Neue Optionen in der Osteoporosetherapie · Fraktur(en) unter Therapie Teriparatid 2 Jahre...

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



Schmerz (VAS)



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


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


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


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


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


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


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


Femoral Neck BMD Through Month 12



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


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


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



DE/RMZ/1704/0004


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


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


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


Femoral Neck BMD Through Month 24



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


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


p=0.008 p = 0.10

Other Key Fracture Endpoints Through Month 24



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


DE/RMZ/1704/0004


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


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©

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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

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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


SubstudyPercent Change from Baseline in Total Hipand femoral neck

Open-label 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

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Perc

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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‡


Percent Change from Baseline in SerumP1NP and CTX Levels through Month 36

Perc

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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.


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

Neue Optionen in der Osteoporosetherapie · Fraktur(en) unter Therapie Teriparatid 2 Jahre...

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