Bone formation in ankylosing spondylitis

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Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

For citation purposes: Slobodin G, Rosner I, Odeh M. Bone formation in ankylosing spondylitis. OA Arthritis 2013 Mar 02;1(1):7

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Bone formation in ankylosing spondylitisG Slobodin1,2*, I Rosner2,3, M Odeh1,2

AbstractIntroductionAnkylosing spondylitis (AS) is a chronic inflammatory rheumatic disorder with unclear pathogenesis. Bone formation is a hallmark fea-ture of AS, precise mechanisms of which are unknown. The aim of this review was to summarize the cur-rent knowledge regarding both clini-cal significance and pathogenesis of bone formation in AS.Materials and methodsArticles, published in the medical literature and chapters in textbooks related to the discussed topic, were critically reviewed and relevant data were selected, collated and organized for the purpose of this manuscript. ResultsConventional radiography is the most valuable classical tool for iden-tification of structural changes in AS. The typical manifestations of bone formation in AS usually involve the axial skeleton, including spine, sac-roiliac and hip joints, and, if prop-erly recognized, have an important role in diagnosing, classifying and monitoring patients. Molecular path-ways leading to bone formation in AS have not been elucidated suffi-ciently. Abnormally active signalling by wingless-type (wnt)-like and bone morphogenic protein (BMP)-medi-ated pathways have been suggested as major contributors to disease-related ossification in AS. The only medicines, shown currently to delay

the process of bone formation in AS patients, are nonsteroidal anti-in-flammatory drugs.ConclusionBetter understanding and prediction of structural damage would help to improve and individualize manage-ment of patients suffering from AS.

IntroductionAnkylosing spondylitis (AS) is a chronic inflammatory rheumatic disorder with unclear pathogenesis. The prevalence of AS in the general population is estimated at 0.5%, and its prominent features include sac-roiliitis, spondylitis, asymmetric pe-ripheral arthritis, enthesitis and an association with the histocompatibil-ity allele HLA-B27. AS disease activ-ity can be appreciated by clinical and laboratory measures, such as the se-verity of the inflammatory back pain, presence of synovial or entheseal inflammation, acute uveitis, constitu-tional symptoms and elevated indices of inflammation in the blood such as erythrocyte sedimentation rate and/or serum levels of C-reactive protein (CRP). The pathologic progression of AS is measured by new bone for-mation, appearance of syndesmo-phytes at vertebral body margins and, eventually, ankylosis of the sac-roiliac joints and vertebral column. The presence of inflammation at the areas of subsequent osseous prolif-eration is considered to be a neces-sary trigger; but, on the other hand, the rate of new bone formation in AS does not seem to be a simple function of the inflammatory activity of the disease, and the precise mechanisms of the progressive ankylosis are un-known. It is also well appreciated that the rate and course of new bone formation can be individually deter-mined, with some AS patients having

radiographic ankylosis already upon first clinical presentation, while oth-ers do not develop ankylosis even af-ter longstanding disease. The factors influencing this significant variability in both rate and magnitude of new bone formation in individuals with AS have not been elaborated. The aim of this review was to summarize the current knowledge regarding both clinical significance and pathogen-esis of bone formation in AS.

Materials and methodsA literature search of the PUBMED database using the crossover of key-words ‘bone formation’ and ‘anky-losing spondylitis’ was conducted, with 227 papers listed. These manu-scripts, as well as other articles pub-lished in the medical literature and chapters in textbooks related to the discussed topic, were critically re-viewed and relevant data were se-lected, collated and organized for the purpose of this article.

ResultsRadiographic features of bone formation in ASBone formation is a characteristic feature of AS, which, if properly rec-ognized, has an important role in di-agnosing, classifying and monitoring patients suffering from the disease. Conventional radiography, while un-able to visualize active inflammation, is the most valuable classical tool for identification of structural changes in AS1. The typical manifestations of bone formation in AS usually involve the axial skeleton, including spine, sacroiliac and hip joints, while ossifi-cation of the entheses may occur also peripherally.

The characteristic radiographic changes in AS, related to bone forma-tion, include2:

* Corresponding author Email: [email protected] Department of Internal Medicine A, Bnai Zion

Medical Center, Haifa, Israel2 Ruth & Bruce Rappaport Faculty of Medicine,

Technion, Haifa, Israel3 Rheumatology Unit, Bnai Zion Medical Center,

Haifa, Israel

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• osseous fusion (ankylosis) of sac-roiliac joints (Figure 1);

• formation of syndesmophytes and the resulting appearance of ‘bam-boo spine’ in advanced disease (Figures 2–4);

• ankylosis of vertebral apophyseal joints (Figure 4);

• ankylosis of costovertebral joints (Figure 3);

• ossifying enthesopathy of pos-terior spinal ligaments and pel-vic entheses, particularly at is-chial tuberosities and iliac crests (Figure 1);

• osteophyte formation on the mar-gins of femoral head with collar-like appearance about the femoral neck (Figure 1).

Computed tomography, superior to conventional radiography by de-picting layer-by-layer changes, has additional value in disclosing bony growth particularly in locations where x-ray imaging is difficult, such as within sacroiliac joints or posterior spinal elements (Figure 5). Magnetic resonance imaging, on the contrary, is more useful in demon-strating signs of active inflammation about joints, while changes related to bone formation may be missed due to the magnetic properties of calcium compounds within new bone.

Bone formation per se is not pathognomonic for AS, as it is also a feature of other spondyloarthropa-thies, as well as of osteoarthritis,

diffuse idiopathic skeletal hyperos-tosis, alkaptonuria and other disor-ders. The pattern of bone formation in each of these diseases, however, is unique, allowing for proper differen-tiation in the majority of cases.

Of note, bone formation is not only a diagnostic feature of AS, but is also a measure of the pathologic progres-sion of the disease. Standard quanti-tative assessment of this new bone formation, used in clinical trials and research of AS, is focused mainly on the cervical and lumbar segments of the spine. Four methods, developed to score structural changes in AS, include the Bath AS Radiology Index (BASRI), the Stoke AS Spinal Score (SASSS), modified SASSS (mSASSS)

Figure 1: Pelvic radiogram of a patient with established AS.1, complete ankylosis of both sacroiliac joints; 2, ossification of posterior spinal ligaments; 3, ‘star’ sign (ossification of the ligaments in the posterosuperior portion of sacroiliac joints); 4, osteophyte formation on the margin of the femoral head with appearance of a collar about the femoral neck (arrowhead); significant narrowing of the right hip joint space is evident, the left hip joint is replaced; 5, enthesopathy of the ischial tuberosity and iliac bone.

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and Radiographic AS Spinal Score (RASSS). The last three methods are primarily based on scoring the pres-ence of ‘squaring’ of vertebral bod-ies, characteristic sclerosis of bone, bony erosions and, particularly, syn-desmophytes and bridging ankylo-sis along the spine, while the BASRI also scores sacroiliac joints and, in its modified form, hip joints (BASRI-hip). mSASSS is currently considered the best method for scoring the ra-diographic progression of AS, while BASRI remains useful as an instru-ment for the staging of AS3.

Pathogenesis of bone formation in ASHistological data available from stud-ies conducted on biopsies and/or autopsies of patients with AS suggest that an active inflammatory process,

probably originating in the subchon-dral bone marrow, precedes new bone formation. As such, early sacro-iliitis is characterized mainly by infil-tration of the synovium, the cartilage and the bone with large number of macrophages, as well as lymphocytes and plasmacytes. Mild osteoblastic activity is already seen at the edges of bone trabeculae at this early stage. More advanced sacroiliitis manifests by osteoclastic resorption of the sub-chondral bone, the ongoing presence of a dense inflammatory infiltrate and appearance of abundant, loose extracellular matrix with many active osteoblasts seen. At a later stage, the sacroiliac joints are filled by granula-tion tissue: with islands of metaplas-tic cartilage, and fibroblasts, chon-drocytes and chondroblasts, some of them hypertrophic and calcified,

present; while osteoblasts synthe-size endochondral bone around vas-cular buds4. This endochondral type of bone formation, with formation of cartilage skeleton which is eventu-ally replaced by bone, has been also shown to be the leading mechanism of the formation of syndesmophytes in patients with AS5. Evidence of membranous type of bone formation, with mesenchymal stem cells differ-entiating directly into osteoblasts, omitting the chondrocyte interme-diate state, has also been seen occa-sionally in patients with AS.

Molecular pathways leading to bone formation in AS have not been elucidated sufficiently. Abnormally active signalling by wingless-type (wnt)-like and bone morphogenic protein (BMP)-mediated pathways have been recently suggested as

Figure 3: Radiogram of the thoracolumbar spine of a pa-tient with AS.Undulating vertebral contour due to extensive syndesmo-phytosis, named ‘bamboo spine’ (black arrows); ankylo-sis of costovertebral junctions (white arrows).

Figure 2: Syndesmophyte formation in a patient with AS.Syndesmophyte formation (ossification within the annulus fibrosus) is seen at the upper anterior vertebral corner of second lumbar vertebrae (arrow).

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major contributors to disease-relat-ed ossification in AS. In the normal bone, BMPs are critical in the trigger-ing of endochondrial bone formation in its early stages, and wnt-related proteins stimulate new bone forma-tion by direct effect on osteoblasts. Studies on animal models of arthri-tis have found that blocking of Dick-koppf-1 (Dkk-1), which is a natural inhibitor of wnt pathway, leads to the formation of osteophytes and ankylosis of sacroiliac joints in tu-mour necrosis factor-a (TNF-a) transgenic mouse model6. Similarly, higher levels of noggin, an inhibitor of BMP signalling, were protective against ankylosis in DBA/1 mice prone to ankylosing enthesopathy7. Additional clinical studies have found some evidence that Dkk-1 is

dysfunctional in AS patients8,9, while reports on correlation of serum lev-els of sclerostin, another inhibitor of wnt pathway, or various proteins of the BMP pathway, with radiographic damage in AS, have not been consist-ent10–13.

The conundrum of bone forma-tion in AS is further complicated by the concurrence of local ossification resulting in the development of syn-desmophytes and ankylosis, on the one hand, and generalized bone loss and osteoporosis, on the other hand, in the same patients (Figure 4)14. These simultaneous phenomena are considered by most authorities to be related, at least partially, to the in-flammation of AS; thus, the specula-tion that osteoporosis may be relat-ed primarily to the systemic effects

of inflammation while bony growth is a function of its local effects seems justified. In this context, the potential local effects of transforming growth factor-β1 (TGF-β1) on AS-related bone formation may be of interest. TGF-β1 was detected in sacroiliac biopsies in patients with advanced AS15, as well as in the synovial fluid of patients with spondyloarthriti-des in increased concentrations as compared with other rheumatic disorders16. The literature suggests that TGF-β1 is heavily involved in the pathogenesis of osteoarthritis17, osteophyte formation18 and ossi-fication of spinal ligaments19, sup-porting the hypothesis that TGF-β1 may be a central cytokine-regulating bone formation in a variety of con-ditions. Convincing evidence for the

Figure 4: Radiogram of cervical spine of a patient with long-standing AS.Extensive syndesmophytosis of cervical spine (arrows) and osteopenia of the vertebral bodies are evident. There is also ankylosis of apophyseal joints and fusion of poste-rior spinal elements (hollow arrows).

Figure 5: Computed tomography of pelvis in a patient with active AS.Sacroiliitis with eroded sacroiliac joint (black arrows) and adjacent osseous sclerosis. Formation of a single bony bridge between iliac and sacral bones can be ob-served (white arrow).

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involvement of TGF-β1 in AS bone formation is, however, still lacking at this point.

The link between inflammation of AS and radiographic disease pro-gression is not linear nor simple, however. While the above noted histological data, as well as experi-ments on the HLA-B27 transgenic animal models20, suggest that in-flammation and bone formation are strongly coupled in AS, more recent data have demonstrated that new bone formation may progress inde-pendently of the inflammatory pro-cess, and may even be accelerated by the resolution of inflammation21. These observations have spawned the proposition of a hypothesis of a disconnect between inflammation and bone formation in AS. Accord-ing to this hypothesis, some aetio-logic trigger simultaneously induces inflammatory reaction and endo-chondral bone formation, but two of these pathways remain uncou-pled during disease development22. MRI-based studies conducted on AS patients treated with anti-TNF-a agents have suggested that early suppression of inflammation may prevent future bone formation, and yet a long-standing inflammatory process, even if eventually effective-ly treated, may proceed, independ-ent of inflammation, to progressive bone formation23.

Clinical aspects of bone formation in ASRadiographic damage in AS is associ-ated with the impairment of spinal mobility and correlates long term with interference in functioning. The clinical measurements of spinal mo-bility, reflecting the structural dam-age in AS patients, are of particular significance in the later stages of the disease, while in the earlier disease, spinal mobility may be more influ-enced by the reversible inflamma-tory process24.

The pattern of spinal damage in AS is unpredictable, with the possibility

of cervical, thoracic or lumbar in-volvement dominant in different persons. Thus, clinical evaluation of spinal mobility in these patients should cover all spinal segments. The measurements of tragus-to-wall, oc-ciput-to-wall distances and cervical rotation can be used for determining limitations of cervical spine mobil-ity; chest expansion measurement allows to detect limitations in move-ment of thoracic spine/costoverte-bral joints, while fingers-to-floor dis-tance, lumbar flexion (Schober test) and lateral lumbar flexion can assess restriction in lumbar spine motion. Maximal inter-malleolar distance is used for the assessment of hip joint involvement.

Of relevance, the rate of new bone formation differs among individuals and is rather slow, with an estimated follow-up duration of at least 2 years necessary to show measurable pro-gression in clinical studies25. Some of the patients with AS will not develop spinal syndesmophytes at all during the disease course. A recent study on 132 patients with established AS showed that only 60% of patients had syndesmophytes at the baseline, and about 50% developed new syn-desmophytes during a 4-year period of follow-up. Of importance, only the presence of existing syndesmophytes was a significant predictor of new bone formation in this study26. Simi-larly, in other studies performed on patients with AS or axial spondyloar-thritis, the presence of pre-existing syndesmophytes has always been found to be the most powerful pre-dictor of future structural damage. Elevated CRP and smoking also seem to drive new syndesmophyte growth in AS patients27. Worthy of note, bone formation occurs faster in males with AS as compared with females. The localization of new syndesmophyte growth may also differ between genders, with females developing more cervical, and males developing predominantly lumbar, syndesmo-phytes28.

The negative long-term conse-quences of bone formation in AS patients reflected in radiographic damage make this an important target for therapeutic intervention. Anti-TNF-a agents, widely used now-adays in the treatment of AS, while highly effective in the alleviation of clinical, laboratory and imaging signs of the inflammatory process related to AS, have failed to prevent or slow the radiographic damage in a series of trials. The only medicines, shown currently to delay the process of bone formation in AS patients, are nonsteroidal anti-inflammatory drugs (NSAIDs), medications tradi-tionally used in AS for many decades. Two studies have demonstrated the dose-dependent efficacy of NSAIDs in slowing syndesmophyte growth in AS patients, purportedly through their anti-prostaglandin action29,30. Physical therapy and intense exercis-ing, while never examined for their propensity to influence the rate of new bone formation in AS, can im-prove spinal mobility and functional status of patients, thus diminishing the negative clinical consequences of structural damage related to bone formation in AS31. Thus, management combining both pharmacological and nonpharmacological approach-es to deal with the long-term conse-quences of AS should be advocated for all patients diagnosed with the disease.

Discussion Beyond amelioration of signs and symptoms of arthritis, disease course modification has become a goal in modern rheumatology in the last decade. The recognized ability of the biologic agents to virtually shut down the process of erosion forma-tion in rheumatoid arthritis (RA) has revolutionized the approach to the management of RA patients, funda-mentally changed the outcomes of their treatment and led to the an-ticipation that a similar approach will result in disease modification

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of other rheumatic disorders, pri-marily AS. The expectation that new bone formation in AS patients will be inhibited by anti-TNF-a medicines, founded on the superb clinical effi-cacy of these medicines with respect to pain and stiffness control, was not confirmed in several 2-year long clin-ical trials. The failure of these biolog-ics to slow radiographic progression of AS has, however, triggered new intense basic research in the field of AS-related bone formation. It has also put to question our ability to recognize, calculate and evaluate the significance of this bone formation in both clinical trials and individual patients. While the recognition of new AS-related ossification is still primarily based on traditional radi-ography, new more sensitive scoring systems, such as mSASSS, have been proposed; and experience in clinical research, learning both the natural history of AS progression and ways to intervene in it, has been gained. Finally, the discoveries in the field gained by basic research open new horizons and inspire hope for fer-reting out the mystery of AS-related bone formation in the near future.

ConclusionBone formation is a hallmark patho-logical feature of AS and the primary cause of long-term disability in these patients. Radiographic features of bone formation in AS are well known, and conventional radiography repre-sents a convenient tool for the meas-urement of disease progression. The pathogenesis of bone formation, as well as its relation to the inflamma-tory process, is poorly understood, but the disease-related breakdown in pathways regulating bone remod-elling may play a role. As the rates and severity of bone formation vary significantly among AS patients, bio-markers for bone formation and pre-diction of structural damage would help to improve and individualize management of patients suffering from AS.

Abbreviations listAS, ankylosing spondylitis; BMP, bone morphogenic protein; CRP, C-reactive protein; NSAID, nonsteroidal anti-in-flammatory drug; RA, rheumatoid ar-thritis; TGF-β1, transforming growth factor-β1; TNF-a, tumour necrosis factor-a; wnt, wingless-type

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Bone formation in ankylosing spondylitis