| Osteoporosis In Rheumatoid Arthritis |

Category: Practitioners

Asgar Ali Kalla – Associate Professor of Medicine. University of Cape Town.

Rheumatoid arthritis (RA) is an inflammatory disease affecting many joints. It is characterised by involvement of the small joints of the hands and feet, but may also affect the large joints. The inflammatory process is related to auto antibodies (rheumatoid factor) in the majority of cases. The cause of RA is unknown but the initiating event is likely to be mediated by an infection. Unfortunately, we have not yet been able to identify a specific virus, bacterium or parasite. It is also clear that the immune system undergoes changes which result in a perpetuation of the inflammatory process, even after the initiating insult is no longer present. The disease is chronic and therapy is lifelong.

The inflammatory process results in the production of cytokines, especially tumour necrosis factor (TNF), which stimulates the osteoclast to resorb bone in excessive amounts. There is secondary damage to cartilage and progressive damage to the joints. The patient may become severely crippled by RA if disease modifying anti-rheumatic drugs (DMARD) are not started early. Numerous non steroidal anti-inflammatory drugs (NSAID) are available for relief of symptoms such as pain and stiffness, but these do not have any effect on the intrinsic damage to the joints. The osteoporosis of RA is usually localised around the affected joints, but it may become generalised and affect the spine and hip, similar to that seen in idiopathic or postmenopausal osteoporosis.

Juxta-articular osteopaenia is one of the earliest radiological features in RA and it often precedes the development of erosions. One of the major limiting factors in the study of osteoporosis has been the difficulty in quantifying bone mass/density. The development of newer techniques for measuring bone mineral density (BMD) has resulted in earlier diagnosis and treatment of a potentially fatal complication of bone loss. The recommended technique is that of dual x-ray absorptiometry (DXA), but quantitative computerised tomography (qCT) scanning, broadband ultrasound attenuation (BUA) and single photon absorptiometry (SPA) have also been used. The World Health Organisation (WHO) has redefined osteoporosis in terms of BMD (measured by DXA) relative to normal young females aged 20-30 years (t-score). Using these definitions, affected individuals are said to have osteopaenia, osteoporosis or severe osteoporosis. Definition of osteoporotic vertebral deformity is also controversial.

The mechanism of the bone loss is thought to be multifactorial and includes a combination of osteoclast activation (cytokine-mediated), physical inactivity due to arthritis and as a complication of corticosteroid (CS) therapy. One of the difficulties in interpreting data from the literature relates to poor control for confounding variables, particularly menopausal status. Another confounder in the ascertainment of pathogenetic mechanisms is the selection of adequate controls for comparison with arthritis sufferers who are functionally independent but who may be severely limited in weight-bearing and sporting activities. The osteoporosis associated with inflammatory diseases such as RA should theoretically be prevented with the use of CS therapy, since CS are potent inhibitors of tumour necrosis factor alpha (TNF) and interleukin 1 (IL-1), both of which are potent stimulants of osteclastic resorption of bone. However, large doses of CS (greater than 10 mg daily) go beyond stimulating the osteoclast and will also inhibit the osteoblast, resulting in a gradual loss of bone.

In RA, the absence of osteopaenia in the hand should lead away from the diagnosis. There is some contention whether RA causes generalised osteoporosis. The confounding effects of corticosteroid (CS) therapy and the menopause further complicates this debate. An additional confounder in the evaluation of osteoporosis in RA is the absence of a linear relationship between lack of physical activity and bone loss. There is also controversy about the relative contributions of inflammation and disability in the pathogenesis of generalised bone loss in RA.

Studies have shown localised and generalised bone loss in RA. Some workers have also shown generalised loss in premenopausal RA patients not receiving CS, confirming that bone loss is likely to occur independently of these two variables. Different sites seem to have different degrees of bone loss, so that bone loss in the hand is greater than loss at the femur, where the loss is greater than at the lumbar spine. It would seem that bone loss at the femur is associated with disability or inflammation, while bone loss at the lumbar spine is strongly correlated with CS therapy. It has also been shown that osteoporosis in RA is complicated by fractures and it seems that CS may contribute to this increased tendency to fracture in RA.

Early synovitis clinics, where patients with RA are seen within 6-12 months of the onset of disease, suggest that bone loss is an early feature of RA, especially in the hands. It has been proposed that hand BMD measurement would be a useful adjunct in deciding about starting DMARD therapy in a patient with early RA. In addition, metacarpal BMD measurement can be used in monitoring the effects of DMARD therapy. Erosions in RA are generally irreversible, while osteoporosis is a dynamic process in RA and is positively influenced by different forms of treatment. One recent report, though, has suggested that CS therapy may modify progression of erosions in RA.

Prophylactic therapy known to improve BMD in idiopathic (postmenopausal) osteoporosis is mandatory in the presence of an underlying rheumatic disease. Further studies are needed to elucidate the mechanisms of bone loss in the different rheumatic diseases. Longitudinal studies of BMD combined with radiology for detecting asymptomatic fractures (especially vertebral) are needed to accurately define the incidence of osteoporosis and fractures in the different rheumatic diseases.

Hormonal factors are clearly important as well. Numerous studies have shown that RA patients have lower levels of androgenic hormones and there is evidence that this may contribute to the osteoporosis of RA. Patients with RA may develop the disease in the 3rd to 5th decades and will continue to have the disease into the menopause. This further reduction in the availability of oestrogens (particularly in females) tends to increase bone loss and hormone (oestrogen) replacement therapy (HRT) is mandatory in the RA patient who is postmenopausal. While RA is known to improve during pregnancy, the use of oral contraceptives has not been shown to reduce the risk of RA in large epidemiological studies.

Several workers have studied whether HRT can be used to alleviate the symptoms of RA. There is no clear evidence of that disease activity is less in users than non-users, although users tend to have significant improvement in articular index and pain, compared to patients taking placebo. The effect of HRT on bone mineral density in RA patients was compared with that of calcium supplementation (400 mg daily) in a study lasting 2 years. In the HRT group, spine BMD increased by +2.2% and femur BMD decreased by –0.4%. In women taking only calcium, the corresponding changes were –1.2% and –0.6%. Thus, HRT appears to have a greater effect on BMD at the spine than the femur and is also effective in RA patients taking corticosteroids.

The many disadvantages of oestrogens have led to the development of a group of agents called selective oestrogen receptor modulators (SERM). These agents display the oestrogen-agonist effects on bone, lipids and clotting, but have oestrogen-antagonistic effects on the breast and uterus. Raloxifene is one such agent which has been shown to have a positive effect on BMD in postmenopausal females. It decreases serum LDL cholesterol concentration, does not stimulate endometrial growth and may decrease the risk of breast cancer. Raloxifine cannot, however, be used to treat postmenopausal symptoms. Unfortunately, there are no studies reporting the use of the agents in patients with RA.

Bisphosphonates are another group of agents that have been developed for the prevention and treatment of osteoporosis. They have been used extensively in the patient with postmenopausal osteoporosis, with positive increases in BMD as well as a concomitant decrease in fractures. Studies have been performed with Alendronate and Residronate and both have been shown to be effective. While Alendronate has to be taken on an empty stomach and the upright posture to prevent oesophageal irritation, Residronate seems not to have the same effect on the gastrointestinal tract. These agents have also been used successfully to treat corticosteroid-induced osteoporosis with good effect. They are an important addition to the armamentarium for treating osteoporosis in rheumatoid arthritis.

Physical activity should be encouraged in patients with RA, since lack of exercise will worsen the bone loss related to inflammation and hormone deficiency. Weight-bearing exercises are clearly important, but patients should be careful not to injure themselves. Exercise helps to maintain muscle tone and strength, which indirectly impact on the outcome following joint replacement surgery at the knee or hip in these patients. This may also allow patients to be more steady on their feet and help in preventing falls, which could result in fracture of the brittle bones.

SUMMARY

Osteoporosis is an important complication in RA and may be due to several mechanisms. The most important factor is the presence of inflammation and the production of cytokines, but hormone deficiencies also contribute significantly to the bone loss. Corticosteroid therapy should be maintained at doses less than 7.5 mg daily and if patients require larger doses, one should preferably consider increasing the use of DMARD therapy. Physical activity should be encouraged as much as possible, but may be limited due to severe joint disease. Hormone replacement therapy is mandatory in postmenopausal females with RA. In situations where HRT is poorly tolerated, the new group of SERMs may be a useful alternative. Bisphosphonates have also been used in RA and are particularly effective in patients taking long-term corticosteroids for control of RA. General measures used in patients with postmenopausal osteoporosis are important in patients with RA, as well.

Published on 2005-06-08