1. Osteoporosis Deprescribing To Stop or Not to Stop Medications Canadian Society of Consultant Pharmacists Medication Management in the Elderly April 1 & 2, 2016 Toronto, Ontario Julia Bareham, MSc, BSP

2. Bonesapart Skellington

4. Objectives Potential risks & benefits of using bisphosphonate therapy in the tx of osteoporosis in older women Evidence to support when, and for whom, a bisphosphonate holiday may be considered Safety concerns related to bisphosphonate therapy, the time-to-benefit, & possible alternatives

5. What is RxFiles? Academic detailing program Not-for-profit program Funded by a grant from Saskatchewan Health Providing objective, comparative drug information to physicians, pharmacists and allied health professionals

6. What is RxFiles? RxFiles continues to serve health providers and educators through newsletter reviews, Q&As, Trial Summaries, and up-to-date drug comparison charts Tools for the front line practitioner wanting to provide the best possible drug therapy for their patients www.rxfiles.ca

7. Bisphosphonates

8. The big question is…. Is there is an appropriate duration of therapy for bisphosphonates??? While the antifracture efficacy & relative safety of the aminobisphosphonates have been well established in clinical trials, there have been concerns that prolonged use of these medications might ↑ the risk of rare, but serious, AEs.

9. Why even consider a holiday? Bisphosphonates can remain bound to bone for many years Those with greater binding affinities possess longer skeletal residency – Zoledronic acid > alendronate > risedronate > etidronate

10. What are the risks?? Osteonecrosis of the jaw (ONJ) Atypical subtrochanteric & diaphyseal femur fractures (AFF) Atrial fibrillation Esophageal cancer

11. ONJ Definition: presence of exposed bone in the maxillofacial region that does not heal within 8 wks of identification by a HCP, in the absence of radiation therapy Evidence suggests that there is a dose- response relationship between bisphosphonate use & the development of ONJ – Mechanism unknown

12. ONJ The development of ONJ with denosumab administration demonstrates that ONJ is not specific to bisphosphonates, but more likely a characteristic of potent antiresorptive agents RARE! With oral treatment (>1-283 in 100,000 pt yr) – Cancer High dose/long-term bisphosphonate use Extensive dental procedures

13. Atypical Subtrochanteric Fracture Occurs with minimal or no trauma Very rare (<1 per 1000) May present as thigh pain/hypersensitivity rxn Prodromal thigh pain

14. Atrial Fibrillation Rare! <1% Reports with zoledronic acid (3 year, phase 3 trial) Large database analyses & meta-analysis concluded that there is no association

15. Esophageal Cancer There is no consistent indication of elevated risk of esophageal cancer with oral bisphosphonates

16. Putting the Risk into Perspective Brown JP, Morin S, Leslie W, et al. Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician. 2014 Apr;60(4):324-33.

17. Bisphosphonate Drug Holiday Theory: to minimize long-term bisphosphonate exposure & avoid potential adverse events while maintaining some degree of antifracture efficacy through the residual antiresorptive activity of retained bisphosphonate.

18. risks FLEX – Fracture Intervention Trial Long-Term Extension Alendronate for 5 years – re-randomized to either continue or placebo for another 5 years HORIZON – Health Outcomes & Reduced Incidence with Zolendronic acid Once Yearly Zolendronic acid for 3 years – re-randomized to either continue infusions or placebo for another 3 years

19. What happened?? Groups that continued therapy: maintenance or small ↑s of BMD & continued bone turnover marker suppression Groups that discontinued therapy: ↓s in hip BMD & gradual ↑s in markers of bone turnover – FLEX: total hip BMD returned to pretreamtnet baseline (FIT) after 5 years of discontinuation

20. Fractures FLEX: # incidences were similar between the 2 groups – Exception: vertebral #s lower in group that continued on (RR=0.45 95% CI 0.24 to 0.85) HORIZON: those who continued with therapy had a significantly lower incidence of vertebral # (OR=0.51, 95% CI 0.26 to 0.95)

21. Other Studies 3 yrs risedronate, then d/c  mean loss of BMD to baseline levels, although significant anti-# efficacy remained at the spine as compared to placebo (RR=0.54, 95% CI 0.34 to 0.86) Bisphosphonate x 2 yrs, then d/c or continue on  active therapy had a significantly lower risk of hip # vs d/c (4.67 vs 8.43 per 1000 person-years, P=0.016) BUT difference was diminished by either longer duration of bisphosphonate administration or by high compliance to therapy

22. EDGE Study Effectiveness of DiscontinuinG bisphosphonatEs Question: whether & when pts can be withdrawn from alendronate without a significant ↑ in # risk – University of Alabama at Birmingham – Recruit 9,700 women over 65 yrs on alendronate for 3 or more yrs; randomized to either continue or d/c & followed over 3 yrs for clinical #s & AEs\ – Estimated study completion date: May 2016

23. When might we consider a bisphosphonate holiday?? FRACTURE RISK LOW <10% 10 year risk LOW <10% 10 year risk MODERATE 10% to 20% 10 year risk MODERATE 10% to 20% 10 year risk HIGH >20% 10 year risk OR Previous fragility # (vertebral or hip) OR >1 fragility # after age 40 HIGH >20% 10 year risk OR Previous fragility # (vertebral or hip) OR >1 fragility # after age 40

24. Calculating Risk CAROC http://www.osteoporosis.ca/multimedia/pdf/CAROC.p df http://www.osteoporosis.ca/multimedia/pdf/CAROC.p df There’s an app for that: http://www.osteoporosis.ca/health-care- professionals/clinical-tools-and-resources/fracture-risk-tool/http://www.osteoporosis.ca/health-care- professionals/clinical-tools-and-resources/fracture-risk-tool/ FRAX http://www.sheffield.ac.uk/FRAX/tool.jsp?country=19 http://www.sheffield.ac.uk/FRAX/tool.jsp?country=19 There’s an app for that too (for $5.99) – add the website to your homepage! https://itunes.apple.com/us/app/frax/id847593214?ls=1&mt=8 https://itunes.apple.com/us/app/frax/id847593214?ls=1&mt=8

25. CAROC Requires BMD to calculate 10 year fragility fracture risk

26. FRAX Does NOT require BMD to calculate 10 year fragility fracture risk

27. No important clinical risk factors for # Holiday Appropriate? YES! At low future # risk, should be withdrawn from therapy  there is no indication for tx Monitor at extended intervals (3 to 5 years) LOW <10% 10 year risk LOW <10% 10 year risk

28. Assess clinical risk factors for # Assess femoral neck BMD Request lateral spine x-ray scan to investigate for any subclinical vertebral #s MODERATE 10% to 20% 10 year risk MODERATE 10% to 20% 10 year risk

29. Holiday Appropriate? Maybe Did you find any vertebral #s? Yes? Then high risk  bisphosphonates No history of fragility #? Consider a holiday if femoral neck BMD T-score is >-2.5 & there are no other important clinical risk factors MODERATE 10% to 20% 10 year risk MODERATE 10% to 20% 10 year risk

30. Holiday Appropriate? No Continue with bisphosphonate treatment or switch to an alternative (e.g. teriparatide or denosumab) HIGH >20% 10 year risk OR Previous fragility # (vertebral or hip) OR >1 fragility # after age 40 HIGH >20% 10 year risk OR Previous fragility # (vertebral or hip) OR >1 fragility # after age 40

31. BUT ….. It might be appropriate to stop if: Limited life expectancy – consider time-to-benefit of ~1 to 3 years for # prevention & conversely, consider that after discontinuation of tx, the benefit of # prevention may persist for 3 to 5 years

33. BUT ….. It might be appropriate to stop if: Limited life expectancy Palliative care Patient preference Polypharmacy (e.g. DIs) Hypersensitivity reactions or AEs Oral agents bioavailability <1%; staying upright for 30 minutes Significant renal impairment

34. Alternatives Teriparatide (Forteo) – parathyroid hormone – Consider if # after 12 months of bisphosphonate use with t-score < -3 & hx of at least 1 other fracture – SC daily for up to 18 months Denosumab (Prolia) – RANK ligand inhibitor – SC every 6 months AVOID denosumab therapy followed by teriparatide, can result in bone loss

35. Alternatives Raloxifene (Evista) – selective estrogen receptor modulator – ↑ risk of stroke & VTE (e.g. pulmonary embolism) in individuals >65 years Hormone Therapy – Efficacy not clear

36. Don’t forget! Lifestyle Management – Adequate vitamin D – Adequate calcium – Weight-bearing activities – Avoidance of smoking & excessive alcohol

37. Restarting a bisphosphonate In your LOW risk pts, restart when the individual becomes high risk, or moderate-risk with additional risk factors (e.g. long-term corticosteroid use). In your MODERATE risk individuals, restart if there is a significant loss of BMD or a # (individualize your care plan!!)

38. Bottomline Bisphosphonate drug holidays can be considered for individuals who have persisted with bisphosphonate therapy for 3 to 5 years AND for those at low risk of fracture. High-risk individuals with osteoporotic bone mineral density or history of fragility # (including prevalent vertebral fracture) are NOT candidates for bisphosphonate holiday.

39. “Duration of treatment & possible discontinuation should be personalized for patients based on their response to treatment, fracture risk, and comorbidities.” – Dr Diane Schneider

40. References 1.Brown JP, Morin S, Leslie W, et al. Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician. 2014 Apr;60(4):324-33. Review. PubMed PMID: 24733321; PubMed Central PMCID: PMC4046542. 2.Jin M, Jensen B. RxFiles Osteoporosis: Treatment Comparison Chart. Dec 2015. 3.Regier L, Bareham J, Jensen B. RxFiles The Frail Elderly & Long-Term Care: Drug Tx and Select Considerations Chart. Dec 2015. 4.Jin M, Bareham J. Geri-RxFiles Osteoporosis in Older Adults. Nov 2015. 5.Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, Grauer A. Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int. 2008 Mar;19(3):365-72. Epub 2007 Oct 16. PubMed PMID: 17938986. 6.Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG. Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int. 2008 Nov;19(11):1613-20. doi: 10.1007/s00198-008-0604-4. Epub 2008 May 16. PubMed PMID: 18483689; PubMed Central PMCID: PMC2574626. 7.Schneider D. Long-Term Bisphosphonate Use: When to Stop? When to Restart? Today’s Geriatric Medicine. Vol 8 No. 2 p. 10.