Abstract
BACKGROUNDS
It has been hypothesized that ankylosing spondylitis is associated with an increased risk of incident hip fractures due to osteoporosis and risk of falls but the supporting evidence is limited and mixed.
OBJECTIVES
To assess the risk of hip fractures in a large cohort of patients with ankylosing spondylitis compared to a matched cohort.
DESIGN
A retrospective cohort study.
SUBJECTS
Men and women diagnosed with ankylosing spondylitis from 1 January 2002 to 31 December 2018. Matching in a 5:1 ratio was based on age and sex. Follow-up ended on 23 June 2019.
MAIN MEASURES
Cox regression models adjusting for confounders defined in a causal inference framework were used to determine the hazard ratio for hip fractures.
KEY RESULT
The final cohorts included 5,909 ankylosing spondylitis patients and 28,671 matched patients. The ankylosing spondylitis cohort had a mean age of 49 (17) years and was composed of 3,762 (64%) men, 3,638 (62%) patients born in Israel, and 1,532 (26%) patients of low residential socioeconomic status. During 45,388 and 224,192 cumulative person-years of follow-up, the ankylosing spondylitis and matched cohorts had 2.47 and 1.63 cases of hip fractures per 1,000 person-years, respectively. Ankylosing spondylitis patients also developed hip fractures earlier (74 [13] vs. 79 [10] years, p = 0.002). Ankylosing spondylitis was associated with hip fractures in the unadjusted (HR = 1.52, 95% CI [1.23–1.88]) and adjusted (HR = 1.56, 95% CI [1.27–1.93]) models. The association was evident in men (HR = 1.65, 95% CI [1.25–2.18]) and women (HR = 1.48, 95% CI [1.07–2.05]).
CONCLUSION
This study found that ankylosing spondylitis patients developed hip fractures earlier and more often compared to a matched cohort. This study suggests that ankylosing spondylitis patients might benefit from more proactive screening, mitigation, and prevention of risk factors for hip fractures.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11606-021-07241-2.
KEY WORDS: ankylosing spondylitis, hip fracture, osteoporosis, falls
INTRODUCTION
Hip fractures are a major source of morbidity and mortality in older adults.1,2 As worldwide life expectancy increases and the senior population grows, hip fractures are likely to become more prevalent.3,4 The burden associated with hip fractures includes hospitalization, surgery, disability, rehabilitation, nursing care, and death.5 In the USA, the direct costs alone per hip fracture exceed $50,000.6
Ankylosing spondylitis is characterized by chronic inflammation of the axial skeleton, manifesting as inflammatory back pain, stiffness, and reduced mobility.7 Osteoporotic vertebral fractures occur more frequently in those with ankylosing spondylitis than in the general population8,9, resulting in postural abnormalities that impair balance and increase the risk of falls.10 In addition to axial pathology, inflammation of the hip is reported to occur in approximately 20% of ankylosing spondylitis patients11 and the condition is also associated with decreased trabecular bone density and osteoporosis of the femoral neck.12,13 Given that both falls and decreased femoral neck bone density are significant risk factors for hip fractures14, it has been hypothesized that ankylosing spondylitis is associated with an increased risk of incident hip fractures. However, previous studies have been small and inconclusive.15–18
The objective of this study was to assess the risk of hip fractures in a large cohort of patients with ankylosing spondylitis compared to a matched cohort.
METHODS
Design
This study was designed as a matched cohort study. The Ethics Committee of the Clalit Health Services approved this study and waived the requirement for written informed consent based on the strict maintenance of participants’ anonymity. The manuscript was written and edited according to the STROBE statement.19
The Chronic Disease Registry of Clalit Health Services
Clalit Health Services is the largest health maintenance organization in Israel, providing health insurance and healthcare services to approximately 4.5 million people (48% of the population). It operates hospitals, pharmacies, and both primary and specialty care clinics. The Clalit Health Services chronic disease registry contains data from pharmaceutical, medical, and administrative databases for both outpatients and inpatients, as described in previous studies.20,21
Study Population
The inclusion criteria for the study were all patients diagnosed with ankylosing spondylitis (ICD-9 Code: 720.0)—as documented by a physician on their medical records—between 1 January 2002 and 31 December 2018.
The age- and sex-matched patients were from the same registry in a 5:1 ratio. In some instances, less than five matches were available. The date of study entry (index date) for matches was assigned as the date their match was recorded as having an ankylosing spondylitis diagnosis.
Patients with a documented hip fracture (ICD-9 Code: 820.0) before the date of study entry were excluded. Whereby an ankylosing spondylitis patient was excluded, all their matches were also excluded. The cohorts were followed until 23 June 2019.
Variables
Data obtained included the following variables: age, sex, residential socioeconomic status, country of birth, ankylosing spondylitis diagnosis, diagnosis of hip fracture, smoking status, obesity, diagnosis of comorbidities (hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, osteoporosis, cognitive decline, and malignancy), and death.
All diagnoses included were defined if documented in a patient’s medical records, which collate primary care visits, outpatient clinic visits and hospitalizations. Comorbidities were only accounted for if they were diagnosed before the date of study entry.
Residential socioeconomic data were based on the location of residence. They were obtained from records of the Israeli Ministry of Interior, which stratifies all municipalities on a 1–10 scale devised by the Israeli Central Bureau of Statistics according to specific economic measures. Variables that affect the residential socioeconomic status include age distribution, level of unemployment, available workforce, level of education (the proportion of students entitled to a high school diploma and the number of undergraduates), average income per capita, and proportion of income-supported residents.22
The country of birth was divided into Israel or others. Age at the time of study entry was calculated from the date of birth to ankylosing spondylitis diagnosis (or the matching index date for the matched patients). The end of follow-up was defined as 23 June 2019. Study endpoints were defined as the date of a hip fracture, the date of death or the end of follow-up (whichever came first). Age at the end of follow-up was calculated from the date of birth to the end of follow-up. Age at the time of hip fracture was calculated for cases from the date of birth to hip fracture.
Statistical Analysis
Data analysis was performed using R version 4.1.1 (R Core Team, Vienna, Austria) and the packages tidyverse, survival, survminer, forester, gtsummary, and ggdag. Categorical variables were presented as n (%) and compared using the chi-square test of independence. Continuous variables were presented as mean (SD) and compared using Student’s t-test. All tests used were two-tailed, with p values < 0.05 considered to be statistically significant.
Interaction between ankylosing spondylitis, sex, and incident hip fractures was assessed using an interaction term and analysis of variance (ANOVA). The incidence of hip fractures was shown using a cumulative incidence plot.
Cox regression models were used to determine the hazard ratio (HR) for hip fractures in ankylosing spondylitis patients compared to the matched patients. The adjusted model, determined using a causal inference framework (Supplementary Figure S1), included adjustment for age, sex, residential socioeconomic status, and country of birth. Secondary analyses used the adjusted model stratified by sex, country of birth, and smoking status. Two subgroup analyses were performed for patients free of osteoporosis and cognitive decline at the time of study entry.
RESULTS
Between 2002 and 2018, 5,930 patients were diagnosed with ankylosing spondylitis. Of them, 21 were excluded due to a prior hip fracture, leaving 5,909 ankylosing spondylitis patients and 28,671 matched patients (Figure 1).
Fig. 1.
Cohort buildup. Matching in a 5:1 ratio was based on age and sex. In some instances, less than five matches were available.
The ankylosing spondylitis cohort was composed of 3,762 (64%) males, 3,638 (62%) patients born in Israel, and 1,532 (26%) patients of low residential socioeconomic status. The mean age was 49 (17) years overall and 43 (15) years in patients born in Israel (Table 1). The interaction between ankylosing spondylitis, sex, and hip fractures was not significant (p = 0.59). Baseline characteristics of the cohorts stratified by sex are presented in Supplementary Table S1.
Table 1.
Baseline characteristics of the cohort (n = 34,580)
| Characteristic | Matched patients, N = 28,6711 | Ankylosing spondylitis, N = 5,9091 |
|---|---|---|
| Sex | ||
| Male | 18,223 (64%) | 3,762 (64%) |
| Female | 10,448 (36%) | 2,147 (36%) |
| Age (years) | 49 (17) | 49 (17) |
| Socioeconomic status | ||
| Low | 8,005 (28%) | 1,532 (26%) |
| Medium | 14,913 (5 2%) | 3,160 (53%) |
| High | 3,942 (14%) | 843 (14%) |
| (Missing) | 1,811 (6.3%) | 374 (6.3%) |
| Country of birth | ||
| Israel | 18,321 (64%) | 3,638 (62%) |
| Other | 10,350 (36%) | 2,271 (38%) |
| Smoking | 9,334 (33%) | 2,030 (34%) |
| Obesity | 4,121 (14%) | 1,136 (19%) |
| Hypertension | 6,427 (22%) | 1,615 (27%) |
| Hyperlipidemia | 9,502 (33%) | 2,167 (37%) |
| Diabetes mellitus | 3,453 (12%) | 863 (15%) |
| Ischemic heart disease | 2,561 (8.9%) | 646 (11%) |
| Osteoporosis | 1,172 (4.1%) | 445 (7.5%) |
| Cognitive decline | 233 (0.8%) | 37 (0.6%) |
| Any malignancy | 1,572 (5.5%) | 429 (7.3%) |
In comparison to the matched cohort, the ankylosing spondylitis cohort had higher rates of smoking (34 vs. 33%, p = 0.007), obesity (19 vs. 14%, p < 0.001), hypertension (27 vs. 22%, p < 0.001), hyperlipidemia (37 vs. 33%, p < 0.001), diabetes mellitus (15 vs. 12%, p < 0.001), ischemic heart disease (11 vs. 9%, p < 0.001), prior malignancy (7 vs. 6%, p < 0.001), and osteoporosis (8 vs. 4%, p < 0.001) at the beginning of follow-up. Similar basline rates of cognitive decline (0.6 vs. 0.8%, p = 0.14) were observed in both groups.
Supplementary Table S2 summarizes the time-to-event data. Ankylosing spondylitis patients and matches were followed for a cumulative period of 45,388 and 224,192 years, respectively. The mean follow-up period was 7.7 (4.8) years in the ankylosing spondylitis group and 7.8 (4.8) years in the matched patients group. The ankylosing spondylitis cohort had 112 cases of hip fractures with an incidence of 2.47 cases per 1,000 person-years. The matched cohort had 366 cases of fractures with an incidence of 1.63 cases per 1,000 person-years. Additionally, ankylosing spondylitis patients developed hip fractures at a younger age in comparison to the matched patients (74 [13] vs. 79 [10] years, p = 0.002).
Figure 2 shows the higher cumulative incidence of hip fractures in patients with ankylosing spondylitis compared to matches (log-rank p < 0.001). Supplementary Fig. S2 portrays the competing risks of hip fractures and death between the two cohorts. Schoenfeld residuals were independent of time for all variables included in the adjusted Cox model (Supplementary Fig. S3).
Fig. 2.
Cumulative incidence of hip fractures in patients with and without ankylosing spondylitis (n = 34,580). Log-rank p < 0.001.
As shown in Figure 3, ankylosing spondylitis was associated with hip fractures in the unadjusted (HR = 1.52, 95% CI [1.23–1.88]) and adjusted (HR = 1.56, 95% CI [1.27–1.93]) models. The association persisted in men (HR = 1.65, 95% CI [1.25–2.18]) and women (HR = 1.48, 95% CI [1.07–2.05]); in patients born in Israel (HR = 1.71, 95% CI [1.17–2.50]) and outside of Israel (HR = 1.50, 95% CI [1.16–1.94]); and in smokers (HR = 1.66, 95% CI [1.06–2.61]) and non-smokers (HR = 1.54, 95% CI [1.21–1.96]). The association also persisted in patients free from osteoporosis (HR = 1.57, 05% CI [1.24–2.01]) and cognitive decline (HR = 1.53, 05% CI [1.24–1.91]) at the time of study entry.
Fig. 3.
The association between ankylosing spondylitis and hip fractures in different Cox models. Residential socioeconomic status was based on residential locality. Smoking status was based on documentation of smoking status before study entry. The hazard ratio is on a logarithmic scale.
DISCUSSION
This study identified an association between ankylosing spondylitis and the development of hip fractures (HR = 1.52, 95% CI [1.23–1.88]), which persisted after adjustment for sex, age, residential socioeconomic status, and country of birth. The association was evident in men, in women, and also in patients free from osteoporosis and cognitive decline at study entry. Furthermore, hip fractures were not only more common in the ankylosing spondylitis cohort but also appeared an average of five years earlier in comparison to a matched cohort.
The male predominance of ankylosing spondylitis patients (64%)23 and the mean age of hip fractures in the matched patients group (79 years)24 found in our study align well with the literature and support the generalizability of the study.
The evidence regarding the risk of hip fractures in ankylosing spondylitis is both limited and mixed. One study with only 265 ankylosing spondylitis patients found an association between ankylosing spondylitis and hip fractures.18 Another, with 758 ankylosing spondylitis patients, did not find such an association.17 Both were case-control studies and limited in their ability to adjust for confounders. Our study—a longitudinal, matched-cohort study that included 5,909 ankylosing spondylitis patients (and 28,671 matches) with a mean follow-up period of 8 years—suggests that ankylosing spondylitis patients have a higher risk of developing hip fractures. This finding is both clinically and statistically significant. Furthermore, the occurrence of hip fractures 5 years earlier in ankylosing spondylitis patients compared to matched patients is similar to the earlier age of onset of vertebral fractures in this population.25
The increased risk of hip fractures in ankylosing spondylitis patients is possibly the result of two separate mechanisms. On the one hand, ankylosing spondylitis and its duration are associated with an increased risk of falls.26,27 This is likely due to an impairment of balance often seen in ankylosing spondylitis patients, which may arise due to a combination of pain, reduced mobility, and irreversible postural changes.10,28 On the other hand, ankylosing spondylitis is associated with bone loss in both the vertebrae and the hip12,29, and the severity of disease is associated with decreased trabecular bone density.30–32 These associations may, in part, be mediated by the release of interleukin-1 and tumor necrosis factor-alpha (TNF-α) during active inflammation of the entheses, in turn inducing bone resorption.33,34 However, while the advent of TNF-alpha blockers has provided a revolution in disease control, they remain limited in their ability to reduce the progressive structural damage seen in the bones of ankylosing spondylitis patients.35–37 The increased resorption and decreased formation of bone occurring in ankylosing spondylitis is likely mediated by the interplay of several complex mechanisms which are yet to be fully understood.38
Regardless of the exact underlying mechanism, the results of this study suggest that ankylosing spondylitis is a risk factor for incident hip fractures. While osteoporosis and vertebral fractures are commonly reported sequelae of ankylosing spondylitis8,9, our study implies that hip fractures are an under-recognized ankylosing spondylitis complication. Since falls are often preventable and osteoporosis is—at least partially—treatable, ankylosing spondylitis patients might benefit from more proactive screening, mitigation, and prevention of risk factors associated with hip fractures in comparison to the general population. Specifically, assessing femur bone density and treatment if low might prevent fractures.
With this being said, our study does have several limitations. Firstly, ankylosing spondylitis and hip fractures were defined based on physicians’ documentation in medical records, which may be inaccurate. Secondly, for cases in which hip fractures resulted in death before arrival to a medical facility, it is possible that they were not documented. Thirdly, we could not assess the effect of disease severity or disease treatment on the risk of hip fractures in the ankylosing spondylitis cohort.
This study found that ankylosing spondylitis patients develop hip fractures earlier and more often in comparison to a matched cohort, suggesting that ankylosing spondylitis is a risk factor for incident hip fractures. The results of this study imply that ankylosing spondylitis patients might benefit from more proactive screening, mitigation, and prevention of risk factors—such as falls and osteoporosis—in order to reduce the burden of hip fractures in this population.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the Central Management of Sheba Medical Center for encouraging, educating, and providing research platforms. We would also like to thank the peer reviewers for their significant contribution in improving the manuscript.
Author Contribution
All authors meet all four criteria for authorship in the ICMJE recommendations. A. M. T. and H. A. designed the study. A. M. T., P. D., A. W., and D. N. conducted the literature review. A. M. T., A. W., A. D. C., and H. A. acquired the data. All authors analyzed the data. A. M. T., P. D., and D. N. drafted the manuscript. All authors critically revised the manuscript. All authors and contributors approved the final version of this manuscript. All authors agree to be accountable for all aspects of the work.
Funding
The Shalvi Foundation for Research supported this study.
Declarations
Ethical Approval Information
The Ethics Committee of the Clalit Health Services approved this study and waived the requirement for written informed consent based on the strict maintenance of participants’ anonymity.
Conflict of Interest
The authors report no conflict of interest.
Patient and Public Involvement
There has been no patient and public involvement in this study.
Data sharing statement
The current manuscript was based on a database with limited access. Summaries and aggregated data may be made available upon request; requests should be directed to avishaitsur@gmail.com.
Footnotes
Prior Presentations
A summary of this study was orally presented at the 12th International Congress on Autoimmunity, Virtual, May 28, 2021, and at the Annual Meeting of the Israel Society of Internal Medicine, Kfar Blum, Israel, July 2, 2021.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Huddleston JM, Whitford KJ. Medical Care of Elderly Patients With Hip Fractures. Mayo Clin Proc. 2001;76(3):295–298. doi: 10.4065/76.3.295. [DOI] [PubMed] [Google Scholar]
- 2.Lyons AR. Clinical outcomes and treatment of hip fractures. Am J Med. 1997;103(2):S51–S64. doi: 10.1016/S0002-9343(97)90027-9. [DOI] [PubMed] [Google Scholar]
- 3.Cummings SR, Rubin SM, Black D. The future of hip fractures in the United States. Numbers, costs, and potential effects of postmenopausal estrogen. Clin Orthop Relat Res. 1990;(252):163-166. http://www.ncbi.nlm.nih.gov/pubmed/2302881 [PubMed]
- 4.Gullberg B, Johnell O, Kanis JA. World-wide Projections for Hip Fracture. Osteoporos Int. 1997;7(5):407–413. doi: 10.1007/PL00004148. [DOI] [PubMed] [Google Scholar]
- 5.Barnea R, Weiss Y, Abadi-Korek I, Shemer J. The epidemiology and economic burden of hip fractures in Israel. Isr J Health Policy Res. 2018;7(1):38. doi: 10.1186/s13584-018-0235-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Adeyemi A, Delhougne G. Incidence and Economic Burden of Intertrochanteric Fracture. JBJS Open Access. 2019;4(1):e0045. doi: 10.2106/JBJS.OA.18.00045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369(9570):1379–1390. doi: 10.1016/S0140-6736(07)60635-7. [DOI] [PubMed] [Google Scholar]
- 8.Mitra D, Elvins DM, Speden DJ, Collins AJ. The prevalence of vertebral fractures in mild ankylosing spondylitis and their relationship to bone mineral density. Rheumatology. 2000;39(1):85–89. doi: 10.1093/rheumatology/39.1.85. [DOI] [PubMed] [Google Scholar]
- 9.Davey-Ranasinghe N, Deodhar A. Osteoporosis and vertebral fractures in ankylosing spondylitis. Curr Opin Rheumatol. 2013;25(4):509–516. doi: 10.1097/BOR.0b013e3283620777. [DOI] [PubMed] [Google Scholar]
- 10.Sinaki M, Brey RH, Hughes CA, Larson DR, Kaufman KR. Balance disorder and increased risk of falls in osteoporosis and kyphosis: Significance of kyphotic posture and muscle strength. Osteoporos Int. 2005;16(8):1004–1010. doi: 10.1007/s00198-004-1791-2. [DOI] [PubMed] [Google Scholar]
- 11.Amor B, Silva Santos R, Nahal R, Listrat V, Dougados M. Predictive factors for the longterm outcome of spondyloarthropathies. J Rheumatol. 1994;21(10):1883-1887. http://www.ncbi.nlm.nih.gov/pubmed/7837155 [PubMed]
- 12.Will R, Bhalla AK, Palmer R, Ring F, Calin A. Osteoporosis in Early Ankylosing Spondylitis: a Primary Pathological Event? Lancet. 1989;334(8678-8679):1483-1485. 10.1016/S0140-6736(89)92932-2 [DOI] [PubMed]
- 13.Kang KY, Chung MK, Kim HN, Hong YS, Ju JH, Park S-H. Severity of Sacroiliitis and Erythrocyte Sedimentation Rate are Associated with a Low Trabecular Bone Score in Young Male Patients with Ankylosing Spondylitis. J Rheumatol. 2018;45(3):349–356. doi: 10.3899/jrheum.170079. [DOI] [PubMed] [Google Scholar]
- 14.Wehren LE, Magaziner J. Hip fracture: Risk factors and outcomes. Curr Osteoporos Rep. 2003;1(2):78–85. doi: 10.1007/s11914-003-0013-8. [DOI] [PubMed] [Google Scholar]
- 15.Pray C, Feroz NI, Nigil Haroon N. Bone Mineral Density and Fracture Risk in Ankylosing Spondylitis: A Meta-Analysis. Calcif Tissue Int. 2017;101(2):182–192. doi: 10.1007/s00223-017-0274-3. [DOI] [PubMed] [Google Scholar]
- 16.Cooper C, Carbone L, Michet CJ, Atkinson EJ, O’Fallon WM, Melton LJ. Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol. 1994;21(10):1877-1882. http://www.ncbi.nlm.nih.gov/pubmed/7837154 [PubMed]
- 17.Vosse D, Landewe R, van der Heijde D, van der Linden S, van Staa T-P, Geusens P. Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study. Ann Rheum Dis. 2009;68(12):1839–1842. doi: 10.1136/ard.2008.100503. [DOI] [PubMed] [Google Scholar]
- 18.Weiss RJ, Wick MC, Ackermann PW, Montgomery SM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases - A case-control study with 53,108 patients with fracture. J Rheumatol. 2010;37(11):2247–2250. doi: 10.3899/jrheum.100363. [DOI] [PubMed] [Google Scholar]
- 19.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–1457. doi: 10.1016/S0140-6736(07)61602-X. [DOI] [PubMed] [Google Scholar]
- 20.Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021;384(15):1412–1423. doi: 10.1056/NEJMoa2101765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Tsur AM, Watad A, Gendelman O, Nissan D, Cohen AD, Amital H. Familial Mediterranean fever and asthma. Rheumatology. Published online February 16, 2021. 10.1093/rheumatology/keab159 [DOI] [PubMed]
- 22.Furer A, Afek A, Sommer A, et al. Adolescent obesity and midlife cancer risk: a population-based cohort study of 2·3 million adolescents in Israel. Lancet Diabetes Endocrinol. 2020;8(3):216–225. doi: 10.1016/S2213-8587(20)30019-X. [DOI] [PubMed] [Google Scholar]
- 23.de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18:196. doi: 10.1186/s13075-016-1093-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.LeBlanc KE, Muncie HL, LeBlanc LL. Hip fracture: diagnosis, treatment, and secondary prevention. Am Fam Physician. 2014;89(12):945-951. http://www.ncbi.nlm.nih.gov/pubmed/25162161 [PubMed]
- 25.Ognjenovic M, Raymond WD, Inderjeeth CA, Keen HI, Preen DB, Nossent JC. The Risk and Consequences of Vertebral Fracture in Patients with Ankylosing Spondylitis: A Population-based Data Linkage Study. J Rheumatol. 2020;47(11):1629–1636. doi: 10.3899/jrheum.190675. [DOI] [PubMed] [Google Scholar]
- 26.Mewes KB, Longo B, Campos APB, Simioni J, Skare TL. Balance and falls in axial Spondyloarthritis: a cross sectional study. Acta Reumatol Port. 44(4):248-253. http://www.ncbi.nlm.nih.gov/pubmed/32281612 [PubMed]
- 27.Dursun N, Sarkaya S, Ozdolap S, et al. Risk of falls in patients with ankylosing spondylitis. J Clin Rheumatol. 2015;21(2):76–80. doi: 10.1097/RHU.0000000000000216. [DOI] [PubMed] [Google Scholar]
- 28.Murray HC, Elliott C, Barton SE, Murray A. Do patients with ankylosing spondylitis have poorer balance than normal subjects? Rheumatology. 2000;39(5):497–500. doi: 10.1093/rheumatology/39.5.497. [DOI] [PubMed] [Google Scholar]
- 29.Klingberg E, Lorentzon M, Göthlin J, et al. Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes. Arthritis Res Ther. 2013;15(6):R179. doi: 10.1186/ar4368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Jun J-B, Joo K-B, Her M-Y, et al. Femoral bone mineral density is associated with vertebral fractures in patients with ankylosing spondylitis: a cross-sectional study. J Rheumatol. 2006;33(8):1637-1641. http://www.ncbi.nlm.nih.gov/pubmed/16881119 [PubMed]
- 31.Klingberg E, Geijer M, Göthlin J, et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol. 2012;39(10):1987–1995. doi: 10.3899/jrheum.120316. [DOI] [PubMed] [Google Scholar]
- 32.van der Weijden MAC, Claushuis TAM, Nazari T, Lems WF, Dijkmans BAC, van der Horst-Bruinsma IE. High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol. 2012;31(11):1529–1535. doi: 10.1007/s10067-012-2018-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Gowen M, Mundy GR. Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone resorption in vitro. J Immunol. 1986;136(7):2478-2482. http://www.ncbi.nlm.nih.gov/pubmed/3081643 [PubMed]
- 34.Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem. 2000;275(7):4858–4864. doi: 10.1074/jbc.275.7.4858. [DOI] [PubMed] [Google Scholar]
- 35.Van Der Heijde D, Landewé R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008;58(10):3063–3070. doi: 10.1002/art.23901. [DOI] [PubMed] [Google Scholar]
- 36.Van Der Heijde D, Landewé R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008;58(5):1324–1331. doi: 10.1002/art.23471. [DOI] [PubMed] [Google Scholar]
- 37.Van der Heijde D, Salonen D, Weissman BN, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther. 2009;11(4):R127. doi: 10.1186/ar2794. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Tam LS, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol. 2010;6(7):399–405. doi: 10.1038/nrrheum.2010.79. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.