Bone involvement in ankylosing spondylitis / E. Toussirot & D. Wendling mass in ankylosing spondylitis

E. Toussirot, D. Wendling

Department of Rheumatology, University ABSTRACT tures and the presence of low bone mass Hospital J. Minjoz, Boulevard A. Fleming, Specific spine ossifications or syndes- in AS. F-25030 Besançon Cédex, France. E-mail: mophytes are considered to be a hall- In 1877, Fagge described for the first [email protected] mark of ankylosing spondylitis (AS) and time bone fragility during an autopsy of Eric Toussirot, MD, PhD (to whom to reflect a process of bone formation. a patient with AS (1). Osteoporosis was correspondence should be addressed); Conversely, AS patients may develop os- then described as a clinical feature of Daniel Wendling, MD, PhD. teoporosis (OP), as suggested by radio- longstanding AS or conversely, as a pri- Clin Exp Rheumatol 2000; 18 (Suppl. 21): graphic studies, an increased frequency mary event of the disease (2). Further S16-S20. of the vertebral fracture rate and reduced reports claimed that this bone involve- © Copyright CLINICAL AND bone mass. Dual energy X-ray absorp- ment could have clinical consequences EXPERIMENTAL RHEUMATOLOGY 2000. tiometry measurements have clearly de- such as fractures and contributes to spi- monstrated decreased bone mineral den- nal deformity of AS patients. Key words: Bone mineral density, sity (BMD) at both the lumbar spine and This review focuses on bone mass and ankylosing spondylitis, DEXA, femoral neck. However, for patients with results of biochemical markers of bone fractures. advanced spinal changes, ossifications turnover in AS. may yield normal or increased values for the lumbar spine BMD. Assessment of Radiological data and frequency of biochemical markers of bone metabolism vertebral fractures in ankylosing have shown that both bone formation spondylitis and resorption are involved, with en- In 1971, a radiographic study performed hanced urinary excretion of markers of by Hanson et al. found moderate to se- collagen breakdown in patients with ac- vere OP in 29/50 patients (3). Only two tive disease and raised inflammatory vertebral crush fractures were observed parameters, and changes in the levels of and the patients had no fractures in the some bone growth factors. The patho- peripheral . Spencer et al. then re- physiology of this osteoporosis in AS ported similar findings with the presence mainly involves disease activity and, very of radiological OP in 30.5% patients (4). likely, inflammatory cytokines. Finally, In these studies, OP strongly correlated vertebral fractures complicating this with disease duration, patient age and bone loss contribute to spine deformity older age at onset. In the same way, a in patients with AS. relationship between axial skeleton OP and the presence of syndesmophytes and/ Introduction or discitis or Romanus lesions was ob- Ankylosing spondylitis (AS) is an in- served in most patients (4). These stud- flammatory rheumatic disease character- ies concluded that OP is a late compli- ized by inflammation of the entheses in cating feature of AS with mild fracture the axial and peripheral skeleton and af- prevalence. fects mainly young male patients. Typi- Morphometric methods for assessing cal clinical features include sacroiliac vertebral fractures were then used and joint pain and backache and progressive- the prevalence of such fractures was eva- ly, the patients could develop a dorsal luated to be 18% (5): in this controlled kyphosis. Specific spine ossifications or study, patients with fractures had increas- syndesmophytes are considered to be a ed formation of syndesmophytes and a hallmark of the disease, reflecting a proc- greater degree of spinal deformity and ess of bone formation. In contrast, AS spine rigidity as evaluated by the Schö- patients may developed osteoporosis ber test, chest expansion, and distance (OP), leading in some cases to fractures. from wall to tragus (5). Additional re- Classically, OP is considered to be a late cent studies have evaluated the preva- and negligible feature of AS. However, lence of vertebral fractures in AS to be

a growing number of studies have re- in the range of 10.3 - 16.7% (6, 7). Surpri- ported an increased frequency of frac- singly, a higher frequency for vertebral

S-16 -pituitary-adrenocortical and -gonadal axis in BoneRA / M.involvement Cutolo in ankylosing spondylitis / E. Toussirot EDITORIAL& D. Wendling fracture (40.9%) was found in a Turkish spine rigidity and also from mechanical nal ossifications, lumbar spine BMD was study (8). In these studies, the common- factors. In this respect, they could be found to be normal or increased. In one est fracture site was the thoracic spine. compared to stress fractures. study, DEXA measurements in both the Ankylosing spondilitis patients with lateral and postero-anterior projections fractures were significantly older, had Bone mass measurements in of the lumbar spine were performed and longer disease duration and more ad- ankylosing spondylitis the lateral projection of L3 was found to vanced spinal limitation with less mo- All of the different methods which are be a more sensitive indicator of the ver- bility (6). The recent study by Mitra et currently available for evaluating bone tebral BMD compared to the postero-an- al. found that vertebral fractures were mass have been used in AS: single and terior projection (16). Most of these stud- also a feature of AS with a mild disease dual photon absorptiometry (SPA and ies included a controlled population and duration (mean duration: 9.8 years) and DPA, respectively), dual energy X-ray the WHO criteria for osteoporosis were without advanced spinal changes (7). absorptiometry (DEXA), quantitative used in some cases, revealing that AS Finally, an epidemiological survey by the computed tomography (QCT) and more patients had osteopenia more frequently Mayo Clinic found that AS patients had recently, quantitative ultrasound tech- (T score: -1 SD to -2.5 SD) and oste- higher risk for vertebral fracture (OR: niques (QUS). oporosis more rarely (T score < -2.5 SD)

7.6; CI: 4.3 - 12.6) while there was no (17, 18). However, some of these results increase in the risk for fracture in the Dual photon absorptiometry and dual should be regarded with caution since the limbs (9). Table I lists the different stud- energy X-ray absorptiometry patients included had psoriasis, inflam- ies evaluating the vertebral fracture rate There are 13 studies in the current lit- matory bowel disease or reactive arthri- in AS. erature that examined bone mass in AS tis and not primary AS (6, 17). Table II

Apart from vertebral crush fractures, by DPA and/or DEXA (5-8, 12-20). shows the results of different studies of spinal fractures which may pass through Taken together, the results were similar bone mass measurements using DPA or the vertebra (transvertebral) or through and decreased values for bone mineral DEXA. the disk (transdiscal) may occur in AS density (BMD) at the femoral neck were Recently, total body measurements were (10). They mainly affect the cervical re- found. The lumbar spine BMD has also performed in AS using DEXA and it was gion after minor trauma and are difficult been found to be reduced in patients with found that patients with OP had a lower to diagnose and manage (11). It is be- early or mild disease without advanced body mass index and fat mass percent- lieved that these fractures result in part spinal changes. Conversely, when the age (17). We also performed total body from the ankylosing process inducing patients had advanced disease with spi- measurements in a series of 57AS pa- tients and found a decreased total BMD. However, no lean and/or fat mass in- Table I. Prevalence of vertebral fractures in ankylosing spondylitis. volvement was evident in our series (20). Author Number of patients Mean age (years) Frequency of (ref.) and controls Sex ratio (M/ F) vertebral fractures Single photon absorptiometry Mean disease dur. (yrs.) (%) Two studies have evaluated the BMD at the radius. No difference between AS Hanson (3) 50 range: 29-75 2/50 (4%) and controls was found (5, 14) no controls 40/10 ND Quantitative computed tomography Ralston (5) 111 41 20/111 (18%) There was only one study evaluating 30 controls 98 /13 lumbar spine BMD using QCT. Quanti- 17 tative computed tomography values were Donnelly (6) 87 44 9/87 (10.3%) found to be lower compared to controls. Controls: population of 62/25 (Controls: 1.9%) Moreover, the QCT measurements were 1035 women 16 compared to those with DPA and the Mitra (7) 66 37.8 11/66 (16.7%) QCT values were in general lower than 39 controls 66/0 (Controls: 2.6%) the DPA values. Additionally, atrophy of 9.8 OR: 5.92; CI: 1.4-23.8 the posterior spinal muscles was also ob- served (14). Sivri (8) 22 36.8 9/22 (40.9%) no controls 20/2 9.8 Quantitative ultrasound measurements Only one study, performed by our group, Cooper (9) 158 33.8 15/158 (9.5%) has evaluated bone mass in a series of Controls: local population 121/37 (Controls 3.4%) corresponding to 2398 ND OR: 7.6; CI: 4.3-12.6 57 AS patients and 60 healthy controls person-years of observation using this new technique. However, QUS measurements (broadband ultrasound M: male; F: female; OR: odds ratio; CI: confidence interval; ND: not done. attenuation, speed of sound and stiffness)

S-17 Bone involvement in ankylosing spondylitis / E. Toussirot & D. Wendling

S-18 Hypothalamus-pituitary-adrenocortical and -gonadal axis in BoneRA / M.involvement Cutolo in ankylosing spondylitis / E. Toussirot EDITORIAL& D. Wendling did not differ between patients and con- rate of bone formation (22). This de- even in the early stage of the disease (7, trols. Conversely, in this study AS pa- creased serum OC concentration was not 13). Although the consequences of this tients had decreased BMD values (in- confirmed in other studies (16, 21, 26). bone fragility, i.e. fractures, mainly in- cluding the lumbar spine, femur [neck, Apart from OC, serum markers of bone volve the spine, both the axial and pe- Ward's triangle and trochanter] and total formation were evaluated in AS, includ- ripheral skeleton showed decreased val- body) as evalutated by DEXA (20). ing alkaline phosphatase and its specific ues in DEXA (20). Spine fractures are isoenzyme, bone alkaline phosphatase generally observed after minor trauma Other methods (BAP). Higher serum levels of BAP were and therefore low bone mass is not the Finally, Reid et al. evaluated total body found in one study (25) while there were only factor contributing to the patho- calcium by in vivo neutron activation in normal levels in two others (16, 23). genesis of these fractures. In addition, AS. Mean total body calcium was reduc- Bone growth factors such as bone pro- the vertebral fractures in AS may go un- ed by 5.3% compared with controls (12). moting factors have also been evaluated recognized and be attributed to exacer- in AS patients and decreased serum lev- bations of the disease. Moreover, com- Biochemical markers of bone els of -like binding pression fractures contribute to spine formation and resorption protein-3 (IGFBP-3) were found in our deformity (5). The serum markers of bone turnover, own series of AS patients, suggesting an Different factors could explain this bone including serum calcaemia and phospho- involvement of the insulin-like growth loss in AS: rus, calcium regulating (PTH, factor-I (IGF-I)/IGFBP-3 axis (27). Con- 1. A reduced range of movement sec- 25 OH D3) were found to be normal in versely, serum concentrations of TGFb1, ondary to spine ossifications. However, AS (21). A trend for increased urinary another bone growth factor involved in bone loss is observed in patients with a excretion of calcium has been reported, bone formation, did not differ between short disease duration and without ad- but was not further confirmed (21, 22). AS and controls, suggesting that this vanced spine changes (7, 13). The fasting urinary calcium/creatinine growth factor does not play an impor- 2. Treatments may in part play a role. ratio was normal in the study by Will et tant role in the bone loss of this disease Corticosteroids are rarely used in AS and al. (13). More recent studies have evalu- (28). it has been proposed that non-steroidal ated the urinary excretion of new mark- antiinflammatory drugs (NSAIDs) could ers of bone resorption, i.e. markers of Histomorphometric studies induce bone loss in animals (30). How- collagen breakdown: pyridinoline, de- There is little data on the bone histology ever, data supporting the contribution of oxypyridinoline and also fragments of C- and histomorphometric changes in the NSAIDs in OP are still lacking. telopeptide of the a 1 chain of type I col- bone of patients with AS. Hanson et al. 3. A hormonal disorder has also been lagen or b-CTX (16, 17, 23-26). In gen- performed histomorphometric analyses suggested and reduced levels eral, the urinary levels of these markers on rib biopsies and showed decreased have been reported in some studies (31, of collagen breakdown were found to be cortical thickness and retarded bone for- 32), but were not further confirmed (33). normal except in patients with high lev- mation (3). No information about can- In addition, no significant correlation be- els of inflammatory activity (26). In fact, cellous bone was available. In another tween sex hormones, BMD, and verte- a good or strong correlation was found study, 16 white males with AS underwent bral fractures were found in male AS between these markers of bone resorp- bone biopsy to evaluate histomorphome- patients (33). tion and indices of disease activity (the tric variables. Osteopenia, mineralization 4. Finally, the most likely explanation erythrocyte sedimentation rate [ESR] defects and osteomalacia were found, for OP in AS is disease activity. Indeed, and acute phase reactants). In a 19-month while bone resorption variables were bone turnover as evaluated by markers follow-up study, Gratacos et al. clearly similar to those obtained in controls. Ad- of collagen breakdown correlated nega- demonstrated the relationship between ditionally, dynamic variables showed a tively with disease activity and inflam- the loss of BMD and disease activity as decreased mineral apposition rate and a mation parameters (ESR, CRP) (26). Pre- evaluated by acute phase reactants and relationship between disease duration sumably, inflammatory cytokines such the serum level of inflammatory cyto- and osteoid volumes, while surface ero- as interleukin-6, but also interleukin-1 kines (interleukin-6) (19). Conversely, sions correlated negatively with the dis- and TNFa, play an important role (19). the biochemical markers of bone resorp- ease duration. These data suggest the pre- It is also likely that bone growth factor tion did not correlate with the spine and sence of mineralization defects and a de- (IGF-I and its binding proteins) is related femoral neck BMD, and this could be pression in bone formation, contrasting to the inflammatory process (27). All of explained by the fact that BMD is a lon- with normal bone resorption indices (29). this data supports the hypothesis of a re- gitudinal variable while markers of bone However, the status of circulating vita- lationship between inflammation mark- resorption or formation are transverse min D was not given in this study. ers and bone metabolism and therefore, variables (19, 26). skeletal bone loss. Serum markers of bone formation in- Pathophysiology of bone impairment clude (OC). In one study, se- in ankylosing spondylitis Treatment rum OC was significantly reduced in AS Thus, OP seems to be a common clini- No specific treatment is available for AS compared to controls, suggesting a low cal feature in AS and may be observed osteoporosis. Bisphosphonates could be

S-19 Bone involvement in ankylosing spondylitis / E. Toussirot & D. Wendling used as these drugs have been found to AJ: The prevalence of vertebral fractures in losing spondylitis. Ann Rheum Dis 1993; 52: be effective in AS. Etidronate was ad- mild ankylosing spondylitis and their relation- 343-6. ministered in a controlled (but unpub- ship to bone mineral density. Rheumatology, 23. MARHOFFER W, STRACKE H, MASOUD I et al.: 2000; 39: 85-9. Evidence of impaired cartilage/bone turnover lished) study, and resulted in improve- 8. SIVRI A, KILLINC S, GÖKCE-KUTSAL Y, ARI- in patients with ankylosing spondylitis. Ann ment in pain, morning stiffness, and also YÜREK M: Bone mineral density in ankylosing Rheum Dis 1995; 54: 556-9. BMD (34). Pamidronate was given in an spondylitis. Clin Rheumatol 1996; 15: 51-4. 24. MACDONALD AG, BIRKINSHAW G, DURHAM open study and a significant improve- 9. COOPER C, CARBONE L, MICHET CJ, ATKIN- B, BUCKNALL RC, FRASER WD: Biochemical SON E, O’FALLON WM, MELTON LJ: Fracture markers of bone turnover in seronegative spon- ment in disease activity (assessed by risk in patients with ankylosing spondylitis: A dylarthropathy: Relationship to disease activ- clinical indexes) and ESR after 6 month- population based study. J Rheumatol 1994; 21: ity. Br J Rheumatol 1997; 36: 50-3. ly infusions was observed (35). How- 1877-82. 25. MITRA D, ELVINS DM, COLLINS AJ: Bio- ever, the use of bisphophonates in AS 10. THORNGREN KG, LIEDBERG E, ASPELIN P: chemical markers of bone metabolism in mild Fractures of the thoracic and lumbar spine in ankylosing spondylitis and their relationship deserves further longitudinal and con- ankylosing spondylitis. Arch Orthop Traumat with bone mineral density and vertebral frac- trolled studies. Surg 1981; 98: 101-7. tures. J Rheumatol 1999; 26: 2201-4. 11. HUNTER T, DUBO HIC: Spinal fractures com- 26. 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