|Ahead of print publication
Prevalence of low bone mineral density in ankylosing spondylitis, correlation with disease activity, and serum sclerostin levels
Anupam Wakhlu1, Akhil Pawan Goel2, Puneet Kumar1
1 Department of Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh; Department of Rheumatology, Manipal Hospital, Jaipur, Rajasthan, India
|Date of Submission||06-Jul-2020|
|Date of Acceptance||06-Jul-2020|
Akhil Pawan Goel,
Manipal Hospital, Sector 5, Main Sikar Road, Vidhyadhar Nagar, Jaipur - 302 013, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Ankylosing spondylitis (AS) involves pathological new bone formation in the cortical zone of vertebrae and excessive loss of trabecular bone in the center of the vertebral body causing osteoporosis (OP). OP expressed as reduced bone mineral density (BMD) is a common complication in AS. Tumor necrosis factor-α (TNF-α) causes induction of Dickkopf-1 and sclerostin, which downregulates bone formation by inhibiting wingless proteins and bone morphogenic proteins.
Materials and Methods: Fifty AS patients were compared with an equal number of age- and sex-matched controls. Various biochemical and radiological parameters of disease activity were calculated. BMD was measured at antero-posterior (AP) lumbar spine, neck of femur, and lateral lumbar spine using the dual-energy X-ray absorptiometry. Serum sclerostin, TNF-α, interleukin-17A (IL-17A), and IL-22 levels were measured using commercial enzyme-linked immunosorbent assay kits.
Results: Mean BMD at various sites was significantly lower in patients. Patients with OP and low BMD at AP and lateral spine were 38% and 72%, respectively; at neck of femur, 20% and 68% of patients had OP and low BMD, respectively. Neck of femur BMD had significant positive correlation with Bath's ankylosing spondylitis disease activity index. Serum sclerostin levels were significantly higher in patients and had significant negative correlation with modified Stoke's ankylosing spondylitis spinal score.
Conclusion: Low BMD is a significant complication in AS, and more prevalent in spine as compared to femur. Neck of femur BMD varies significantly with disease activity. Low sclerostin plays a significant role in the formation of syndesmophytes.
Keywords: Ankylosing spondylitis, osteoporosis, reduced bone mineral density, serum sclerostin
|How to cite this URL:|
Wakhlu A, Goel AP, Kumar P. Prevalence of low bone mineral density in ankylosing spondylitis, correlation with disease activity, and serum sclerostin levels. Indian J Rheumatol [Epub ahead of print] [cited 2020 Oct 27]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=291586
| Introduction|| |
Ankylosing spondylitis (AS) is a chronic, debilitating rheumatic disease characterized by inflammatory back pain, restricted spine mobility, peripheral arthritis, enthesitis, and acute anterior uveitis. Inflammatory enthesopathy progressing to ossification and ankylosis is the principal pathological basis for the disease. In AS, two increased but opposite bone remodeling processes take place; these are the pathological formation of new bone in the cortical zone of the vertebrae, the facet joints and excessive loss of trabecular bone in centre of the vertebral body leading to osteoporosis (OP).
OP being expressed as reduced bone mineral density (BMD) is a common complication in AS patients that have been shown to exist in mild AS patients and during early disease. The decrease in BMDs can be observed both in the hip and spine and varies according to the duration of the disease and the presence of syndesmophytes in the spine.
In advanced AS, it may be difficult to interpret lumbar spine BMD as determined by dual-energy X-ray absorptiometry (DEXA) in the anteroposterior (AP) projection, as the presence of syndesmophytes may lead to a false increase in the BMD, a problem not present at the hip sites BMD. The new bone formation in AS causes a false overestimation of the total BMD, and the values can be normal or high, even when OP is present.
Bone remodeling in AS is a dynamic process involving many molecules interconnected within the multilevel positive and negative feedback networks. Tumour necrosis factor alpha (TNF-α), an essential pro-inflammatory cytokine in AS, is responsible for induction of Dickkopf-1 (Dkk-1) and sclerostin, which, in turn, cause downregulation of bone formation by inhibiting Wingless proteins (Wnt) and bone morphogenic proteins. The latter two are the key inducers of increase in osteoblastic activity and new bone formation.,
In recent years, the interleukin (IL)-23/IL-17 pathway has been observed to have significance in the pathogenesis of AS. Multiple genetic polymorphisms within T-helper 17/23 (Th17/23) pathway genes have been reported in common between AS, inflammatory bowel disease and psoriasis, suggesting a common pathogenic role. Therapeutic strategies targeting the Th17 response have proved beneficial in AS.
Aims and objectives
- To study the prevalence of low BMD in patients of AS
- To correlate low BMD with disease activity in AS
- To correlate serum sclerostin and cytokines-TNF-α, IL-17A, IL-22 with clinicoradiological and laboratory parameters of disease activity and BMD in AS.
| Materials and Methods|| |
The study was conducted at the Department of Rheumatology, King George's Medical University (KGMU), Lucknow, Uttar Pradesh, India.
It was an observational, cross-sectional study.
Duration of study
The duration of the study was 10 months (January 2018–October 2018).
Patients attending the rheumatology outpatient department and inpatient department were screened for AS. Fifty consecutive patients fulfilling the ASAS 2009 classification criteria for axial spondyloarthritis were enrolled; however, all other secondary spondyloarthropathies were excluded from the study. An equal number of age- and sex-matched healthy controls were recruited from the same geographical area.
- Other spondyloarthropathies such as psoriatic arthritis, inflammatory bowel disease-related arthritis, and reactive arthritis
- Pregnant women
- Age ≤16 years
- Those in whom BMD could not be performed
- Chronic diseases such as chronic liver disease, chronic kidney disease, chronic obstructive lung disease, congestive heart failure, malabsorption syndromes, and type 1 and 2 diabetes mellitus
- Thyroid disorders or patients on medications for thyroid disorders
- Bone disorders such as primary hyperparathyroidism and Paget's disease
- Patients on anticonvulsants
- Patients on bisphosphonates/teriparatide/calcitonin
- Patients on ≥5 mg/day prednisone or equivalent for ≥3 months
- Patients on TNF-α inhibitor or any other “biologic”
- Patients of tuberculosis/HIV/active infection
- Patients with Vitamin D levels <15 ng/ml
- Current smoker – person who has smoked >100 cigarettes in his lifetime, smoked in the last 28 days
- Heavy alcoholic – heavy alcohol intake is defined as ≥8 drinks/week in women and ≥15 drinks/week in men (one standard drink is = 14 g of pure alcohol).
Institutional ethical clearance was obtained before starting the study.
(Ref. Code: 82nd ECM II-B-Thesis/P23).
A detailed history was taken, and thorough physical examination was done. Details were collected regarding the duration of symptoms, duration, and the dose of medicines used such as nonsteroidal anti-inflammatory drugs (NSAIDs) within previous month, steroids, highest tolerated dose of disease modifying anti-rheumatic drugs (DMARDs) – sulfasalazine/methotrexate/leflunomide, calcium, and Vitamin D intake. For each patient, Bath's ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS) – erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were calculated. All participants gave informed written consent in accordance with the declaration of Helsinki.
Radiography and dual-energy X-ray absorptiometry
An AP and lateral radiograph of cervical and dorso-lumbar spine and AP radiograph of pelvis was obtained in all patients and modified Stoke's ankylosing spondylitis spinal score (mSASSS) was calculated. mSASSS was independently confirmed by a rheumatologist trained in the evaluation of mSASSS scores and who was blinded to the rest of the data. BMD measurements of lumbar spine (AP lumbar spine – L1-L4), hip (neck of femur and total proximal femur) or in the opposite hip if the examination was not feasible in the other hip, for instance if there had been hip replacement, and lateral lumbar spine (B2-B3) were measured using the Lunar Prodigy Advance dual-energy X-ray absorptiometry System (analysis version: 12.20) manufactured by GE Healthcare, USA. BMD of the distal 1/3rd of the radius was also recorded. Lumbar vertebra/vertebrae that had been fractured/collapsed was excluded in BMD. All measurements were conducted by a single trained technician.
The results of BMD were expressed in g/cm2 as well as in a Z- and T-score using the reference curves supplied by the manufacturer. The Z-score is the number of standard deviations (SDs) above or below the values of healthy adults of the same age and same sex. The T-score is the number of SDs above or below the values of young adults of the same sex.
Z-score was used for premenopausal women and in males <50 years. OP at a particular site was defined as Z-score <−2 SD (21). Patients with Z-score between − 1 to − 2 SD were defined to have osteopenia.
T-score was used for postmenopausal women and in men ≥50 years. The World Health Organization (WHO) defines osteopenia as a T-score of between −1 and −2.5 and OP as a T-score of ≤−2.5. For lateral spine BMD measurement, definitions of low bone mass and OP were the same as at other sites.
Blood samples were obtained in a fasting state. For patients, investigations such as complete blood count, ESR (Westergren's method), CRP, liver function test, kidney function test, random blood sugar, serum ionized calcium, serum phosphorus, serum alkaline phosphatase, and 25(OH) Vitamin D were done immediately by standard laboratory techniques.
Serum samples of both the patients and controls were stored at −80°C until assayed. The stored samples were thawed and for patients, commercial sandwich enzyme-linked immunoassay (ELISA) kits were used for TNF-α, IL-17A, IL-22, sclerostin, and parathormone (PTH) in accordance with the manufacturer's protocol. The funding for the kits came from the intramural seed grant sanctioned for this study by KGMU, Lucknow, UP, India. ELISA kit for sclerostin was from BioString Company, USA. ELISA kit for IL-17A was from R&D systems, USA. ELISA kits for TNF-α, IL-22 were from peprotech company, USA. ELISA kit for PTH was from biomerica company, USA. For thawed sera of the controls, commercial sandwich ELISA kits were used for estimating TNF-α, IL-17A, IL-22, and sclerostin levels in accordance with the manufacturer's protocol.
The baseline characteristics will be presented as mean ± SD for the continuous variables and as frequency and percentage for discrete ones. Continuous variables were compared between the groups using the unpaired t-test. The Chi-square test was used for comparing the categorical variables. Correlations between the continuous variables were tested using the Pearson correlation coefficient (r) and multivariate linear regression. All tests were two-tailed, and P < 0.05 was considered statistically significant. All statistical analyses were done using Statistical Package for Social Sciences (SPSS) software (Version 23.0. IBM Corp., Armonk, NY, USA).
| Results|| |
The mean age of the patients was 38 ± 10 years, whereas that of controls was 36 ± 11 years. Ninety-two percent (n = 46) of the patients were males and 8% (n = 4) were females. Similar percentage of males and females was observed in controls. The mean total duration of illness was 9 ± 6 years. Twenty percent (n = 10) of the patients had active peripheral arthritis, 10% (n = 5) had history of uveitis, and 4% (n = 2) had enthesitis. Eighty-eight percent (n = 44) of the patients were on NSAID; 34% (n = 17) of the patients were on low-dose steroids (<5 mg prednisolone/day for <4 weeks); 38% (n = 19) of patients were taking at least one DMARD (sulfasalazine/methotrexate/leflunomide); and 42% (n = 21) of the patients were on calcium and Vitamin D supplements. The mean 25 (OH) Vitamin D level of patients was 33.64 ± 18.76 ng/ml. The mean iPTH level of patients was 19.41 ± 14.28 pg/ml (reference range: 10.4–66.5 pg/ml).
The mean BMD (g/cm2) at AP lumbar spine (L1-L4), neck of femur, and lateral lumbar spine (B2-B3) was significantly lower in patients as compared to the controls, as described in [Table 1].
The mean Z scores at L1-L4, neck of femur, and lateral lumbar spine (B2-B3) were significantly lower in patients as compared to controls, as described in [Table 2].
The mean T scores as applicable in six cases and controls at L1-L4, neck of femur, and lateral lumbar spine (B2-B3) are described in [Table 3].
The percentage of patients having osteopenia (ON), OP, and low BMD at L1-L4, neck of femur, and B2-B3 are described in [Table 4].
|Table 4: Percentage of osteopenia, osteoporosis and low bone mineral density at L1-L4, neck of femur, B2-B3|
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The mean values of ASDAS-ESR, ASDAS-CRP, and BASDAI were 3.65 ± 1.07, 3.51 ± 0.99, and 3.62 ± 1.48, respectively. The mean value of serum sclerostin was significantly higher in patients as compared to controls. It was 5.86 ± 9.24 ng/ml (controls: 1.01 ± 6.26, P = 0.0076). The mean values of serum TNF-α, IL-17A, and IL-22 were found to be significantly higher in patients as compared to controls.
BMD at L1-L4 had no significant correlation with ESR, CRP, ASDAS-ESR, ASDAS-CRP, BASDAI, and mSASSS.
BMD at the neck of femur had significant positive correlation with BASDAI, as depicted in [Figure 1].
|Figure 1: Correlation between BMD at neck of femur and Bath's ankylosing spondylitis disease activity index|
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BMD at neck of femur had no significant correlation with ESR, CRP, ASDAS-ESR, ASDAS-CRP, and mSASSS.
BMD at lateral lumbar spine (B2-B3) had significant negative correlation with ASDAS-CRP (r = −0.291, P = 0.041) but had no significant correlation with ESR, CRP, ASDAS-ESR, BASDAI, and mSASSS.
BMD at L1-L4, neck of femur, and B2-B3 had no significant correlation with the duration of the disease. A subgroup study of correlating BMD at various sites with high and low disease activity was also done. High-disease activity was defined as BASDAI ≥4 and low-disease activity as <4. In terms of ASDAS-ESR and CRP, score of >3.5 is defined as very high activity, 2.1–3.5 as high activity, 1.3–2.1 as moderate activity, and <1.3 as inactive disease. It did not show any additional significant correlation.
Serum sclerostin had significant negative correlation with mSASSS as described in [Figure 2].
|Figure 2: Correlation between modified Stoke's ankylosing spondylitis spinal score and sclerostin|
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Correlation of serum sclerostin, TNF-α, IL-17A, and IL-22 with clinicoradiological and laboratory parameters of disease activity is described in [Table 5].
|Table 5: Correlation of serum sclerostin, tumour necrosis factor a, interleukin-17A, interleukin-22 with clinical, laboratory and radiological parameters of disease activity|
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Correlation of BMD at various sites with serum sclerostin, TNF-α, IL-17A, IL-22 is described in [Table 6].
|Table 6: Correlation of bone mineral density (g/cm2) at various sites with serum sclerostin, tumour necrosis factor α, interleukin-17A, interleukin-22|
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| Discussion|| |
The prevalence of low BMD in our study was much higher as compared to previous studies. Low BMD at spine and femur has been well observed in AS. The prevalence of low BMD in AS in various studies ranges from 19% to 62%. Literature search for the prevalence of decreased BMD and OP in AS within the first decade after the diagnosis reported a high mean prevalence of low BMD between 51% at the femoral neck and 54% at the lumbar spine. In addition, the prevalence of OP was 16% for lumbar spine and 13% for femoral neck.
In our study, we used the latest ASAS 2009 classification criteria for axial spondyloarthropathy which was in accordance with the modified 1984 New York classification criteria used by the previous studies.,
Most of the other studies have used the WHO definition of osteopenia and OP for all age groups which can give rise to inaccurate prevalence of osteopenia and OP. We used Z-score for premenopausal women and in males <50 years. T-score was used for postmenopausal women and in men ≥50 years. Discordance between T-scores and Z-scores may occur when there are differences in ethnicity in the reference databases used. Thus, we used Z-score in 44 of patients and T-score in six of patients. Similar criteria of BMD applied for controls.
Studies by Donnelly et al. and Devogelaer et al. demonstrated that patients with AS had significantly lower femoral neck BMD in proportion to disease severity and duration. They also observed that lumbar spine BMD was reduced in early disease, but it was considerably increased in patients with advanced AS.,
In our study, mean BMD of the patients was lower in the lateral lumbar spine than the AP spine. Although BMD at B2-B3 failed to show significant correlation with mSASSS, one male patient having mSASSS of 37, had OP at B2-B3 but normal BMD at L1-L4 and neck of femur. Mermerci Başkan et al. observed that lumbar spine BMD was significantly lower in AS patients compared with healthy controls when measured by lateral projection DEXA but not when measured by AP DXA scan.
BMD at neck of femur had significant positive correlation with BASDAI. This can be explained on the basis that BASDAI is increased in early disease due to increased inflammation while femoral BMD is not much affected in early disease but decreases in late disease, as shown in another study., This result was also highlighted by Grazio et al., who reported that the relationship between low BMD and high levels of disease activity parameters in AS patients was reflected more reliably at the proximal femoral sites than at the lumbar spine.
BMD at lateral lumbar spine (B2-B3) had significant negative correlation with ASDAS-CRP.
This was in accordance with a study by Mermerci Başkan et al. who showed a negative relation between the lateral lumbar BMD values and ESR, CRP, and BASDAI scores of AS patients.
In our study, high value of serum sclerostin in patients in comparison to controls was a significant finding. This was in sharp contrast with the study by Appel et al. who were among the first researchers to estimate serum sclerostin levels in AS patients. They compared 46 AS patients and 50 healthy controls and reported that sclerostin levels were lower in the AS patients.
Our study was in accordance with Korkosz et al. who reported that sclerostin levels were significantly higher and Dkk-1 levels lower in patients with high disease activity; this contradiction might indicate that there exists a complex interaction between disease activity and inhibitors of bone formation in AS.
The lack of significant correlation of serum sclerostin with ESR, CRP, ASDAS-ESR, ASDAS-CRP, BASDAI in our study was supported by other studies.,
The significant negative correlation of serum sclerostin with mSASSS was a highlight of our study as low levels of sclerostin could be used as a potential biomarker for syndesmophytes formation. This was in accordance with the study by Appel et al., who also reported that serum sclerostin had a negative correlation with formation of new syndesmophytes.
A study by Perrotta et al. demonstrated that no significant correlations were observed between serum sclerostin levels and mSASSS.
Our study reported no significant correlation between serum sclerostin and BMD at various sites indicating the role of other markers of bone modeling along with sclerostin to cause OP. Our study was in accordance with the study by Abdel and Wael, who also reported similar results.
Our study revealed that, the significant high level of TNF-α, IL-17A, and IL-22 as compared to controls proved the persistent ongoing inflammation in AS patients.
In our study, BMD at B2-B3 had a significant negative correlation with serum IL-22. Increase in IL-22 can cause osteopenia and OP at lateral lumbar spine.
| Conclusion|| |
Low BMD is a significant complication in AS, and more prevalent in spine as compared to femur. Neck of femur BMD varies significantly with disease activity. Low sclerostin plays a significant role in the formation of syndesmophytes.
Financial support and sponsorship
The financial support for kits for various cytokines came from the intramural seed grant sanctioned by KGMU, Lucknow, UP, India.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]