Neue Optionen in der Osteoporosetherapie - Stephan Scharla Praxis Bad Reichenhall, Innere Medizin und Endokrinologie/Diabetologie
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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 Committee
Recommends 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-menopausaler Osteoporose (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
Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final
Results of a 78-Week Randomized Clinical Trial
Knochendichte
am
Schenkelhals
Journal of Bone and Mineral Research
Volume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0003Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final
Results of a 78-Week Randomized Clinical Trial
Schmerz (VAS)
Journal of Bone and Mineral Research
Volume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0006Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final
Results of a 78-Week Randomized Clinical Trial
Timed up and
go test
(Sekunden)
Journal of Bone and Mineral Research
Volume 32, Issue 5, pages 1040-1051, 26 JAN 2017 DOI: 10.1002/jbmr.3067
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.3067/full#jbmr3067-fig-0005Data –Switch-Studie: Denosumab nach Teriparatid Nach Umsetzen von Teriparatid auf Denosumab steigt die Knochendichte weiter an
Anhaltende Senkung des Frakturrisikos auch nach
Absetzen von Teriparatid
Prince et al. JBMR 2005;20:1507 Scharla et al. Osteologie 2013;22:214Sequenztherapie bei schwerer
Osteoporose
Fraktur(en)
unter Therapie
Standardtherapie Anschlusstherapie mit
Bisphosphonat Teriparatid 2 Jahre Bisphosphonat oder
Östrogen/Serm DenosumabTeriparatid Frakturheilung
Wirkungsweise von Romosozumab
• Der Wirkmechanismus von
Romosozumab beinhaltet die Romosozumab
Stimulation der
Knochenneubildung und die
Hemmung der Resorption.1,2
• Die klinische Evidenz belegt
ebenfalls einen dualen Effekt auf
den Knochen, mit Erhöhung der
Knochenanbaumarker (P1NP)
und Suppression der
Knochenabbaumarker (CTX).2
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 reservedRomosozumab 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 reservedFRAME Phase 3 Study Design
FRActure study in postmenopausal woMen with ostEoporosis
Inclusion:
• 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
*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 reservedStatistical Testing Sequence1
New vertebral Nonvertebral
fracture through fracture through
Month 12 Month 12
Clinical fracture Clinical fracture
through through
Month 12 Month 24
New vertebral Nonvertebral
fracture through fracture through
Month 24 Month 24 Additional endpoints
tested in sequence
Co-Primary: Secondary: Secondary:
Need statistical significance Test at α = 0.05 Controlled by Hochberg2
(≤ 0.05) procedure; if both p-values ≤
on both to proceed 0.05, claim statistical
significance on both; if larger
p-value > 0.05, test smaller
one
at α = 0.025
1. Adapted from: Cosman F, et al; Figure S1 Supplementary Appendix – N Engl J Med. 2016, 375(16):1532-1543
2. Hochberg Y, et al. Biometrika. 1988;75(4):800-802. DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reservedSubject 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 reservedBaseline Characteristics & Subject Disposition
N = Number of subjects randomized. Percentages based on number of subjects randomized. Vertebral fracture grade based on Genant semi-
quantitative scale
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 reservedPercent 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 reservedLumbar 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; ∆, difference
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 reservedFemoral 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; ∆, difference
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 reservedIncidence 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 (
Time to First Clinical Fracture
Through Month 12
cebo n = 3
Placebo 3,591
591 3,316
3 316 3
3,134
134
Romosozumab n = 3,589 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 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reservedOther Key Fracture Endpoints
Through Month 12
Placebo n = 59 90 75 55 63 59 13
Romosozumab n = 16 58 56 37 38 17 7
p (nominal) < 0.001 0.008 0.096 0.06 0.012 < 0.001 0.18
p (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 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reservedSubject Incidence of Nonvertebral Fracture in
Latin 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 reservedP1NP 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 reservedLumbar 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; ∆, difference
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 reservedFemoral 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; ∆, difference
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 reservedSubject Incidence of New Vertebral
Fracture Through Month 24
0.7%
n/N1 = 59/3
59/3,322
322 16/3
16/3,321
321 84/3
84/3,327
327 21/3,325
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 (Time to First Clinical Fracture and Nonvertebral
Fracture Through Month 24
p=0.008 p = 0.10
Placebo-to-
o-to-
denosumab b n = 3,591 3,316 3,134 3,037 2,955 3,591 3,318 3,145 3,052 2,967
Romosozumab-to-
denosumab n = 3,589 3,317 3,148 3,050 2,968 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 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reservedOther Key Fracture Endpoints
Through Month 24
Placebo n = 84 129 147 101 110 84 22
Romosozumab
mosozumab n = 21 96 99 67 68 22 11
p (nominal) < 0.001 0.029 0.002 0.009 0.002 < 0.001 0.059
p (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 DE/RMZ/1704/0004
UCB Pharma GmbH, 2017. All rights reservedSubject 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 reservedRomosozumab or Alendronate
for Fracture Prevention in
©UCB Pharma GmbH, 2017. All rights reserved. DE/RMZ/1710/0007
Women with Osteoporosis
Active-contRolled fracture study in postmenopausal women with
osteoporosis 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
Saag KG, et al. N Engl J Med. 2017. 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.ARCH Phase 3 Study Design
Active-contRolled fraCture study in postmenopausal women with
osteoporosis at High risk of fracture
4,093
Primary Analysis*
Patients Double-blind Open-label
Enrolled
Romosozumab
210 mg SC QM Alendronate
N = 2,046 70 mg PO QW
Alendronate
70 mg PO QW Alendronate
N = 2,047 70 mg PO QW
500 to 1,000 mg calcium and 600 to 800 IU vitamin D daily
Month 0 6 12 18 24 36
Spine and
thoracic x-rays
DXA
BTMs
*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
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Demographics and Clinical
Characteris
tics
at Baseline
Characteristic Romosozumab Alendronate
(N = 2,046)* (N = 2,047)*
Age, years 74.4 ± 7.5 74.2 ± 7.5
Bone mineral density T score
Femoral neck –2.89 ± 0.49 –2.90 ± 0.50
Lumbar spine –2.94 ± 1.25 –2.99 ± 1.24
Total 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 ± 10.1
Body-mass index, kg/m2 25.46 ± 4.41 25.36 ± 4.42
Median 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)
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
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Subject Enrollment By Geographic Region
North America
Asia-Pacific or South Africa 2.4%
10.5%
Latin America
Western Europe, Australia,
34.2%
or New Zealand
13.0%
Central or Eastern Europe
or Middle East
39.9%
Total N = 4,093
Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Incidence of New Vertebral Fracture
Through Month 24
12 Months* 24 Months* (primary endpoint)
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
15 15
RRR = 48%‡
P < 0.001
11.9%
10 10
Subjects (%)
Subjects (%)
243/2,047
RRR = 37%†
P = 0.003
6.3% 6.2%
5 5
128/2,047 127/2,046
4.0%
82/2,046
0 0
n/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 reduction
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Primary Endpoint
Incidence of Clinical Fracture at
Analysis Primary
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
Primary Analysis
25 Romosozumab Open-label
vs alendronate alendronate
% Cumulative Incidence
At Month 12:
RRR = 28% RRR = 27%
20 P = 0.027 P < 0.001
15
10
5
Median time on study at primary analysis:
33 months (IQR: 27–40)
0
0 6 12 18 22 30 36 42 48
n= Month
Romo-to-Aln 2,046 1,865 1,770 1,683 1,615 1,103 705 347 109
Aln-to-Aln 2,047 1,868 1,743 1,645 1,564 1,066 680 325 108
n = number of subjects at risk for event at time point of interest.
Aln = alendronate; IQR = interquartile range; Romo = romosozumab; RRR = relative risk reduction
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Incidence of Nonvertebral Fractures* at Primary
Analysis
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
Primary Analysis
20
Median time on study at primary analysis:
33 months (IQR: 27–40)
% Cumulative Incidence
15 RRR = 19%
P = 0.04
10
5
0
0 6 12 18 24 30 36 42 48
Month
n=
Romo-to-Aln 2,046 1,867 1,776 1,693 1,627 1,114 714 350 109
Aln-to-Aln 2,047 1,873 1,755 1,661 1,590 1,097 697 330 110
*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 reduction
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Other Fracture Endpoints at Primary Analysis
RRR = 35%
Romosozumab-to-Alendronate Alendronate-to-Alendronate
N = 2,046 N = 2,047 P < 0.001§
20%
19.1%
n = 392
RRR = 27%
Subject Incidence (%)
P < 0.001§,** RRR = 19%
15% P = 0.037§
RRR = 27% RRR = 32%
P = 0.004§ P < 0.001§
13.0%
13.0%
n = 266
n = 266
10% 10.6%
RRR = 38% 10.2%
9.7% n = 217 9.6%
P = 0.015§ n = 209
n = 198 8.7% n = 196
n = 178
7.1% 7.1%
5% n = 146 n = 146
3.2%
n = 66
2.0%
n = 41
0% Nonvertebral Major Major Osteoporotic
Clinical Fracture Hip Fracture
Fracture †† Nonvertebral Osteoporotic Fracture ***
Fracture ‡‡ Fracture §§
§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
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 reduction
Adapted 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.Substudy
Percent Change from Baseline in
Lumbar BMD
Lumbar Spine†
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
Romosozumab Open-label
Percent Change from Baseline
vs alendronate alendronate
24%
Romosozumab-to-Alendronate: n=84‡
Alendronate-to-Alendronate: n = 79‡
20%
16.9%* 16.9%*
16.0%*
16% 13.7%*
11.3%*
12%
7.9%
7.4%
6.7%
8%
4.8%
3.7%
4%
0%
0 6 12 18 24 30 36
Month
*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-forward
Adapted 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.Substudy
Percent Change from Baseline in Total Hip
and femoral neck
Total Hip† Femoral Neck†
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
Romosozumab Open-label Romosozumab Open-label
vs alendronate alendronate vs alendronate alendronate
14% 14%
Romosozumab-to-Alendronate: n=85‡ Romosozumab-to-Alendronate: n=85‡
Alendronate-to-Alendronate: n = 80‡ Alendronate-to-Alendronate: n = 80‡
Percent Change from Baseline
Percent Change from Baseline
12% 12%
10% 10% 7.9%*
7.8%* 7.7%* 7.6%*
7.4%* 7.5%*
8% 6.3%* 8%
5.8%*
6% 4.5%* 6%
3.9%*
3.5% 3.4%
3.1% 2.6%
4% 2.6% 4% 2.3% 2.3%
2.2% 1.7%
2% 2% 1.0%
0% 0%
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Month Month
*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-forward
Adapted 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.Percent Change from Baseline in Serum
P1NP and CTX Levels through Month 36
P1NP β-CTX
Romosozumab Alendronate Romosozumab-to-Alendronate Alendronate-to-Alendronate
200 200
Romosozumab: N = 137 Romosozumab: N = 137
Alendronate: N = 128 Alendronate: N = 127
150
Percent Change from Baseline
Percent Change from Baseline
150
100 100
50 50
0 0
–50 –50
–100 –100
–150 –150
01 3 6 9 12 15 18 24 36 01 3 6 9 12 15 18 24 36
Month Month
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 propeptide
Adapted from: Saag KG, et al. N Engl J Med. 2017, 377(15):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Adverse Events and Events of
Interest
Event
Romosozumab
Month 12:
Double-Blind Period
Alendronate
Primary Analysis:
Double-Blind and Open-Label Period*
Romosozumab to
Alendronate (N
Alendronate to
Alendronate
(N = 2,040) (N = 2,014) = 2,040) (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 70 (3.4%) 64 (3.2%) 133 (6.5%) 146 (7.2%)
trial regimen
Event leading to discontinuation of 30 (1.5%) 27 (1.3%) 47 (2.3%) 43 (2.1%)
trial participation
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%)
*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.
†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,
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):1417-1427
Reactive material for unsolicited request. Provided to the HCP for his/her personal medical information.Serious Adverse Events
Event Primary Analysis: Double-Blind and
Month 12: Double-Blind Period Open-Label Period*
Romosozumab to Alendronate to
Romosozumab Alendronate Alendronate (N Alendronate
(N = 2,040) (N = 2,014) = 2,040) (N = 2,014)
Serious adverse event 262 (12.8%) 278 (13.8%) 586 (28.7%) 605 (30.0%)
Adjudicated serious 50 (2.5%) 38 (1.9%) 133 (6.5%) 122 (6.1%)
cardiovascular (CV) event†
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%)
Noncoronary 3 (0.1%) 5 (0.2%) 6 (0.3%) 10 (0.5%)
revascularization
Peripheral vascular ischemic 0 2 (Comparison of Cardiovascular Risk Factors
in
Patients with Positively Adjudicated CV
SAEs Overall Study Population
Romosozumab Alendronate
Patients With Adjudicated
Cardiovascular SAEs
in the Double-Blind Period
(N = 2,040) (N = 2,014)
Romosozumab Alendronate
(N = 50) (N = 38)
Age (years), mean ± SD 74.4 ± 7.5 74.2 ± 7.5 76.3 ± 7.3 76.3 ± 7.7
Age ≥ 75 years 1,070 (52.5%) 1,049 (52.1%) 33 (66.0%) 22 (57.9%)
Cardiovascular risk score,* 4 (2, 7) 4 (2, 7) 6.5 (3, 10) 7 (3, 10)
median (Q1, Q3)
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 147 (7.2%) 183 (9.1%) 7 (14.0%) 6 (15.8%)
disorder
History of 708 (34.7%) 674 (33.5%) 25 (50.0%) 14 (36.8%)
hypercholesterolemia
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 –Risiko von Folgefrakturen
• Risiko einer Folgefraktur bei Frauen
RR: 1,80
Initiale Fraktur Folgefraktur 95% KI: 1,45-2,25
89
RR: 2,36 (73-109)
90 RR: 1,97
Risiko pro 1000 Patientenjahre (95% KI)
95% KI: 1,71-2,26 95% KI: 1,91-2,92
75 62 63 Nach einer initialen Fraktur hatten Frauen ein
(55-70) (52-76)
RR: 1,65 50 höheres Risiko für eine Folgefraktur, als durch
60 95% KI: 1,18-2,32
(45-55)
32 36
einen Anstieg des Alters um 10 Jahre
45
(26-48)
(32-34) 27
22 (24-30)
30
(18-25)
Studienhintergrund:
15 • 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)
N=905 N=253 N=147 N=43 N=378 N=111 N=380 N=99 • Frakturen eingeteilt in die Gruppe Hüft-, schwere und geringe Fraktur
0 • Schwere Frakturen: Wirbelkörper, Becken, distale Femur, Rippen (multipel) &
proximale Oberarmknochen
Alle 60-69 70-79 ≥80 • Geringe Frakturen: alle anderen Frakturen, außer Finger und Zehen
• Vertebrale Frakturen: zufälliger Befund, ohne vorheriges systematisches Screening
Altersgruppe (Jahre) nach einer Fraktur
RR: relatives Risiko • Klinische vertebrale Fraktur: Befund durch von X-Ray aufgrund von
KI: Konfidenzintervall Rückenschmerzen und ohne dass eine Fraktur zuvor vorlag
• Modifiziert nach Center JR et al.; JAMA 2007; 297: 387-394
55Änderung des BMD – T-Score (1)
FRAME + FREEDOM
Lendenwirbelsäule
Romosozumab (N=3.170) Denosumab (N=3.261)
1,6
FREEDOM EXTENSION
1,4
FRAME
Mittlere Änderung des T-
1,2
Scores von Baseline
1,0
0,8
0,6
0,4 Zunahme des BMD T-Scores an der LWS
0,2
unter ein Jahr Romosozumab gefolgt
0,0
0 1 2 3 4 5 6 7 8 9 10 von einem Jahr Denosumab
Studienjahr
FRAMEa n=3.170 150 3.141 59 2.855
Freedomb n=3.261 222 212 206 3.158 2.166 2.059 1.605 1.565 1.263
vergleichbar mit der BMD-Zunahme
nach etwa sieben Jahren unter
a. BMD häufiger gemessen (Monat 6+18) in einer Subgruppe die an einer FRAME DXA-Substudie teilgenommen haben; zusätzlich in
b.
Monat 6 gemessen bei Frauen aus Argentinien
BMD häufiger gemessen in einer Subgruppe, die in der FREEDOM DXA-Substudie teilgenommen haben Denosumab
LWS: Lendenwirbelsäule
• Modifiziert nach Cosman F et al.; Journal of Bone and Mineral Research 2018; DOI: 10.1002/jbmr.3427
56Inzidenz neuer vertebraler Frakturen
FRAME
Im ersten Jahr Über 2 Jahre Im zweiten Jahr
RRR: 76%
3,0% PGrüße aus den Alpen!
Stephan Scharla Bad ReichenhallGrüße aus den Alpen!
Stephan Scharla Bad ReichenhallGrüße aus den Alpen!
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