Skip to main content
SpringerLink
Log in

Relationship Between Bone Mineral Density and Risk of Vertebral Fractures with Denosumab Treatment in Japanese Postmenopausal Women and Men with Osteoporosis

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment.

ClinicalTrials.gov identifier: NCT00680953.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Br Med J 312:1254–1259

    Article  CAS  Google Scholar 

  2. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, Black DM (2002) Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112:281–289

    Article  CAS  Google Scholar 

  3. Wasnich RD, Miller PD (2000) Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 85:231–236

    Article  CAS  Google Scholar 

  4. Delmas PD, Li Z, Cooper C (2004) Relationship between changes in bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses. J Bone Miner Res 19:330–337

    Article  CAS  Google Scholar 

  5. Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD (2002) Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 87:1586–1592

    Article  CAS  Google Scholar 

  6. Bouxsein ML, Eastell R, Lui LY, Wu LA, de Papp AE, Grauer A, Marin F, Cauley JA, Bauer DC, Black DM, FNIH Bone Quality Project (2019) Change in bone density and reduction in fracture risk A meta-regression of published trials. J Bone Miner Res 34:632–642

    Article  Google Scholar 

  7. Bruyere O, Roux C, Badurski J, Isaia G, de Vernejoul MC, Cannata J, Ortolani S, Slosman D, Detilleux J, Reginster JY (2007) Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate. Curr Med Res Opin 23:3041–3045

    Article  CAS  Google Scholar 

  8. Bruyere O, Roux C, Detilleux J, Slosman DO, Spector TD, Fardellone P, Brixen K, Devogelaer JP, Diaz-Curiel M, Albanese C, Kaufman JM, Pors-Nielsen S, Reginster JY (2007) Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab 92:3076–3081

    Article  CAS  Google Scholar 

  9. Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH (2006) Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res 21:1785–1790

    Article  CAS  Google Scholar 

  10. Li Z, Meredith MP, Hoseyni MS (2001) A method to assess the proportion of treatment effect explained by a surrogate endpoint. Stat Med 20:3175–3188

    Article  CAS  Google Scholar 

  11. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD (2002) Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 17:1–10

    Article  CAS  Google Scholar 

  12. Watts NB, Cooper C, Lindsay R, Eastell R, Manhart MD, Barton IP, van Staa TP, Adachi JD (2004) Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 7:255–261

    Article  Google Scholar 

  13. Watts NB, Geusens P, Barton IP, Felsenberg D (2005) Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res 20:2097–2104

    Article  Google Scholar 

  14. Miller PD, Delmas PD, Huss H, Patel KM, Schimmer RC, Adami S, Recker RR (2010) Increases in hip and spine bone mineral density are predictive for vertebral antifracture efficacy with ibandronate. Calcif Tissue Int 87:305–313

    Article  CAS  Google Scholar 

  15. Jacques RM, Boonen S, Cosman F, Reid IR, Bauer DC, Black DM, Eastell R (2012) Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:1627–1634

    Article  CAS  Google Scholar 

  16. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C, for the FREEDOM Trial (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765

    Article  CAS  Google Scholar 

  17. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwiński E, Krieg MA, Man Z, Mellström D, Radominski SC, Reginster JY, Resch H, Román Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG (2012) Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 27:694–701

    Article  CAS  Google Scholar 

  18. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S (2013) The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 98:4483–4492

    Article  CAS  Google Scholar 

  19. Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, Brandi ML, Czerwiński E, Franek E, Lakatos P, Mautalen C, Minisola S, Reginster JY, Jensen S, Daizadeh NS, Wang A, Gavin M, Libanati C, Wagman RB, Bone HG (2015) The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int 26:2773–2783

    Article  CAS  Google Scholar 

  20. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Shiraki M, Fukunaga M (2014) Clinical trials express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab 99:2599–2607

    Article  CAS  Google Scholar 

  21. Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer DC, Bianchi G, Bolognese MA, Christiansen C, Eastell R, Grauer A, Hawkins F, Kendler DL, Oliveri B, McClung MR, Reid IR, Siris ES, Zanchetta J, Zerbini CA, Libanati C, Cummings SR, for the FREEDOM Trial (2012) Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res 27:687–693

    Article  CAS  Google Scholar 

  22. McClung MR, Boonen S, Torring O, Roux C, Rizzoli R, Bone HG, Benhamou CL, Lems WF, Minisola S, Halse J, Hoeck HC, Eastell R, Wang A, Siddhanti S, Cummings SR (2012) Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res 27:211–218

    Article  CAS  Google Scholar 

  23. Sugimoto T, Matsumoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Fukunaga M, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Okubo N, Shiraki M, Nakamura T (2015) Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). Osteoporos Int 26:765–774

    Article  CAS  Google Scholar 

  24. Orimo H, Sugioka Y, Fukunaga M, Muto Y, Hotokebuchi T, Gorai I, Nakamura T, Kushida K, Tanaka H, Ikai T, Oh-hashi Y, The Committee of the Japanese Society for Bone, and Mineral Research for Development of Diagnostic Criteria of Osteoporosis (1998) Diagnostic criteria of primary osteoporosis. J Bone Miner Metab 16:139–150

    Article  Google Scholar 

  25. Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR, for the Study of Osteoporotic Fractures Research Group (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res 11:984–996

    Article  CAS  Google Scholar 

  26. Soen S, Fukunaga M, Sugimoto T, Soen T, Fujiwara S, Endo N, Gorai I, Shiraki M, Hagino H, Hosoi T, Ohta H, Yoneda T, Tomomitsu T, Japanese Society for Bone, and Mineral Research, and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis (2013) Diagnostic criteria for primary osteoporosis; year 2012 revision. J Bone Miner Metab 31:247–257

    Article  Google Scholar 

  27. Liang KY, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73(1):13–22

    Article  Google Scholar 

  28. Cosman F, Lewiecki EM, Ebeling PR, Hesse E, Napoli N, Matsumoto T, Crittenden DB, Rojeski M, Yang W, Libanati C, Libanati C, Ferrari S (2020) T-score as an indicator of fracture risk during treatment with romosozumab or alendronate in the ARCH trial. J Bone Miner Res. https://doi.org/10.1002/jbmr.3996

    Article  Google Scholar 

  29. Leslie WD, Martineau P, Bryanton M, Lix LM (2019) Which is the preferred site for bone mineral density monitoring as an indicator of treatment-related anti-fracture effect in routine clinical practice? A registry-based cohort study. Osteoporos Int 30:1445–1453

    Article  CAS  Google Scholar 

  30. Ferrari S, Libanati C, Lin CJF, Brown JP, Cosman F, Czerwiński E, de Gregόrio LH, Malouf-Sierra J, Reginster JY, Wang A, Wagman RB, Lewiecki EM (2019) Relationship between bone mineral density T-score and nonvertebral fracture risk over 10 years of denosumab treatment. J Bone Miner Res 34:1033–1040

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was sponsored by Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Funding

The study was funded by Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Author information

Authors and Affiliations

  1. Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Naoki Okubo, Taisuke Osakabe, Ko Watanabe & Hideo Takami

  2. Nagoya University Graduate School of Medicine, Nagoya, Japan

    Shigeyuki Matsui

  3. Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan

    Toshio Matsumoto

  4. Eikokai Ono Hospital, Hyogo, Japan

    Toshitsugu Sugimoto

  5. Kenkoin Clinic, Tokyo, Japan

    Takayuki Hosoi

  6. Research Institute and Practice for Involutional Diseases, Nagano, Japan

    Masataka Shiraki

  7. Touto Sangenjaya Rehabilitation Hospital, Tokyo, Japan

    Toshitaka Nakamura

Authors
  1. Naoki Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigeyuki Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshio Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshitsugu Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takayuki Hosoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taisuke Osakabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ko Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideo Takami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masataka Shiraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toshitaka Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TM, TS, TH, MS, and TN provided substantial contributions to the study conception and design. TO, KW, and HT were involved in the design and conduct of the study and in collecting data. NO and SM were responsible for statistical analysis of the data. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Corresponding author

Correspondence to Naoki Okubo.

Ethics declarations

Conflict of interest

Naoki Okubo, Taisuke Osakabe, Ko Watanabe, and Hideo Takami are Daiichi Sankyo employees. Shigeyuki Matsui has received consulting fees from Daiichi Sankyo. Toshio Matsumoto has received consulting fees from Daiichi Sankyo, Chugai, Amgen, and Teijin. Toshitsugu Sugimoto has received consulting fees from Asahi-Kasei and Daiichi Sankyo. He has also received research grants from Eli Lilly Japan, Eisai, Chugai, Daiichi Sankyo, and Astellas. Takayuki Hosoi has received consulting fees from Daiichi Sankyo. Masataka Shiraki has received consulting fees from Daiichi Sankyo, Chugai, Teijin, Asahi-Kasei, and MSD. Toshitaka Nakamura has received consulting fees from Teijin, Daiichi Sankyo, Chugai, Asahi-Kasei, and Amgen.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

223_2020_750_MOESM1_ESM.tif

Supplemental Fig. 1 Relationship between incidence of new or worsening vertebral fracture over 2 years and T-score at baseline in (a) total hip BMD, (b) femoral neck BMD, and (C) lumbar spine BMD. The predicted curves with 95% confidence intervals are presented for each treatment group. Data represent the 5th to 95th percentiles in total hip BMD for each treatment group. The solid lines represent the denosumab group and the dashed lines represent the placebo group. (TIF 1262 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okubo, N., Matsui, S., Matsumoto, T. et al. Relationship Between Bone Mineral Density and Risk of Vertebral Fractures with Denosumab Treatment in Japanese Postmenopausal Women and Men with Osteoporosis. Calcif Tissue Int 107, 559–566 (2020). https://doi.org/10.1007/s00223-020-00750-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-020-00750-y

Keywords

Search

Navigation