CHANGES OF CLINICAL AND RADIOGRAPHIC PARAMETERS DURING DENOSUMAB THERAPY IN RHEUMATOID ARTHRITIS PATIENTS RECEIVING GLUCOCORTICOIDS: PRELIMINARY RESULTS

When treating rheumatoid arthritis (RA), it is important not only to suppress inflammation, but also to prevent local and generalized bone loss, particularly in patients receiving glucocorticoids (GC). Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor kappa B ligand (RANKL), prevents its interaction with receptor on osteoclasts, reduces their activity, and inhibits bone resorption.

Objective: to evaluate the effect of 12-month therapy with denosumab on bone mineral density (BMD) of the axial
and peripheral skeleton and destructive changes in the hand and foot joints of RA patients receiving GC.
Subjects and methods. Fifty-two postmenopausal women with RA concurrent with osteoporosis received subcutaneous denosumab 60 mg twice: at baseline and 6 months later. BMD was measured before drug administration and after 12 months of a follow-up, by applying dual-energy X-ray absorptiometry of three sections: the lumbar spine (LI–IV), femoral neck (FN), and distal forearm (DF). Radiographic changes in the hand and foot joints were assessed using the Sharp method modified by van der Heijde (SVH) at baseline and 12 months later.

Results and discussion. The patients’ mean age was 58.4±6.4 years; the mean RA duration – 19.0±10.9 years. Antiinflammatory
therapy was performed in all the patients, including 30 (57.7%) who received GC. The mean BMD during follow-up increased from 0.814±0.101 to 0.848±0.103 g/cm2 in LI–IV (p<0.001), from 0.629±0.089 to 0.641±0.090 g/cm2 in FN (p=0.02), and from 0.497±0.094 to 0.502±0.091 g/cm2 in DF (р=0.34). The patients receiving and not  receiving GC showed a significant increase in LI–IV BMD and a tendency for its rise in FN and DF. There was a significant increase of X-ray changes in the hand and foot joints. Seven of the 52 patients were found to have a larger number of erosions: 33.0 [4.0; 78.0] at baseline and 39.0 [5.0; 90.0] after 12 months (p=0.017); 5 patients had a larger number of narrowed joint spaces: 119.0 [18.0; 140.0] and 124.0 [20.0; 146.0] (р=0.043); the total SVH score increased in 8 patients: 175.5 [54.0; 221.5] and 182.0 [57.0; 235.0] (р=0.011), respectively. Moreover, dividing the patients into groups according to the use of GC revealed significant increase of the number of erosions and total SVH scores only in the patients receiving GC.

Conclusion. Therapy with subcutaneous denosumab 60 mg twice a year at a 6-month interval could significantly increase LI–IV BMD regardless of GC intake. Progression of radiographic joint changes was noted mainly in patients receiving GC

1. Насонов ЕЛ, Насонова ВА, редакторы. Ревматология. Национальное руководство. Москва: ГЭОТАР-Медиа; 2008, C. 290 [Nasonov EL, Nasonova VA, editors. Revmatologiya. Natsional'noe rukovodstvo [Rheumatology. National guidelines]. Moscow: GEOTAR-Media; 2008. P. 290].

2. Goldring SR. Inflammation-induced bone loss in the rheumatic diseases. In: Primer on metabolic bone disease and disorders of mineral metabolism. Hoboken: John Wiley and Sons, Inc; 2009. Chapter 59.

3. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/ RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490–5. doi: 10.1001/jama.292.4.490

4. Saag KG, Koehnke R, Caldwell JR, et al. Low dose longterm corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96(2):115–23. doi: 10.1016/0002-9343(94)90131-7

5. Maricic M. Update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2011;37(3):415–31. doi: 10.1016/j.rdc.2011.07.003

6. Tannirandorn P, Epstein S. Drug-induced bone loss. Osteoporosis Int. 2000;11:637–59. doi: 10.1007/s001980070062

7. Лесняк ОМ, Беневоленская ЛИ, редакторы. Остеопороз. 2-е изд., перераб. и доп. Москва: ГЭОТАР-Медиа; 2009.271 с. [Lesnyak OM, Benevolenskaya LI, editors. Osteoporoz [Osteoporosis]. 2nd ed. Moscow: GEOTAR-Media; 2009. 271 p.].

8. Лесняк ОМ, Баранова ИА, Торопцова НВ. Диагностика, профилактика и лечение глюкокортикоидного остеопороза у мужчин и женщин 18 лет и старше: Клинические рекомендации. Ярославль: ИПК «Литера»; 2013. 48 с. [Lesnyak OM, Baranova IA, Toroptsova NV. Diagnostika, profilaktika i lechenie glyukokortikoidnogo osteoporoza u muzhchin i zhenshchin 18 let i starshe: Klinicheskie rekomendatsii [Diagnosis, prevention and treatment of glucocorticoid osteoporosis in men and women 18 years and older: Clinical Guidelines]. Yaroslavl': IPK «Litera»; 2013. 48 p.].

9. Gotzsche PC, Johansen HK. Short-term, low-dose corticosteroids vs placebo and nonsteroidal anti-inflammatory drugs in rheumatoid arthritis. Cochrane Database Syst Rev. 2004;(3):CD000189.

10. Criswell LA, Saag KG, Sems KM, et al. Moderate-term, lowdose corticosteroids for rheumatoid arthritis. Cochrane Database Syst Rev. 2000;(2):CD001158.

11. Подворотова ММ, Дыдыкина ИС, Таскина ЕА и др. Факторы риска переломов у больных ревматоидным артритом (предварительные результаты по материалам многоцентровой программы «Остеопороз при ревматоидном артрите: диагностика, факторы риска, переломы, лечение»). Научно-практическая ревматология. 2013;51(2):154–8 [Podvorotova MM, Dydykina IS, Taskina EA, et al. Risk factors for fractures in patients with rheumatoid arthritis (preliminary results of the multicenter program «Osteoporosis in rheumatoid arthritis: diagnosis, risk factors, fractures, treatment»). Nauchnoprakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(2):154–8 (In Russ.)].

12. Таскина ЕА, Алексеева ЛИ, Дыдыкина ИС и др. Факторы риска развития остеопоропоза у больных ревматоидным артритом (предварительные результаты по материалам многоцентровой программы «Остеопороз при ревматоидном артрите: диагностика, факторы риска, переломы, лечение»). Научно-практическая ревматология. 2014;52(4):393–7 [Taskina EA, Alekseeva LI, Dydykina IS, et al. Risk factors for osteoporosis in patients with rheumatoid arthritis (preliminary results according to the materials of the multicenter program «Osteoporosis in rheumatoid arthritis: Diagnosis, risk factors, fractures, treatment»). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(4):393–7 (In Russ.)]. doi: 10.14412/1995-4484-2014-393-397

13. Ghazi M, Kolta S, Briot K, et al. Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids. Osteoporos Int. 2012 Feb;23(2):581–7. doi: 10.1007/s00198-011-1584-3

14. Haugeberg G, Strand A, Kvien TK, Kirwan JR. Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial. Arch Intern Med. 2005;165:1293–7. doi: 10.1001/archinte. 165.11.1293

15. Van Everdingen AA, Jacobs JW, Siewertsz van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, diseasemodifying properties, and side effects: a randomized, doubleblind, placebo-controlled clinical trial. Ann Intern Med. 2002;136(1):1–12. doi: 10.7326/0003-4819-136-1-200201010- 00006

16. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155–92. doi: 10.1210/er.2007-0014

17. Лесняк ОМ, редактор. Российская ассоциация по остеопорозу. Клинические рекомендации по профилактике и ведению больных с остеопорозом. Ярославль: ИПК «Литера»; 2012. 24 с. [Lesnyak OM, editor. Rossiiskaya assotsiatsiya po osteoporozu. Klinicheskie rekomendatsii po profilaktike i vedeniyu bol'nykh s osteoporozom [Russian Association of Osteoporosis. Clinical practice guidelines for the prevention and management of patients with osteoporosis]. Yaroslavl': IPK «Litera»; 2012. 24 p.].

18. Dore RK, Cohen SB, Lane NE, et al. Effects of denosumab on bone mineral density and bone turnover in patients with RA receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis. 2010;69:872–5. doi: 10.1136/ard.2009.112920

19. Deodhar AA, Dore RK, Mandel D, et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res. 2010;62(4):569–74. doi: 10.1002/acr.20004

20. Deodhar AA, Brabyn J, Pande I, et al. Hand bone densitometry in rheumatoid arthritis, a five year longitudinal study: an outcome measure and a prognostic marker. Ann Rheum Dis. 2003;62:767–70. doi: 10.1136/ard.62.8.767

21. Sharp JT, Tsuji W, Ory P, et al. Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res. 2010;62(4): 537–44. doi: 10.1002/acr.20172

22. Takeuchi T. Dose-response effects of denosumab, a novel subcutaneous rankl inhibitor, on the progression of bone erosion in japanese patients with rheumatoid arthritis treated with methotrexate: results of phase II DRIVE study-A twelve month placebo controlled, randomized, double blind study. Arthritis Rheum. 2013;65:S1198.

23. Tanaka Y. Denosumab for the treatment of joint and bone diseases. Inflam Regenerat. 2011;31(4):344–8. doi: 10.2492/inflammregen.31.344

24. Zebaze RM, Ghasem-Zadech A, Bohte A, et al. Intracortical remodeling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet. 2010;375:1729–36. doi: 10.1016/S0140-6736(10)60320-0