Calcified Tissue International

, Volume 105, Issue 6, pp 630–641 | Cite as

Treatment Effects of Bisphosphonates and Denosumab on Survival and Refracture from Real-World Data of Hip-Fractured Patients

  • Martina BehanovaEmail author
  • Berthold Reichardt
  • Tanja A. Stamm
  • Jochen Zwerina
  • Klaus Klaushofer
  • Roland Kocijan
Original Research


We examined differences in patients’ survival after hip fracture (HF) and risk for subsequent HF among patients treated with oral and intravenous bisphosphonates (oBPs, iBPs), denosumab (DMAB), and patients without therapy. We used data from all patients in Austria aged ≥ 50 who sustained a HF between 2012 and 2017 and were followed for a subsequent HF and all-cause mortality until 2017. Antiosteoporotic treatment-naïve patients, who were incident users of BPs and DMAB, were eligible for propensity score matching 1:1 to obtain comparable user groups. We applied competing risk approach and calculated cumulative incidence functions and subdistribution-hazards for refracture. Cox regression models were applied for mortality risk. A total of 54,145 hip-fractured patients were observed (1919 oBPs; 1870 iBPs; 555 DMAB users; and 42,795 untreated patients were included in the matched sets) and followed up for a median (interquartile range) of 22.6 months (26.2). Patients treated with antiresorptive medications had significantly longer survival time than patients without treatment. Receiving treatment significantly decreased a hazard of dying only for women by 17% for iBPs (HR 0.83, 95% CI 0.71–0.98, p = 0.023). For DMAB and oBPs, the results were not statistically significant. Higher risk of a subsequent HF was observed in women on DMAB (SHR 1.77, 95% CI 1.08–2.91) and on iBP (SHR 1.81, 95% CI 1.35–2.41), and in men on oBPs (SHR 2.89, 95% CI 1.58–5.30). Patients who were treated with antiresorptive medications after HF had longer survival than patients without treatment, highlighting the importance of initiation of antiresorptive treatment after HF.


Hip fracture Bisphosphonates Denosumab Subsequent hip fracture Mortality Competing risk regression 



We thank the members of the Pharmacoeconomics Advisory Council of the Austrian Sickness Funds for provision of the data.

Compliance with Ethical Standards

Conflict of interest

Martina Behanova, Berthold Reichardt, Tanja A Stamm, Jochen Zwerina, Klaus Klaushofer, and Roland Kocijan declare that they have no conflict of interests.

Human and Animal Rights and Informed Consent

The research was performed in accordance with the Declaration of Helsinki and was approved by the Ethical Committee of the City of Vienna (Approval number: EK 18-101-VK). Obtaining informed consent from participants was not applicable as this was a retrospective register-based study and all data were pseudonymized.

Supplementary material

223_2019_611_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)
223_2019_611_MOESM2_ESM.docx (31 kb)
Supplementary material 2 (DOCX 31 kb)


  1. 1.
    Haentjens P, Magaziner J, Colon-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, Boonen S (2010) Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 152:380–390PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Hansen L, Petersen KD, Eriksen SA, Langdahl BL, Eiken PA, Brixen K, Abrahamsen B, Jensen J-EB, Harsløf T, Vestergaard P (2015) Subsequent fracture rates in a nationwide population-based cohort study with a 10-year perspective. Osteoporos Int 26:513–519PubMedCrossRefGoogle Scholar
  3. 3.
    Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA, Berger M (2000) Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 15(4):721–739PubMedCrossRefGoogle Scholar
  4. 4.
    Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, Eisman J, Fujiwara S, Garnero P, Kroger H, McCloskey EV, Mellstrom D, Melton LJ, Pols H, Reeve J, Silman A, Tenenhouse A (2004) A meta-analysis of previous fracture and subsequent fracture risk. Bone 35:375–382PubMedCrossRefGoogle Scholar
  5. 5.
    Lönnroos E, Kautiainen H, Karppi P, Hartikainen S, Kiviranta I, Sulkava R (2007) Incidence of second hip fractures. A population-based study. Osteoporos Int 18(9):1279–1285PubMedCrossRefGoogle Scholar
  6. 6.
    Kuiper BW, Graybill S, Tate JM, Kaufman N, Bersabe D (2018) After the fall: improving osteoporosis treatment following hip fracture. Osteoporos Int 29:1295–1301PubMedCrossRefGoogle Scholar
  7. 7.
    Benjamin B, Benjamin MA, Swe M, Sugathan S (2016) Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis. Osteoporos Sarcopenia 2:77–81PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Saito T, Sterbenz JM, Malay S, Zhong L, MacEachern MP, Chung KC (2017) Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and meta-analysis. Osteoporos Int 28(12):3289–3300PubMedCrossRefGoogle Scholar
  9. 9.
    Iwamoto J, Sato Y, Takeda T, Matsumoto H (2008) Hip fracture protection by alendronate treatment in postmenopausal women with osteoporosis: a review of the literature. Clin Interv Aging 3:483–489PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hopkins RB, Goeree R, Pullenayegum E, Adachi JD, Papaioannou A, Xie F, Thabane L (2011) The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women. BMC Musculoskelet Disord 12:209PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Khosla S, Bilezikian JP, Dempster DW, Lewiecki EM, Miller PD, Neer RM, Recker RR, Shane E, Shoback D, Potts JT (2012) Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab 97(7):2272–2282PubMedCrossRefGoogle Scholar
  12. 12.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR, Pivotal Fracture Trial HORIZON (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356(18):1809–1822PubMedCrossRefGoogle Scholar
  13. 13.
    Jansen JP, Bergman GJ, Huels J, Olson M (2011) The Efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in Osteoporosis: a network meta-analysis. Semin Arthritis Rheum 40(4):275–284PubMedCrossRefGoogle Scholar
  14. 14.
    Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809PubMedCrossRefGoogle Scholar
  15. 15.
    Lee YK, Ha YC, Choi HJ, Jang S, Park C, Lim YT, Shin CS (2013) Bisphosphonate use and subsequent hip fracture in South Korea. Osteoporos Int 24(11):2887–2892PubMedCrossRefGoogle Scholar
  16. 16.
    Goessl C, Katz L, Dougall WC, Kostenuik PJ, Zoog HB, Braun A et al (2012) The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. Ann N Y Acad Sci 1263:29–40PubMedCrossRefGoogle Scholar
  17. 17.
    Boonen S, Adachi JD, Man Z, Cummings SR, Lippuner K, Törring O, Gallagher JC, Farrerons J, Wang A, Franchimont N, San Martin J, Grauer A, McClung M (2011) Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab 96(6):1727–1736PubMedCrossRefGoogle Scholar
  18. 18.
    Austin M, Yang Y-Ch, Vittinghof E, Adami S, Boonen S et al (2012) Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res 27(3):687–693PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS et al (2016) Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab 101(8):3163–3170PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Fahrleitner-Pammer A, Papaioannou N, Gielen E, Tepie FM, Toffis C et al (2017) Factors associated with high 24-month persistence with denosumab: results of a real-world, non-interventional study of women with postmenopausal osteoporosis in Germany, Austria, Greece, and Belgium. Arch Osteoporos 12:58PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hadji P, Papaioannou N, Gielen E, Feudjo Tepie M, Zhang E, Frieling I, Geusens P, Makras P, Resch H, Möller G, Kalouche-Khalil L, Fahrleitner-Pammer A (2015) Persistence, adherence, and medication-taking behavior in women with postmenopausal osteoporosis receiving denosumab in routine practice in Germany, Austria, Greece, and Belgium: 12-month results from a European non-interventional study. Osteoporos Int 26(10):2479–2489PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD, Reginster JY, Törring O, Kendler DL, Daizadeh NS, Wang A, O’Malley CD, Wagman RB, Libanati C, Lewiecki EM (2015) Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int 26(12):2763–2771PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    McClung M (2017) Denosumab for the treatment of osteoporosis. Osteoporos Sarcopenia 3:8–17PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    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 361:756–765PubMedCrossRefGoogle Scholar
  25. 25.
    Cummings SR, Ferrari S, Eastell R, Gilchrist N, Beck Jensen JE, McClung M, Roux Ch, Törring O, Valter I, Wang AT, Brown JP (2018) Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 33:188–189CrossRefGoogle Scholar
  26. 26.
    Symonds Ch, Kline G (2018) Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ 190:E485–E486PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Center JR, Bliuc D, Nguyen ND, Nguyen TV, Eisman JA (2011) Osteoporosis medication and reduced mortality risk in elderly women and men. J Clin Endocrinol Metab 96(4):1006–1014PubMedCrossRefGoogle Scholar
  28. 28.
    Brozek W, Reichardt B, Zwerina J et al (2016) Antiresorptive therapy and risk of mortality and refracture in osteoporosis-related hip fracture: a nationwide study. Osteoporos Int 27:387PubMedCrossRefGoogle Scholar
  29. 29.
    Sambrook PN, Cameron ID, Chen JS, March LM, Simpson JM, Cumming RG, Seibel MJ (2011) Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. Osteoporos Int 22:2551–2556PubMedCrossRefGoogle Scholar
  30. 30.
    Bondo L, Eiken P, Abrahamsen B (2013) Analysis of the association between bisphosphonate treatment survival in Danish hip fracture patients-a nationwide register-based open cohort study. Osteoporos Int 24(1):245–252PubMedCrossRefGoogle Scholar
  31. 31.
    Pintilie M (2006) Competing risks: a practical perspective. Wiley, West SussexCrossRefGoogle Scholar
  32. 32.
    Sekhon JS (2011) Multivariate and propensity score matching. software with automated balance optimization: the matching package for RGoogle Scholar
  33. 33.
    Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94(446):496–509CrossRefGoogle Scholar
  34. 34.
    Scrucca L, Santucci A, Aversa F (2007) Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 40(4):381–387PubMedCrossRefGoogle Scholar
  35. 35.
    Scheike Thomas H, Zhang Mei-Jie (2011) Analyzing competing risk data using the R timereg package. J Stat Softw 38(2):1–15CrossRefGoogle Scholar
  36. 36.
    IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM CorpGoogle Scholar
  37. 37.
    R Core Team (2018) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.
  38. 38.
    van Geel TACM, Bliuc D, Geusens PPM, Center JR, Dinant GJ, Tran T, van den Bergh JPW, McLellan AR, Eisman JA (2018) Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: a prospective cohort study. PLoS ONE 13(6):e0198006. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Baron R, Ferrari S, Russell RG (2011) Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48(4):677–692PubMedCrossRefGoogle Scholar
  40. 40.
    Corrado A, Santoro N, Cantatore FP (2007) Extra-skeletal effects of bisphosphonates. Joint Bone Spine 74(1):32–38PubMedCrossRefGoogle Scholar
  41. 41.
    Colón-Emeric CS, Mesenbrink P, Lyles KW, Pieper CF, Boonen S, Delmas P, Eriksen EF, Magaziner J (2010) Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 25(1):91–97PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ferrari-Lacraz S, Ferrari S (2010) Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int 22:435–446PubMedCrossRefGoogle Scholar
  43. 43.
    Bergman J, Nordström A, Nordström P (2018) Bisphosphonate use after clinical fracture and risk of new fracture. Osteoporos Int 29(4):937–945PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Lindsay R (2015) Osteoporosis treatment and fracture outcomes. JAMA Intern Med 175(6):921–922PubMedCrossRefGoogle Scholar
  45. 45.
    Lobo FS, Wagner S, Gross CR, Schommer JC (2006) Addressing the issue of channeling bias in observational studies with propensity scores analysis. Res Soc Adm Pharm 2(1):143–151CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of the WGKK and AUVA Trauma Center, 1st Medical Department at Hanusch HospitalViennaAustria
  2. 2.Sickness Fund Burgenland, Burgenländische GebietskrankenkasseEisenstadtAustria
  3. 3.Section for Outcomes Research, Center for Medical Statistics, Informatics and Intelligent SystemsMedical University of ViennaViennaAustria

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