Tools for Practice


#282 Osteoporosis treatment for post-menopausal women


CLINICAL QUESTION
How effective are bisphosphonates and denosumab in preventing fractures in post-menopausal women?

BOTTOM LINE
Bisphosphonates and denosumab are similarly effective at reducing risk of fracture in post-menopausal women. Over 1-4 years, bisphosphonates or denosumab provide an absolute reduction of ~0.5-1.0% for hip fractures, ~1.5-3% for non-vertebral fractures and ~3-6% for vertebral fractures compared to placebo.  


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EVIDENCE
Differences statistically significant unless noted.
  • Bisphosphonates:
    • 11 systematic reviews1-11 compared alendronate, risedronate, or zoledronate to placebo:
      • Systematic reviews with best quality/reporting: over 1-4 years, bisphosphonates reduce:
        • Hip fracture [4-7 randomized controlled trials (RCTs), 9,863-11,859 patients]:1,2,3
          • 0.5-2.0% versus 1-3% placebo, number needed to treat (NNT)=100-200.
        • Non-vertebral fracture (4-6 RCTs, 9,625-12,397 patients):1,2,4
          • ~9% versus ~11% placebo, NNT=35-65.
        • Vertebral fracture (2-6 RCTs, 3139-7802 patients):1,2,3
          • 3-8% versus 7-13% placebo, NNT=16-33.
    • Consistent with other systematic reviews.3,5,7,8,10
    • Systematic reviews rarely distinguish true primary and secondary prevention.1-2 Best available data12 suggests similar relative benefits in primary and secondary prevention. Example alendronate:
      • Non-vertebral fracture: Relative risk 0.74 versus 0.81.
      • Vertebral fracture: Relative risk 0.60 versus 0.53.
  • Denosumab:
    • Five systematic reviews5,6,10,13,14 compared denosumab versus placebo: Absolute event rates by fracture type not reported.
    • Largest RCT15 (7868 post-menopausal women, T-score ≤-2.5) compared denosumab and placebo over 3 years:
      • Hip fracture: 0.7% versus 1.1% placebo, NNT=230.
      • Non-vertebral fracture: 6.1% versus 7.5% placebo, NNT=72.
      • Vertebral fracture: 2.3% versus 7.1% placebo, NNT=21.
  • Bisphosphonates versus denosumab:
    • 6 systematic reviews6,10,16-19 compared bisphosphonates and denosumab:
      • One systematic review10 reported no difference in hip, non-vertebral and vertebral fractures.
      • Four systematic reviews16-19 (4-11 RCTs, 1942-5446 patients) reported no difference in clinical fracture risk.
  • Overall limitations: Event rates infrequently reported, variable outcome definitions, industry funding of RCTs.
  Context:
  • Previous articles provide guidance for screening osteoporosis20 and treatment duration.21
    • Atypical fracture risk with bisphosphonates increases with duration of therapy, particularly beyond 5 years.22
      • Fractures prevented outnumber atypical fractures at ~14-100:1 with 5 years of treatment.
  • Decision aids23 assess fracture risk and describe potential benefit to patients.
  • Drug cost only (per year):24
    • Risedronate and alendronate: ~$480.
    • Zoledronate IV infusion: ~$350.
    • Denosumab SC injection: ~$800.

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Author(s):

  • G. Michael Allan MD CCFP
  • Samantha Moe PharmD

1. Wells GA, Cranney A, Peterson J, et al. Cochrane Database Syst Rev. 2008; 1: CD001155.

2. Wells Ga, Cranney A, Peterson J, et al. Cochrane Database Syst Rev. 2008; 1: CD004523.

3. Serrano AJ, Beona L, Anitua E, et al. Gynecol Endocrinol. 2013; 29(12):1005-14.

4. Wang C. Am J Therap. 2017; 24:e544-552.

5. Freemantle N, Cooper C, Diez-Perez A, et al. Osteoporos Int. 2013; 24(1):209-17.

6. Jin YZ, Lee JH, Xu B, et al. BMC Musculoskeletal Disorders. 2019; 20:399

7. Liu GF, Wang ZQ, Liu L, et al. J Cel Biochem. 2018; 119:4469-81.

8. Saito T, Sterbenz JM, Malay S, et al. Osteoporos Int. 2017; 28:3289-3300.

9. Yang XC, Deng ZH, Wen T, et al. Cell Physiol Biochem. 2016; 40:781-95.

10. Barrionuevo, P, Kapoor E, Asi N, et al. J Clin Endrocrinol Metab. 104:1623-30.

11. Zhang J, Wang R, Zhao YL, et al. Asian Pacific Journal of Tropical Medicine. 2012: 743-48.

12. Stevenson M, Lloyd Jones M, De Nigris E, et al. Health Technol Assess. 2005; 9(22).

13. Anastasilakis AD, Toulis KA, Goulis DG, et al. Horm Metab Res. 209;41:721-9.

14. Von Keyserlingk C, Hoopkins R, Anastasilakis A, et al. Semin Arthritis Rheum. 2011; 41:178-86.

15. Cummings, SR, San Martin J, McClung MR, et al. New Engl J Med. 2009; 361;756-65.

16. Beaudoin C, Jean S, Bessette L, et al. Osteoporos Int. 2016; 27:2835-44.

17. Lin T, Wang C, Cai XZ, et al. Int J Clin Prac. 2012; 66(4):399-408.

18. Lyu H, Jundi B, Xu C. J Clin Endocrinol Metab. 2019; 104:1753-65.

19. Wu J, Zhang Q, Yan G, et al. J Orthop Surg Res. 2018; 13(1):194

20. Korownyk C, McCormack J, Allan GM. CFP. 2015; 61(7):612.

21. Turgeon RD, Kolber MR, Korownyk C, et al. Bisphosphonate: Forever of Five Years and Stop? Tools for Practice online publication #33. Available at: https://gomainpro.ca/wp-content/uploads/tools-for-practice/1527265870_updatedtfp33stopbisphosphonates.pdf. Accessed: Nov 19, 2020.

22. Black DM, Geiger EJ, et al. N Engl J Med. 2020; 383(8):743-53.

23. Mayo Clinic. Bone health Choice: Decision Aid. Available at: https://osteoporosisdecisionaid.mayoclinic.org/index.php/osteo/index. Accessed: Nov 20, 2020.

24. Hanley DA. Osteoporosis. RxTx, Online Edition. Canadian Pharmacists Association. Accessed Oct 16, 2020.

Authors do not have any conflicts of interest to declare.