Skip to main content
Download PDF

Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis

Arthritis Research & Therapy volume 20, Article number: 202 (2018) Cite this article

Abstract

Background

In the present study, we investigated bone geometry, microstructure, and volumetric bone mineral density (vBMD) in a cohort of patients with nonradiographic axial spondyloarthritis (nr-axSpA) in order to define the early bone changes occurring in axial spondyloarthritis (axSpA) and to define potential factors for deterioration of bone microstructure.

Methods

Patients with axSpA (n = 107) and healthy control subjects (n = 50) of similar age and sex were assessed for geometric, volumetric, and microstructural parameters of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius. Additionally, demographic and disease-specific characteristics of patients with axSpA were recorded.

Results

Patients with nr-axSpA and control subjects were comparable in age, sex, and body mass index. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p = 0.022) and cortical thickness (p = 0.006) in patients with nr-axSpA compared with control subjects. Total and cortical vBMD were significantly reduced in patients with nr-axSpA (p = 0.042 and p = 0.007, respectively), whereas there was no difference in trabecular vBMD. Patients with a short disease duration (< 2 years; n = 46) also showed significant reduction of cortical thickness and cortical area compared with control subjects. Patients with disease duration > 2 years (n = 55) additionally developed a decrease of cortical and total vBMD. Multiple regression models identified male sex to be associated with lower cortical vBMD and female sex to be associated with lower trabecular vBMD.

Conclusions

Bone microstructure in patients with nr-axSpA is characterized primarily by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of the disease.

Background

Spondyloarthritis (SpA) comprises a group of diseases with shared genetic and pathophysiologic backgrounds affecting the axial and peripheral skeleton. Axial disease comprises nonradiographic axial SpA (nr-axSpA) and ankylosing spondylitis (AS). Axial inflammation leads to local bone formation with progressive ankylosis of sacroiliac joints as well as syndesmophyte formation. Nonetheless, systemic bone loss and increased vertebral and nonvertebral fracture risk have been described in AS [1].

Authors of a recent review of the literature on bone mass in AS reported a prevalence of osteoporosis varying from 3% to 47% according to different measurement techniques and patient selection criteria, whereas osteopenia has been reported in up to 88% of patients [2]. These variations may be based on the fact that bone analysis in nr-axSpA and AS is challenging, particularly in the axial skeleton, where it is confounded by local new bone formation. Especially in patients with syndesmophytes, dual-energy X-ray absorptiometry (DXA) is unreliable because it sums up new bone formation with bone loss owing to its two-dimensional nature [3, 4]. However, bone loss has also been found at the hip of patients with AS [5,6,7,8]. Furthermore, quantitative computed tomography (QCT), which separately measures trabecular and cortical volumetric bone density, has supported the occurrence of bone loss in AS, showing reduced trabecular volumetric bone mineral density (vBMD) in the lumbar spine in severe AS with syndesmophyte formation [9].

Systemic inflammation is at least partly responsible for systemic bone loss in patients owing to proinflammatory cytokines leading to a direct activation of osteoclastogenesis [10]. In prior studies, patients with AS showed significant bone loss as measured by DXA at the lumbar spine compared with patients with mechanical back pain [11]. Further, in the DESIR (DEvenir des Spondyloarthrites Indifférenciées Récentes) cohort, 71.4% of patients with inflammatory back pain fulfilled Assessment of Spondyloarthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), and in multiple logistic regression analyses, bone marrow edema seen on magnetic resonance imaging scans, markers of inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and male sex were associated with lower bone mineral density (BMD) at any site [12]. Inhibition of tumor necrosis factor (TNF)-α has been reported to show a beneficial effect on BMD and bone turnover markers of patients with AS, thereby supporting the role of systemic inflammation on bone metabolism [13,14,15]. In accordance with this, vertebral fractures in patients with AS are associated with the longer disease duration independent of age [16].

Bone strength depends not only on BMD but also on bone geometry and microarchitectural aspects of cancellous and cortical bone [17, 18]. High-resolution quantitative computed tomography (HR-pQCT) permits a noninvasive, three-dimensional assessment of bone geometry, volumetric BMD, and microarchitecture, which resembles a virtual bone biopsy of peripheral bone [19, 20]. HR-pQCT data have been shown to correlate with BMD results obtained by DXA and with incident fracture risk in the radius, hip, and spine in postmenopausal women [21, 22].

The aim of the present study was to investigate bone microstructure, geometry, and vBMD using HR-pQCT in a large cohort of patients with nr-axSpA in early stages of disease and to search for potential risk factors for deterioration of bone microstructure. In this context, it is important to mention that patients with AS with long-standing disease are characterized by reduction of total and cortical vBMD and cortical thickness, as well as increased cortical porosity [23, 24]. Data on early disease, however, which may reflect the initial changes of bone in nr-axSpA, are missing to date.

Methods

Patients and control subjects

A total of 107 Caucasian patients with a diagnosis of nr-axSpA were recruited at the Department of Internal Medicine 3 of the University of Erlangen-Nuremberg, Germany. All patients fulfilled the ASAS classification criteria. Patients with AS were not included in this study because we were specifically seeking to study a population with early bone changes. Recruitment of healthy control subjects has been described elsewhere, and these individuals were matched by age and sex [25]. Briefly, exclusion criteria for being a healthy control subject were (1) presence or history of chronic joint pain/swelling, (2) presence of systemic diseases, (3) documented osteopenia/osteoporosis, (4) present or past use of bisphosphonates or prednisolone, and (5) positivity for anticitrullinated protein antibodies (ACPA) or rheumatoid factor. This study was approved by the local ethics committee and the national radiation safety agency (Bundesamt fur Strahlenschutz). Informed consent was obtained from each patient, and the study was performed in accordance with the Declaration of Helsinki.

Demographic and disease-specific characteristics

Demographic characteristics, disease duration, features of SpA (psoriasis, inflammatory bowel disease [IBD], uveitis), human leukocyte antigen (HLA)-B27 status, ESR, and serum CRP levels were recorded in all patients. Current disease activity was determined by Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP; inactive disease ASDAS-CRP < 1.3, 1.3–2.0 moderate disease activity, 2.1–3.5 high disease activity, > 3.5 very high disease activity). Spinal mobility was assessed by Bath Ankylosing Spondylitis Metrology Index (BASMI). For the assessment of present enthesitis, the Maastricht Ankylosing Spondylitis Enthesitis Score was used. Peripheral arthritis was assessed by 78 tender and 76 swollen joint counts. The Spondylitis Disease Activity Index (BASDAI) was assessed as a secondary disease activity measure, and the Bath Ankylosing Spondylitis Functional Index (BASFI) was used for patient-reported outcomes.

The use of conventional disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, azathioprine, leflunomide, chloroquine, gold) and biologic agents (TNF inhibitors [TNFi]) was recorded. Further, the current or previous use of systemic glucocorticoid (GC) treatment exceeding continuous treatment with 5 mg of prednisolone-equivalent daily for more than 3 months was assessed. Treatment with nonsteroidal anti-inflammatory drugs was also recorded (on demand, daily). History of nontraumatic fractures, diagnosis of osteoporosis, and previous or ongoing antiresorptive treatment or supplementation of 25(OH)vitamin D3 and calcium was taken.

High-resolution peripheral quantitative computed tomography

HR-pQCT imaging was performed in all patients and 50 healthy age- and sex-matched control subjects using the XtremeCT scanner (SCANCO Medical, Brüttisellen, Switzerland). The scan region was selected according to the manufacturer’s standard in vivo protocol of the ultradistal radius of the dominant hand. For measurement, the patient’s hand was immobilized using a carbon fiber shell to reduce movement. Standardization of measurements was ensured by daily cross-calibrations with a standardized control phantom (QRM, Moehrendorf, Germany). The ROI was determined with an anteroposterior scout view and was fixed 9.5 mm proximal from the reference line. The effective dose for each scan was < 3 μSv. The reference line was set manually. The scan ROI was examined in 110 parallel slices (82-μm voxel size) with a total measurement time of 2.8 minutes. All measurements and evaluations were performed using the manufacturer’s standard software. Motion grading (1–5) of each scan was performed using SCANCO Medical standard operating procedure scale, and scans graded > 3 were excluded from analysis.

vBMD, bone microstructure, and geometry were measured with HR-pQCT. Three-dimensional vBMD of the total radius (total BMD in mg of hydroxyapatite [HA]/cm3), the cortical shell (Ct. BMD, mg HA/cm3), and the trabecular compartment (Tb.BMD, mg HA/cm3) were extracted. Additional, distinctive results of trabecular BMD adjacent to bone cortex (mg HA/cm3) and central medullary trabecular BMD (mg HA/cm3) were expressed. Results of bone microstructure included bone volume fraction (BV/TV, %), trabecular number (mm−1), trabecular thickness (μm), trabecular separation (Tb.Sp, μm), inhomogeneity of the trabecular network (μm), cortical thickness (Ct.Th, μm), and cortical porosity (Ct.Po, %). Furthermore, bone geometry was represented by total, cortical, and trabecular bone area (mm2). All these parameters were calculated by using automated software. Reliability of the automated contouring method of the Xtreme CT scanner software has recently been shown [26].

Statistical analysis

Data were collected, organized, and analyzed using IBM SPSS Statistics software (IBM, Armonk, NY, USA). If not stated otherwise, categorical variables are presented as number and percent, and continuous variables are provided as median (IQR). Inferential comparisons comprised chi-square tests for categorical variables (indicated as number and percent in the tables) to check for observed deviations from expected frequencies, as well as the Kruskal-Wallis and Mann-Whitney U tests to compare data derived from interval scales. To investigate potential relationships of total, cortical, and trabecular vBMD with disease-related or demographic parameters, multiple linear regression models were computed with an enter procedure including all predictors at a single step. The first model incorporated sex, age, BMI, and smoking status. The second model included sex, age, BMI, remission status, disease duration, treatment with TNFi, prior GC treatment, HLA-B27 status, and peripheral arthritis. A p value less than 0.05 was considered significant.

Results

Characteristics of patients with nr-axSpA and healthy control subjects

A total of 107 patients with nr-axSpA and 50 healthy control subjects were recruited for this bone analysis. Six patients with nr-axSpA could not be further analyzed, owing to unacceptable motion artefacts, leaving 101 patients with nr-axSpA to be analyzed. Demographic and disease-specific characteristics are shown in Table 1. Patients with nr-axSpA and control subjects were comparable in age (median [IQR], 45.0 [15.0] vs. 44.76 [26.0] years, p = 0.917), sex (females, 41.6% vs. 40%, p = 0.852), and BMI (median [IQR], 26.3 [6.5] vs. 23.8 [5.2], p = 0.118). Of the patients, 37.6% were former or current smokers, with no significant difference compared with healthy control subjects.

Table 1 Demographic and disease-specific characteristics of patients with nonradiographic axial spondyloarthritis and healthy control subjects
Full size table

Of patients with nr-axSpA, 75% showed HLA-B27 positivity, and 12.9% of the patients had psoriasis, 7.9% had anterior uveitis, and 6.9% had IBD in their medical history. Systemic inflammation markers were only minimally elevated, with CRP at 6.2 (4.0) mg/L and ESR at 12.7 (10.5) mm. Median disease duration was 6.5 (9.0) years. Disease activity as assessed by ASDAS-CRP was 2.1 (1.4). Only 14.9% of patients were in ASDAS-CRP remission, despite 58.4% of patients being on TNFi treatment with a median (IQR) duration of 2.0 (4.0) years of treatment. Details on the characteristics of patients with nr-axSpA receiving a TNFi and those without a TNFi are summarized in Additional file 1. Clinical assessment by BASMI showed mild impairment of spinal mobility with a median (IQR) score of 1.1 (2) units, whereas patient-reported outcomes revealed a BASDAI of 3.5 (3.6) units and a BASFI of 2.9 (3.8).

Serum 25(OH)vitamin D3 level (median (IQR)) was 32.4 (16.3) ng/ml. Fractures after inadequate trauma were reported in seven patients (6.9%), five patients had prior or current antiresorptive treatment, 7.9% had supplementation with calcium, and 25.7% had supplementation with 25(OH)vitamin D3.

Bone geometry and vBMD in patients with nr-axSpA

Bone geometry showed a significant difference in the cortical area between patients with nr-axSpA and control subjects (p = 0.022), whereas there was no difference in the total bone area (p = 0.700) or the trabecular area (p = 0.374) (Table 2). Cortical vBMD suggested a reduction in patients with axSpA (compared with control subjects; p = 0.007), whereas trabecular BMD showed no difference (p = 0.376). Also, no difference between nr-axSpA and control subjects was found for the central medullary and peripheral trabecular density adjacent to cortex (p = 0.310 and p = 0.941, respectively). Overall total vBMD was different in patients with axSpA, showing lower values than in control subjects (p = 0.042), which was based on the differences in cortical BMD.

Table 2 Bone microstructure in patients with nonradiographic axial spondyloarthritis assessed by high-resolution peripheral quantitative computed tomography
Full size table

Bone microstructure in patients with nr-axSpA

Assessment of parameters of bone microstructure showed results very consistent with bone geometry and vBMD with reduced cortical thickness (p = 0.006). Trabecular bone structure showed no reduction in trabecular bone volume (p = 0.383), number (p = 0.799), thickness (p = 0.486), or increased inhomogeneity (p = 0.828) or trabecular separation (p = 0.602). Further cortical analysis showed no increases in cortical porosity (p = 0.685) or in pore volume and pore diameter (p = 0.919 and p = 0.827, respectively). (Figs. 1 and 2a).

Fig. 1
figure1

High-resolution peripheral quantitative computed tomographic scans of the ultradistal radius of patients with axial spondyloarthritis (axSpA) and healthy control subjects. Three-dimensional reconstruction of the cortical bone of the total scan region of patients with axSpA and healthy control subjects displays cortical thinning in patients with spondyloarthritis

Full size image
Fig. 2
figure2

Differences in bone microarchitecture in patients with nonradiographic axial spondyloarthritis (nr-axSpA). a Changes of total, cortical, and trabecular bone mineral density (BMD) and bone microarchitecture reflected by total bone volume (BV/TV) and cortical thickness (Ct.Th) between patients with axial spondyloarthritis (SpA) and healthy control subjects. b Changes of total, cortical, and trabecular BMD and bone microarchitecture reflected by BV/TV and Ct.Th between patients with nr-axSpA with or without a history of treatment with > 5 mg prednisolone equivalent for more than 3 months. GC Glucocorticoids, N.S. Not significant, HA Hydroxyapatite. *p <  0.05

Full size image

Bone microarchitecture and vBMD with respect to disease duration in patients with nr-axSpA

The overall disease duration was 6.5 (9) years, with men having longer disease duration than women (5.0 [10] vs. 2.0 [4], p = 0.021). To assess the impact of disease duration on bone microstructure and vBMD, patients were divided into two groups. Forty-six patients had a disease duration of less than 2 years. Comparison between the two groups and healthy control subjects revealed a significant difference in cortical vBMD (p = 0.012), cortical thickness (p = 0.015), and cortical pore diameter (p = 0.007). No difference in trabecular bone density and microstructure was observed (Table 3). Further intergroup comparisons showed that cortical vBMD is decreased in patients with long-standing disease compared with control subjects (p = 0.004), whereas there was only a trend in early SpA (p = 0.096). Cortical thickness, however, is already decreased in early nr-axSpA (p = 0.050), but the decrease is more prominent in patients with long-standing disease than in control subjects (p = 0.007).

Table 3 Bone microstructure in patients with nonradiographic axial spondyloarthritis with short and longer disease duration and in healthy control subjects
Full size table

Bone microarchitecture and vBMD with respect to glucocorticoid treatment in patients with nr-axSpA

Patients were divided into two groups according to their prior exposure to GC treatment (> 5 mg of prednisolone equivalent over ≥ 3 months) in their medical history. Patients treated with GC showed a reduced trabecular vBMD compared with GC-naïve patients (p = 0.044), whereas there was no difference in total or cortical vBMD. Further, especially vBMD of the centrally located trabecular network (p = 0.014) showed a reduction, whereas there was no difference of trabecular bone adjacent to cortex (p = 0.209). Bone microstructure showed deterioration of the trabecular network with reduced trabecular bone volume (BV/TV; p = 0.045) as well as increased inhomogeneity index (p = 0.007) and Tb.Sp (p = 0.037) in patients treated with prednisolone. Cortical thickness showed no significant difference (p = 0.959). (Fig. 2b).

Factors associated with cortical bone changes in nr-axSpA

The first multiple logistic regression model for demographic variables included sex, age, BMI, and smoking status. Male sex was associated with lower cortical vBMD (p = 0.001), whereas female sex was associated with lower trabecular vBMD (p <  0.001). The model for total vBMD revealed no demographic predictor (Table 4). In a second model, sex, age, BMI, remission status, disease duration, treatment with TNFi, prior GC treatment, HLA-B27 status, and peripheral arthritis were included. In these models, male sex again was associated with lower cortical vBMD (p = 0.004), whereas female sex was associated with lower trabecular vBMD (p = 0.001). The model for total vBMD identified no predictors. Prior GC treatment was associated with lower trabecular vBMD (p = 0.041). Interestingly, disease duration was positively associated with trabecular vBMD (p = 0.010). All further parameters, including age, BMI, remission status, treatment with TNFi, HLA-B27 status, and peripheral arthritis, did not show significant results.

Table 4 Predictors of reduced total, cortical, and trabecular bone mineral density in patients with nonradiographic axial spondyloarthritis
Full size table

Discussion

Bone loss is a well-known phenomenon in axSpA, especially in long-standing disease. In the present study, we performed a detailed analysis of bone microstructure in a large cohort of patients with axSpA, with disease duration of less than 2 years in nearly 50% of patients. Our analysis shows that patients with nr-axSpA are characterized by a virtually exclusive cortical but not trabecular bone pathology, which is remarkable. Cortical bone changes characterized by changed geometry, BMD, and microstructure were found early in the disease course of axSpA.

To date, different structural and compartmental changes in bone have been identified using HR-pQCT in systemic inflammatory diseases. Whereas in rheumatoid arthritis a significant deterioration of cortical and trabecular bone has been described, especially in ACPA-positive patients, patients with psoriatic arthritis show predominantly changes of trabecular bone [27, 28]. In contrast, in patients with IBD, primarily a loss of cortical bone has been found [29]. The described changes of cortical bone in nr-axSpA reflect bone structural changes found in patients with IBD.

Our study shows that cortical bone loss as evidenced by cortical thinning happens early in axSpA and can already be found within the first 2 years of disease. In accordance with this, a previous HR-pQCT study of male patients with established AS showed a reduction of cortical vBMD and increased cortical porosity [24]. In this study, however, patients had long-standing disease, with a median duration of symptoms longer than 20 years. Cortical thinning and low cross-sectional area in the peripheral skeleton in patients with AS were strongly associated with the presence of vertebral fractures [24]. These findings are in accordance with the previously described association of cortical thinning and loss of cortical BMD at the radius and the tibia with the occurrence of vertebral fractures in men in the general population [30]. The median disease duration in our study was much shorter (6.5 years) than in the aforementioned study. Nonetheless, about half of the patients with nr-axSpA did not have early disease (< 2 years) anymore and were treated with TNFi. The fact that some patients had a disease duration longer than 2 years may also explain the observation that 7% of the patients with axSPA already had a history of low traumatic fracture. Overall, however, our data show systemic deterioration of cortical bone microstructure even at an early stage of disease in patients with nr-axSpA.

Data are so far limited regarding the factors that influence bone microarchitecture in patients with nr-axSpA and patients with AS. Multiple logistic regression identified male sex to be associated with lower cortical vBMD. Interestingly, loss of cortical vBMD was independent of standard disease-related features such as age, BMI, remission status, anti-TNF treatment, HLA-B27 status, and peripheral arthritis. In contrast to cortical vBMD, trabecular vBMD was lower in women than in men. These findings are in accordance with previous population-based studies showing higher trabecular vBMD in men, whereas cortical vBMD is higher in women [31]. Disease duration was associated positively with higher trabecular vBMD in the present study, which can be explained by longer disease duration in men than in women. These results confirm previous findings of Haroon et al., who investigated sex differences among patients with AS and showed decreased cortical vBMD in men, whereas trabecular vBMD was worse in women [23].

Although nr-axSpA specifically affects cortical bone, an evaluation of those patients treated with GCs > 5 mg daily for > 3 months in the past showed specific loss of trabecular bone associated with reduction of trabecular vBMD, lower total bone volume, and higher trabecular separation and inhomogeneity. Sutter et al. investigated postmenopausal women treated with oral GCs for > 3 months and age-/race-matched control subjects using HR-pQCT and DXA. In their study, despite no difference in areal BMD, GC-treated women showed an impairment of cortical and trabecular vBMD and bone microarchitecture [32]. Moreover, later stages of the disease, particularly in patients with severe AS with syndesmophyte formation, also trabecular vBMD appears to decrease, which is reflected by a study from Devogelaer and colleagues [9].

The strength of the present study is a detailed assessment of bone macro- and microarchitecture using HR-pQCT in patients with axSpA. To date, this is the largest nr-axSpA cohort with detailed bone analysis by HR-pQCT. A further strength and novelty of this work is the assessment of patients with short disease duration. A limitation is, of course, that HR-pQCT cannot analyze the spine but is confined to peripheral sites. However, several studies have previously shown that structural changes in the peripheral bones reflect bone changes as well as fracture risk in the axial skeleton [22, 23].

The reason why nr-axSpA virtually exclusively affects cortical bone is not entirely clear. It can be speculated that such changes reflect increased cortical bone remodeling. For instance, it has long been known that the remodeling of cortical bone is highly dependent on strain [33], and later concepts even suggested that cortical bone remodeling may even be entirely dependent on microcracks [34]. Hence, altered bone responses to mechanical forces in nr-axSpA may be triggers for increased cortical bone remodeling and bone loss. In accordance with this, prostaglandin E2, a prototype inflammatory mediator released upon injury and having a central role in nr-axSpA, has been shown to enhance cortical bone remodeling [35]. The disbalance in cortical bone in patients with nr-axSpA, however, may stem from cytokines such as interleukin-17, which effectively suppress bone formation but at the same time increase bone resorption [36, 37].

Conclusions

In this study, we show that axSpA specifically leads to an early and virtually exclusive loss of cortical bone, thereby contrasting with many other inflammatory diseases but resembling features of bone loss observed in patients with IBD. In contrast, trabecular bone does not appear to be directly influenced by axSpA.

Abbreviations

ACPA:

Anticitrullinated protein antibodies

AS:

Ankylosing spondylitis

ASAS:

Assessment of Spondyloarthritis international Society

ASDAS:

Ankylosing Spondylitis Disease Activity Score

BASDAI:

Bath Ankylosing Spondylitis Disease Activity Index

BASMI:

Bath Ankylosing Spondylitis Metrology Index

BMD:

Bone mineral density

BMI:

Body mass index

BV/TV:

Bone volume per tissue volume

CRP:

C-reactive protein

Ct:

Cortical bone

Ct.Po:

Cortical porosity

Ct.Th:

Cortical thickness

DMARD:

Disease-modifying antirheumatic drug

DXA:

Dual-energy x-ray absorptiometry

ESR:

Erythrocyte sedimentation rate

GC:

Glucocorticoid

HA:

Hydroxyapatite

HLA-B27:

Human leukocyte antigen B27

HR-pQCT:

High-resolution quantitative computed tomography

IBD:

Inflammatory bowel disease

MASES:

Maastricht Ankylosing Spondylitis Enthesitis Score

SpA:

Spondyloarthritis

Tb:

Trabecular bone

Tb.Sp:

Trabecular separation

TNF:

Tumor necrosis factor α

TNFi:

Inhibition of tumor necrosis factor α

vBMD:

Volumetric bone mineral density

References

  1. 1.

    Donnelly S, Doyle DV, Denton A, Rolfe I, McCloskey EV, Spector TD. Bone mineral density and vertebral compression fracture rates in ankylosing spondylitis. Ann Rheum Dis. 1994;53:117–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Kilic E, Ozgocmen S. Bone mass in axial spondyloarthritis: a literature review. World J Orthop. 2015;6:298–310.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Klingberg E, Lorentzon M, Mellstrom D, Geijer M, Gothlin J, Hilme E, et al. Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment. Arthritis Res Ther. 2012;14:R108.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lange U, Kluge A, Strunk J, Teichmann J, Bachmann G. Ankylosing spondylitis and bone mineral density—what is the ideal tool for measurement? Rheumatol Int. 2005;26:115–20.

    Article  PubMed  Google Scholar 

  5. 5.

    Speden DJ, Calin AI, Ring FJ, Bhalla AK. Bone mineral density, calcaneal ultrasound, and bone turnover markers in women with ankylosing spondylitis. J Rheumatol. 2002;29:516–21.

    PubMed  Google Scholar 

  6. 6.

    Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J. Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes. J Rheumatol. 2005;32:1290–8.

    PubMed  Google Scholar 

  7. 7.

    Meirelles ES, Borelli A, Camargo OP. Influence of disease activity and chronicity on ankylosing spondylitis bone mass loss. Clin Rheumatol. 1999;18:364–8.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Singh A, Bronson W, Walker SE, Allen SH. Relative value of femoral and lumbar bone mineral density assessments in patients with ankylosing spondylitis. South Med J. 1995;88:939–43.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Devogelaer JP, Maldague B, Malghem J, Nagant de Deuxchaisnes C. Appendicular and vertebral bone mass in ankylosing spondylitis: a comparison of plain radiographs with single- and dual-photon absorptiometry and with quantitative computed tomography. Arthritis Rheum. 1992;35:1062–7.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Schett G, David JP. The multiple faces of autoimmune-mediated bone loss. Nat Rev Endocrinol. 2010;6:698–706.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Akgol G, Kamanli A, Ozgocmen S. Evidence for inflammation-induced bone loss in non-radiographic axial spondyloarthritis. Rheumatology (Oxford). 2014;53:497–501.

    Article  CAS  Google Scholar 

  12. 12.

    Briot K, Durnez A, Paternotte S, Miceli-Richard C, Dougados M, Roux C. Bone oedema on MRI is highly associated with low bone mineral density in patients with early inflammatory back pain: results from the DESIR cohort. Ann Rheum Dis. 2013;72:1914–9.

    Article  PubMed  Google Scholar 

  13. 13.

    Allali F, Breban M, Porcher R, Maillefert JF, Dougados M, Roux C. Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumour necrosis factor α. Ann Rheum Dis. 2003;62:347–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Arends S, Spoorenberg A, Houtman PM, Leijsma MK, Bos R, Kallenberg CG, et al. The effect of three years of TNFα blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2012;14:R98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Kang KY, Ju JH, Park SH, Kim HY. The paradoxical effects of TNF inhibitors on bone mineral density and radiographic progression in patients with ankylosing spondylitis. Rheumatology (Oxford). 2013;52:718–26.

    Article  CAS  Google Scholar 

  16. 16.

    Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E, Hedberg M, Carlsten H, Forsblad-D’Elia H. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol. 2012;39:1987–95.

    Article  PubMed  Google Scholar 

  17. 17.

    Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250–61.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Stein EM, Kepley A, Walker M, Nickolas TL, Nishiyama K, Zhou B, et al. Skeletal structure in postmenopausal women with osteopenia and fractures is characterized by abnormal trabecular plates and cortical thinning. J Bone Miner Res. 2014;29:1101–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:6508–15.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Cheung AM, Adachi JD, Hanley DA, Kendler DL, Davison KS, Josse R, et al. High-resolution peripheral quantitative computed tomography for the assessment of bone strength and structure: a review by the Canadian Bone Strength Working Group. Curr Osteoporos Rep. 2013;11:136–46.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Amstrup AK, Jakobsen NF, Moser E, Sikjaer T, Mosekilde L, Rejnmark L. Association between bone indices assessed by DXA, HR-pQCT and QCT scans in post-menopausal women. J Bone Miner Metab. 2016;34:638–45.

    Article  PubMed  Google Scholar 

  22. 22.

    Engelke K, Libanati C, Fuerst T, Zysset P, Genant HK. Advanced CT based in vivo methods for the assessment of bone density, structure, and strength. Curr Osteoporos Rep. 2013;11:246–55.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Haroon N, Szabo E, Raboud JM, McDonald-Blumer H, Fung L, Josse RG, et al. Alterations of bone mineral density, bone microarchitecture and strength in patients with ankylosing spondylitis: a cross-sectional study using high-resolution peripheral quantitative computerized tomography and finite element analysis. Arthritis Res Ther. 2015;17:377.

    Article  CAS  Google Scholar 

  24. 24.

    Klingberg E, Lorentzon M, Gothlin J, Mellstrom D, Geijer M, Ohlsson C, et al. Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes. Arthritis Res Ther. 2013;15:R179.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Simon D, Kleyer A, Stemmler F, Simon C, Berlin A, et al. Age- and sex-dependent changes of intra-articular cortical and trabecular bone structure and the effects of rheumatoid arthritis. J Bone Miner Res. 2017;32:722–30.

    Article  PubMed  Google Scholar 

  26. 26.

    de Waard EAC, Sarodnik C, Pennings A, de Jong JJA, Savelberg HHCM, van Geel TA, et al. The reliability of HR-pQCT derived cortical bone structural parameters when using uncorrected instead of corrected automatically generated endocortical contours in a cross-sectional study: the Maastricht study. Calcif Tissue Int. 2018; https://doi.org/10.1007/s00223-018-0416-2.

  27. 27.

    Kocijan R, Finzel S, Englbrecht M, Engelke K, Rech J, Schett G. Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity. Ann Rheum Dis. 2014;73:2022–8.

    Article  PubMed  Google Scholar 

  28. 28.

    Kocijan R, Englbrecht M, Haschka J, Simon D, Kleyer A, Finzel S, et al. Quantitative and qualitative changes of bone in psoriasis and psoriatic arthritis patients. J Bone Miner Res. 2015;30:1775–83.

    Article  PubMed  Google Scholar 

  29. 29.

    Haschka J, Hirschmann S, Kleyer A, Englbrecht M, Faustini F, Simon D, et al. High-resolution quantitative computed tomography demonstrates structural defects in cortical and trabecular bone in IBD patients. J Crohns Colitis. 2016;10:532–40.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Szulc P, Boutroy S, Vilayphiou N, Chaitou A, Delmas PD, Chapurlat R. Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: the STRAMBO study. J Bone Miner Res. 2011;26:1358–67.

    Article  PubMed  Google Scholar 

  31. 31.

    Khosla S, Riggs BL, Atkinson EJ, Oberg AL, McDaniel LJ, Holets M, et al. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res. 2006;21:124–31.

    Article  PubMed  Google Scholar 

  32. 32.

    Sutter S, Nishiyama KK, Kepley A, Zhou B, Wang J, McMahon DJ, et al. Abnormalities in cortical bone, trabecular plates, and stiffness in postmenopausal women treated with glucocorticoids. J Clin Endocrinol Metab. 2014;99:4231–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Carter DR. Mechanical loading histories and cortical bone remodeling. Calcif Tissue Int. 1984;36:S19–24.

    Article  PubMed  Google Scholar 

  34. 34.

    Martin RB. Is all cortical bone remodeling initiated by microdamage? Bone. 2002;30:8–13.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Jee WS, Mori S, Li XJ, Chan S. Prostaglandin E2 enhances cortical bone mass and activates intracortical bone remodeling in intact and ovariectomized female rats. Bone. 1990;11:253–66.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Uluckan O, Jimenez M, Karbach S, Jeschke A, Graña O, Keller J, et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med. 2016;8:330ra337.

    Article  CAS  Google Scholar 

  37. 37.

    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Bundesministerium fuer Bildung und Forschung (BMBF project METARTHROS), the Deutsche Forschungsgemeinschaft (CRC1181), the Marie Curie project Osteoimmune and the Innovative Medicines Initiative-funded project Be The Cure (BTCure). CPF was supported by Cienciassem Fronteiras from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil.

Funding

This study was supported by the Deutsche Forschungsgemeinschaft (CRC1181), the Bundesministerium für Bildung und Forschung (BMBF; project METARTHROS) and the Innovative Medicine Initiative-funded project Rheuma Tolerance for Cure (RTCure).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Author information

Author notes

  1. Anna Neumann and Judith Haschka contributed equally to this work.

Affiliations

  1. Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nurnberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany

    Anna Neumann, Judith Haschka, Arnd Kleyer, Louis Schuster, Matthias Englbrecht, Andreas Berlin, Camille P. Figueiredo, David Simon, Jürgen Rech & Georg Schett

  2. St. Vincent Hospital, VINFORCE Study Group, Medical University of Vienna, Vienna, Austria

    Judith Haschka, Christian Muschitz, Roland Kocijan & Heinrich Resch

  3. Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

    Camille P. Figueiredo

Authors
  1. Anna Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Judith Haschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnd Kleyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louis Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Englbrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andreas Berlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Camille P. Figueiredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christian Muschitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roland Kocijan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Heinrich Resch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jürgen Rech
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Georg Schett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AN, JH, and AK collected and analyzed the data. LS performed the scan evaluation and motion grading. JH and ME performed the statistical analysis. AB provided data of healthy control subjects. AN, JH, AK, ME, CPF, DS, CM, RK, HR, JR, and GS interpreted the data and revised the manuscript. AN, JH, and GS wrote the manuscript. The present work was performed in fulfillment of the requirements for obtaining the ‘Dr. med.’ degree by AN. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Georg Schett.

Ethics declarations

Ethics approval and consent to participate

Ethical approval was obtained from the institutional review board of the Universitatsklinikum Erlangen. Patients provided written informed consent.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Additional file

Additional file 1:

Table S1 Demographic parameters, disease-specific characteristics, and bone microstructure in patients with nonradiographic axial spondyloarthritis (nr-axSpA) with or without TNFi treatment. (DOCX 16 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Neumann, A., Haschka, J., Kleyer, A. et al. Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis. Arthritis Res Ther 20, 202 (2018). https://doi.org/10.1186/s13075-018-1620-1

Download citation

Keywords

  • Spondyloarthritis
  • Bone loss
  • Computed tomography

Arthritis Research & Therapy

ISSN: 1478-6362

Contact us