Rheumatology International

, Volume 37, Issue 6, pp 999–1005 | Cite as

Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study

  • Masahiro Tada
  • Kentaro Inui
  • Yuko Sugioka
  • Kenji Mamoto
  • Tadashi Okano
  • Shohei Anno
  • Tatsuya KoikeEmail author
Observational Research


Although patients with rheumatoid arthritis (RA) are prone to osteoporosis, tight control of disease activity might have a positive effect on bone metabolism. We aimed to determine whether bisphosphonate use is still important to improve bone mineral density (BMD) in RA patients whose disease activity was tightly controlled and the dose of glucocorticoid was reduced. This study was a sub-analysis of the 10-year prospective cohort TOtal Management Of Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality: the TOMORROW which started from 2010. We compared BMD between 192 patients with RA and age- and sex-matched volunteers between 2010 and 2013 using dual-energy X-ray absorptiometry (DXA) in whole body mode. We then determined ratios of changes in BMD (%ΔBMD) to assess factors influencing increases in BMD among the patients using multivariate logistic regression analysis. The BMD was significantly lower in the patients than in the controls at all sites surveyed during 2010 and 2013. The %ΔBMD of the total spine was significantly higher among the patients treated with, than without bisphosphonate (6.2 vs. 1.8%, P = 0.0001). Multivariate logistic regression analysis revealed that use of bisphosphonate was a significant factor contributing to BMD increase (odds ratio 2.13; 95% confidence interval, 1.03–4.38, P = 0.041). Meanwhile, use of biologic agents, reducing glucocorticoid dose, and control of disease activity were not significant factors for gain of BMD. The BMD was lower among patients with RA than non-RA controls. Use of bisphosphonate significantly increased the BMD of the spine in patients over a period of 3 years and was important for maintaining the BMD among patients with RA under the control of inflammation and disease activity.


Cohort Fragile fracture Osteoporosis Inflammatory disease Dual-energy X-ray absorptiometry 



We thank Atsuko Kamiyama, Tomoko Nakatsuka and the Center for Drug and Food Clinical Evaluation, Department of Radiology and Department of Central Clinical Laboratory in Osaka City University Hospital for serving as research coordinators in terms of recruiting participants, collecting data and managing the quality of the data. We greatly appreciate the cooperation of the patients with RA and the healthy volunteers who participated in this study.

Author contribution statement

Study design: M.T. and T.K., Study implementation: T.K., Data collection: T.O., Y.S., S.A, and K.M., Data analysis: M.T. and T.K., Data interpretation: M.T., T.K., and K.I., Drafting the manuscript: M.T., T.K., and K.I., Approving the final version of the manuscript: all authors.

Compliance with ethical standards

Conflict of interest

Dr. Koike has received grant fees, research fees, consulting fees, or other remuneration from AbbVie, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB. None of the other authors has any conflict of interest to disclose.

Ethical standards

The Ethics Committee at Osaka City University approved the study protocol. We obtained written informed consent from all patients and volunteers to participate in this study in accordance with the Declaration of Helsinki.


  1. 1.
    Deodhar AA, Woolf AD (1996) Bone mass measurement and bone metabolism in rheumatoid arthritis: a review. Br J Rheumatol 35(4):309–322CrossRefPubMedGoogle Scholar
  2. 2.
    Peel NF, Moore DJ, Barrington NA, Bax DE, Eastell R (1995) Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis. Ann Rheum Dis 54(10):801–806CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C (2006) Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 54(10):3104–3112. doi: 10.1002/art.22117 CrossRefPubMedGoogle Scholar
  4. 4.
    Wright NC, Lisse JR, Walitt BT, Eaton CB, Chen Z (2011) Arthritis increases the risk for fractures–results from the women’s health initiative. J Rheumatol 38(8):1680–1688. doi: 10.3899/jrheum.101196 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, Burckhardt P, Cooper C, Christiansen C, Cummings S, Eisman JA, Fujiwara S, Gluer C, Goltzman D, Hans D, Krieg MA, La Croix A, McCloskey E, Mellstrom D, Melton LJ 3rd, Pols H, Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van Staa T, Watts NB, Yoshimura N (2007) The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 18(8):1033–1046. doi: 10.1007/s00198-007-0343-y CrossRefPubMedGoogle Scholar
  6. 6.
    Watts NB, Lewiecki EM, Miller PD, Baim S (2008) National Osteoporosis Foundation 2008 Clinician’s Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom 11(4):473–477. doi: 10.1016/j.jocd.2008.04.003 CrossRefPubMedGoogle Scholar
  7. 7.
    Braun T, Schett G (2012) Pathways for bone loss in inflammatory disease. Curr Osteoporos Rep 10(2):101–108. doi: 10.1007/s11914-012-0104-5 CrossRefPubMedGoogle Scholar
  8. 8.
    Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15(6):993–1000. doi: 10.1359/jbmr.2000.15.6.993 CrossRefPubMedGoogle Scholar
  9. 9.
    Tromp AM, Smit JH, Deeg DJ, Bouter LM, Lips P (1998) Predictors for falls and fractures in the Longitudinal Aging Study Amsterdam. J Bone Miner Res 13(12):1932–1939. doi: 10.1359/jbmr.1998.13.12.1932 CrossRefPubMedGoogle Scholar
  10. 10.
    Okano T, Koike T, Tada M, Sugioka Y, Mamoto K, Wakitani S, Nakamura H (2014) The limited effects of anti-tumor necrosis factor blockade on bone health in patients with rheumatoid arthritis under the use of glucocorticoid. J Bone Miner Metab 32(5):593–600. doi: 10.1007/s00774-013-0535-9 CrossRefPubMedGoogle Scholar
  11. 11.
    Vis M, Guler-Yuksel M, Lems WF (2013) Can bone loss in rheumatoid arthritis be prevented? Osteoporos Int 24(10):2541–2553. doi: 10.1007/s00198-013-2334-5 CrossRefPubMedGoogle Scholar
  12. 12.
    Lange U, Teichmann J, Muller-Ladner U, Strunk J (2005) Increase in bone mineral density of patients with rheumatoid arthritis treated with anti-TNF-alpha antibody: a prospective open-label pilot study. Rheumatology (Oxford) 44(12):1546–1548. doi: 10.1093/rheumatology/kei082 CrossRefGoogle Scholar
  13. 13.
    Mamoto K, Inui K, Okano T, Sugioka Y, Tada M, Koike T, Nakamura H (2017) Incidence rate of falls and its risk factors in patients with rheumatoid arthritis compared to controls: four years of the TOMORROW study. Mod Rheumatol 27(1):8–14. doi: 10.1080/14397595.2016.1176625 CrossRefPubMedGoogle Scholar
  14. 14.
    Tada M, Inui K, Sugioka Y, Mamoto K, Okano T, Koike T, Nakamura H (2016) Reducing glucocorticoid dosage improves serum osteocalcin in patients with rheumatoid arthritis-results from the TOMORROW study. Osteoporos Int 27(2):729–735. doi: 10.1007/s00198-015-3291-y CrossRefPubMedGoogle Scholar
  15. 15.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefPubMedGoogle Scholar
  16. 16.
    Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48CrossRefPubMedGoogle Scholar
  17. 17.
    Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon NP (1983) Assessment of patient satisfaction in activities of daily living using a modified stanford health assessment questionnaire. Arthritis Rheum 26(11):1346–1353CrossRefPubMedGoogle Scholar
  18. 18.
    Haugeberg G, Orstavik RE, Uhlig T, Falch JA, Halse JI, Kvien TK (2002) Bone loss in patients with rheumatoid arthritis: results from a population-based cohort of 366 patients followed up for two years. Arthritis Rheum 46(7):1720–1728. doi: 10.1002/art.10408 CrossRefPubMedGoogle Scholar
  19. 19.
    Steiger P, Cummings SR, Black DM, Spencer NE, Genant HK (1992) Age-related decrements in bone mineral density in women over 65. J Bone Miner Res 7(6):625–632. doi: 10.1002/jbmr.5650070606 CrossRefPubMedGoogle Scholar
  20. 20.
    Seriolo B, Paolino S, Sulli A, Ferretti V, Cutolo M (2006) Bone metabolism changes during anti-TNF-alpha therapy in patients with active rheumatoid arthritis. Ann N Y Acad Sci 1069:420–427. doi: 10.1196/annals.1351.040 CrossRefPubMedGoogle Scholar
  21. 21.
    Neovius M, Sundstrom A, Simard J, Wettermark B, Cars T, Feltelius N, Askling J, Klareskog L (2011) Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009. Scand J Rheumatol 40(1):8–15. doi: 10.3109/03009742.2010.493895 CrossRefPubMedGoogle Scholar
  22. 22.
    Yamanaka H, Seto Y, Tanaka E, Furuya T, Nakajima A, Ikari K, Taniguchi A, Momohara S (2013) Management of rheumatoid arthritis: the 2012 perspective. Mod Rheumatol 23(1):1–7. doi: 10.1007/s10165-012-0702-1 CrossRefPubMedGoogle Scholar
  23. 23.
    Ward KD, Klesges RC (2001) A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif Tissue Int 68(5):259–270CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryOsaka City General HospitalOsakaJapan
  2. 2.Department of RheumatosurgeryOsaka City University Medical SchoolOsakaJapan
  3. 3.Center for Senile Degenerative Disorders (CSDD)Osaka City University Medical SchoolOsakaJapan
  4. 4.Department of Orthopaedic SurgeryOsaka City University Medical SchoolOsakaJapan
  5. 5.Search Institute for Bone and Arthritis Disease (SINBAD), Shirahama Foundation for Health and WelfareWakayamaJapan

Personalised recommendations