Bone health

Long-term osteoporosis management requires long-term thinking


The optimal duration of osteoporosis treatment remains controversial. To understand the considerations on the minds of local and international clinicians, the limbic listened in to a break-out session from the International Osteoporosis Foundation Regional 7th Asia-Pacific Osteoporosis Conference taking place in Sydney last week. Professors Peter Ebeling from the Department of Medicine, School of Clinical Sciences at Monash University and Serge Ferrari from the Service of Bone Diseases at Geneva University Hospital Switzerland presented their considerations for managing patients long-term on denosumab.

Clinicians now have the freedom to look back at more than 10 years of evidence

“We now have the benefit of long-term clinical trial evidence to back up our clinical decisions when it comes to the management of patients with osteoporosis. In particular, the FREEDOM study and its extension not only gives us confidence in the safety profile of denosumab, its virtual twin-mapping placebo approach highlights the continued benefit of long-term treatment with denosumab,” notes Prof. Ferrari.1-3

As Prof. Ferrari highlighted, the FREEDOM study was a Phase III, randomised, double-blind, placebo-controlled study in 7,808 postmenopausal women which examined the incidence of new vertebral fractures at 3 years and the time to first non-vertebral and hip fractures.4 The 7-year extension study examined 4,550 patients who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of treatment. Women (n=2,207) who had received placebo during the initial study crossed over to denosumab in the extension study. While the aim of the extension study was to examine the long-term safety of treatment, the rate of new vertebral, hip and non-vertebral fractures as well as bone mineral density (BMD) were also examined.2

So, should we be keeping patients on therapy for as long as possible? Prof. Ferrari explains how the FREEDOM extension study confirmed the ongoing benefit for patients who can tolerate denosumab and continue to have a response to treatment (T-score ≥-2.0 to -1.5).5 “Long-term treatment with denosumab over 10 years enabled a substantial proportion of women with osteoporosis to achieve non-osteoporotic T-scores.5 The treatment continuously increased BMD at the spine and hip which results in a reduction in fragility fractures beyond three years with low rates of skeletal adverse events, such as atypical femur fractures or osteonecrosis of the jaw.6 So long as patients are achieving a T-score ≥-1.5 at the hip, long-term treatment with denosumab continues to reduce the risk of non-vertebral fractures. The virtual twin placebo mapping further emphasised the benefit of treatment compared to a placebo control even up to 10 years on therapy.6  

As Prof. Ferrari explained, the results from FREEDOM study were not just an artefact of the extension inclusion criteria. Patients who continued into the extension study were no more low risk than the overall cohort enrolled in the original study.7

“We were encouraged to find that in the extension study, the women who continued with long-term treatment were not particularly low-risk – as we might suspect that those who discontinued treatment throughout the initial 3-year study would be at a higher risk of fracture than those who continued treatment.7 So, the positive effect of denosumab on fracture risk is real, and not a result of positive patient selection,” adds Prof. Ferrari.7

What should we be thinking about when we need to discontinue denosumab?

Both Prof. Ferrari and Prof. Ebeling weighed in on the considerations for managing patients when denosumab is discontinued. Both clinicians emphasised the importance of continued treatment, even when patients achieve T-scores in the non-osteoporotic range.8-12 But for cases where discontinuation is unavoidable, understanding how denosumab and bisphosphonates work is important for choosing a discontinuation strategy.

“During denosumab treatment, long-term BMD changes are proportional to the level of suppression of bone turnover.13 Compared to bisphosphonates or selective oestrogen receptor modulators, we believe there is less remodelling-based bone loss observed with denosumab.13,14 After denosumab, a brief (1 year) course of bisphosphonates is warranted to maintain BMD, particularly in patients not previously exposed to bisphosphonates,” notes Prof. Ferrari. “We’ve seen some positive results where lumbar spine and total hip BMD is maintained with alendronate or BMD loss is minimised with zoledronic acid after denosumab discontinuation.8-12

Prof. Ebeling added, “for those patients who need to discontinue treatment, we need to recall that the effects of denosumab are reversible when discontinued without follow-on therapy.15-17 The overall risk of fracture, including vertebral fracture returns to that of untreated patients. For those who experience a single off-treatment vertebral fracture, there is speculation that it alters spine alignment and further increases risk of subsequent fractures due to increased vertebral strain.15,18-22 So, to prevent the cascade, preventing the microstructural changes in the first place is important – that’s why follow-on therapy post-discontinuation of denosumab is critical.”

During the discussion, Professors Ebeling and Ferrari highlighted that it is likely clinicians will face situations where some patients require discontinuation of denosumab. Dental surgery is a common reason, and the risk of osteonecrosis of the jaw and the risk of vertebral fracture must be weighed carefully.23

“Multiple vertebral fractures can occur fairly early on,” adds Prof. Ebeling. “When we looked at the time to fracture, they can occur very soon after the next dose of denosumab was scheduled. A number occurred within 6 months of the next dose being due.24 So, it can all happen very fast. There’s even been a recent case report from Melbourne this year where a patient acquired a rebound vertebral fracture in the dental chair during a tooth extraction whilst on a treatment holiday from denosumab.25 Therefore, I can’t emphasise enough how important it is to ensure discontinuation is followed up with oral therapy so we don’t undo all the good work so soon.”  

Professor Ebeling’s key considerations for long-term osteoporosis management

  1. Goal of treatment is fracture prevention
  2. Treatment with denosumab will increase BMD at all sites and reduce risk of fracture
  3. Denosumab treatment should be continued, however, if stopped an oral bisphosphonate should be used for 12-24 months to mitigate BMD loss

 

This article was sponsored by Amgen. The content is independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.

References:

  1. Ferrari S. Long-term treatment of osteoporosis: Denosumab benefits/risk profile. Presented at Amgen Symposium, IOF Regional Sydney ’18, 30 November 2018.
  2. Bone HG, et al. Lancet Diabetes Endocrinol 2017;5(7):513-523.
  3. Bone HG, et al. J Clin Endocrinol Metab. 2013;98:4483-4492.
  4. Cummings SR, et al. N Engl J Med. 2009;361(18):756-765.
  5. Ferrari S, et al. (in revision)
  6. Ferrari S, et al. ASBMR 2017
  7. Adachi JD, et al. BMC Musculoskelet Dis. 2017;18:174.
  8. McClung MR, et al. Presented at: The International Society for Clinical Densitometry; April 6-9, 2011; Miami, FL. Poster 116.
  9. Freemantle N, et al. Osteoporos Int. 2012;23:317–26.
  10. Lehman T, et al. Osteoporos Int. 2017;28:3067–68.
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  16. Brown JP, et al. J Bone Miner Res. 2013;28:746–52.
  17. Cummings SR, et al. J Bone Miner Res. 2018;33:190–98.
  18. Hernandez CJ, et al. J Bone Miner Res. 2006;21:1248–55.
  19. Dempster DW, et al. J Bone Miner Res. 2000;15:20–23.
  20. Ferrari S, et al. ENDO 2017 Presentation OR08-3.
  21. Slyfield CR, et al. Bone. 2012;50:1281–87.
  22. Anderson DE, et al. 2013. In: Osteoporosis, Marcus R, ed. 4th Edition. Waltham, MA: Academic Press, 497–516. Briggs AM, et al. Osteoporos Int. 2007;18:575–84.
  23. Daly C. Aust Prescr. 2016;39(2):47-48.
  24. Brown JP, et al. J Bone Miner Res. 2013;28(4):746-752.
  25. Leaney A, Sztal-Mazar S. Bone. 2018;108:43.

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