Transcript Osteoporosis Deprescribing To Stop or Not to Stop Medications

Osteoporosis Deprescribing
To Stop or Not to Stop Medications
Julia Bareham, MSc, BSP
Canadian Society of Consultant Pharmacists
Medication Management in the Elderly
April 1 & 2, 2016
Toronto, Ontario
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
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 doseresponse 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
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•
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. 2014 Apr;60(4):324-33.
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=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)
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%
MODERATE
10% to 20%
10 year risk
10 year risk
HIGH
>20% 10 year risk OR
Previous fragility # (vertebral
or hip) OR
>1 fragility # after age 40
Calculating Risk
CAROC
http://www.osteoporosis.ca/multimedia/pdf/CAROC.p
df
• There’s an app for that: http://www.osteoporosis.ca/health-careprofessionals/clinical-tools-and-resources/fracture-risk-tool/
FRAX
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
CAROC
• Requires BMD to calculate 10 year fragility
fracture risk
FRAX
• Does NOT require BMD to calculate 10 year
fragility fracture risk
LOW
<10%
10 year 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)
MODERATE
10% to 20%
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
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
HIGH
>20% 10 year risk OR
Previous fragility # (vertebral or hip) OR
>1 fragility # after age 40
Holiday Appropriate?
• No
• Continue with bisphosphonate treatment or
switch to an alternative (e.g. teriparatide or
denosumab)
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 – 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 – RANK ligand inhibitor
– SC every 6 months
AVOID denosumab therapy followed by teriparatide,
can result in bone loss
Alternatives
• Raloxifene – 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
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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.
Jin M, Jensen B. RxFiles Osteoporosis: Treatment Comparison Chart. Dec 2015.
Regier L, Bareham J, Jensen B. RxFiles The Frail Elderly & Long-Term Care: Drug Tx and Select Considerations
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Jin M, Bareham J. Geri-RxFiles Osteoporosis in Older Adults. Nov 2015.
Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, Grauer A. Fracture risk remains reduced
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Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG. Risk of hip fracture after bisphosphonate discontinuation:
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Schneider D. Long-Term Bisphosphonate Use: When to Stop? When to Restart? Today’s Geriatric Medicine. Vol
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References
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Maraka S, Kennel KA. Bisphosphonates for the prevention and treatment of osteoporosis. BMJ. 2015 Sep
2;351:h3783. doi: 10.1136/bmj.h3783. Review. PubMed PMID: 26333528.
PL Detail-Document, Comparison of Medications for Osteoporosis. Pharmacist’s Letter/Prescriber’s Letter. July
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