malang pain update yearly bisphosphonate
TRANSCRIPT
Osteoporosis management
Efficacy and safety of yearly bisphosphonate
Osteoporosis Increase morbidity and mortality
Who to treat ?
Prior h/o hip/vertebral #
or
T Score < -2.5
orT Score -1 to -2.5 &10 yr risk (FRAX) :
HIP # > 3 % or major osteoporotic # > 20 %
Postmenopausal women /men > 50 yrs
with
Anti-resorptive
Anabolic
‘Dual action’
Bone marrow precursors
OsteoblastsOsteoclast
Lining cells
Stimulators of Bone Formation
FluoridePTH analogs
Sr Ranelate (?)
Inhibitors ofBone Resorption Estrogen, SERMs
BisphosphonatesCalcitonin
Inhibitors ofRANKL
Cathepsin K
Therapeutic strategies
Treatments & Efficacy Vertebral Fx Non-vertebral Fx
Other Fx Hip FxOralHRT Yes Yes YesEtidronate* YesAlendronate* Yes Yes YesRisedronate* Yes Yes YesIbandronate* Yes [Yes]Raloxifene* Yes Calcitriol* YesStrontium Ranelate* Yes Yes [Yes]
Vertebral Fx Non-vertebral FxOther Fx Hip Fx
Subcutaneous
Teriparatide* Yes Yes 1-84 PTH* Yes Denosumab* Yes Yes Yes Intravenous Pamidronate Ibandronate*
Zoledronate* Yes Yes Yes Intranasal or Subcutaneous Calcitonin* Yes
Vertebral Fx Nonvertebral Fx
Other Fx Hip Fx
Alendronate* Yes Yes Yes
Risedronate* Yes Yes Yes
Zoledronic acid* Yes Yes Yes
PTH* Yes Yes ???
Strontium ranelate* Yes Yes ???
Denosumab* Yes Yes Yes
Appropriate use of appropriate treatments can halve the incidence of fractures
* plus calcium + vitaminD
Mainstay of treatment : BisphosphonatesApproval in US for osteoporosis• Alendronate : 1995• Risedronate : 2000• Ibandronate : 2005• Zoledronate : 2007.
Contraindications
Duration of treatment
Hot topics
HIP FRACTURE – Female Age 75 and overGive single oral dose 100,000 IU vitaminD @ as soon as feasible post hip fracture & start 1000mg
CaCO3+800IU vitaminD asap, (if on this already – continue)
Already on a BP(bisphosphonate)?
No
YesGood prognosis & eGFR 30 or over
Duration of treatment?Yes No
1. Patient or resident carer understand concepts of osteoporosis, fracture risk reduction & protocol for ingesting oral BPAND2. No contraindications to oral BPs [dysphagia / oesophageal stricture / achalasia /hypocalcaemia].
Yes
Oral ALN 70mg / wk
No
Patient suitable for IV BP& eGFR 35 or over
Yes No
Arrange IV zoledronic acid 5mg infusion (over at least 15min),
4-6/52 after hip fracture
Consider oral BP or, if at risk equivalent to that of fracture
plus T-score -2.4 or less, consider strontium ranelate.
Continue b.d. calcium + vitaminD
Continue b.d.oral calcium + vitaminD
More than 2yr 2yr or less
Optimal compliance with / adherence to BP & BP well tolerated
YesNo
Continue oral BPIF eGFR is 30 or moreOtherwise continue
b.d. calcium + vitaminD
GREATER GLASGOW & CLYDE PROTOCOL FOR FRACTURE SECONDARY PREVENTION AFTER HIP FRACTURE IN WOMEN AGE 75+
Zoledronic acid 5 mg IV once a year
Once Yearly Zoledronic Acid Reduces Fractures
HORIZON Pivotal Fracture Trial Multi-national, multi-center, RCT 7,736 women age 65-89 with T-score <
-2.5 or fracture plus T-score < -1.5 Calcium 1000-1500 mg/day vit D (400-
1200 IU/day) Zoledronic acid IV infusion 5 mg
Black et al. NEJM 356:1809-1822, 2007
ZOL reduces hip fracture
*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
P = .0024
1
2
3
0
Placebo (n = 3861) ZOL 5 mg (n = 3875)
Cu
mu
lati
ve I
nci
den
ce (
%)
Time to First Hip Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36
41%*(17%, 58%)
P < .0001
Cu
mu
lati
ve I
nci
den
ce (
%)
Time to First Clinical Vertebral Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36
77%(63%, 86%)
Placebo (n = 3861) ZOL 5 mg (n = 3875)
1
2
3
0
ZOL reduces vertebral fx
*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
P = .0002
Time to First Clinical Non-vertebral Fracture (months)
2
4
6
8
10
12
0 3 6 9 12 15 18 21 24 27 30 33 36
25%(13%, 36%)
Placebo (n = 3861) ZOL 5 mg (n = 3875)
0
Cu
mu
lati
ve I
nci
den
ce (
%)
ZOL reduces non-vertebral fx
*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
Zoledronic Acid will Improve Patient Compliance as Once-Yearly IV Therapy is Preferred
Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.
16.4
18.9
Both Are EqualOnce-Yearly IV
Once-Weekly Pill
More convenient
More willing to take long term
Overall preference
N = 122
66.4
59.8
0 20 40 60 80 100
68.0
66.4
15.618.0
20.5
15.6
19.713.9
% of Patients
More satisfying
24
J Bone Miner Res. 2012;27:240–242
HORIZON-PFT 3-years data:Black DM, et al. N Engl J Med. 2007;356:1809-1822
(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly)
HORIZON-Pivotal Fracture Trial Extention
25
• 3-year, randomized, double-blind, placebo-controlled extension trial • 2456 postmenopausal women• Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3• Secondary endpoints: BMD at other sites, BTMs, fracture incidence, safety
HORIZON-PFT Extension: Study Overview
Black DM, et al. J Bone Miner Res. 2012;27:240–242
26
Primary Endpoint: % Change of ZOL 5 mg Treatment in Femoral Neck BMD at Years 6 VS Years 3
*P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables**P value computed from 2-way ANOVA with treatment and region as explanatory variables.MITT = modified intention to treat1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
Z6 n= 589 609 608 600 524 450
Z3P3 n= 599 613 606 602 540 467
Z3 n= 3851
PBO n= 3845
27
ZOL n= 268 262 236 228
PBO n= 265 258 226 212
Z6 n= 101 100
Z3P3 n= 102 84ZOL n= 268 262 236 228
PBO n= 265 258 226 212
Z6 n= 101 100
Z3P3 n= 102 84
*P = 0.1910 **P < 0.00011Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
Secondary Endpoint: % Change of ZOL 5 mg Treatment in Lumbar Spine BMD at Years 6 VS Years 3
28
Secondary Endpoint: 6 years of annual ZOL 5 mg infusions provides continued fracture protection
Discontinuation of ZOL 5 mg treatment after 3 years still giving residual effect on prevention
nonvertebral fractures
Continuation of ZOL 5 mg treatment for 6 years significantly reduced New Morphometric
Vertebral Fractures
Core study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 and Year 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-Meier estimate at Month 36 in the extension study1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
*P = 0.0348
*P < 0.001
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A single infusion of ZOL 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mg
(Urine NTX) (Serum β-CTX )
* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-CTX: Serum β-C-telopeptide of type I collagen
Saag, et al. Bone 2007;40:1238-1243
30
Safety: Overall No Increase in Risk of AEs or SAEs With Long-term(6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment
CategoryZ6 (N=613)
n (%)Z3P3 (N=616)
n (%)P-value
Total no. of patients with an AE 552 (90) 552 (89) 0.85
Serious AEs 191 (31) 168 (27) 0.15
Deaths 26 (4) 18 (3) 0.22
Cardiovascular AE
Atrial fibrillation AEs 21 (3.4%) 13 (2.1%) 0.17
Atrial fibrillation SAEs* 11 (1.8%) 6 (1.0%) 0.23
Stroke related AEs 26 (4.2%) 19 (3.1%) 0.29
Stroke SAEs 19 (3.1%) 9 (1.5%) 0.06
Stroke deaths* 1 (0.2%) 0 (0%) 0.50
New hypertension AEs† 48 (7.8%) 94 (15.2%) <0.001
*P = 0.1910 **P < 0.00011Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
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Safety: Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) and declined markedly with subsequent infusions
0
2
4
6
8
10
12
14
16
Annual Infusion
Pyrexia
Myalgia
Flu-like illnessHeadache Arthralgia
1 2 3 1 2 3 1 2 3 1 2 3 1 2 3
Incid
en
ce (
%)
15%
2%
1%1% 2%
1%2%
1%2%
1%
8%
7%6% 5%
Placebo values cross-hatched
1%
Treatment with antipyretic analgesics appeared to mitigate these symptoms2
Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion3
1Black DM, et al. N Engl J Med. 2007;356:1809-1822
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ZOL= 3595 3574 3284 2989
PBO= 3624 3615 3338 3031
Z6= 613 572 517 459
Z3P3= 616 584 537 475
Renal Safety: 6 Years of ZOL Therapy Has No Cumulative Impact on Creatinine Clearance
1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
HORIZON-PFT Extension Study: Summary
• Long-term efficacy - 6 years of ZOL therapy led to:– Significantly greater increases from baseline in FN, TH
and trochanter BMD than stopping treatment at 3 years – Significant risk reduction in vertebral morphometric
fracture risk vs stopping treatment at 3 years– Maintenance of bone turnover markers within
reference range– Losses in BMD and BTMs in discontinuation group were
modest
33Black DM, et al. J Bone Miner Res. 2012;27:240–242
Long-term safety
• No new safety concerns identified in women with PMO
• No statistical difference in AF SAEs vs discontinuation of ZOL
• No long-term effect on renal function vs discontinuation of ZOL
• No increase in risk for ONJ events vs discontinuation of ZOL
• No cases of atypical fractures
Summary
• Reduce frequent dosing with bisphosphonates may improve compliance as an important thing for the success of osteoporosis treatment.
• Six years of annual ZOL 5 mg infusion preserves bone mass and discontinuation after 3 years still provided residual benefit of fracture protection.
• It may be beneficial for some women, particularly those at high vertebral fracture risk, to continue ZOL for an additional 3 years
351Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
Summary • A single infusion of zoledronic acid 5 mg compared to weekly
oral alendronate produced More rapid effect on tone turn over marker
• In both HORIZON-PFT ZOL 5 mg and extension were generally safe and well tolerated
• Clinical experience with more than 1 million infusions worldwide
• Once-yearly IV zoledronic acid 5 mg may be the answer of unmet need of current osteoporosis treatments
Thank youKeep your bone healthy