Antiresorptive therapy : when to
start? When to have a drug Holiday?
Jean-Marc Kaufman
Endocrinologie UZGent [email protected]
BMS Brussels October 14th 2017
• No potential conflicts of interest to declare
Long term management of osteoporosis: why? A disorder throughout the life course
~50% of hip fracture patients have experienced prior fractures
Kanis JA & Johnell O. J Endocrinol Invest 1999;30:583-588
Age, lower BMD and prior fracture are major risk factors so that
fracture risk will increase and morbidity accumulate if untreated.
Nele 1
Mother hipfracture at age 83y
No fracture history; no other risk facors
Nele then 54y had a DXA:
T-score L1-L4: -2.7
T-score femoral neck: -2.0
T-score total hip: -0.7
R/ calcium+vit D & raloxifene, after 3 months stop
(VMS, leg cramps) and changed to
alendronate 70mg/week
Now 61y; 6,5y alendronate; GP asks advise
further management
Laura Wrist fracture at age 52y
Clinical fracture D12 at age 72y
RX: fracture D12 and old fracture D7
Past smoker; COPD Gold II
46kg; 162 cm (BMI 17,5)
DXA
T-score L1-L4: -3.7
T-score femoral neck: - 3.0
R/ calcium+vitD; alendronate 70mg/week
Now 77j; 5 years alendronate
Further treatment?
Kristel 1
Non traumatic fracture D10 at age 61y
Surgical menopause at 44y;
smoking; reflux (R/ PPI)
62kg; 167 cm
DXA
T-score L1-L4: -3.4
T-score femoral neck -2.8
R/ calcium + vitamine D; risedronate 35mg/week
Now 66jaar; risedronate 5years. Further?
Long-term management of osteoporosis
• Is long-term treatment efficacious?
• Is long-term treatment safe?
• What happens when treatment is discontinued?
• Prolonged treatment for whom? How long?
• What are the alternatives?
• Practical approach?
Long-term (7yrs) effects of risedronate
Mellström et al Calcif Tissue Int 2004:75:462-468
urinary NTX Total hip BMD
Annualized vertebral
fracture incidence
BMD = bone mineral density.
Adapted from Bone HG, et al. N Engl J Med. 2004;350:1189–1199. FOSAMAX® (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
0
2
4
6
8
10
12
14 Spine (P<0.001)
Mean
(±S
E)
% C
han
ge
0
Year
1 2 3 4 5 6 7 8 9 10
(P<0.001)
Hip Trochanter
(P<0.001)
n=196 n=151 n=122 n=86
alendronate 10 mg daily
Long-term effects of alendronate on BMD
Eigth vs five years denosumab in women with
postmenopausal osteoporosis
CTX ng/ml BMD % change from baseline Yearly incidence%
Papapoulos et al Osteoporosis Int 2015;26:2773-83
Denosumab vs placebo in women on aromatase
inhibitor for non metastatic breast carcinoma
Percentage risk of fracture based on Kaplan–Meier time-to-event analysis within each treatment group at 6-month intervals. The HR and P value were calculated from a Cox model including
treatment groups as the independent variable and stratified by the randomisation stratification factors. Error bars are 95% CIs. CI, confidence interval; HR, hazard ratio.
HR = 0.50 (95% CI: 0.39–0.65)
P < 0.0001
Percentage risk of fracture
Placebo
Denosumab
36 30 42 12 6 18 24 0 0
5
10
15
20
25
30
Ris
k o
f fr
ac
ture
(%
)
48
Months since randomisation
54 60 66 72
Number at risk
Placebo 1709 1660 1470 1265 1069 921 785 637 513 384 275 185 112
Denosumab 1711 1665 1488 1297 1118 965 823 688 549 432 305 221 116
Overall cumulative incidence of first clinical fractures
Placebo: n = 176
Denosumab: n = 92
Gnant M, et al. Lancet 2015;386:433–43.
Persistence for alendronate therapy (Belgium)
Persistence of 39% at 12 months
For each % decrease in persistence, 0.4% increase in hip fracture risk
Rabenda et al Osteoporosis Int 2008;19:811
Effect of poor bisphosphonate adherence on
fracture risk (Meta-analysis)
≤80% compliance:
Fracture risk +46%
vertebral +43%
Hip +28%
Non-vertebral +16%
Imaz et al Osteoporos Int 2010;21:1943-51
Risks associated with prolonged strong suppression of bone turnover?
Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621.
Physiological Range
Bo
ne
Str
en
gth
Bone Turnover
Excessive turnover
• Increase in stress risers (weak zones)
• Increase in perforations
• Loss of connectivity
Insufficient turnover
• Accumulation of microdamage
• Increased brittleness due to
excessive mineralization
? Osteoporosis
Potential adverse effects?
• Acute phase reactions
• Gastroesophageal irritation
• Impaired renal function
• Hypocalcemia
• Infections??
• Atrial fibrillation ??
• Oesophageal cancer??
• Cardiovascular disease??
• Osteonecrosis of the jaw (ONJ)
• Atypical femoral fracture (AFF)
Osteonecrosis of the jaw (ONJ)
• Exposed necrotic bone in maxillofacial region for at least 8 weeks of
appropriate treatment.
• No history of radiation therapy to the jaw
• Increased risk associated with use of potent antiresorptive agents
(bisfosfonates;denosumab) and anti-angiogenic agents
• Mostly in cancer patients on high dose BP or denosumab
• Risk factors: glucortocoids; poor oral hygiene; diabetes; smoking
• Estimated incidence under
treatment with bisphosphonates
for osteoporosis:
1/10,000 to 1/100,000 patient
treatment years*
• No clear indication for treatment
duration effect
*Khosla et al J Bone Miner Res 2007;22:1479-91
(JBMR 2010)
Atypical femoral fracture (AFF)
• Subtrochanteric + at least 4 out of 5 major diagnostic criteria
(besides not obligatory minor criteria)
• Indication for bisphosphonate exposure duration relationship
• Age-adjusted incidence rate*:
1.8/100,000 per year
with a 2y BP exposure
to
113/100,000 per year with
8 to 9.9y BP exposure
*Dell et al J Bone Miner Res 2012;27:2544-50
Bisphosphonate use-associated risks into perspective
Adler et al J Bonne Miner Res 2016; 31: 16-35 (Task Force ASBMR)
Treatment with BP for 5 years:
175 hip fractures, 1470 vertebral fractures, 945 wrist fractures (total: 2590)
potentially averted for risk of 16 AFF
What happens after discontinuation?
• Drugs that work
while you take them: – Calcium/vitamin D
– HRT
– Raloxifene
– Denosumab
– Teriparatide
• Bisphosphonates:
– What do we learn from the
FLEX (FIT extension) trial? –
alendronate offset
– What do we learn from the
HORIZON extension trial? –
zoledronic acid offset
– Other bisphosphonates?
0
2
4
12
14
16
0 1 2 3 4
BM
D C
ha
ng
e F
rom
FIT
Ba
se
lin
e, M
ea
n %
b
Year
FIT FLEX 3.7%
P<0.001
6
8
10
0
2
4
12
14
16
0 1 2 3 4
Year
6
8
10
5
Number
FOSAMAX/FOSAMAX 662 660 658 656 460c 657 642 628 599 580 553
FOSAMAX/placebo 437 435 436 432 297c 437 428 415 401 380 361
Fit long term extension (FLEX) trial
Alendronate 5/10mg/day 5yrs followed by
randomization to alendronate 10mg/day or placebo
Lumbar Spine
Black et al JAMA 2006;296:2927
Year Year
alendronate/alendronate alendronate/placebo
Fit long term extension (FLEX) trial
0
2
4
12
14
16
0 1 2 3 4
BM
D C
ha
ng
e F
rom
FIT
Ba
se
lin
e, M
ea
n %
b
Year
FIT FLEX
2.4%
P<0.001
6
8
10
0
2
4
12
14
16
0 1 2 3 4
Year
6
8
10
5
Number
FOSAMAX/FOSAMAX 662 660 658 656 460c 657 642 628 599 580 553
FOSAMAX/placebo 437 435 436 432 297c 437 428 415 401 380 361
Total Hip
Black et al JAMA 2006;296:2927
alendronate/alendronate alendronate/placebo
Year Year
Small reduction in lumbar spine BMD during off treatment period, while total hip BMD
returned to pre-treatment baseline value after 5 years of ALN discontinuation.
0
0.05
0.10
0.15
0.20
0.25
0 1 2 3 4
Me
an
Va
lue
, n
g/m
Lb
Year
FIT FLEX
0 1 2 3 4
Year
5 Number
alendronate/alendronate 129 57c 45d 129 124 129
alendronate/placebo 87 48c 32d 87 87 87
0
0.05
0.10
0.15
0.20
0.25
55,6%
P<0.001
Fit long term extension (FLEX) trial
Serum CTX (bone resorption marker)
alendronate/alendronate alendronate/placebo
Black et al JAMA 2006;296:2927
Fra
ctu
re I
ncid
en
ce, %
Clinical Vertebral Vertebral Morphometric Nonvertebral 0
RR=0.86
95% CI (0.60, 1.22)
RR=1.00
95% CI (0.76, 1.32)
5.3%
2.4%
11.3% 9.8%
18.9% 19.0%
RR=0.45
95% CI (0.24, 0.85)
5
10
15
20
25 alendronate/alendronate (n=662)
alendronate/placebo (n=437)
Fit long term extension (FLEX) trial
Fracture incidence during extension
Black et al JAMA 2006;296:2927
Fit long term extension (FLEX) trial: prediction of clinical fracture after alendronate
discontinuation (post-hoc analyses)
Age, per 5 y increase:
RR 1.54 (1.26-1.85)
Bauer et al JAMA 2014;174:1126-34
Z6 n= 589 609 608 600 524 450
Z3P3 n= 599 613 606 602 540 467
Time (Years From Core Study Baseline)
Z6 Z3P3
0
Core + Extension study
–2.0
–1.0
0.0
1.0
2.0
3.0
4.0
–3.0
5.0
Start of extension trial
3 6 1 2 4 5
1.36%P < 0.0007 +4.5%
+3.1%
Horizon extension trial: femoral neck BMD
Black et al J Bone and Min Res 2012;27:243-254
Percentage Change (%)
Horizon extension trial: serum P1NP
• Mean values remained within the premenopausal reference range throughout
0
20
40
60
0 1 2 3 4 5 6 Time (years)
Mean
seru
m P
1N
P
(n
g/
mL)
Start of extension trial
Z6 Z3P3
* *
Black et al J Bone and Min Res 2012;27:243-254
Horizon extension trial:
fracture rates during extension
Black et al J Bone and Min Res 2012;27:243-254
Power 99% Power 33%
Morphometric vertebral fractures Non-vertebral fractures
Incident Morphometric Vertebral Fracture Rates: Stratification by FN BMD
FN BMD ≤-2.5
Z3P3 Z6
FN BMD >-2.5
BMD, bone mineral density; CI, confidence interval; FN, femoral neck;
NNT, number needed to treat; OR, odds ratio
3.0%
(7/235) 2.4%
(5/210)
OR: 0.79 (95% CI: 0.23, 2.53)
P = 0.70
3.5%
(9/257)
9.2%
(23/250)
OR: 0.36 (95% CI: 0.15, 0.77)
P = 0.01
0
5
10
15
NNT = 18
NNT = 167
Pro
po
rtio
n o
f P
ati
en
ts (
%)
Treatment subgroup interactions not significant
Cosman et al J Clin Endocrinol Metab 2014;99:4546-54
Incident Morphometric Vertebral Fracture Rates Stratification by Incident Vertebral Fracture During Core Study
CI, confidence interval; NNT, number needed to treat; OR, odds ratio
Differences between Z6 and Z3P3 groups were analyzed using Fisher’s exact test for categorical variables
Incident Vertebral
Fracture During Core
Z3P3 Z6
5.6%
(26/467) 2.6%
(12/454) NA
(0/11)
25%
(4/16)
0
10
20
30
OR: 0.46 (95% CI: 0.22, 0.90)
P = 0.03
P = 0.12
NNT = 4
NNT = 34
Pro
po
rtio
n o
f P
ati
en
ts (
%)
No Incident Vertebral
Fracture During Core
Treatment subgroup interactions not significant
Cosman et al J Clin Endocrinol Metab 2014;99:4546-54
Horizon extension trial:
6 or 9 y of treatment
P1NP
βCTX
Total Hip
Femoral Neck
Black J Bone Miner Res 2015;30:934-44
Offset after 7 years of risedronate
Eastell et al, J Clin Endocrinol Metab. 2011 96: 3367–3373.
Effects of denosumab
treatment and discontinuation
Bone et al J Clin Endocrinol Metab 2011;96:972-80
Effects of denosumab
treatment and discontinuation
Bone et al J Clin Endocrinol Metab 2011;96:972-80
Practical approach to
long-term management?
Key questions for an individualized approach
• What was the baseline fracture risk?
• What is the present treatment?
• How good is the adherence to this treatment?
• What is the reassessed present fracture risk?
Recent incident fracture? FN T-score ≤ -2.5?
drugs affecting bone? Falls? secondary causes?
country-specific FRAX?
Management of postmenopausal women on
long-term bisphosphonate therapy
Adler et al, JBMR, 31, 16-35 (2016) (ASBMR Task Force)
Some limitations
• Based on data Caucasian postmenopausal
women only
• Based on data with alendronate and zoledronic
acid only
• No data beyond 10 years
• No data on the effect on fracture of switching to
another therapy
• Need for more validation of tools such as FRAX
for reassessment of risk under treatment
• No validated criteria for decision if/when to
reinstate treatment following drug holiday
Nele 1
Mother hipfracture at age 83y
No fracture history; no other risk facors
Nele then 54y had a DXA:
T-score L1-L4: -2.7
T-score femoral neck: -2.0
T-score total hip: -0.7
R/ calcium+vit D & raloxifene, after 3 months stop
(VMS, leg cramps) and changed to
alendronate 70mg/week
Now 61y; 6,5y alendronate; GP asks advise
further management
Nele 2
healthy; 58kg; 164cm
No clinical fractures
No new risk factors
DXA:
T-score L1-L4: - 2.1
T-score femoral neck: -1.8
T-score total hip: -0.4
Screening vertebral fracture (IVA): negative
Nele 3
FRAX (including DXA) original at start treatment:
Major osteoporotic fracture: 7,5%/10j
Hip fracture: 1.2%/10j
FRAX (including DXA) present (?) Major osteoporotic fracture: 10%
Hip fracture: 1.1%
Laura 1 Wrist fracture at age 52y
Clinical fracture D12 at age 72y
RX: fracture D12 and old fracture D7
Past smoker; COPD Gold II
46kg; 162 cm (BMI 17,5)
DXA
T-score L1-L4: -3.7
T-score femoral neck: - 3.0
R/ calcium+vitD; alendronate 70mg/week
Now 77j; 5 years alendronate
Further treatment?
Laura 2
RX: fractures D7, D11 & D12
COPD Gold III ; 46kg 161cm
DXA
T-score L1-L4: -2.9
T-score femoral neck: - 2.4
FRAX original:
Major osteoporotic fracture 22%/10j
Hip fracture 9.1%/10j
Kristel 1
Non traumatic fracture D10 at age 61y
Surgical menopause at 44y;
smoking; reflux (R/ PPI)
62kg; 167 cm
DXA
T-score L1-L4: -3.4
T-score femoral neck -2.8
R/ calcium + vitamine D; risedronate 35mg/week
Now 66jaar; risedronate 5years. Further?
Kristel 2 In general few problems
(R/ PPI and lisinopril)
60kg; 167 cm
DXA
T-score L1-L4: -3.0
T-score femoral neck: -2.6
screening vertebral fracture (IVA): D10
FRAX initial:
Major fracture: 20%
Hip fracture: 11%
Research needs and future directions
• Validation of tools for reassessment of
fracture risk under treatment
• More long-term / offset fracture reduction
data needed
• Effects of combined/sequential treatments
• Alternative treatment regimens for
available compounds
Effect of single-dose (5mg) zoledronic acid
in frail elderly women
Greenspan et al JAMA Intern Med 2015;&è(:913-21
Effects over 5yrs of a single dose (5mg) zoledronic
acid in osteopenic postmenopausal women
Grey et al Bone 2012;50:1389-93
βCTX
P1NP
BMD Spine
BMD
Total Hip
BMD
Total Body
Take Home Messages
• Treatment should not be initiated unless
sufficiently high fracture risk
• Poor adherence to treatment is a major problem
• Reassessment after 3 to 5 years is recommended
• Further management is mainly dependent on risk
profile of the patient and which drug she/he is on
• Concerns for risk of feared adverse events (ONJ &
AFF) during long-term treatment should play only
a secondary role in decision making.
Thank you