, aseptic cause for revision and death as events. In addition, for all-cause mortality the relative survival compared to the general Swedish population was estimated, matched on gender and age. Relative survival is the ratio between observed survival and expected survival with a ratio over 1 indicating better survival than the general population and a ratio below 1 indicating excess mortality.

Results

Patient population

The prevalence of IBD at primary THA was slightly higher in females (1.9%) than males (1.5%, Table 1) with a prevalence ratio of 1.26 (95% CI: 1.16 to 1.36). The IBD and non-IBD patient’s mean age at the time of primary THA was 67.6 and 68.1 years, respectively. The categories of implant fixation included cemented, uncemented, hybrid (cemented fixation of the femoral component and cementless fixation of the acetabular component) and reverse hybrid (uncemented fixation of the femoral component and cemented fixation of the acetabular component). The type of fixation was different between the IBD and non-IBD groups (Table 1). Follow-up time (the time from THA to the last day of observation, 31 December 2017, or death) was slightly greater in the non-IBD group (8.9 years versus 7.3 years). The Elixhauser comorbidity index was higher in the IBD group than in the non-IBD group with 50.2% vs 36.5% of the patients, respectively, having a score above zero (p-value < 0.001).

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Table 1. THA patient demographics by IBD diagnose at index THA surgery.

https://doi.org/10.1371/journal.pone.0257310.t001

The relative survival of IBD THA patients was worse than the general Swedish population, while the relative survival of non-IBD THA patients was somewhat better than the general Swedish population (Fig 2).

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Fig 2. Relative survival of THA patients with and without IBD.

With IBD, there is increased mortality compared to the general Swedish population. A curve above 1 indicates a lower risk for non-IBD THA patients compared to the general population. Dotted black line- general Swedish population. Solid black line- non-IBD, solid red line- IBD. Dotted black and red lines- 95% CI.

https://doi.org/10.1371/journal.pone.0257310.g002

Although the fraction of patients who died during follow-up did not differ among IBD (27.0%, 704/2,604) and non-IBD (28.2%, 41,560/147,469) groups, the median time to death was 1.5 years shorter for IBD patients, 14.8 years (95% CI: 13.9 to 16.6) compared to 16.3 years (95% CI: 16.2 to 16.4) (Fig 3, log-rank test: p<0.0001).

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Fig 3. Patient mortality after primary THA.

Kaplan-Meier curve stratified by IBD and non-IBD patients. THA patients with IBD have higher mortality compared to non-IBD THA patients (1.5 year shorter expected median survival). Solid aqua line- IBD, solid red line- non-IBD diagnosis, shaded areas- 95% CI.

https://doi.org/10.1371/journal.pone.0257310.g003

Risk of revision

IBD patients had a significant increased risk of revision compared to non-IBD patients (Fig 4, log-rank test, p-value = 0.0049). The probability of revision became significantly different 10 years after THA surgery. While the observed proportion of patients requiring revision during the follow-up period, which ranged from a minimum of 3 years to a maximum of 18 years, was not different between non-IBD and IBD patients (4.6% in both groups, Table 2), an adjusted Cox PH model including age, gender, comorbidity and IBD/non-IBD diagnosis showed an increased probability of revision for IBD compared to non-IBD patients (HR of 1.24, 95% CI: 1.03 to 1.48, S1 Table).

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Fig 4. Kaplan Meier: Risk of revision after primary THA in patients with and without IBD at the time of index THA.

Solid aqua line- IBD, solid red line- non-IBD diagnosis, shaded areas- 95% CI. Note that due to the sample size the red shaded area for the non-IBD CI is tightly fit to the red line.

https://doi.org/10.1371/journal.pone.0257310.g004

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Table 2. Causes of revision.

https://doi.org/10.1371/journal.pone.0257310.t002

In addition, there was a difference in the proportion of revisions due to septic and aseptic causes (p = 0.004). For septic cause, the observed risk of revisions was lower in non-IBD patients (2.1%) than in IBD patients (2.7%), (RR 0.77, 95% CI: 0.61 to 0.98). In contrast, the risk of revision due to aseptic causes was higher in non-IBD patients (2.5%) compared to IBD patients (1.9%), (RR 1.31, 95% CI: 0.99 to 1.74). The specific categories for aseptic revision were comparable between non-IBD and IBD patients (p = 0.924). The risk for revision due to septic cause, aseptic cause, or death was explored in a competing risk model (S1 Fig), which showed a higher risk of revision for sepsis in IBD patients compared to non-IBD patients (p = 0.02, S1 Table). The difference between IBD and non-IBD patients seen in the competing risk model seems to be driven largely by revisions due to septic causes.

Discussion

With the occurrence of joint arthroplasty expected to increase steadily over the next 30 years, it is important to understand how bowel health impacts arthroplasty performance. Our study tested the hypothesis that there is an association between a diagnosis of IBD at the time of THA and decreased implant survivorship. We found that having IBD led to a greater risk of revision when age, gender and comorbidity index were included in the model. Specifically, there was a higher risk of revision for septic cause in IBD patients and a higher risk of revision for aseptic causes in non-IBD patients.

Our study highlighted the risk of septic complication of THA in patients with IBD and thus orthopedic surgeons should be aware of this risk and consider it when evaluating and discussing THA with IBD patients. Recently, increased effort has been applied to identifying risk factors for periprosthetic joint infection following joint replacement [41]. IBD could be a risk factor added to the list orthopedic surgeons use in risk stratification when considering whether surgery is worthwhile. Our study raises questions about whether additional steps could be taken to mitigate risk in IBD THA patients, including prolonged perioperative antibiotics, timing of surgery in relation with IBD disease activity or time of surgery in relation with time of IBD therapeutic administration or use of antibiotic cement. However, at this time, our study cannot provide any specifics on recommendations to mitigate increased risk. Our study does provided strong scientific rationale for future studies to determine the therapeutic approaches to mitigate this increase risk in IBD patients.

Our finding that IBD patients had a higher prevalence of sepsis as a cause for revision agrees with one study that found an increased risk of complications, including infection, post-THA surgery in IBD patients [33]. In contrast, a 2018 study found that IBD patients are not at increased risk of infection after orthopedic procedures [42]. Sepsis has been the second leading cause of implant failure, after aseptic loosening, for decades [43, 44]. Sepsis [45] and IBD [11, 12, 18, 20] have each been associated with decreased BMD. Although not measured in our study, low BMD, especially in the peri-implant region in the aged population, may contribute to the observed increase in risk of revision. CD-related low BMD is attributed to many factors including corticosteroid therapeutics, low vitamin D levels, being male and Asian ethnicity [46], amongst others. Corticosteroids, a commonly prescribed anti-inflammatory drug for IBD, have been shown to increase risk of osteoporotic fracture[22, 47] and vitamin D deficiency has been noted in both osteoporotic patients [48, 49] and IBD patients with decreased micronutrient absorption in the gut [34, 35, 49]. Together, these factors likely promote poor quantity and quality of peri-implant bone stock, contributing to implant failure.

Inflammation and the innate immune response are also altered in IBD patients [50] and may play a role in implant performance. In IBD patients, C-reactive protein (CRP), a systemic biomarker of inflammation, is significantly increased especially in CD [51] and pro-inflammatory macrophages and mast cells are found in higher concentrations in the intestine [50] compared to the general population. These inflammatory cells and associated inflammatory markers increase with age [52]. Age alone is a contributing factor in both IBD manifestation [5, 7] and THA survivorship and risk of revision [53]. Therefore, when all three factors present simultaneously, amplification of post-operative complications are likely to increase. While IBD is commonly thought of as a chronic disease of young adulthood, there is growing recognition of patients being diagnosed later in life, > 60 years of age [8]. The average age of patients in this study is ~68 years, with ~45% of the IBD patients being 70+ years old. The average age of patients undergoing primary arthroplasty is ~70 years [54] and revision surgeries occur later in life. These studies support that chronic inflammation, exacerbated by age, likely contribute to both gut health and arthroplasty outcomes.

Our findings suggest that gut health can play a role in THA outcomes. It is known that the intestinal microbiome of IBD patients is altered compared to non-IBD patients [55]. CD specifically is characterized by microbial dysbiosis and decreased diversity of the gut microbiome [9], even as early as the time of diagnosis prior to any therapeutic administration [55]. Alterations to the intestinal microbiome have also been shown to increase risk for systemic infection [56], affect bone mass [57, 58], and whole bone strength [59] in both humans and animal models. Disruption of the gut microbiome that results in abundance of pathogenic bacteria and decrease in short-chain fatty acid production are both factors in the risk and severity of sepsis [56]. Extensive rodent studies have shown that the gut milieu contributes to bone health [60]. Specifically, manipulation of the gut microbiota was shown to alter osteoarthritis [61, 62], rheumatoid arthritis [63, 64], fracture healing [65] and osteolysis [66]. Further studies using probiotic treatment showed increased bone density [67] and prevented bone loss following ovariectomy [68]. Taking into account the local and systemic effects IBD has on the body and the recognized importance of the gut-bone interaction, our results support that IBD is likely to affect arthroplasty outcomes.

In our study population, the prevalence of IBD was higher in females than males, which is consistent with previously published studies [69–71]. Effect modifiers that may have affected our results include sex and type of implant fixation. Sex may be an effect modifier because there are known disease differences between females and males. Type of implant fixation is known to influence implant survivorship [72, 73]. However, no major difference in revision among IBD and non-IBD patients was observed as a function of implant fixation type.

While, the relative survival of IBD THA patients was worse than the general Swedish population, non-IBD THA patients had better relative survival compared to the general Swedish population. This was likely because the non-IBD patients included in this study were healthy enough to benefit from THA.

Limitations of this study are inherent to registry studies, which include limited availability of data on potential confounding factors and under-reporting of outcomes if a patient leaves the registry or is not adequately followed up [74]. Our study also focuses only on patients that had primary surgeries within the 18 year time frame, and excludes patients with THA prior to January 1, 1999. There were a number of confounding factors that may be of interest for future studies, but which were not accessible in the data bases we used. The first is prescription drug use among our study population. IBD-associated medication including steroids, immune modulators (Azathioprine) and biologics (TNF antibody) increase risk of post-operative infection complication. Unfortunately, our database did not include a medication list and thus we cannot determine whether the increase risk of revision is due to medication or IBD. We were also unable to determine if IBD patients had an active or inactive disease state at the time of arthroplasty and the frequency and severity of active disease after their index THA. In addition, the lack of subgroup analysis of UC and CD is an important study limitation because their effects on the skeletal system may differ [16, 22, 23]. We explored stratifying the analyses by IBD disease subgroup, however, too much statistical power was lost, meaning that we may have masked important disease-specific effects.

Conclusion

A history of IBD at the time of THA was associated with long-term greater risk of revision surgery due to sepsis.

Supporting information

S1 Fig. Probability of death and probability of revision due to aseptic and septic causes.

Revisions due to septic cause occur earlier than revision due to aseptic cause regardless of IBD or non-IBD. Solid line- IBD, Dotted line- non-IBD, Black lines- death, red lines- septic cause for revision and blue lines- aseptic cause for revision.

https://doi.org/10.1371/journal.pone.0257310.s001

(DOCX)

S1 Table. Adjusted Cox PH model: Hazard ratio for time to first revision.

Cox PH model including gender, age, comorbidity and IBD as main effects. No interaction effect was included.

https://doi.org/10.1371/journal.pone.0257310.s002

(DOCX)

Acknowledgments

We acknowledge Drs. Joshua Jacobs and Christopher Forsyth for the time they devoted to discussing this project. Emma Nauclér (currently), Erik Bulow and Szilard Nemes (formerly) of the Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden contributed to statistical analysis in early versions of this manuscript.

References

  1. 1. Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Frontiers in Immunology. 2012;3:107. PubMed PMID: PMC3347037. pmid:22586430
  2. 2. Sohrabpour AA, Malekzadeh R, Keshavarzian A. Current therapeutic approaches in inflammatory bowel disease. Curr Pharm Des. 2010;16(33):3668–83. Epub 2010/12/07. pmid:21128898.
  3. 3. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17–30. Epub 2019/10/28. pmid:31648971; PubMed Central PMCID: PMC7026709.
  4. 4. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785–94. Epub 2011/05/03. pmid:21530745.
  5. 5. Taleban S, Colombel JF, Mohler MJ, Fain MJ. Inflammatory bowel disease and the elderly: a review. Journal of Crohn’s & colitis. 2015;9(6):507–15. Epub 2015/04/15. pmid:25870198.
  6. 6. Shrestha MP, Ruel J, Taleban S. Healthcare maintenance in elderly patients with inflammatory bowel disease. Annals of gastroenterology. 2017;30(3):273–86. Epub 2017/05/05. pmid:28469357; PubMed Central PMCID: PMC5411377.
  7. 7. del Val JH. Old-age inflammatory bowel disease onset: a different problem? World journal of gastroenterology. 2011;17(22):2734–9. Epub 2011/07/08. pmid:21734781; PubMed Central PMCID: PMC3122261.
  8. 8. Gisbert JP, Chaparro M. Systematic review with meta-analysis: inflammatory bowel disease in the elderly. Aliment Pharmacol Ther. 2014;39(5):459–77. Epub 2014/01/11. pmid:24405149.
  9. 9. Ahmed I, Roy BC, Khan SA, Septer S, Umar S. Microbiome, Metabolome and Inflammatory Bowel Disease. Microorganisms. 2016;4(2). Epub 2016/09/30. pmid:27681914; PubMed Central PMCID: PMC5029486.
  10. 10. Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World journal of gastroenterology. 2014;20(5):1165–79. Epub 2014/02/28. pmid:24574793; PubMed Central PMCID: PMC3921501.
  11. 11. Compston JE, Judd D, Crawley EO, Evans WD, Evans C, Church HA, et al. Osteoporosis in patients with inflammatory bowel disease. Gut. 1987;28(4):410. pmid:3583068
  12. 12. Pigot F, Roux C, Chaussade S, Hardelin D, Pelleter O, Du Puy Montbrun T, et al. Low bone mineral density in patients with inflammatory bowel disease. Dig Dis Sci. 1992;37(9):1396–403. Epub 1992/09/01. pmid:1505291.
  13. 13. Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology. 1996;111(5):1263–71. Epub 1996/11/01. pmid:8898640.
  14. 14. Compston JE. Can biochemical markers be used to screen patients with inflammatory bowel disease for osteoporosis? European journal of gastroenterology & hepatology. 2002;14(6):587–9. Epub 2002/06/20. pmid:12072590.
  15. 15. Silvennoinen J, Risteli L, Karttunen T, Risteli J. Increased degradation of type I collagen in patients with inflammatory bowel disease. Gut. 1996;38(2):223–8. Epub 1996/02/01. pmid:8801201; PubMed Central PMCID: PMC1383027.
  16. 16. van Staa TP, Cooper C, Brusse LS, Leufkens H, Javaid MK, Arden NK. Inflammatory bowel disease and the risk of fracture. Gastroenterology. 2003;125(6):1591–7. Epub 2004/01/16. pmid:14724810.
  17. 17. Vazquez MA, Lopez E, Montoya MJ, Giner M, Perez-Temprano R, Perez-Cano R. Vertebral fractures in patients with inflammatory bowel disease compared with a healthy population: a prospective case-control study. BMC Gastroenterol. 2012;12:47. Epub 2012/05/16. pmid:22584049; PubMed Central PMCID: PMC3438096.
  18. 18. Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P, Bianchi Porro G. Altered bone metabolism in inflammatory bowel disease: there is a difference between Crohn’s disease and ulcerative colitis. Journal of internal medicine. 2000;247(1):63–70. Epub 2000/02/15. pmid:10672132.
  19. 19. Pappa H, Thayu M, Sylvester F, Leonard M, Zemel B, Gordon C. ‘A CLINICAL REPORT ON SKELETAL HEALTH OF CHILDREN AND ADOLESCENTS WITH INFLAMMATORY BOWEL DISEASE”. Journal of pediatric gastroenterology and nutrition. 2011;53(1):11–25. PubMed PMID: PMC3122140. pmid:21694532
  20. 20. Sylvester FA, Wyzga N, Hyams JS, Davis PM, Lerer T, Vance K, et al. Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease. Inflammatory bowel diseases. 2007;13(1):42–50. Epub 2007/01/09. pmid:17206638.
  21. 21. Ali T, Lam D, Bronze MS, Humphrey MB. Osteoporosis in Inflammatory Bowel Disease. The American journal of medicine. 2009;122(7):599–604. PubMed PMID: PMC2894700. pmid:19559158
  22. 22. Card T, West J, Hubbard R, Logan RFA. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251–5. PubMed PMID: PMC1774916. pmid:14724159
  23. 23. 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):795–9. Epub 2000/11/21. pmid:11085842.
  24. 24. Sigurdsson GV, Schmidt S, Mellstrom D, Ohlsson C, Kindblom JM, Lorentzon M, et al. Bone Mass Development from Childhood into Young Adulthood in Patients with Childhood-onset Inflammatory Bowel Disease. Inflammatory bowel diseases. 2017;23(12):2215–26. Epub 2017/10/25. pmid:29064856.
  25. 25. Sylvester FA. Inflammatory Bowel Disease: Effects on Bone and Mechanisms. Adv Exp Med Biol. 2017;1033:133–50. Epub 2017/11/05. pmid:29101654.
  26. 26. Veerappan SG O’Morain CA, Daly JS, Ryan BM. Review article: the effects of antitumour necrosis factor-alpha on bone metabolism in inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(12):1261–72. Epub 2011/04/28. pmid:21521250.
  27. 27. Loftus EV Jr., Crowson CS, Sandborn WJ, Tremaine WJ, O’Fallon WM, Melton LJ 3rd. Long-term fracture risk in patients with Crohn’s disease: a population-based study in Olmsted County, Minnesota. Gastroenterology. 2002;123(2):468–75. Epub 2002/07/30. pmid:12145800.
  28. 28. Bernstein CN, Leslie WD. The pathophysiology of bone disease in gastrointestinal disease. European journal of gastroenterology & hepatology. 2003;15(8):857–64. Epub 2003/07/18. pmid:12867794.
  29. 29. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53 Suppl 5:V1–16. Epub 2004/08/13. pmid:15306569; PubMed Central PMCID: PMC1867788.
  30. 30. Hylander E, Ladefoged K, Jarnum S. Calcium Absorption after Intestinal Resection: The Importance of a Preserved Colon. Scandinavian Journal of Gastroenterology. 1990;25(7):705–10. pmid:2396084
  31. 31. Vogelsang H, Ferenci P, Woloszczuk W, Resch H, Herold C, Frotz S, et al. Bone disease in vitamin D-deficient patients with Crohn’s disease. Dig Dis Sci. 1989;34(7):1094–9. Epub 1989/07/01. pmid:2743850.
  32. 32. Voss B, Kurdi A, Skopec A, Saleh J, El-Othmani MM, Lane JM, et al. Renal and Gastrointestinal Considerations in Joint Replacement Surgery. Journal of nature and science. 2015;1(2):e46–e. pmid:25811046.
  33. 33. Kapadia BH, Issa K, Nagrare N, Pivec R, Banerjee S, Mont MA. Higher revision and complication rates following total hip arthroplasty in patients with inflammatory bowel disease. J Arthroplasty. 2014;29(3):596–600. Epub 2013/11/16. pmid:24231436.
  34. 34. Morrison RJM, Bunn D, Gray WK, Baker PN, White C, Rangan A, et al. VASO (Vitamin D and Arthroplasty Surgery Outcomes) study—supplementation of vitamin D deficiency to improve outcomes after total hip or knee replacement: study protocol for a randomised controlled feasibility trial. Trials. 2017;18(1):514. pmid:29096686
  35. 35. Traven SA, Chiaramonti AM, Barfield WR, Kirkland PA, Demos HA, Schutte HD, et al. Fewer Complications Following Revision Hip and Knee Arthroplasty in Patients With Normal Vitamin D Levels. J Arthroplasty. 2017;32(9s):S193–s6. Epub 2017/04/05. pmid:28372917.
  36. 36. Culliford D, Maskell J, Judge A, Cooper C, Prieto-Alhambra D, Arden NK. Future projections of total hip and knee arthroplasty in the UK: results from the UK Clinical Practice Research Datalink. Osteoarthritis Cartilage. 2015;23(4):594–600. Epub 2015/01/13. pmid:25579802.
  37. 37. Nemes S, Rolfson O, A WD, Garellick G, Sundberg M, Karrholm J, et al. Historical view and future demand for knee arthroplasty in Sweden. Acta Orthop. 2015;86(4):426–31. Epub 2015/03/26. pmid:25806653; PubMed Central PMCID: PMC4513596.
  38. 38. Nemes S, Gordon M, Rogmark C, Rolfson O. Projections of total hip replacement in Sweden from 2013 to 2030. Acta Orthop. 2014;85(3):238–43. Epub 2014/04/25. pmid:24758323; PubMed Central PMCID: PMC4062789.
  39. 39. Inacio MCS, Paxton EW, Graves SE, Namba RS, Nemes S. Projected increase in total knee arthroplasty in the United States—an alternative projection model. Osteoarthritis Cartilage. 2017;25(11):1797–803. Epub 2017/08/13. pmid:28801208.
  40. 40. Inacio MCS, Graves SE, Pratt NL, Roughead EE, Nemes S. Increase in Total Joint Arthroplasty Projected from 2014 to 2046 in Australia: A Conservative Local Model With International Implications. Clin Orthop Relat Res. 2017;475(8):2130–7. Epub 2017/05/11. pmid:28488253; PubMed Central PMCID: PMC5498389.
  41. 41. Risk Factors for Periprosthetic Joint Infection Following Primary Total Hip Arthroplasty: A 15-Year, Population-Based Cohort Study. J Bone Joint Surg Am. 2020;102(6):503–9. Epub 2019/12/27. pmid:31876641.
  42. 42. Tanenbaum JE, Kha ST, Benzel EC, Steinmetz MP, Mroz TE. The association of inflammatory bowel disease and immediate postoperative outcomes following lumbar fusion. Spine J. 2017. Epub 2017/11/21. pmid:29155253.
  43. 43. Bozic KJ, Kurtz SM, Lau E, Ong K, Vail TP, Berry DJ. The epidemiology of revision total hip arthroplasty in the United States. J Bone Joint Surg Am. 2009;91(1):128–33. pmid:19122087
  44. 44. Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty. 2008;23(7):984–91. Epub 2008/06/07. pmid:18534466.
  45. 45. Hongo T, Kotake K, Muramatsu H, Omura D, Yano Y, Hasegawa D, et al. Loss of bone mineral density following sepsis using Hounsfield units by computed tomography. Acute Med Surg. 2019;6(2):173–9. pmid:30976444.
  46. 46. Abraham BP, Prasad P, Malaty HM. Vitamin D deficiency and corticosteroid use are risk factors for low bone mineral density in inflammatory bowel disease patients. Dig Dis Sci. 2014;59(8):1878–84. Epub 2014/03/13. pmid:24619280.
  47. 47. Manolagas SC. Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res. 2000;15(6):1001–5. Epub 2000/06/07. pmid:10841168.
  48. 48. Rizzoli R, Eisman JA, Norquist J, Ljunggren O, Krishnarajah G, Lim SK, et al. Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study. Int J Clin Pract. 2006;60(8):1013–9. Epub 2006/08/09. pmid:16893446.
  49. 49. Weisshof R, Chermesh I. Micronutrient deficiencies in inflammatory bowel disease. Current opinion in clinical nutrition and metabolic care. 2015;18(6):576–81. Epub 2015/09/30. pmid:26418823.
  50. 50. Goncalves P, Magro F, Martel F. Metabolic inflammation in inflammatory bowel disease: crosstalk between adipose tissue and bowel. Inflammatory bowel diseases. 2015;21(2):453–67. Epub 2014/09/24. pmid:25248003.
  51. 51. Vermeire S, Van Assche G, Rutgeerts P. The role of C-reactive protein as an inflammatory marker in gastrointestinal diseases. Nature clinical practice Gastroenterology & hepatology. 2005;2(12):580–6. Epub 2005/12/06. pmid:16327837.
  52. 52. Sanada F, Taniyama Y, Muratsu J, Otsu R, Shimizu H, Rakugi H, et al. Source of Chronic Inflammation in Aging. Frontiers in cardiovascular medicine. 2018;5:12-. pmid:29564335.
  53. 53. Makarewich CA, Anderson MB, Gililland JM, Pelt CE, Peters CL. Ten-year survivorship of primary total hip arthroplasty in patients 30 years of age or younger. The bone & joint journal. 2018;100-b(7):867–74. Epub 2018/06/30. pmid:29954212.
  54. 54. Chidambaram R, Cobb AG. CHANGE IN THE AGE DISTRIBUTION OF PATIENTS UNDERGOING PRIMARY HIP AND KNEE REPLACEMENTS OVER 13 YEARS–AN INCREASE IN THE NUMBER OF YOUNGER MEN HAVING HIP SURGERY. Orthopaedic Proceedings. 2009;91-B(SUPP_I):152-.
  55. 55. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell host & microbe. 2014;15(3):382–92. Epub 2014/03/19. pmid:24629344; PubMed Central PMCID: PMC4059512.
  56. 56. Adelman MW, Woodworth MH, Langelier C, Busch LM, Kempker JA, Kraft CS, et al. The gut microbiome’s role in the development, maintenance, and outcomes of sepsis. Critical Care. 2020;24(1):278. pmid:32487252
  57. 57. Hernandez CJ, Guss JD, Luna M, Goldring SR. Links Between the Microbiome and Bone. J Bone Miner Res. 2016;31(9):1638–46. Epub 2016/06/19. pmid:27317164.
  58. 58. McCabe L, Britton RA, Parameswaran N. Prebiotic and Probiotic Regulation of Bone Health: Role of the Intestine and its Microbiome. Current osteoporosis reports. 2015;13(6):363–71. Epub 2015/10/01. pmid:26419466; PubMed Central PMCID: PMC4623939.
  59. 59. Guss JD, Horsfield MW, Fontenele FF, Sandoval TN, Luna M, Apoorva F, et al. Alterations to the Gut Microbiome Impair Bone Strength and Tissue Material Properties. J Bone Miner Res. 2017;32(6):1343–53. Epub 2017/03/01. pmid:28244143; PubMed Central PMCID: PMC5466506.
  60. 60. Hadjiargyrou M, O’Keefe RJ. The convergence of fracture repair and stem cells: interplay of genes, aging, environmental factors and disease. J Bone Miner Res. 2014;29(11):2307–22. Epub 2014/09/30. pmid:25264148; PubMed Central PMCID: PMC4455538.
  61. 61. Guss JD, Ziemian SN, Luna M, Sandoval TN, Holyoak DT, Guisado GG, et al. The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis. Osteoarthritis Cartilage. 2019;27(1):129–39. Epub 2018/09/22. pmid:30240938; PubMed Central PMCID: PMC6309743.
  62. 62. Schott EM, Farnsworth CW, Grier A, Lillis JA, Soniwala S, Dadourian GH, et al. Targeting the gut microbiome to treat the osteoarthritis of obesity. JCI Insight. 2018;3(8). Epub 2018/04/20. pmid:29669931; PubMed Central PMCID: PMC5931133.
  63. 63. Catrina AI, Deane KD, Scher JU. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology (Oxford). 2016;55(3):391–402. pmid:25539828; PubMed Central PMCID: PMC4746430.
  64. 64. Scher JU, Littman DR, Abramson SB. Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases. Arthritis Rheumatol. 2016;68(1):35–45. pmid:26331579; PubMed Central PMCID: PMC4789258.
  65. 65. McGinty T, Mallon PWG. Fractures and the gut microbiome. Current opinion in HIV and AIDS. 2018;13(1):28–37. Epub 2017/10/20. pmid:29049037.
  66. 66. Wang Z, Xue K, Bai M, Deng Z, Gan J, Zhou G, et al. Probiotics protect mice from CoCrMo particles-induced osteolysis. International journal of nanomedicine. 2017;12:5387–97. Epub 2017/08/11. pmid:28794630; PubMed Central PMCID: PMC5538695.
  67. 67. McCabe LR, Irwin R, Schaefer L, Britton RA. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol. 2013;228(8):1793–8. Epub 2013/02/08. pmid:23389860; PubMed Central PMCID: PMC4091780.
  68. 68. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014;229(11):1822–30. Epub 2014/03/29. pmid:24677054; PubMed Central PMCID: PMC4129456.
  69. 69. Betteridge JD, Armbruster SP, Maydonovitch C, Veerappan GR. Inflammatory bowel disease prevalence by age, gender, race, and geographic location in the U.S. military health care population. Inflammatory bowel diseases. 2013;19(7):1421–7. Epub 2013/03/23. pmid:23518811.
  70. 70. Hausmann J, Blumenstein I. [Gender differences and inflammatory bowel disease]. Zeitschrift fur Gastroenterologie. 2015;53(8):774–8. Epub 2015/08/19. pmid:26284324.
  71. 71. Wagtmans MJ, Verspaget HW, Lamers CB, van Hogezand RA. Gender-related differences in the clinical course of Crohn’s disease. The American journal of gastroenterology. 2001;96(5):1541–6. Epub 2001/05/26. pmid:11374696.
  72. 72. Wyatt M, Hooper G, Frampton C, Rothwell A. Survival outcomes of cemented compared to uncemented stems in primary total hip replacement. World journal of orthopedics. 2014;5(5):591–6. Epub 2014/11/19. pmid:25405087; PubMed Central PMCID: PMC4133466.
  73. 73. Hailer NP, Garellick G, Karrholm J. Uncemented and cemented primary total hip arthroplasty in the Swedish Hip Arthroplasty Register. Acta Orthop. 2010;81(1):34–41. Epub 2010/02/26. pmid:20180715; PubMed Central PMCID: PMC2856202.
  74. 74. Registries for Evaluating Patient Outcomes: A User’s Guide. 4th ed. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2020 September 2020.