Embed Size (px)
Citation preview
OOC
Michael R. McClung, MD, FACP, FASBMR
Professorial Fellow, Mary MacKillop Institute for Health ResearchAustralian Catholic University, Melbourne, VIC
Director, Oregon Osteoporosis CenterPortland, Oregon, USA
XXVII Congreso de Osteologia
Santiago de Chile
May 10, 2019
Bisphosphonate Therapy for Osteoporosis What to Do After 5 Years?
R2
R1
C
OOH
OH
OH
OHO
P
P
OOC
Disclosures
I am disclosing financial relationships as follows:
Scientific Advisory Boards: Amgen
Honorarium for speaking: Amgen, Radius
Michael McClung, MD 2019
OOC
Osteoporosis
Definition:
A disorder due to bone loss that damages
skeletal architecture, weakens the skeleton and
predisposes a patient to fracture
• Osteoporosis is a chronic disease requiring
prolonged treatment
• It is important to develop a strategy for long-term
management
• Objectives of therapy
• improve bone strength
• reduce risk of fracture
• prevent rapid bone loss (less commonly)
Images Courtesy of
Drs. David Dempster & Roger Zambezi
Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62
OOC
• Anti-remodeling agents
• estrogen
• estrogen agonist/antagonist (raloxifene)
• bisphosphonates – 80% of the market
• RANK ligand inhibitor (denosumab)
• calcitonin (no longer used)
• Remodeling stimulating agents (anabolic)
• teriparatide and abaloparatide
• Modeling stimulating agent (true anabolic)
• romosozumab (in USA and Japan)
Drug Therapies for Osteoporosis
Image Courtesy of Dr. John Kanis
OOC
Osteoporosis: Treatment Choices
Raloxifene
Bisphosphonate
Teriparatide
Denosumab
When concerned
about hip fracture
For women at low risk for hip fracture
For patients at very high
risk of vertebral fracture
After 18-24 months
After 18-24 months
Bisphosphonates and
denosumab are the only agents
we consider for long-term use
McClung M. Personal opinion, 2018
OOC
Bisphosphonates
BENEFITS
• Effective fracture protection
• begins within months of starting therapy
• continues with long-term therapy
• Fracture reduction compared to placebo
vertebral fracture by 50-70%
multiple vertebral fractures by 75-95%
hip fracture by 40-50%
non-vertebral fracture by 20-35%
• in general are well tolerated
• in clinical trials, have a favorable safety profile
1. Seeman E et al. Bone 2004;17 Suppl 2:23S-29S
2. McClung M et al. Amer J Med 2013;126:13-20
OOC
Alendronate and Risk of Fracture
Vertebral Fracture Hip Fracture
Black DM et al. J Clin Endocrinol Metab 2000;85:4118–24.
Protection from fracture risk occurs soon after starting therapy.
No evidence of loss of effect over 3 years.
OOC
Bisphosphonates Preserve Skeletal Architecture
• Bisphosphonates do not reconstruct trabecular skeletal architecture and thus, do not cure osteoporosis
• In cortical bone, BMD increases; risedronate but not alendronate may decrease cortical porosity
Baseline 12 Months
Risedronate preserves
trabecular microarchitecture
in early postmenopausal
women
Dufresne TE et al. Calcif Tissue Int. 2003;73:423-32
Borah B et al. J Bone Miner Res 2010;25:41-7
OOC
Long-term Bisphosphonate Therapy
• Effects on remodeling persist for 9-10 years
• Hip BMD levels plateau after 4-5 years
• Fracture risk reduction persists but does not
improve with long term therapy
• Fracture risk protection is gradually lost over
1-3 years when treatment is stopped10
8
6
4
2
0
-2
Long-term Denosumab
FREEDOM Extension9.2%
% C
ha
ng
e F
rom
Ba
se
lin
e
Study Year1 2 3 4 50 6 7 8 9 10
Zoledronic acid 5 mg/y1
Denosumab1
Black DM et al. J Bone
Miner Res 2015;30:934-44
Femoral neck BMD
Me
an
Pe
rce
nt C
ha
ng
e (
±S
E)
Years
-80
-60
-40
-20
0
0 1 2 3 4 5 6 7 8 9 10
Placebo * ALN 10 mg
*Patients enrolled in the
original, 3 year study
OOC
Fracture Protection with Risedronate Persists
with Long Term Therapy
Fracture protection persists with long term therapy
0
2
4
6
8
10
12
14
Placebo Ris 5 mg Placebo Ris 5 mg Ris 5 mg Ris 5 mg
VERT-MN: Radiographic Vertebral Fracture*
Years 0-3 Years 4-5
Inc
ide
nc
e p
er
Ye
ar
(%)
Years 6-7
Subjects switched to
risedronate 5 mgat end of year 5
49%
P=0.001
59%
P=0.011
7.6% 4.7% 12.3% 5.2% 3.8% 3.8%
Mellstrom DD et al. Calcif Tissue Int 2004;75:462-8
OOC
Vertebral Fractures with Zoledronic Acid
3.0%
(14/469)
% P
ati
en
ts
Morphometric Vertebral Fractures
3.3%
(92/2822)
10.9%
(310/2853)
70%†(62, 76)
ZOL PBO
0
5
10
15P = <0.001
Years 4-6
Fracture protection persists with
long term therapy
Years 1-3
4.4%
(3/68)
Years 7-9
Core study Extension study
Black DM et al. N Engl J Med 2007;356:1809–22
Black DM et al. J Bone Miner Res 2012;27:243-54
Black DM et al. J Bone Miner Res 2015;30:934-44
OOC
Long-term Bisphosphonate Therapy
• Effects on remodeling persist for 9-10 years
• Hip BMD levels plateau after 4-5 years
• Fracture risk reduction persists but does
not improve with long term therapy
• Fracture risk protection is gradually lost
over 1-3 years when treatment is stopped
0 1 2 4 5
Cu
mu
lati
ve
In
cid
en
ce
of
Cli
nic
al
Ve
rte
bra
l
Fra
ctu
res
(%
)
Years Since FIT3
0
1
2
3
4
5
6
ALN 5 years → Placebo 5 yearsAlendronate 10 years
5.4%
RR 55%P = 0.013
2.5%
Black DM et al. JAMA 2006;296:2927-38
OOC Black DM, et al. N Engl J Med. 2007;356:1809–22
Vertebral Fractures with Zoledronic Acid
6.2%(30/486)
3.0%(14/469)
52%*(10, 74)
% P
ati
en
ts
Morphometric Vertebral Fractures
3.3%(92/2822)
Core study1 Extension study
10.9%(310/2853)
70%†(62, 76)
Z3P3 Z6
ZOL PBO
0
5
10
15
P = 0.0348
P = <0.001Absolute risk of new vertebral fracture
if therapy is stopped = 1%/year
OOC
Bisphosphonate Therapy: Limitations
• Complex but necessary dosing regimen
• Poor adherence
• Poor compliance with dosing rules
• Poorer persistence of therapy - <50% at 12 months
• Concerns about safety issues
OOC
• Hypocalcemia
• Intolerance
• Upper GI symptoms: oral drugs
• Bone and muscle pain
• Inflammatory eye problems
• Renal failure with IV therapy
• Esophageal cancer: oral drugs
• Atrial fibrillation: IV zoledronic acid
• Osteonecrosis of the jaw
• Estimated risk 1:10,000 – 1/100,000
• Fractures with atypical features
Bisphosphonates: Risks and Concerns
None increase with
long-term therapy
Minimal evidence of increased
risk with long-term therapy
Concern here of risk of
long-term therapy
Not proven to be associated
with bisphosphonate therapy
OOC
Long-term Bisphosphonate TherapySafety
• Duration-dependent risk of atypical
femoral fracture
• Risk decreases by 44-70% within 1
year of stopping therapy 1
• Risk highest in
• Asian women
• hypophosphatasia
• higher baseline BMD
AF
F p
er
10
0,0
00
pt-
ye
ars
Years of bisphosphonate therapy
0
20
40
60
80
100
120
2 5 8-9.9
Dell RM et al. J Bone Miner Res. 2012;27:2544-50
Black et al. ASBMR 2018, abstract 1007
1. Schilcher J et al. N Engl J Med 2011;364:1728-37
2/100,000
~1/1000
OOC
Alendronate and Femur Fractures
• Open register based cohort study containing two nested case control studies.
• Nationwide study of population of Denmark.
• Participants 61,990 men and women aged 50-94 at the start of treatment, who had not
previously taken alendronate, 1996-2007.
Abrahamsen B et al. BMJ 2016;353:i3365
No increase risk of femoral shaft/subtrochanteric
fractures over 10 years of therapy
Projected hip
fracture incidence
OOC
Alendronate and Femur Fractures
• Incidence of hip and femoral shaft fractures over 10 years of
alendronate therapy
Abrahamsen B et al. BMJ 2016;353:i3365
OOC
Benefits and Risk of Long-term
Bisphosphonate Therapy
• 1000 women, age 71 with femoral neck T-score value = -2.5
• Treatment with alendronate for 10 years
Events prevented Adverse skeletal events
Clinical fractures 160
Hip fracture 30
Death 10
Atypical femur fracture 1
Adapted from Cummings SR et al. JAMA 1998;280:2077-82 and
Dell RM et al. J Bone Miner Res. 2012;27:2544-50
OOC
Atypical Femoral Fracture: Management Tips
• At least 70% of patients have prodomal thigh pain weeks to
months before complete fracture occurs
• Periosteal stress reaction may be evident on DXA scan even in
patients without symptoms
2000 2010
68 year old woman treated for “osteopenia” with alendronate
for 10 years
OOC
Atypical Femoral Fracture: Management Tips
• At least 70% of patients have prodomal thigh pain weeks to
months before complete fracture occurs
• Periosteal stress reaction may be evident on DXA scan even in
patients without symptoms
• In patients in therapy for 3 years or more,
• counsel to report new thigh pain
• consider extending DXA scan further down the femoral shaft
OOC
Bisphosphonate “Drug Holiday”
• Justification
• Protection from fragility fracture persists 1-2 years upon stopping
therapy
• Risk of atypical fracture may decrease when treatment stopped
• After 3-5 years of bisphosphonate therapy:
• Patients at moderate fracture risk: consider a “holiday”
• Patients at high risk (low BMD, prior vertebral fracture, elderly):
continue to treat and follow to 10 years
Whitaker et al. N Engl J Med 2012;366:2048-51
OOC Adler R et al. J Bone Miner Res 2016; 31:16–35
Low riskHigh risk
OOC
Bisphosphonate “Drug Holiday”
• After 3-5 years of bisphosphonate therapy:
• Consider a “bisphosphonate holiday” if the patient no longer meets
criteria for therapy
McClung M. Personal opinion, 2019
OOC
Bisphosphonate “Drug Holiday”
• Most if not all patients given
bisphosphonates will need long-term
therapy
• Most patients who are appropriately
chosen for therapy are NOT candidates
for a “bisphosphonate holiday” after 3-5
years of therapy
• Risk of fragility fracture returns within 1
year of stopping risedronate and within
2 years of stopping alendronate
Curtis et al. ASBMR 2018, abstract 1006
Relative risk of hip fracture vs continued
bisphosphonate use among >160,000
patients I US Medicare database with
average follow-up of 2.7 years
OOC
Operationalizing a “Bisphosphonate Holiday”
• Discontinuation of therapy should probably not exceed
• 12 months after risedronate
• 2 years after alendronate or zoledronic acid
• Neither bone turnover markers nor BMD are helpful in identifying patients who fracture
after stopping alendronate
• Re-start therapy if fracture or bone loss occurs or when the patient again meets criteria
for therapy
Adler R et al. J Bone Miner Res 2016; 31:16–35
McClung M. Personal opinion, 2019
OOC
Osteoporosis: Long-term Treatment Plan
Raloxifene
Bisphosphonate
Teriparatide
Denosumab
3-5 years
Low risk
High risk
Consider drug holiday
Re-treat
Denosumab
Continue therapy
McClung M. Personal opinion, 2019
OOC
Effects of Long-term Therapy on Hip BMD
Black DM et al. J Bone Miner Res 2015;30:934-44
Hip BMD plateaus after 4-5 years of
bisphosphonate therapy
Persistent but no progressive
reduction in fracture risk with long-
term bisphosphonate treatment
Long-term Denosumab
FREEDOM Extension9.2%
Pe
rce
nta
ge
Ch
an
ge
Fro
m B
as
eli
ne
Study Year
1 2 3 4 50 6 7 8 9 10
Zoledronic acid 5 mg per year
Denosumab1
10
8
6
4
2
0
-2
Femoral neck BMD
OOC
Switching From Bisphosphonates to Denosumab
Data are least-squares means and 95% confidence intervals. *p < 0.0001 denosumab vs BP.
(1) Roux C et al. Bone. 2014;58:48-54. (2) Recknor C et al. Obstet Gynec 2013;121:1291-9. (3) Kendler DL et
al. J Bone Miner Res. 2010;25:72-81. (4) Miller PD et al. J Clin Endo Metab. 2016;101:3163-70.
IBN
ALN
ZOL
RIS
1.6%*1.4%*
0.9%* 1.3%*
To
tal
Hip
Perc
en
t C
ha
ng
e F
rom
Baseli
ne
0.5% 0.9% 1.1% 0.6%2.0% 2.2% 1.9% 1.9%0.0%
1.0%
2.0%
3.0%
4.0%
vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4)
Patients who had previously been treated with bisphosphonates
randomly assigned to a bisphosphonate or denosumab.
OOC
Teriparatide After Bisphosphonate Therapy
Boonen S et al. J Clin Endocrinol Metab 2008;93:852–60
% c
han
ge i
n B
MD
fro
m b
aselin
e
Non-bisphosphonate
245 women previously treated with antiresorptive drugs began
teriparatide therapy for 24 months (EUROFORS)
Alendronate Risedronate
Lumbar spine
Total hip
Large increase in spine BMD and moderate increase in hip BMD
with teriparatide after bisphosphonates
No evidence of “blunted” response
10
4
6
8
0
2
Prior therapy
OOC
Bisphosphonates: Long-term Treatment Plan
Bisphosphonate
Teriparatide
Denosumab
3-5 years
Low risk
High risk
Consider drug holiday
Re-treat
Denosumab
Continue therapy
McClung M. Personal opinion, 2019
OOC
Bisphosphonates: Long-term Treatment Plan
Bisphosphonate
Teriparatide
Denosumab
3-5 years
Low risk
High risk
Consider drug holiday
Re-treat
Denosumab
Continue therapyX
• No justification for continuing
bisphosphonate therapy for
more than 5 years
• no improved efficacy
• increasing risk of AFF
McClung M. Personal opinion, 2019
OOC
Osteoporosis: Long-term Treatment Plan
Bisphosphonate
Teriparatide
Denosumab
After 18-24 months
After 18-24 months
3-5 years
Low risk
High risk
Consider drug holiday
Re-treat
Denosumab Bisphosphonate
If “target” is met
or drug stopped
McClung M. Personal opinion, 2019
OOC
Bisphosphonate Therapy for OsteoporosisSummary
• Life-long management is required for patients with osteoporosis
• Appropriate choice of initial therapy and use of drugs in sequence
optimize clinical response and can further minimize the risks of
long-term therapy
• Bisphosphonates remain an important part of the treatment choices
for osteoporosis
• If the right patients are treated, the benefit:risk profile of
bisphosphonates remains very favorable for at least 10 years
• However, consider limiting the continuous use of bisphosphonates
to only 5 years in attempt to minimize risk of rare side effects
McClung M. Personal opinion, 2019
OOC
Thank you
Michael R. McClung, MD, FACPOregon Osteoporosis Center
Portland, Oregon, USA
Mt Hood, Oregon
