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

Bonesapart Skellington

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

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Bisphosphonates

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.

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

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

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

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

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

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

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

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 Apr;60(4):

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.

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

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

Fractures FLEX: # incidences were similar between the 2 groups – Exception: vertebral #s lower in group that continued on (RR= % 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)

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

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

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

Calculating Risk CAROC df df There’s an app for that: professionals/clinical-tools-and-resources/fracture-risk-tool/ professionals/clinical-tools-and-resources/fracture-risk-tool/ FRAX There’s an app for that too (for $5.99) – add the website to your homepage!

CAROC Requires BMD to calculate 10 year fragility fracture risk

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

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

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

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

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

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

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

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

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

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

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!!)

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.

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

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 Apr;60(4): Review. PubMed PMID: ; PubMed Central PMCID: PMC Jin M, Jensen B. RxFiles Osteoporosis: Treatment Comparison Chart. Dec Regier L, Bareham J, Jensen B. RxFiles The Frail Elderly & Long-Term Care: Drug Tx and Select Considerations Chart. Dec Jin M, Bareham J. Geri-RxFiles Osteoporosis in Older Adults. Nov 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 Mar;19(3): Epub 2007 Oct 16. PubMed PMID: Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG. Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int Nov;19(11): doi: /s Epub 2008 May 16. PubMed PMID: ; PubMed Central PMCID: PMC Schneider D. Long-Term Bisphosphonate Use: When to Stop? When to Restart? Today’s Geriatric Medicine. Vol 8 No. 2 p. 10.