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Neue Optionen in der Osteoporosetherapie
Stephan Scharla
Praxis Bad Reichenhall, Innere Medizin und Endokrinologie/Diabetologie& Ludwig Maximilians Universität München
Quelle: IOF
Offenlegung von Interessenkonflikten
Innerhalb der letzten drei Jahre habe ich von folgenden Institutionen Zuwendungen erhalten:
- Alexion- Amgen- Astra-Zenica- Lilly- Novartis - Roche- Shire
Honorar für Vortrags- und/oder Beratertätigkeit Übernachtungs- und Reisekosten Forschungs- und Studiengelder
Neue Therapieoptionen• Antiresorptiv
• Odanacatib (Cathepsin K-Inhibitor): wegen potentieller Nebenwirkungen wurde die klinische Entwicklung abgebrochen
• Anabol• Teriparatid: bisher einzige Therapiemöglichkeit:
• Neue Daten belegen Überlegenheit gegenüber Antiresorptiva• Abaloparatid (Parathormon-Analogon): wurde von der
Europäischen Zulassungsbehörde nicht zugelassen• Romosozumab (Evenity ) , Sklerostinantikörper, vor der
Zulassung in den U.S.A. (FDA Advisory CommitteeRecommends Approval)
Anabole, Knochenaufbauende Therapie: hPTH-1-34 und Anti-Sklerostin
Teriparatid als Option zur initialen Therapie bei schwerer Osteoporose ?
• Sehr niedrige Knochendichte• Multiple Frakturen
Teriparatid versus Risedronat bei schwerer post-menopausalerOsteoporose (VERO)Kendler et al., Lancet 2017 Nov 9. pii: S0140-6736(17)32137-2. doi: 10.1016/S0140-6736(17)32137-2. ;
• Postmenopausale Frauen• ≥ 1 schwere Fraktur oder ≥ 2 moderate Frakturen• BMD –Score ≤ -1,5• Primärer Endpunkt: radiologische Wirbelbrüche• 20 μg Teriparatid tgl, oder 35 mg Risedronat/Woche
Lebensqualität und Schmerz:kein Unterschied
EEffect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78-Week Randomized Clinical Trial
Journal of Bone and Mineral ResearchVolume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0003
Knochendichte am Schenkelhals
EEffect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78-Week Randomized Clinical Trial
Journal of Bone and Mineral ResearchVolume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0006
Schmerz (VAS)
EEffect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78-Week Randomized Clinical Trial
Journal of Bone and Mineral ResearchVolume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0005
Timed up andgo test(Sekunden)
Data –Switch-Studie:Denosumab nach Teriparatid
Nach Umsetzen von Teriparatid auf Denosumab steigt die Knochendichte weiter an
Anhaltende Senkung des Frakturrisikos auch nachAbsetzen von Teriparatid
Scharla et al. Osteologie 2013;22:214Prince et al. JBMR 2005;20:1507
Sequenztherapie bei schwerer Osteoporose
StandardtherapieBisphosphonatÖstrogen/Serm
Fraktur(en)unter Therapie
Teriparatid 2 JahreAnschlusstherapie mit Bisphosphonat oder Denosumab
Teriparatid Frakturheilung
Wirkungsweise von Romosozumab• Der Wirkmechanismus von
Romosozumab beinhaltet die Stimulation der Knochenneubildung und die Hemmung der Resorption.1,2
• Die klinische Evidenz belegtebenfalls einen dualen Effekt auf den Knochen, mit Erhöhung der Knochenanbaumarker (P1NP) und Suppression der Knochenabbaumarker (CTX).2
Romosozumab
1. Bandeira L, etal. Expert Opin Biol Ther. 2017, 17(2):255-263; 2. Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543; (figure adapted from) Ominsky M, et al. Bone. 2017, 96:63-75 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Romosozumab Treatment in Postmenopausal Women with Osteoporosis
FRActure Study in Postmenopausal WoMen with OstEoporosis (FRAME)
F. Cosman, D.B. Crittenden, J.D. Adachi, N. Binkley, E. Czerwinski, S. Ferrari, L.C. Hofbauer, E. Lau, E.M. Lewiecki, A. Miyauchi, C.A.F. Zerbini, C.E. Milmont, L. Chen, J.
Maddox, P.D. Meisner, C. Libanati, and A. Grauer
Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 doi:10.1056/NEJMoa1607948.
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
FRAME Phase 3 Study DesignInclusion:
• Postmenopausal women age 55 to 90 years
• BMD T-score ≤ –2.5 at the total hip or femoral neck
Exclusion:
• BMD T-score ≤ –3.5 at the total hip or femoral neck
• History of hip fracture, or any severe or more than 2 moderate vertebral fractures
• Recent osteoporosis therapy (washout period varied by agent)
Co-Primary Endpoints:
• Subject incidence of new vertebral fracture through 12 and 24 months
Secondary Fracture Endpoints:
• Subject incidence of clinical, nonvertebral, and other fracture categories through 12 and 24 months
FRActure study in postmenopausal woMen with ostEoporosis
*A loading dose of 50,000 - 60,000 IU vitamin D was given to subjects with a baseline serum vitamin D 25(OH)D level of ≤ 40 ng/mL.Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Statistical Testing Sequence1
1. Adapted from: Cosman F, et al; Figure S1 Supplementary Appendix – N Engl J Med. 2016, 375(16):1532-15432. Hochberg Y, et al. Biometrika. 1988;75(4):800-802.
Statistical Testing SequenceNew vertebral
fracture through Month 12
Clinical fracture through
Month 12
Nonvertebral fracture through
Month 12
Nonvertebral fracture through
Month 24
Co-Primary:Need statistical significance
(≤ 0.05) on both to proceed
Secondary:Test at α = 0.05
Secondary:Controlled by Hochberg2
procedure; if both p-values ≤ 0.05, claim statistical
significance on both; if larger p-value > 0.05, test smaller
one at α = 0.025
Clinical fracture through
Month 24
New vertebral fracture through
Month 24 Additional endpoints tested in sequence
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Subject Enrollment by Geographic Region
Total N = 7,180.Cosman F, et a. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Baseline Characteristics & Subject Disposition
N = Number of subjects randomized. Percentages based on number of subjects randomized. Vertebral fracture grade based on Genant semi-quantitative scaleAdapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Percent Change in Serum P1NP and CTX Relative to Placebo Through Month 12
P1NP, romosozumab n=62, placebo n=62; CTX, romosozumab n=61, placebo n=62. Data presented as bootstrapped median treatment difference and 95% CI.Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Lumbar Spine and Total Hip BMD Through Month 12
*p < 0.001 compared with placebo. Data are least square means (95% CI) adjusted for relevant baseline covariates.BMD = bone mineral density; CI = confidence interval; ∆, differenceAdapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Femoral Neck BMD Through Month 12
*p < 0.001 compared with placebo. Data are least square means (95% CI) adjusted for relevant baseline covariates.BMD = bone mineral density; CI = confidence interval; ∆, differenceAdapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Incidence of New Vertebral Fracture Through Month 12
n/N1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fractures; p-value based on logistic regression model adjusted for age (<75, ≥75) and prevalent vertebral fracture.Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Time to First Clinical FractureThrough Month 12
Placebo n =Romosozumab n =
3,591 3,316 3,1343,589 3,317 3,148
Kaplan Meier curve based on data through month 24. Clinical fractures included all nonvertebral and symptomatic vertebral fractures. Non-vertebral fractures comprised the majority (more than 85%) of clinical fractures and excluded fractures of the skull, facial bones, metacarpals, fingers, and toes, pathologic fractures and fractures associated with high trauma. n = number of subjects at risk for event at time point of interest. P-value based on RRR.Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543
cebo n = 3 591 3 316 3 134
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Other Key Fracture Endpoints Through Month 12
Placebo n = 59 90 75 55 63 59 13Romosozumab n = 16 58 56 37 38 17 7
p (nominal) < 0.001 0.008 0.096 0.06 0.012 < 0.001 0.18p (adjusted) < 0.001 0.008 0.096 0.096 NA* 0.096 0.18
Variables to the right of the line are considered exploratory (due to be being tested after non-vertebral fracture) or were not part of testing sequence (i.e. not adjusted for multiplicity).Major nonvertebral fracture: pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm and hip, excluding high trauma and pathologic fractures. Major osteoporotic fractures: clinical vertebral, hip, forearm, and humerus, excluding pathologic fractures. *Not part of testing sequence, thus no adjusted p-value obtained. n = number of subjects with fractures.Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543
Placebo n = 59 90 75 55 63 59 13Romosozumab n = 16 58 56 37 38 17 7
p (nominal) < 0.001 0.008 0.096 0.06 0.012 < 0.001 0.18p (adjusted) < 0.001 0.008 0.096 0.096 NA* 0.096 0.18
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Subject Incidence of Nonvertebral Fracture inLatin America vs Rest-of-World Through Month 12
n/N1 = number of subjects with fractures/number of subjects in the full analysis set. *Regions excluding Latin America grouped post hoc.Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
P1NP and CTX Through Month 24
Data are median and interquartile range. Placebo-to-denosumab n=62; romosozumab-to-denosumab n=62 (P1NP), n=61 (CTX)Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Lumbar Spine and Total BMD Through Month 24
*p < 0.001 compared with placebo. Data are least square means (95% CI) adjusted for relevant baseline covariates.BMD = bone mineral density; CI = confidence interval; ∆, differenceAdapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543. DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Femoral Neck BMD Through Month 24
*p < 0.001 compared with placebo. Data are least square means (95% CI) adjusted for relevant baseline covariates.BMD = bone mineral density; CI = confidence interval; ∆, differenceAdapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Subject Incidence of New Vertebral Fracture Through Month 24
n/N1 = 59/3,322 16/3,321 84/3,327 21/3,325
n/N1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fractures; RRR = relative risk reduction. p –value based on logistic regression model adjusted for age (<75, ≥75) and prevalent vertebral fracture.Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543
n/N1 = 59/3 322 16/3 321 84/3 327 21/3 325
0.7%
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Time to First Clinical Fracture and NonvertebralFracture Through Month 24
Placebo-to-denosumab n = 3,591 3,316 3,134 3,037 2,955
Romosozumab-to-denosumab n = 3,589 3,317 3,148 3,050 2,968
3,591 3,318 3,145 3,052 2,967
3,589 3,318 3,149 3,051 2,970
Clinical fractures included all nonvertebral and symptomatic vertebral fractures. Non-vertebral fractures comprised the majority (more than 85%) of clinical fractures and excluded fractures of the skull, facial bones, metacarpals, fingers, and toes, pathologic fractures and fractures associated with high trauma. n = number of subjects at risk for event at time point of interest. P-value based on RRR.Adapted from: Cosman F, et al; Table S.2 Supplementary Appendix – N Engl J Med. 2016, 375(16):1532-1543
o-to-b
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
p=0.008 p = 0.10
Other Key Fracture Endpoints Through Month 24
Placebo n = 84 129 147 101 110 84 22Romosozumab n = 21 96 99 67 68 22 11
p (nominal) < 0.001 0.029 0.002 0.009 0.002 < 0.001 0.059p (adjusted) < 0.001 0.057 0.096 0.096 NA* 0.096 0.12
Variables to the right of the line are considered exploratory (due to be being tested after non-vertebral fracture) or were not part of testing sequence (i.e. not adjusted for multiplicity). Major non-vert Fxs: pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm and hip, excluding high trauma and pathologic fractures. Major OP Fxs: clinical vertebral, hip, forearm and humerus, excluding pathologic fractures. *Not part of testing sequence, thus no adjusted P-value obtained. n = number of subjects with fractures.Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543
Placebo n = 84 129 147 101 110 84 22mosozumab n = 21 96 99 67 68 22 11
p (nominal) < 0.001 0.029 0.002 0.009 0.002 < 0.001 0.059p (adjusted) < 0.001 0.057 0.096 0.096 NA* 0.096 0.12
DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Subject Incidence of Adverse Events Through 24 Months
The population for this analysis included all the patients who underwent randomization and received at least one dose of placebo or romosozumab in the 12-month double-blind period. At month 12, patients made the transition to denosumab for the second year of the trial. † The events listed are the most frequent adverse events in the double-blind period that occurred in 10% or more of the patients in either group. ‡ The events listed include adverse events that were adjudicated as positive by an independent adjudication committee. Cardiovascular deaths include fatal events that were adjudicated as being cardiovascular-related or undetermined (presumed to be cardiac-related). §Events of interest were those that were identified by prespecified Medical Dictionary for Regulatory Activities search strategies. ¶Seven patients in the romosozumab group had serious adverse events during the 12-month double-blind period. Events that were reported by the investigator as being related to romosozumab included dermatitis, allergic dermatitis, and macular rash, all of which resolved; the drug was withdrawn or withheld in these cases. ‖The most frequent adverse events of injection-site reactions (occurring in >0.1% of the patients) in the romosozumab group during the 12-month double-blind period included injection-site pain (in 1.7% of the patients), erythema (1.5%), bruising (0.8%), pruritus (0.7%), swelling (0.4%), hemorrhage (0.4%), rash (0.3%), and hematoma (0.2%).Adapted from: Cosman F, et al. N Engl J Med. 2016, 375(16):1532-1543 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reserved
Romosozumab or Alendronatefor Fracture Prevention in Women with Osteoporosis
Saag KG, et al. N Engl J Med. 2017. 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Active-contRolled fracture study in postmenopausal women withosteoporosis at High risk of fracture (ARCH)
KG Saag, J Petersen, ML Brandi, AC Karaplis, M Lorentzon, T Thomas,J Maddox, M Fan, PD Meisner and A Grauer©
UC
B P
harm
a G
mbH
, 201
7.A
ll rig
hts
rese
rved
. DE
/RM
Z/17
10/0
007
ARCH Phase 3 Study DesignActive-contRolled fraCture study in postmenopausal women with osteoporosis at High risk of fracture
500 to 1,000 mg calcium and 600 to 800 IU vitamin D daily
12 18 24Month 0Spine and
thoracic x-raysDXABTMs
6
Romosozumab 210 mg SC QM
N = 2,046Alendronate
70 mg PO QW
Alendronate70 mg PO QW
4,093Patients Enrolled
36
*Median time on study at primary analysis was 33 months (IQR: 27–40).BTM = bone turnover marker; DXA = dual-energy x-ray absorptiometry; IQR = interquartile range; IU = international units; PO = orally; QM = once monthly; QW = once weekly; SC = subcutaneously
Alendronate 70 mg PO QW
N = 2,047
Double-blind Open-labelPrimary Analysis*
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Demographics and ClinicalCharacteris
ticsat Baseline
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Plus–minus values are means ± SD. There were no significant between-group differences at baseline. Percentages may not total 100 because of rounding. *Number of patients who were randomly assigned to the 12-month double-blind period of the trial. †Assessed using the Genant grading scale. ‡Excludes pathologic or high-trauma hip fracture. §FRAX® is a registered trademark of Professor JA Kanis, University of Sheffield.**Data shown for 266 patients (128 in the alendronate group and 138 in the romosozumab group) who were enrolled in the biomarker substudy and who had measurements of bone-turnover markers both at baseline and at one or more visits after baseline.β-CTX = β-isomer of C-terminal telopeptide of type I collagen; BMD = bone mineral density; FRAX= Fracture Risk Assessment Tool; IQR = interquartile range; OP = osteoporotic; P1NP = procollagen type 1 N-terminal propeptide; SD = standard deviation
Characteristic Romosozumab(N = 2,046)*
Alendronate(N = 2,047)*
Age, years 74.4 ± 7.5 74.2 ± 7.5Bone mineral density T score
Femoral neck –2.89 ± 0.49 –2.90 ± 0.50Lumbar spine –2.94 ± 1.25 –2.99 ± 1.24Total hip –2.78 ± 0.68 –2.81 ± 0.67
Previous osteoporotic fracture at ≥ 45 yr of age 2,022 (98.8%) 2,029 (99.1%)Prevalent vertebral fracture 1,969 (96.2%) 1,964 (95.9%)
Grade of most severe vertebral fracture†
Mild 68 (3.3%) 73 (3.6%)Moderate 532 (26.0%) 570 (27.8%)Severe 1,369 (66.9%) 1,321 (64.5%)
Previous nonvertebral fracture at ≥ 45 yr of age 767 (37.5%) 770 (37.6%)Previous hip fracture‡ 175 (8.6%) 179 (8.7%)10-year risk of major OP fracture by FRAX®§ 20.2 ± 10.2 20.0 ± 10.1Body-mass index, kg/m2 25.46 ± 4.41 25.36 ± 4.42Median 25-hydroxyvitamin D, ng/mL (IQR) 28.4 (24.0–34.8) 27.6 (24.0–34.2)Median serum P1NP**, μg/L (IQR) 50.6 (37.5–64.7) 44.7 (32.7–64.4)Median serum β-CTX**, ng/L (IQR) 276.0 (166.0–407.0) 230.0 (137.0–388.0)
Subject Enrollment By Geographic Region
Total N = 4,093
NorthAmerica 2.4%Asia-Pacific or SouthAfrica
10.5%
Western Europe,Australia,or New Zealand
13.0%
LatinAmerica34.2%
Central or Eastern Europeor Middle East
39.9%
Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Incidence of New Vertebral FractureThrough Month 24
4.0%82/2,046
0 0n/N1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fractures.*Missing fracture status was imputed by multiple imputation for patients without observed fracture at an earlier time point. n and % are based on the average across 5 imputed datasets.†RRR at 12 months by LOCF: 36% (nominal P = 0.008): Romosozumab: 3.2% (55/1,696) vs Alendronate: 5.0% (85/1,703).‡RRR at 24 months by LOCF: 50% (nominal P < 0.001): Romo-to-Aln: 4.1% (74/1,825) vs Aln-to-Aln: 8.0% (147/1,843).Aln = alendronate; LOCF = last-observation-carried-forward; Romo = romosozumab; RRR = relative risk reductionAdapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
6.2%127/2,046
11.9%243/2,047
5
10
24 Months* (primary endpoint)Romosozumab-to-Alendronate Alendronate-to-Alendronate
15RRR = 48%‡
P < 0.001
Subj
ects
(%)
6.3%128/2,047
5
10
15
RRR = 37%†
P = 0.003
Subj
ects
(%)
12 Months*AlendronateRomosozumab
Primary EndpointIncidence of Clinical Fracture atPrimaryAnalysis
RRR = 27%P < 0.001
%C
umul
ativ
eIn
cide
nce
0
15
10
5
20
25
0 6 12 18 22 30 36 42Month
48
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
n =Romo-to-Aln 2,046 1,865
1,8681,7701,743
1,6831,645
1,6151,564
1,1031,066
705680
347325
109108Aln-to-Aln 2,047
n = number of subjects at risk for event at time point of interest.Aln = alendronate; IQR = interquartile range; Romo = romosozumab; RRR = relative risk reductionAdapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Primary AnalysisRomosozumab Open-label
alendronate
Median time on study at primary analysis: 33 months (IQR: 27–40)
vs alendronateAt Month 12:RRR = 28%P = 0.027
Incidence of Nonvertebral Fractures* at PrimaryAnalysis
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
Primary Analysis
%C
umul
ativ
eIn
cide
nce RRR = 19%
P = 0.04
24Month
n =
0
10
5
15
20
12 30 480 6 18 36 42
Median time on study at primary analysis: 33 months (IQR: 27–40)
Romo-to-Aln 2,046
Aln-to-Aln 2,047
1,867
1,873
1,776
1,755
1,693
1,661
1,627
1,590
1,114
1,097
714
697
350
330
109
110*Secondary endpoint. †Not adjusted for multiplicity. n = number of subjects at risk for event at time point of interest. Aln = alendronate; Romo = romosozumab; RRR = relative risk reductionAdapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Other Fracture Endpoints at Primary Analysis
9.7%n = 198
from higher than the height of a stool, chair, first rung on a ladder or equivalent (> 20 inches), or severe trauma other than a fall per investigator judgment. RRR = relative risk reductionAdapted from: Saag KG, et al. N Engl J Med. 2017, Supplementary materials 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
8.7%n = 178 7.1%
n = 146
2.0%n = 41
7.1%n = 146
13.0%n = 266
13.0%n = 266
10.6%9.6%
n = 196
3.2%n = 66
10.2%n = 209
19.1%n = 392
0%
5%
10%
15%
20%
Clinical Fracture Nonvertebral Fracture††
Major Nonvertebral
Fracture‡‡
Hip Fracture Major Osteoporotic
Fracture §§
Osteoporotic Fracture***
RRR = 27%P < 0.001§,**
Alendronate-to-Alendronate N = 2,047
Romosozumab-to-Alendronate N = 2,046
Subj
ectI
ncid
ence
(%) RRR = 19%
P = 0.037§RRR = 27%P = 0.004§
RRR = 38%P = 0.015§
RRR = 32%P < 0.001§
RRR = 35%P < 0.001§
n = 217
§Risk ratios and P-values based on a Cox proportional hazards model adjusting for age strata, baseline total hip BMD T score and presence of severe vertebral fracture at baseline.**The nominal P-value for new vertebral fracture at month 24 using the logistic regression model was < 0.001 and < 0.001 for clinical fracture at primary analysis using the Cox proportional hazards model described above. The larger of the 2 P-values is less than 0.05, thus both endpoints were statistically significant using the Hochberg procedure and the statistical testing continued to the secondary endpoints in the testing sequence as defined on Slide 6. ††Nonvertebral fractures excluded fractures of the skull, facial bones, metacarpals, fingers, and toes. Pathologic or high trauma fractures were also excluded. ‡‡Major nonvertebral fracture included fractures of the pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip. §§Major osteoporotic fracture include fractures of the hip, forearm, and humerus that are not associated with a pathologic fracture regardless of trauma severity, and clinical vertebral fractures. ***Osteoporotic fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures.Note: All fracture types, including nonvertebral fractures, excluded severe trauma (except major osteoporotic fractures) or pathologic fractures. Severe trauma was defined as a fall
SubstudyPercent Change from Baseline in Lumbar BMD
Lumbar Spine†
AlendronateRomosozumab Alendronate-to-AlendronateRomosozumab-to-Alendronate
Perc
entC
hang
efr
omB
asel
ine
Open-labelalendronate
Romosozumabvs alendronate
4.8%3.7%
4%
0%
*Nominal P < 0.001 (not-adjusted for multiplicity).Data are least-squares (LS) means (95% CI). The substudy population was representative of the overall study (data not shown).†ANCOVA model using LOCF adjusted for treatment, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.‡Number of subjects with values at baseline and at least one post-baseline visit at month 6 or month 18.ANCOVA = analysis of covariance; BMD = bone mineral density; CI = confidence interval; LOCF = last-observation-carried-forwardAdapted from: Saag KG, et al. N Engl J Med. 2017, Supplementary materials 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
6.7% 7.4% 7.9%
11.3%*12%
13.7%*
16.0%*16.9%* 16.9%*
8%
16%
20%
24%
0 6 12 18Month
24 30 36
Romosozumab-to-Alendronate: n=84‡
Alendronate-to-Alendronate: n = 79‡
2.2%2.6%
3.5% 3.1% 3.4%4.5%*
6.3%*
7.8%* 7.4%* 7.5%*
0%
2%
4%
6%
8%
10%
12%
14%
0 6 12 18Month
24 30 36
Open-label alendronate
Romosozumabvs alendronate
SubstudyPercent Change from Baseline in Total Hipand femoral neck
Open-label alendronate
Romosozumabvs alendronate
Total Hip† Femoral Neck†
18Month
1.0%
1.7%2.3% 2.3% 2.6%
3.9%*
5.8%*
7.7%* 7.6%* 7.9%*
0%
2%
4%
6%
8%
10%
12%
14%
0 6 12 24 30 36
Perc
entC
hang
efr
omB
asel
ine
Perc
entC
hang
efr
omB
asel
ine
Romosozumab-to-Alendronate: n=85‡
*Nominal P < 0.001 (not-adjusted for multiplicity).Data are least-squares (LS) means (95% CI). The substudy population was representative of the overall study (data not shown).†ANCOVA model using LOCF adjusted for treatment, presence of severe vertebral fracture at baseline, baseline BMD value, machine type, and baseline BMD value-by-machine type interaction.‡Number of subjects with values at baseline and at least one post-baseline visit at month 6 or month 18.ANCOVA = analysis of covariance; BMD = bone mineral density; CI = confidence interval; LOCF = last-observation-carried-forwardAdapted from: Saag KG, et al. N Engl J Med. 2017, Supplementary materials 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Alendronate-to-Alendronate: n = 80‡Romosozumab-to-Alendronate: n=85‡
Alendronate-to-Alendronate: n = 80‡
AlendronateRomosozumab Alendronate-to-AlendronateRomosozumab-to-Alendronate
Percent Change from Baseline in SerumP1NP and CTX Levels through Month 36
Perc
entC
hang
efr
omB
asel
ine
Perc
entC
hang
efr
omB
asel
ine
β-CTXP1NP
01 3 6 9 12 15 18Month
24 36
0
–50
–100
50
150
100
200
150
100
50
0
–50
–100
–15001 3 6 9 12 15 18
Month24 36
200
–150
Romosozumab: N = 137 Alendronate: N = 128
Romosozumab: N = 137 Alendronate: N = 127
The substudy population was representative of the overall trial population.P < 0.001 for the comparisons at months 1, 3, 6, 9, and 12. Bars indicate interquartile ranges for the levels of P1NP and β-CTX. β-CTX = β-isomer of C-terminal telopeptide of type I collagen; P1NP = procollagen type 1 N-terminal propeptideAdapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
AlendronateRomosozumab Alendronate-to-AlendronateRomosozumab-to-Alendronate
Adverse Events and Events ofInterest
enostosis, extraskeletal ossification, and vertebral foraminal stenosis.‡‡Potential cases of osteonecrosis of the jaw and atypical femoral fracture were adjudicated by independent committees.Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
*Incidence rates at the time of the primary analysis were cumulative and included all events in the double-blind and open-label period (to February 27, 2017) inpatients who received at least one dose of open-label alendronate.
†Shown are events that occurred in 10% or more of the patients in either group during the double-blind period.‡Events of interest were those that were identified by prespecified Medical Dictionary for Regulatory Activities search strategies.§Prespecified events were osteoarthritis, spinal osteoarthritis, exostosis, arthritis, polyarthritis, arthropathy, monoarthritis, and interspinous osteoarthritis.**The most frequent adverse events of injection-site reactions (occurring in > 0.1% of the patients) in the romosozumab group during the double-blind period included injection-site pain (1.6% of patients), erythema (1.3%), pruritus (0.8%), hemorrhage (0.5%), rash (0.4%), and swelling (0.3%).††Prespecified events were exostosis (mostly reported as heel spurs), lumbar spinal stenosis, spinal column stenosis, cervical spinal stenosis,
Event Month 12:Double-Blind Period
Romosozumab Alendronate(N = 2,040) (N = 2,014)
Primary Analysis:Double-Blind and Open-Label Period*
Romosozumab to Alendronate (N= 2,040)
Alendronate to Alendronate (N = 2,014)
Adverse event during treatment 1,544 (75.7%) 1,584 (78.6%) 1,766 (86.6%) 1,784 (88.6%)Back pain† 186 (9.1%) 228 (11.3%) 329 (16.1%) 393 (19.5%)Nasopharyngitis† 213 (10.4%) 218 (10.8%) 363 (17.8%) 373 (18.5%)
Event leading to discontinuation of trial regimen
70 (3.4%) 64 (3.2%) 133 (6.5%) 146 (7.2%)
Event leading to discontinuation of trial participation
30 (1.5%) 27 (1.3%) 47 (2.3%) 43 (2.1%)
Event of interest‡
Osteoarthritis§ 138 (6.8%) 146 (7.2%) 247 (12.1%) 268 (13.3%)Hypersensitivity 122 (6.0%) 118 (5.9%) 205 (10.0%) 185 (9.2%)Injection-site reaction** 90 (4.4%) 53 (2.6%) 90 (4.4%) 53 (2.6%)Cancer 31 (1.5%) 28 (1.4%) 84 (4.1%) 85 (4.2%)Hyperostosis†† 2 (< 0.1%) 12 (0.6%) 23 (1.1%) 27 (1.3%)Hypocalcemia 1 (< 0.1%) 1 (< 0.1%) 4 (0.2%) 1 (< 0.1%)Atypical femoral fracture‡‡ 0 0 2 (< 0.1%) 4 (0.2%)Osteonecrosis of the jaw‡‡ 0 0 1 (< 0.1%) 1 (< 0.1%)
Serious Adverse Events
analysis snapshot and was not included in the analysis of fatal events. Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
*Incidence rates at the time of the primary analysis were cumulative and included all events in the double-blind and open-label period (to February 27, 2017) in patients who received at least one dose of open-label alendronate.†Serious CV adverse events were adjudicated by the Duke Clinical Research Institute. CV deaths include fatal events that were adjudicated as being CV-related or undetermined (and, therefore, possibly CV-related).‡One patient had a non-treatment-related serious adverse event of pneumonia that was incorrectly flagged as death in the primary
EventMonth 12: Double-Blind Period
Romosozumab Alendronate(N = 2,040) (N = 2,014)
Primary Analysis: Double-Blind and Open-Label Period*
Romosozumab to Alendronate (N= 2,040)
Alendronate to Alendronate (N = 2,014)
Serious adverse event 262 (12.8%) 278 (13.8%) 586 (28.7%) 605 (30.0%)
Adjudicated serious cardiovascular (CV) event†
50 (2.5%) 38 (1.9%) 133 (6.5%) 122 (6.1%)
Cardiac ischemic event 16 (0.8%) 6 (0.3%) 30 (1.5%) 20 (1.0%)
Cerebrovascular event 16 (0.8%) 7 (0.3%) 45 (2.2%) 27 (1.3%)
Heart failure 4 (0.2%) 8 (0.4%) 12 (0.6%) 23 (1.1%)
Death 17 (0.8%) 12 (0.6%) 58 (2.8%) 55 (2.7%)
Noncoronaryrevascularization
3 (0.1%) 5 (0.2%) 6 (0.3%) 10 (0.5%)
Peripheral vascular ischemic event not requiring revascularization
0 2 (<0.1%) 2 (<0.1%) 5 (0.2%)
Death 30 (1.5%) 21 (1.0%)‡ 90 (4.4%) 90 (4.5%)‡
Adapted from: 1. Saag KG, et al. N Engl J Med. 2017, Supplementary materials 377(15):1417-14272. Samelson EJ, et al. J Bone Miner Res. 2014, 29:450-457
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.
Comparison of Cardiovascular Risk FactorsinPatients with Positively Adjudicated CV SAEs
Data are n (%) unless otherwise noted.*Modified after Samelson EJ, et al.2 The score was determined as follows: ischemic heart disease or central nervous system hemorrhages and cerebrovascular conditions (4 points), diabetes mellitus (3 points), age ≥ 70 years (2 points), age 65 to 69 years (1 point ), current/former smoker(1 point), hypertension (1 point), and hyperlipidemia (1 point); if positive for all three criteria: smoking, hypertension, and hyperlipidemia,1 extra point was added (ie, total of 4 points).
CNS = central nervous system; CV = cardiovascular; eGFR = estimated glomerular filtration rate; Q1 = 25th percentile; Q3 = 75th percentile; SAE = serious adverse event; SD = standard deviation
Overall Study Population Romosozumab Alendronate
(N = 2,040) (N = 2,014)
Patients With Adjudicated Cardiovascular SAEs
in the Double-Blind PeriodRomosozumab
(N = 50)Alendronate
(N = 38)Age (years), mean ± SD 74.4 ± 7.5 74.2 ± 7.5 76.3 ± 7.3 76.3 ± 7.7Age ≥ 75 years 1,070 (52.5%) 1,049 (52.1%) 33 (66.0%) 22 (57.9%)Cardiovascular risk score,* median (Q1, Q3)
4 (2, 7) 4 (2, 7) 6.5 (3, 10) 7 (3, 10)
Any history of CV risk factor 1,625 (79.7%) 1,607 (79.8%) 48 (96.0%) 35 (92.1%)History of CV disease 1,497 (73.4%) 1,456 (72.3%) 46 (92.0%) 34 (89.5%)History of CNS vascular disorder
147 (7.2%) 183 (9.1%) 7 (14.0%) 6 (15.8%)
History of hypercholesterolemia
708 (34.7%) 674 (33.5%) 25 (50.0%) 14 (36.8%)
History of hypertension 1,248 (61.2%) 1,227 (60.9%) 42 (84.0%) 32 (84.2%)History of diabetes 664 (32.5%) 658 (32.7%) 24 (48.0%) 18 (47.4%)
Current/former smoker 533 (26.1%) 591 (29.3%) 20 (40.0%) 12 (31.6%)eGFR 30 – <60 mL/min/1.73 m2 508 (24.9%) 476 (23.6%) 17 (34.0%) 12 (31.6%)eGFR 60 – <90 mL/min/1.73 m2 1,257 (61.6%) 1,189 (59.0%) 27 (54.0%) 22 (57.9%)
Risiko von Folgefrakturen
55
• Risiko einer Folgefraktur bei Frauen
• Modifiziert nach Center JR et al.; JAMA 2007; 297: 387-394
RR: relatives RisikoKI: Konfidenzintervall
32(32-34)
22(18-25)
27(24-30)
50(45-55)
62(55-70)
36(26-48)
63(52-76)
89(73-109)
0
15
30
45
60
75
90
Alle 60-69 70-79 ≥80
Risi
ko p
ro 1
000
Patie
nten
jahr
e (9
5% K
I)
Initiale Fraktur Folgefraktur
Altersgruppe (Jahre)
RR: 1,9795% KI: 1,71-2,26
RR: 1,6595% KI: 1,18-2,32
N=905
RR: 1,8095% KI: 1,45-2,25
RR: 2,3695% KI: 1,91-2,92
N=253 N=147 N=43 N=378 N=111 N=380 N=99
Nach einer initialen Fraktur hatten Frauen ein
höheres Risiko für eine Folgefraktur, als durch
einen Anstieg des Alters um 10 Jahre
Studienhintergrund:• Prospektive Kohortenstudie mit 2.245 Frauen und 1.760 Männer im Alter von 60
Jahren oder älter in Australien• Nachbeobachtungszeit von 16 Jahren (Juli 1989 bis April 2005)• Frakturen eingeteilt in die Gruppe Hüft-, schwere und geringe Fraktur• Schwere Frakturen: Wirbelkörper, Becken, distale Femur, Rippen (multipel) &
proximale Oberarmknochen• Geringe Frakturen: alle anderen Frakturen, außer Finger und Zehen• Vertebrale Frakturen: zufälliger Befund, ohne vorheriges systematisches Screening
nach einer Fraktur• Klinische vertebrale Fraktur: Befund durch von X-Ray aufgrund von
Rückenschmerzen und ohne dass eine Fraktur zuvor vorlag
Änderung des BMD – T-Score (1)
56• Modifiziert nach Cosman F et al.; Journal of Bone and Mineral Research 2018; DOI: 10.1002/jbmr.3427
Zunahme des BMD T-Scores an der LWS
unter ein Jahr Romosozumab gefolgt
von einem Jahr Denosumab
vergleichbar mit der BMD-Zunahme
nach etwa sieben Jahren unter
Denosumaba. BMD häufiger gemessen (Monat 6+18) in einer Subgruppe die an einer FRAME DXA-Substudie teilgenommen haben; zusätzlich in
Monat 6 gemessen bei Frauen aus Argentinienb. BMD häufiger gemessen in einer Subgruppe, die in der FREEDOM DXA-Substudie teilgenommen haben
Lendenwirbelsäule
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,00 1 3 42 5 6 8 97 10
FRAMEa n=3.170Freedomb n=3.261
150
222
3.141212
2.855206
59
3.158 2.166 2.059 1.605 1.565 1.263
Studienjahr
Mitt
lere
Änd
erun
g de
s T-
Scor
es v
on B
asel
ine
FRAME
FREEDOM EXTENSION
Romosozumab (N=3.170) Denosumab (N=3.261)
FRAME + FREEDOM
LWS: Lendenwirbelsäule
Inzidenz neuer vertebraler Frakturen
57• Modifiziert nach Cosman F et al.; Journal of Bone and Mineral Research 2018; DOI: 10.1002/jbmr.3427
Signifikant weniger neue vertebrale Frakturen über die gesamten 2 Jahre unter
Romosozumab bzw. Romosozumab gefolgt von Denosumab
FRAME
Placebo
Romosozumab
Placebo Denosumab
Romosozumab Denosumab1,8%
0,5%
2,5%
0,6%
0,9%
0,2%
0,0%
0,5%
1,0%
1,5%
2,0%
2,5%
3,0%
Inzi
denz
neu
e ve
rteb
rale
Fra
ktur
en
RRR: 73%
P<0,001
RRR: 76%
P<0,001
RRR: 81%
P<0,001
Im ersten Jahr Über 2 Jahre Im zweiten Jahr
n/N159/3.322
n/N116/3.321
n/N184/3.327
n/N121/3.325
n/N127/2.980 n/N1
5/2.953
RRR: Relative Risiko Reduktionn/N1: Anzahl von Patienten mit Fraktur / Anzahl von Patienten im Analyse-Set
Grüße aus den Alpen!
Stephan Scharla Bad Reichenhall
Grüße aus den Alpen!
Stephan Scharla Bad Reichenhall
Grüße aus den Alpen!
Stephan Scharla Bad Reichenhall