Rheumatoid arthritis is a chronic disease characterized by inflammation of the synovium of the joints. In a later stage, there is a rapid division and growth of cells, or pannus, which causes the synovium to thicken. The inflamed cells release enzymes that may digest bone and cartilage, leading to structural changes such as joint space narrowing and bone erosions. This process often causes an involved joint to lose its shape and alignment and is accompanied by more pain and decreased range of motion. Over time, the disease can lead to long-term joint damage, chronic pain, loss of function, and disability.¹

Prevalence and Impact

Rheumatoid arthritis affects an estimated 0.5% to 1% of the population worldwide. ² Onset usually occurs between the ages of 30 and 50. The disease affects 2 to 3 times as many women as men up until age 65, after which point the ratio of women and men affected is approximately the same. ^2,3

Rheumatoid arthritis shortens survival and significantly impacts quality of life in most affected patients. ² Daily joint pain is an inevitable consequence of the disease. ⁴ From an economic standpoint, the cost of the medical and surgical treatment for rheumatoid arthritis and the wages lost because of disability caused by the disease add up to billions of dollars annually. ⁴

Current Treatments and Guidelines

Bone erosions are a nearly universal sequela of rheumatoid arthritis. A recent radiologic study of 181 patients initially diagnosed with early rheumatoid arthritis (<1 year) found that 49% had bone erosions after 1 year, 90% after 2 years, and 96% after 10 years following diagnosis. ⁵ Biologic agents (drugs such as etanercept, infliximab and adalimumab, which target specific cytokines that play a role in inflammation) are used to help slow or stop the progression of joint damage and erosions from rheumatoid arthritis.

Depending on the country, glucocorticoids are often prescribed for the treatment of rheumatoid arthritis, which can trigger significant bone loss. (See Treatment-induced Bone Loss.)  According to the American College of Rheumatology, the benefits of systemic glucocorticoids should be weighed against their adverse effects. Potential adverse effects should be discussed in detail with the patient before glucocorticoid therapy is begun. For long-term disease control, the glucocorticoid dosage should be kept to a minimum. For the majority of patients with rheumatoid arthritis being treated with glucocorticoids, this means 10 mg of prednisone per day. ⁶

Glucocorticoid use has been associated with bone loss in patients who do not have rheumatoid arthritis. Rheumatoid arthritis is associated with an increased risk of osteoporosis independently of glucocorticoid therapy. Patients taking glucocorticoids at dosages as low as 5 mg/day should have a densitometry to assess bone loss at regular intervals for the duration of glucocorticoid treatment. Glucocorticoid-treated patients should receive 1500 mg of elemental calcium per day (including diet and supplements) and 400 to 800 IU of vitamin D per day. Antiresorptive agents may also be used at the time glucocorticoid therapy is initiated to help prevent bone loss. ⁶

Role of RANKL in Rheumatoid Arthritis

The receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone erosions in rheumatoid arthritis. Levels of RANKL are significantly elevated within the inflamed synovium by activated T cells and synoviocytes. ^7,8 Cytokines differentially regulate RANKL and OPG, thereby favoring bone resorption via excess RANKL activity. ^7,8

In preclinical studies of arthritis, increased RANKL was found to lead to focal osteolytic lesions and significant bone loss. Inhibition of RANKL helped to prevent the loss of bone mineral density in adjuvant arthritis. ^9,10 In addition, RANKL inhibition prevented cartilage destruction in rats. ⁸

Both local and systemic levels of RANKL protein were also found to increase during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might play a key role in bone erosions and systemic osteopenia in this condition. ⁹ RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition may be a promising new approach for treating bone loss and bone erosions in arthritis. ⁹

References

1. Harris ED. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Saunders; 2005: 996.
2. Goldman L. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: WB Saunders; 2004:1644-1646.
3. Grassi W, De Angelis R, Lamanna G, et al. Eur J Radiol. 1998:27(suppl 1):S18-S24.
4. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Rheumatoid arthritis: handout on health. May 2004: publication no. 04-4179.
5. Lindqvist E, Jonsson K, Saxne T, et al. Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis. Ann Rheum Dis. 2003;62:611-616.
6. American College of Rheumatology. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum. 2001;44(7):1496-1503.
7. Amgen, data on file.
8. Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteroprotegerin ligand. Nature. 1999;402:304-309.
9. Stolina M, et al. RANKL is a marker and mediator of local and systemic bone loss. J Bone Miner Res. 2005;20:1756-1765.
10. Campagnuolo G, Bolon B, Feige U. Kinetics of bone protection by recombinant osteoprotegerin therapy in Lewis rats with adjuvant arthritis. Arthritis Rheum. 2002;46:1926-1936.