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The Amgen-sponsored symposium at the FFN (Fragility Fracture Network) 2017 Congress provided an interactive educational opportunity for delegates, and was led by Mattias Lorentzon (Sweden) as meeting chair. He was joined by Bente Langdahl (Denmark) who presented on the treatment options and optimal timing for post-fracture care

What are the treatment options and optimal timing for post-fracture care?

Bente Langdahl

As fractures in elderly patients are associated with life-changing events, there is a need to prevent fractures in this population. Evidence demonstrates that patients who have recently experienced a fracture are at risk of experiencing a subsequent fracture. Professor Langdahl highlighted imminent fracture risk in specific populations including the elderly, and summarized the effects and optimal timing of two therapeutic options for the management and treatment of fractures. Many post-menopausal women falsely perceive their risk of fracture as low [1]. Fractures are perceived as random events linked to environmental hazards, accidental falls and unsafe behavior, rather than to an underlying condition such as osteoporosis [2, 3].

Risk factors for first and subsequent fractures

There are many known risk factors for first and subsequent fractures; in addition to risk of falling, these are most commonly associated with poor bone quality and include reduced bone mass, increased bone turnover, and compromised bone architecture. Risk factors for future fracture include demographic factors (such as age, previous fractures, family history of osteoporosis, smoking, alcohol consumption), and diseases and drugs affecting bone quality [4].

Imminent fracture risk

Several studies provide evidence of an increased risk of fracture following a previous fracture [5-7]. A prospective cohort study conducted in Australia assessed the annual risk of developing a first and subsequent fracture, and showed that the risk of a subsequent fracture was almost 2-fold higher in women and approximately 3.5-fold higher in men, than the risk of experiencing a first fracture [5]. The study showed that 41% and 52% of subsequent fractures in women and men, respectively, occurred within 2 years of the initial fracture [5]. Further evidence from two cohort studies similarly demonstrated that the imminent fracture risk remains highest in the initial years following a first fracture, but even after many years post-fracture, the fracture risk remains higher than that in patients with no previous fracture [6, 7]

More research is needed to determine exact risk factors for imminent fracture risk, but current factors include [4]:

  • The presence of the underlying condition that led to the first fracture
    • Diseases, pharmacological treatments, etc.
  • Fracture treatment and post-fracture care
    • Walking aids, plastering and impaired coordination
    • Surgery may cause cognitive impairment
  • Immobilization
    • Bone loss

The location of the first fracture can also provide predictive information about the location of subsequent fractures, and should be considered when assessing a patient’s risk of subsequent fractures. For example, vertebral fractures are known to predict subsequent vertebral fractures [8, 9], and non- vertebral fractures are known to predict subsequent non-vertebral fractures [10]. Increased risk of hip fracture, however, is associated with any type of prior fracture, including previous humeral and wrist fractures [11, 12].

Strategies for the prevention of subsequent fractures

There are various strategies in place to help reduce patients’ risk of subsequent fractures, particularly in patient populations identified as high-risk. The inclusion of patients in the Fracture Liaison Services (FLS) programme is associated with reduced risk of subsequent fractures and mortality, notably in patients who have already experienced hip fractures [13].

A number of antiresorptive therapy options exist for prevention of osteoporotic fragility fractures, and Professor Langdahl reviewed data on the bisphosphonate zoledronic acid, and Prolia® (denosumab), a fully human monoclonal antibody. These two treatment options work differently. Prolia® targets RANK ligand, and prevents it from binding to its receptor, RANK, thereby inhibiting the formation, function and survival of osteoclasts [14, 15]. By contrast, bisphosphonates bind to bone mineral and likely inhibit osteoclast function by being taken up by osteoclasts at sites of bone resorption [14]. There is evidence that both of these treatment options reduce the risk of first and subsequent fractures.

A large, randomized, double-blind trial, The Health Outcome and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, studied the effects of zoledronic acid in post-menopausal women with osteoporosis (≥65 years old), and showed that an annual 5 mg dose of intravenous zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip and non-vertebral fractures [16]. The HORIZON Recurrent Fracture Trial also showed that zoledronic acid significantly reduced the risk of all clinical fractures in men and women (≥50 years old) when administered within 90 days of surgical repair of a hip fracture [17] Data suggest that drug efficacy is reduced in patients dosed within 2 weeks of their fracture repair [18].

The long-term efficacy and safety of Prolia® has been established in the FREEDOM trial and its extension [19]. Treatment with Prolia® significantly reduced the risk of new vertebral, non-vertebral and hip fractures in post-menopausal women with osteoporosisin the 3-year FREEDOM trial [20]. The FREEDOM extension data show that treatment with Prolia® is associated with increases in BMD over 10 years without therapeutic plateau, and sustained low incidence of vertebral and non-vertebral fractures [19, 21]. A post hoc analysis of the FREEDOM data provided evidence that Prolia® effectively prevented subsequent fractures in patients with a previous fracture [22]. To evaluate if Prolia® treatment impacts fracture healing, a further post hoc analysis of the FREEDOM trial was performed [23]. This analysis showed that in patients experiencing a non vertebral fracture, there were no delays in fracture healing within 6 weeks of Prolia® administration, indicating that Prolia® can be administered at any time post-fracture [23]. In patients who had recently received a knee implant, Prolia® was found to reduce the migration of the implant when administered within 24 hours of surgery [24].

Professor Langdahl concluded her presentation by summarizing that an initial fragility fracture is a clear warning of subsequent fractures, and the risk of subsequent fractures should be assessed as soon as possible. This can be done by evaluating the patient’s risk factors, bone mass, and risk of falling. Measures to help prevent secondary fracture must be put in place (e.g. FLS) and anti-osteoporosis treatment should be initiated. In addition, it is hugely important to educate patients and their relatives on the serious consequences and chronicity of osteoporosis.

References

  1. Siris ES, Gehlbach S, Adachi JD, et al. Failure to perceive increased risk of fracture in women 55 years and older: the Global Longitudinal Study of Osteoporosis in Women (GLOW). Int. 2010;22(1):27-35. doi: 10.1007/s00198-010-1211-8.
  2. van Griensven M, Alami S, Hervouet L, et al. Barriers to Effective Postmenopausal Osteoporosis Treatment: A Qualitative Study of Patients’ and Practitioners’ Views. PLoS One. 2016;11(6):e0158365. doi: 10.1371/journal.pone.0158365.
  3. Sale JEM, Gignac MA, Hawker G, et al. Patients do not have a consistent understanding of high risk for future fracture: a qualitative study of patients from a post-fracture secondary prevention program. Int. 2015;27(1):65-73. doi: 10.1007/s00198-015-3214-y.
  4. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Int. 2014;25(10):2359-2381. doi: 10.1007/s00198-014-2794-2.
  5. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of Subsequent Fracture After Low-Trauma Fracture in Men and Women. JAMA. 2007;297(4):387. doi: 10.1001/jama.297.4.387.
  6. van Geel TACM, van Helden S, Geusens PP, et al. Clinical subsequent fractures cluster in time after first fractures. Rheum. Dis. 2008;68(1):99-102. doi: 10.1136/ard.2008.092775.
  7. Johansson H, Siggeirsdóttir K, Harvey NC, et al. Imminent risk of fracture after fracture. Int. 2016;28(3):775-780. doi: 10.1007/s00198-016-3868-0.
  8. Lindsay R. Risk of New Vertebral Fracture in the Year Following a Fracture. JAMA. 2001;285(3):320. doi: 10.1001/jama.285.3.320.
  9. Roux C, Fechtenbaum J, Kolta S, et al. Mild prevalent and incident vertebral fractures are risk factors for new fractures. Int. 2007;18(12):1617-1624. doi: 10.1007/s00198-007-0413-1.
  10. Huntjens KMB, Kosar S, van Geel TACM, et al. Risk of subsequent fracture and mortality within 5 years after a non-vertebral fracture. Int. 2010;21(12):2075-2082. doi: 10.1007/s00198-010-1178-5.
  11. Clinton J, Franta A, Polissar NL, et al. Proximal Humeral Fracture as a Risk Factor for Subsequent Hip Fractures. The Journal of Bone and Joint Surgery-American Volume. 2009;91(3):503-511. doi: 10.2106/jbjs.g.01529.
  12. Schousboe JT, Fink HA, Taylor BC, et al. Association Between Self-Reported Prior Wrist Fractures and Risk of Subsequent Hip and Radiographic Vertebral Fractures in Older Women: A Prospective Study. Bone Miner. Res. 2004;20(1):100-106. doi: 10.1359/jbmr.041025.
  13. Huntjens KMB, van Geel TACM, van den Bergh JPW, et al. Fracture Liaison Service. The Journal of Bone & Joint Surgery. 2014;96(4):e29. doi: 10.2106/jbjs.l.00223.
  14. Baron R, Ferrari S, Russell RGG. Denosumab and bisphosphonates: Different mechanisms of action and effects. Bone. 2011;48(4):677-692. doi: 10.1016/j.bone.2010.11.020.
  15. Prolia® Summary of Product Characteristics. Last revised: June 2017.
  16. Black DM, Delmas PD, Eastell R, et al. Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. Engl. J. Med. 2007;356(18):1809-1822. doi: 10.1056/NEJMoa067312.
  17. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. Engl. J. Med. 2007;357(18):1799-1809. doi: 10.1056/NEJMoa074941.
  18. Eriksen EF, Lyles KW, Colón-Emeric CS, et al. Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture. Bone Miner. Res. 2009;24(7):1308-1313. doi: 10.1359/jbmr.090209.
  19. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. The Lancet Diabetes & Endocrinology. 2017;5(7):513-523. doi: 10.1016/s2213-8587(17)30138-9.
  20. Cummings SR, Martin JS, McClung MR, et al. Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis. Engl. J. Med. 2009;361(8):756-765. doi: 10.1056/NEJMoa0809493.
  21. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Int. 2015;26(12):2773-2783. doi: 10.1007/s00198-015-3234-7.
  22. Palacios S, Kalouche-Khalil L, Rizzoli R, et al. Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis. Climacteric. 2015;18(6):805-812. doi: 10.3109/13697137.2015.1045484.
  23. Adami S, Libanati C, Boonen S, et al. Denosumab Treatment in Postmenopausal Women with Osteoporosis Does Not Interfere with Fracture-Healing. The Journal of Bone and Joint Surgery-American Volume. 2012;94(23):2113-2119. doi: 10.2106/jbjs.k.00774.
  24. Ledin H, Good L, Aspenberg P. Denosumab reduces early migration in total knee replacement. Acta Orthop. 2017;88(3):255-258. doi: 10.1080/17453674.2017.1300746.