Endocrinology Metabolism

Ankylosing Spondylitis and Osteoporosis

Are You Sure the Patient Has Ankylosing Spondylitis and Osteoporosis?

Ankylosing spondylitis (AS) is a chronic inflammatory disorder that primarily affects the axial skeleton and inflammation at sites of bony insertions for tendons and ligaments (enthesitis). It is associated with a strong genetic predisposition with HLA-B27. Extra-skeletal involvement can include: uveitis, aortitis (rare), conduction rhythm abnormalities, pulmonary involvement (interstitial and restrictive lung disease), cauda equina syndrome, and amyloidosis.

Clinical presentation is most often encountered in men in their 40s whose spines have stiffened as a result of AS, either without symptoms or symptoms so remote in a patient's life that it has been forgotten until brought to light by direct history questioning. The pains originate from an area of the spine where there is still some movement, the spine above and below being rigid. The most common complaints are in the lower dorsal and upper lumbar regions; referred pains from these levels may simulate renal, pancreatic or gastrointestinal disease.

There are other disorders in which there is limitation of back movement. Senile ankylosing hyperostosis is a not uncommon condition usually found incidentally on lateral radiographs of elderly people; a thick sheet of new bone is seen running down the anterolateral aspects of the vertebral bodies and disc spaces usually to the right of the mid-line. In vitamin-D resistant rickets, there may be severe limitation of spinal movements with bridging of the disc spaces very similar to that in ankylosing spondylitis together with sclerosis of the apophyseal joints and new bone formation on the articular processes and around the pelvis.

Ossification of the ligaments may also result in bridging of the upper parts of the sacro-iliac joints but in there is no erosion of the joint margins and the lower parts of the joints remain normal. In alkaptonuria, the sacro-iliac joints may be abnormal and the spine limited in movement, but the characteristic appearance of wafer-like calcification in the collapsed discs differentiates this condition from AS.

In the approximately 15% of AS patients who present initially with arthritis in the limbs there may be much greater difficulty in diagnosis. In the majority of these patients the involvement is of the large joints, and often of only one joint, such as the knee or hip, and the possibility of infectious or crystalline arthritis then arises. The differential diagnosis between spondylitic and infectious joint involvement is important since there is a serious danger of rapid and severe loss of mobility in spondylitic joints which are immobilized, and in joint destruction in septic arthritis.

The condition most often confused with AS is reactive arthritis. The latter diagnosis is usually made from the co-occurrence of the other features of the syndrome, particularly the onset of arthritis in relation to an attack of urethritis or dysentery, and that the peripheral joints are almost invariably involved in the arthritis.

What Else Could the Patient Have?

The sacroiliitis associated with ankylosing spondylitis should be differentiated from sacroiliitis caused by other diseases. Bilateral, symmetrical sacroiliac joint disease may be found in conditions such as psoriasis, Reiter disease, enteropathic arthropathy, hyperparathyroidism, and osteitis condensans ilii. Rarely, atypical chest pain may be the presenting symptom of AS, most often arising from painful involvement of the costovertebral joints, but sometimes of the manubriosternal joint or focal tender areas on the rib cage. The symptoms may superficially simulate pleurisy.

Sometimes a picture resembling angina can be produced. In these cases the clues in the history is usually exacerbation of chest pain in the morning. Diagnosis can also be confirmed by reproducing the pain by compressing the affected joints.

Key Laboratory and Imaging Tests

There is a strong genetic predisposition of HLA-B27 in AS, however HLA B27 is also a perfectly normal gene found in 8% of the caucasian population. Generally speaking, no more than 2% of people born with this gene will eventually get spondylitis.

In addition, it is important to note that the HLA-B27 test is not a diagnostic test for AS and the association between AS and HLA-B27 varies in different ethnic and racial groups. It can be a very strong indicator in that over 95% of people in the caucasian population who have AS test HLA-B27 positive. However, only 50% of African American patients with AS possess HLA-B27, and it is close to 80% among AS patients from Mediterranean countries.

Since there is no single blood test for AS, laboratory work may not be of help in the diagnosis. An elevated sedimentation rate is seen in less than 70% of people with AS.

Plain x-rays are the single most important imaging technique for the detection, diagnosis, and follow-up monitoring of patients with ankylosing spondylitis. Overall bony morphology and subtle calcifications and ossifications may be demonstrated well radiographically. The diagnosis may be reliably made if the typical radiographic features of ankylosing spondylitis are identified, however plain radiographs are limited in detecting early sacroiliitis and in demonstrating subtle changes in the posterior elements of the vertebrae.

Computed tomography (CT) scanning is useful in selected situations (eg, in equivocal cases of sacroiliitis and in cases in which subtle radiographic changes are present) and in the evaluation of complications. One caveat is that normal variations of the sacroiliac joints may simulate the findings of inflammation. Magnetic resonance imaging (MRI) is useful in assessing early cartilage abnormalities and bone marrow edema; MRI is limited by its relatively poor ability to detect calcification, ossification, and cortical bony changes.

Radiographically, the earliest sign of sacroiliitis is indistinctness of the sacroiliac joints; they initially widen before they narrow. Subchondral bony erosions on the iliac side of the joint are seen; these are followed by subchondral sclerosis and bony proliferation. With eventual bony fusion the sclerosis resolves, and at the end stage, the sacroiliac joint may be seen as a thin, dense line, or it may not be visible at all.

Sacroiliitis typically is symmetrical, although it may be asymmetrical in the early stages of the disease.

In the spine, the early stages of spondylitis are manifested as small erosions at the corners of the vertebral bodies. The areas are surrounded by reactive sclerosis and have been termed the shiny corner sign, or Romanus sign.

Squaring of the vertebral body is another characteristic feature of ankylosing spondylitis; it is caused by a combination of corner erosions and periosteal new bone formation along the anterior aspect of the vertebral body. This is best seen in the lumbar spine, in which the anterior cortex of the vertebral body normally is concave.

Enthesopathy is seen radiographically as ill-defined erosions with adjacent sclerosis at the sites of ligamentous and tendinous attachments. With healing, sclerosis decreases and new bone proliferation occurs. Lesions typically are bilateral and symmetrical in distribution. Enthesopathic changes are particularly prominent at certain sites around the pelvis, such as the ischial tuberosity, iliac crest and femoral trochanter.

Other Tests That May Prove Helpful Diagnostically

There is no association with ankylosing spondylitis and rheumatoid factor and antinuclear antibodies.

Management and Treatment of the Disease

Treatment for the inflammatory and pain component of AS includes nonsteroidal anti-inflammatories and cyclooxygenase-2 selective inhibitors as first-line therapy, and anti-TNF treatment should be offered to all patients with high disease (etanercept, infliximab, and adalimumab are all FDA approved for AS). Spinal osteoporosis is frequently observed and increases with patient age and disease duration as spinal immobility worsens. Reid et al showed that men with AS lose bone at a rate of 2.2% annually with a 2.9% annual loss of total body calcium, compared with an annual loss of only 0.7% of total body calcium in men without AS over the age of 50 years.

Both increased severity of AS and bone loss is more common in males. More osteoporosis is also seen in patients with syndesmophytes, cervical fusion, and peripheral joint involvement. Caution must be used in interpreting lumbar bone density in patients with syndesmophytes, as the extra bone may falsely elevate bone density readings. Although bone loss increases with disease duration the risk of vertebral compression fractures increase significantly within the first five years of diagnosis. As seen in other rheumatic diseases, cytokines such as TNF-alpha and IL-6 may play an important role in the pathogenesis of bone loss in early AS; the same proinflammatory cytokines have been found to be higher in AS patients than in subjects with noninflammatory back pain.

The risk of a vertebral fracture occurring after a thirty year period in AS patients is 14%, compared to 3.4% of controls. There is a higher incidence of spinal cord injury following spinal fracture in patients with AS. The ankylosed spine may break like a long bone with a transverse fracture line. It is often more transdiscal (is across syndesmophytes) than transvertebral. The rigidity of the spine increases fracture risk even after relatively minor trauma and may even be asymptomatic.

In late AS the extraspinal bone may divert compressive and motional support away from the vertebral trabeculae resulting in diminished trabecular density. An aseptic spondylodiscitis, mostly in the midthoracic spine, can occur without trauma and is usually asymptomatic; it is relatively more common in those in whom spondylitis also involves the cervical spine. Fractures in a severely ankylosed spine can be difficult to see on plain x-ray and may need bone scan and/or MRI for diagnosis. The most severe AS complication is fracture of the cervical spine, usually at the C5-6 or C6-7 level, which may result in quadriplegia.

Treatment of osteoporosis in AS is limited to bisphosphonates, in fact pamidronate has shown some mild clinical and radiological improvement in AS patients through MRI studies of inflammatory lesions, although it was transient.

Given the male predominance and relatively young age of the patients there is a limited role for hormone replacement therapy.

What’s the Evidence?/References

Jacobson, JA. "Radiographic evaluation of arthritis: inflammatory conditions". Radiology. Aug. vol. 248. 2008. pp. 378-89.

(A good review of how to recognize arthritis on plain x-rays (joint erosions, osteopenia, joint space narrowing) and how to differentiate infection, versus, degenerative, versus, inflammatory arthritis by x-ray alone.)

Karasick, D. "Fractures of the vertebrae with spinal cord injuries in patients with ankylosing spondylitis: imaging findings". AJR Am J Roentgenol. Nov. vol. 165. 1995. pp. 1205-8.

(A very important review of how spinal ankylosis affects biomechanics of the spine, predisposing AS patients to fracture, with illustrative examples of different radiologic images.)

Toussirot, E. "Antinflammatory treatment with bisphosphonates in ankylosing spondylitis". Curr Opin Rheumatol. vol. 19. 2007. pp. 340-5.

(A review of both the anti-osteoclastic and anti- inflammatory properties of bisphosphonates and how the latter property can potentially ameliorate AS by modulating pro-inflammatory cytokines.)

Gratacos, J. "Significant loss of bone mass in patients with early, active ankylosing spondylitis: a follow up study". Arthritis Rheum. vol. 42. 1999. pp. 2319-2324.

(An analysis of how inflammatory activity affects early bone loss in AS.)

Reid, DM. "Bone mass in ankylosing spondylitis". J Rheumatol. vol. 13. 1986. pp. 932-935.

(An assessment of total body calcium and bone turnover in AS patients.)
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