seminar 23-11-2016 dr. w.f. lems

1-12-2016

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Prof Dr Willem F LemsDepartment of Rheumatology, EULAR Centre of Excellence;ARC, location VU University medical centre and Reade, Amsterdam, the Netherlands

behandeling.

IWO, Utrecht 23 November

(potentiële) belangenverstrengeling Prof Dr Willem Lems

Voor bijeenkomst mogelijk relevante relaties met bedrijven

Honorarium of andere (financiële) vergoeding

Eli Lilly, MSD, Amgen, Novartis, Will Pharma

Disclosures

- Wat is het behandeldoel?- Hoe monitor je therapie bij osteoporose?- (Hoe lang is behandeling zinnig?)

- Nieuwe medicamenten op komst ?!

Zijn er nieuwe inzichten in:-Epidemiologie-Diagnostiek osteoporose?-Niet-medicamenteuze behandeling?-Medicamenteuze behandeling.

New York Times, 1 June 20166

New York Times, 1 June 20166

JBMR 2015

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Crisis in the treatment of osteoporosis

• In theorie is het natuurlijk mogelijk dat andere middelen, zoals denosumab of teriparatide, vaker voorgeschreven worden.

• Andere verklaringen worden gezocht in de angst voor bijwerkingen, waaronder atypische femurfracturen en aseptische necrose van de kaak.

• Geopperd werd dat er meer aandacht zou moeten zijn voor educatie aan huisartsen, en ook voor het initiëren van meer engagement voor osteoporose bij huisartsen (toch is zoiets makkelijk gezegd in een dergelijke sessie, dan gedaan: huisartsen worden ook met veel andere problematiek geconfronteerd!)

• Niet genoemd: wellicht speelt de introductie van generieke middelen en een zich terugtrekkende farmaceutische industrie hier een rol.

• In VS: vergoeding DXA 33 dollar!

[1077] Hip fractures and declining DXA testing: at a breaking point?

• Data from the 2002-2014

• 5% sample of Medicare fee-for-service beneficiaries to identify persons with at least one Medicare-paid DXA scan in each year (sample size~0.9 million /year)

Congress Highlights ASBMR 2016 Annual Meeting

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• Examine the latest national trends in hip fracture rates

PARTICIPANTS

• Persons with at least one Medicare-paid DXA scan in each year (using health care claims + enrollment data 2002-2014)

• DXA providers = any paid DXA service with technical component for office-based and freestanding providers, + any DXA bill for hospital outpatient departments, during a year

METHODS

• Presence of hip fracture identified by: ICD-9-CM diagnosis code of 820.0x, 820.2x, or 820.8x

• Exclusion of traumaANALYSES

Brauer CA et al,. 2009, 302, 1573-1579; DXA: dual X-ray absorptiometry

E. MICHAEL LEWIECKI, UNM HEALTH SCIENCES CENTER, ALBUQUERQUE, USA


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RESULTS

DXA: dual X-ray absorptiometry

2002-2006 2007-2012 >2014

Medicare payment $139 $82 $42

Decline of age-adjusted hip fracture rates from 2002 to 2012

Decline of DXA testing and diagnosis of osteoporosis

Overall decrease of osteoporosis prescriptions

[1077] Hip fractures and declining DXA testing: at a breaking point?

E. MICHAEL LEWIECKI, UNM HEALTH SCIENCES CENTER, ALBUQUERQUE, USA

Reproduced with permission from the American Society for Bone and Mineral Research

Reactie deel 1

• Onze reactie ligt, zoals verwacht mag worden, geheel in de lijn van de multidisciplinaire CBO-richtlijn Osteoporose en Fractuurpreventie (2011)

• Uitgangspunt voor ons is niet de patient met osteoporose of osteopenie, maar de patient met een door de arts vastgesteld verhoogd fractuurrisico (in de praktijk meestal een patient met osteoporose, soms met osteopenie en risicofactoren, zoals bijvoorbeeld prednison-gebruik)

• Bij deze patienten is er indicatie voor behandeling, meestal met bisfosfonaten, soms met andere medicatie (denosumab, teriparatide, raloxifen). Van al deze medicamenten is fractuurreductie aangetoond in onderzoekingen waarin alle patienten ook calcium en vitamine D voorgeschreven kregen.

• Om een optimaal effect van deze middelen te verkrijgen, is het dus passend dat voldoende calcium en vitamine D kan worden voorgeschreven aan deze patienten. Wij zijn dan ook van mening dat calcium en vitamine D vergoed behoren te worden aan patienten waarbij door de behandelend arts een verhoogd fractuurrisico is vastgesteld.

Reactie deel 2

• Daarnaast is er een grote groep individuen waarbij bij de DXA meting geen verhoogd fractuurrisico wordt vastgesteld. Deze patienten krijgen in de regel lifestyle adviezen: voldoende calcium, vitamine D, en lichaamsbeweging.

• Het ZINrapport over zelfzorgmiddelen lijkt de keuze te maken dit niet te willen vergoeden. Aangezien deze adviezen langdurig/levenslang gelden, gaat dit met kosten gepaard die voor patienten aan de (financiele) onderkant van de samenleving een bezwaar kunnen vormen.

• Dit kan leiden tot relatieve calcium en vitamine D deficienties, en onnodig verhoogd val- en fractuurrisico bij deze individuen. Wij laten de verantwoordelijkheid daarvoor bij de commissie van het ZINrapport

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[LB-MO0361] Persistence of excess mortality following individual types of fragility fracture: a relative survival analysis

• All Danish individuals aged 50+ years who first experienced fragility fractures in 2001

• 9,500 men (67±12 y) and 21,000 women (72± 13y) with a first fragility fracture in 2001 followed by 3,198 and 6,589 deaths


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• Examine contribution of fracture on mortality at precise time intervals following fracture

PARTICIPANTS

• Death ascertained from the Danish death registerMETHODS

• Excess mortality associated with individual types of fracture ANALYSES

THACH TRAN, GARVAN INSTITUTE OF MEDICAL RESEARCH, SYDNEY, AUSTRALIA

Relative survival at 1 year following fragility fracture

Year 1 interval Last year post-fracture of significantexcess mortality

Observedsurvival

Expectedsurvival

Relative survival(95% CI)

Year Relative survival(95% CI)

Women

Hip 0.72 0.91 0.8 (0.79, 0.83) Year 10 0.95 (0.93, 0.97)

Other femur 0.70 0.92 0.77 (0.72, 0.82) Year 7 0.97 (0.89, 0.99)

Pelvis 0.77 0.92 0.55 (0.91, 0.59) Year 7 0.94 (0.88, 0.99)

Vertebra 0.84 0.94 0.89 (0.86, 0.92) Year 5 0.96 (0.93, 0.99)

Clavicle 0.89 0.95 0.94 (0.9, 0.95) Year 4 0.95 (0.91, 0.99)

Rib 0.90 0.95 0.95 (0.91, 0.99) Year 2 0.95 (0.91, 0.99)

Proximalhumerus

0.90 0.95 0.95 (0.94, 0.96) Year 6 0.97 (0.96, 0.93)

Distal humerus 0.91 0.95 0.96 (0.91, 1.01) N/A

Distal forearm 0.96 0.96 1.0 (0.99, 1.01) N/A

Knee 0.97 0.97 1.0 (0.98, 1.02) N/A

Lower leg 0.93 0.96 0.97 (0.95, 0.99) Year 4 0.93 (0.96, 0.99)

Ankle 0.98 0.98 1.0 (0.99, 1.01) N/A

Rotative survival = observed survival following fracture in the study group/ expected survival from the age,, sex and calendar year-specific Danish background population. Significant results bolded


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Reproduced with permission from the authors

RESULTS

[LB-MO0361] Persistence of excess mortality following individual types of fragility fracture: a relative survival analysis

THACH TRAN, GARVAN INSTITUTE OF MEDICAL RESEARCH , SYDNEY AUSTRALIA

[1007] The effect of bisphosphonates on all-cause and post-fracture mortality risk in the population-based Canadian Multicentre

Osteoporosis Study (CaMOS)

• 5526 women and 2163 men (CaMOS)

• Age 50+, all community dwelling


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• Determine the overall effect of bisphosphonates on risk of all-cause mortality• Determine the effect of BP and nitrogen-containing BP on mortality risk following

fracture

PARTICIPANTS

• Fracture and mortality over 15 years (1996-2011)

• Co-morbidities, medication and life-style measured (to assess healthy user bias)METHODS

• Time dependent Cox Model to assess overall effect of BP on mortality risk

• Survival analysis to assess effects of individuals BPs

• Hormone therapy used as a treatment comparator

ANALYSES

BP: bisphosphonates; BP: bisphosphonate

DANA BLIUC, GARVAN INSTITUTE OF MEDICAL RESEARCH, SYDNEY, AUS


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RESULTS

BP: bisphosphonates; n-BP: nitrogen-containing BP; HR: hazard ratio; CI: confidence interval

• In men: mortality risk was reduced in current [HR 0.70 (0.49-0.94)] and past BP users [HR 0.49 (0.34-0.70)]

• In women with fractures (n=1100)

Mortality risk was reduced for nitrogen-containing (n-BP): multivariable HR

0.63 (0.47-0.85) for alendronate

0.48 (0.30-0.76) for risedronate

but not for etidronate : HR: 1.00 (0.75-1.33)

This decreased mortality effect was not related to a reduction in subsequent fractures

[1007] The effect of bisphosphonates on all-cause and

post-fracture mortality risk in the population-based

Canadian Multicentre Osteoporosis Study (CaMOS)

DANA BLIUC, GARVAN INSTITUTE OF MEDICAL RESEARCH, SYDNEY, AUS

[1076] Measurement of cortical and trabecular deterioration identifies postmenopausal women at imminent risk for

fracture: the OFELY study

• 589 French postmenopausal women (42-94 years old)

• 135 incident fracture over 9.4 yrs


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• Determine whether identification of women at risk for imminent fracture (1-2 years) can be done by quantification of microarchitecture deterioration

PARTICIPANTS

• Structure Fragility Score (SFS) combining trabecular and cortical index by HRpQCTat the distal radius

• FN BMD and FRAX scoresMETHODS

• Comparison of FN BMD and FRAX score to identify patients at risk for imminent fracture within the first 2 years of follow-up

• Analysis with Strax software

ANALYSES

HRpQCT: High Resolution peripheral Quantitative Computed Tomography; SFS: Structure Fragility Score, FN: Femoral neck; BMD: bone mineral density

STEPHANIE BOUTROY, INSERM UMR 1033, UNIVERSITY OF LYON, FRANCE


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• 4.7 fold increased imminent fracture risk at SFS=22

• Independent prediction of imminent and overall fracture when SFS =22 in a multivariate model (FN T-score<-2.5 and FRAX>20%)

• 3 variables predicted incident fractures during 9.4 years follow-up: HR [95%CI]: 1.7 and 1.6 for a SD decrease in SFS and FN T-Score respectively and 1.04 for an unit increase in FRAX

RESULTS

FN: Femoral Neck; SFS: Structure Fragility Score; HR: Hazard Ratio; SD: Standard Deviation; CI: Confidence interval

Fracture

cases

(135)

Non-fracture

controls

(454)

SFS 23.9 ± 9.7* 28.3 ± 9.6

FN T-score -1.6 ± 0.8 * -1.3 ± 0.8

FRAX score 13.9 ± 10.8 * 10.0 ± 9.2

Sensitivity

Imminent

fractures

(specificity %)

All

fractures

FN T-Score<-2.5 18% (95%) 10% (90%)

FRAX>20% 22% (95%)19% (90%)

SFS <2260% (75%)

50% (75%)*p<0.0001

[1076] Measurement of cortical and trabecular deterioration identifies postmenopausal women at imminent risk for fracture: the OFELY study

STEPHANIE BOUTROY, INSERM UMR 1033, UNIVERSITY OF LYON, FRANCE

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- Wat is het behandeldoel?- Hoe monitor je therapie bij osteoporose?- (Hoe lang is behandeling zinnig?)

- Nieuwe medicamenten op komst ?!

Zijn er nieuwe inzichten in:-Epidemiologie-Diagnostiek osteoporose?-Niet-medicamenteuze behandeling?-Medicamenteuze behandeling.

Non-medical treatment: new insights?

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[1108] Calcium and/ or vitamin D supplementation are not associated with ischaemic heart disease: findings from the UK Biobank cohort

• UK Biobank population-based cohort• 502,664 men and women (45.5%/54.5%) aged 40-69 years• Median age of 58 years


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• Investigate the association between calcium (with or without vitamin D) supplementation and risk of myocardial infarction

PARTICIPANTS

• Self-reported supplementation with Ca and/ or vitamin D

• Information available on incident hospital admission for ischaemic heart disease, any cardiovascular event and death

METHODS

• Cox Proportional Hazards models, with adjustment for age, BMI, smoking, alcohol, educational level, physical activity, and in a further model, HRT use

ANALYSES

BMI: body mass index; HRT: hormonal replacement therapy

NICHOLAS HARVEY, MRC LIFECOURSE EPIDEMIOLOGY UNIT, UNIVERSITY OF SOUTHAMPTON, UK


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• 34,890 participants using Ca supplements

• 20,004 participants using vit D supplements

• 10,406 participants using both

• There were no associations between use of Ca supplements & risk of incident hospital admission with IHD, any cardiovascular event or death following either admission category

• Likewise vitamin D & combination supplementation was not associated with any outcome in either sex

RESULTS

IHD: ischaemic heart disease; HR: hazard ratio; Ca: calcium

Patients HR for IHD admission The adjusted HRs for

death from IHD

Women taking Ca supplements 1.06 (95% CI:0.85, 1.31) 0.71 (95%CI: 0.32, 1.61)

Men taking Ca supplements 1.02 (95%CI: 0.80, 1.30) 0.92 (95%CI: 0.52, 1.62)

[1108] Calcium and/ or vitamin D supplementation are not associated with ischaemic heart disease: findings from the UK Biobank cohort

NICHOLAS HARVEY, MRC LIFECOURSE EPIDEMIOLOGY UNIT, UNIVERSITY OF SOUTHAMPTON , UK

[FR0001] Serum 25-hydroxyvitamin D values and risk of all-cause mortality: a population-based, retrospective, cohort study

• 11,022 persons over age 18


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• Establish in the United States the relationship of low and high serum vitamin D levels with all-cause mortality

PARTICIPANTS

• T0: 30 days after first 25(OH)D measurement

• Patients followed until last clinical visit or death

• Vitamin D examined as a categorical variable using predetermined ranges of interest: 25(OH)D values <12, 12-19, 20-50 (reference range), and >50 ng/mL

METHODS

• Kaplan-Meier estimates and Cox proportional hazards regression• Analysis adjusted for age, gender, race, month of 25(OH)D measurement, Charlson comorbidity

index at time of 25(OH)D measurementANALYSES

T0: time 0

DANIEL DUDENKOV, MAYO CLINIC, MINNESOTA, USA


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RESULTS

Characteristics Total 25(OH)

D <12

ng/mL

25(OH)

D 12-19

ng/mL

25(OH)

D 20-50

ng/mL

25(OH)

D >50

ng/mL

Total patients 11022 643 1605 8210 564

Age, mean

(SD)

54.3

(17.2)

51.4

(18.0)

51.8

(17.0)

54.9

(17.1)

55.8

(18.0)

Sex, n women

(%)

8496

(77.1%)

463

(72.0%)

1176

(73.3%)

6357

(77.4%)

500

(88.7%)

Race, n white

(%)

9653

(87.6%)

420

(65.3%)

1209

(75.3%)

7482

(91.1%)

542

(96.1%)

25(OH)D,

mean (SD)

30.0

(12.9)

8.5 (2.1) 15.9

(2.3)

32.4

(7.6)

60.9

(15.5)

Charlson

index, mean

(SD)

3.37

(3.4)

3.75

(4.1)

3.23

(3.5)

3.36

(3.4)

3.54

(3.2)

SD: standard deviation



DANIEL DUDENKOV, MAYO CLINIC, MINNESOTA, USA


• RESULTS


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• Daniel Dudenkov, Mayo Clinic, minnesota, usa


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Medical treatment, new insights?

Medical treatment, new insights?


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• In a real-life clinical setting in patients with severe OP, the risk of clinical Fxdecreased significantly during 24 mo of TPTD treatment

• This was associated with a reduction in back pain and improvements in QoL

• These changes were maintained for up to 24 mo after TPTD termination

• Results should be interpreted in the context of a non-controlled observational study

AUTHOR’S CONCLUSION

• With teriparatide and subsequent antiresorptive therapy, quality-of-life, back pain, and fracture risk reduction are maintained

• This suggests a lingering beneficial effect of initial teriparatide therapy in patients with severe osteoporosis

CLINICAL IMPACT FROM

REVIEWER’S PERSPECTIVE

OP: osteoporosis; fx: fracture, TPTD: teriparatide; mo: month

[SU0284] Fracture incidence and changes in back pain and Quality of Life in patients with osteoporosis treated with teriparatide: Results from the

European Extended Forsteo® Observational Study (ExFOS)

BENTE LANGDAHL, UNIVERSITY HOSPITAL, AARHUS, DENMARK

Back to TOC


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RESULTS

FN: femoral neck ; TUG: timed up-and-go; BMD: bone mineral density

[FR0284] Effect of teriparatide or risedronate in BMD and fracture recovery in elderly patients with a recent pertrochanteric hip fracture: final results of a 78-week randomized clinical trial

JORGE MALOUF, INTERNAL MEDICINE; HOSPITAL SAN PABLO, BARCELONA, SPAIN



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RESULTS

FN: femoral neck ; TUG: timed up-and-go; BMD: bone mineral density




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RESULTS

FN: femoral neck ; TUG: timed up-and-go; VAS: visual analog scale





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RESULTS

FN: femoral neck ; TUG: timed up-and-go




[1100] Discontinuation of denosumab and associated fracture incidence: analysis from FREEDOM and its extension

• 1001 subjects who discontinued DMAb during FREEDOM or Extension


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• Describe VFx risk and possible determinants in subjects who discontinued DMAb during the 3-yr FREEDOM or 7-yr extension

PARTICIPANTS

• Subjects with ≥2 doses of IP (DMAb 60 mg Q6M or PBO) and then discontinuation of IP but stayed in study ≥7 months after the last dose

METHODS

• Patients who discontinued DMAb from FREEDOM or Extension were analyzed as one group

ANALYSES

IP:investigational product- DMAb 60 mg Q6M or PBO; DMAb: denosumab,; VFx: vertebral fracture

JACQUES P BROWN, LAVAL UNIVERSITY AND CHU DE QUÉBEC (CHUL) , CANADA

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• BMD and bone turnover marker effects of discontinuing denosumab

RESULTS

BMD: Bone Mineral Density; CTX: collagen type 1 cross-linked C-telopeptide

Reproduced with permission from the author




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FREEDOM PBO FREEDOM + Extn DMAb

All subjects off treatment N = 470 N = 1001

New VFx, n (%) 29 (6.2%) 56 (5.6%)

Multiple new VFX, n (%) [among all subjects] 10 (2.1%) 34 (3.4%)

Multiple new VFX, n (%) [among all subjects with new

VFx] 10 (34.5%) 34 (60.7%)

Subjects with prior VFx before treatment N=122 (26%) N=255 (25%)

Off-treatment new VFx, n (%) 12 (9.8%) 19 (7.5%)

Off-treatment multiple new VFx, n (%) [among subjects

with prior VFx]5 (4.1%) 15 (5.9%)

Off-treatment multiple new VFx, n (%) [among subjects

with prior VFx and new VFx] 5 (41.7%) 15 (78.9%)

On-treatment new VFx (per 100 subject-years) 11.6 1.9

Off-treatment new VFx (per 100 subject-years) 14.4 12.1

RESULTS

DMAb: denosumab; VFx: Vertebral Fracture; PBO: Placebo; Extn: Extension


Multiple new VFx: > 2 vertebral Fx after DMAb cessation




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• Discontinuation of DMAb is associated with an increase in VFx rate to levels comparable to PBO

• Among subjects who sustained new VFx after DMAb cessation, there was a greater incidence of multiple new VFx than in PBO

• Subjects with prior VFx are at high risk for off-treatment new VFx and should continue osteoporosis therapy

• Those who discontinue DMAb should transition to another therapy

AUTHOR’S

CONCLUSION

• Drug holiday concept is frequently generalized to therapies other than bisphosphonate

• Discontinuing DMAb may lead to increases in bone resorption putting patients at risk of fracture

• Fracture rates return to PBO levels on discontinuation of DMAb, however there is an increasein multiple VFx perhaps associated with the overshoot in BTMs

• Research is required to confirm that switching to a bisphosphonate is effective to preventdeclines in BMD and increases in fracture risk



DMAb: Denosumab; VFx: vertebral fracture; PBO: placebo; BTM: bone turnover marker; BMD: body mass index


JACQUES P BROWN, LAVAL UNIVERSITY AND CHU DE QUÉBEC (CHUL), CANADABack to TOC

[FR0294] Fracture risk after discontinuation of denosumab

• Females aged ≥ 65 years

• On DMAb for ≥ 12 months prior to the treatment index date


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• Evaluate Fx risk among discontinuers of Denosumab who remained off therapy without reinitiating or switching treatment

PARTICIPANTS

• Treatment discontinuation = the absence of a DMAb claim within 6 months + 8 weeks following a previous claim

METHODS

• Endpoints were clinical vertebral Fx and Fx at any skeletal site other than skull/face/finger/toe (‘any Fx’)

• Comparison of Fx incidence rates between 3 periods using IRR: early (first 90 days of treatment), on-treatment (day 91 to discontinuation), and off-treatment (discontinuation to end of follow-up) periods

ANALYSES

Fx: fracture; IRR: incidence rate ratios; DMAb: denosumab

AKEEM YUSUF, CHRONIC DISEASE RESEARCH GROUP, MINNEAPOLIS, USA


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• 7,855 denosumab-treated patients, mean age 79.4 ± 7.5 years; (88.5% white)

• 1,988 patients had prior exposure to other osteoporosis medications; 857 patients had a previous Fx

• Compared to the early treatment period, incidence rates of vertebral Fx & any Fxdecreased during the on-treatment period by 52.8% and 32.6%

• Fx incidence rates increased during the off-treatment period but remained below the baseline rates observed during the early treatment period

RESULTS

Fx: fracture




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RESULTS

Fx: fracture

Fracture incidence rates in patients threated with denosumab who later discontinued

and remained off treatment

Vertebral fractures Any fracture *

Fracture incidence rates/100 patient-

years

Early period 4.39 12.62

On-treatment 2.07 8.51

Off-treatment 3.09 11.40

Fracture incidence rate ratio (95% CI)

On-treatment vs. Early period 0.47 (0.35 – 0.63) 0.67 (0.57 – 0.79)

On-treatment vs. Off-treatment 0.67 (0.51- 0.87) 0.75 (0.65 – 0.85)

Off-treatment vs. Early period 0.70 (0.54 – 0.93) 0.90 (0.77 – 1.06)

*’Any fracture’ was a composite endpoint of fracture at any skeletal side other than skull/face/finger/toe




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• This large, population-based study of older women showed reductions in Fx rates during the on-treatment period with denosumab, followed by an increase in Fxrates during the off-treatment period

• Fx rates during the approximately 6-12 month off-treatment period remained lower than the observed baseline rates in this population


• This study supports previous work that suggesting that bisphosphonates beinitiated when denosumab is discontinued



Fx: fracture


AKEEM YUSUF, CHRONIC DISEASE RESEARCH GROUP, MINNEAPOLIS, USABack to TOC

[1005] Effect of 10 years of Denosumab treatment on bone histology and histomorphometry in the FREEDOM extension study

• 22 patients with 10 years of DMAb exposure from FREEDOM Extension study• Originally, 3902 DMAb and 3906 placebo subjects enrolled for 3 years• Bone biopsy were compared at 2,3, and 10 years treatment


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• Determine bone safety of denosumab in iliac crest biopsies after 10 years of treatment

PARTICIPANTS

• Transiliac bone biopsy

• Tetracycline/demeclocycline labeling (6 months after their last DMAb dose)

• Samples prepared according to standard procedures

METHODS

• Continuous and categorical variables computed using descriptive statisticsANALYSES

DMAb: Denosumab

DAVID W DEMPSTER, COLUMBIA UNIVERSITY, NEW-YORK, USA


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RESULTS

• No sign of osteomalacia, woven bone or marrow fibrosis

FREEDOM Extension

Year 2/3 Year 5 Year 10

Placebo

N = 45

Denosumab

N = 47

Cross-over

N = 13

Long-term

N = 25

Long-term

N = 22

Denosumab

exposure (years)0 2-3 2 5 10

Parameter Median (Q1, Q3)

Eroded surface/

bone surface (%)1.0 (0.6, 1.9) 0.2 (0.0, 0.7) 0.2 (0.0, 0.4) 0.1 (0.0, 0.3) 0.3 (0.0, 0.9)

Osteoid surface

(%)6.8 (3.6, 10.1) 0.4 (0.2, 1.2) 0.5 (0.2, 0.7) 0.1 (0.0, 0.8) 0.1 (0.0, 0.2)

Osteroid width (mm) 8.7 (6.4, 11.0) 5.4 (4.4, 7.4) 5.6 (3.3, 6.6) 3.3 (0.0, 7.4) 4.2 (0.0, 7.4)

Mineral apposition

rate (mm/d)0.8 (0.7, 0.8) 0.3 (0.3, 0.5) 0.6 (0.5, 0.7) 0.4 (0.3, 1.1) 0.3 (0.3, 0.3)

BFR, volume based

(%/yr )14.6 (8.6, 21.8) 0.4 (0.2, 0.3) 1.2 (0.7, 1.3) 2.2 (0.2, 4.7) 0.3 (0.2, 2.8)

Activation frequency

(years -1)

0.200 (0.120,

0.330)

0.002 (0.001,

0.004)

0.017 (0.001,

0.071)

0.031 (0.001,

0.071)

0.001 (0.001,

0.012)


[1005] Effect of 10 years of denosumab treatment on bone histology and histomorphometry in the FREEDOM extension study

DAVID W DEMPSTER, COLUMBIA UNIVERSITY, NEW-YORK, USA


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DMAb: Denosumab

• Normal bone microarchitecture by bone histology

• Histomorphometry was consistent with DMAb mechanism of action

• No evidence of further reductions in remodelling with long-term DMAb

• Cancellous and cortical bone structures were maintained

• Anti-resorptive effect of denosmab was maintained

• DMAb reduced bone resorption, increased bone mineral density, and decreased new vertebral, hip, and nonvertebral fracture risk in postmenopausal women with osteoporosis in the FREEDOM trial

• The data suggest that DMAb maintains anti-resorptive efficacy, maintaining normal microarchitecture for 10 years

• Although the sample size is small, the present study further supports the safety of long-term DMAb treatment for osteoporosis

[1005] Effect of 10 years of denosumab treatment on bone histology and histomorphometry in the FREEDOM extension study

DAVID W DEMPSTER, COLUMBIA UNIVERSITY, NEW-YORK, USA Back to TOC

Differential Effects of Teriparatide and Denosumab on Intact PTH and Bone Formation Indices: AVA Osteoporosis Study

David W. Dempster, Hua Zhou, Robert R. Recker, Jacques P. Brown, Christopher P. Recknor, E. Michael Lewiecki, Paul D. Miller, Sudhaker D. Rao, David L. Kendler, Robert Lindsay, John H. Krege, Jahangir Alam, Kathleen A. Taylor, Boris Janos, Valerie A. Ruff

Citation: Dempster, et al. J Clin Endocrinol Metab 2016;101(4):1353-63.

Study Design

* Bone turnover markers measured were P1NP and CTX

Abbreviations: BTMs, bone turnover markers; CTX, carboxyterminal cross-linking telopeptide of type 1 collagen; DEM, demeclocycline; DMAb, denosumab; iPTH, intact parathyroid hormone; P1NP, procollagen type 1 N-terminal propeptide; TET, tetracycline; TPTD, teriparatide

DEM TET TETDEM

Month 33:12:3labelingschedule

TPTD (20 μg/day) or DMAb (60 mg once) Treatment (open-label)

BTMsiPTHBone Biopsy

BTMsiPTH

Month 6

BTMs*iPTH

Month 1

BTMsiPTH

▲▲ ▲3:12:3labelingschedule

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Values are medians with interquartile range

*p<0.001 for between treatment group comparison at baseline or Month 3 in each envelope†p<0.001 for within treatment group comparison from baseline to Month 3 in each envelope

Abbreviations: BFR/BS, bone formation rate per bone surface

Changes in Bone Formation Rate (BFR/BS)

Cancellous

Month0 3

Ca

nc

ello

us

BF

R/B

S

(mm

3/m

m2

/ye

ar)

0.000

0.025

0.050

0.075

†

*†

Intracortical

Month0 3

Intr

ac

ort

ica

l B

FR

/BS

(mm

3/m

m2

/ye

ar)

0.000

0.025

0.050

0.075

0.100

†

*†

Periosteal

Month

0 3

Pe

rio

ste

al B

FR

/BS

(mm

3/m

m2

/ye

ar)

0.000

0.005

0.010

0.015

0.020

†

*†

–– Teriparatide–– Denosumab

Endocortical

Month0 3

En

do

co

rtic

al B

FR

/BS

(mm

3/m

m2

/ye

ar)

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

†

*†

Values are medians with interquartile range.

*p<0.001 for between treatment group comparison at baseline or Month 3 in each envelope†p<0.001 for within treatment group comparison from baseline to Month 3 in each envelope±p<0.05 for between treatment group comparison at baseline or Month 3 in each envelope

€p<0.05 for within treatment group comparison from baseline to Month 3 in each envelopeAbbreviations: MAR, mineral apposition rate

Changes in Mineral Apposition Rate (MAR)

Cancellous

Month0 3

Ca

nc

ello

us

MA

R µ

m/d

ay

0.00

0.25

0.50

0.75

*†

±

Endocortical

Month0 3

En

do

co

rtic

al M

AR

µm

/da

y

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

€

*†

±

Intracortical

Month0 3

Intr

ac

ort

ica

l M

AR

µm

/da

y

0.0

0.5

1.0

†

*†

Periosteal

Month0 3

Pe

rio

ste

al M

AR

µm

/da

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

–– Teriparatide–– Denosumab

Values are medians with interquartile range.

*p<0.001 for between treatment group comparison at baseline or Month 3 in each envelope±p<0.05 for between treatment group comparison at baseline or Month 3 in each envelope

†p<0.001 for within treatment group comparison from baseline to Month 3 in each envelope¥p<.01 for within treatment group comparison from baseline to Month 3 in each envelopeAbbreviations: dLS/BS, double labels per bone surface

Changes in Double-Label Surface (dLS/BS)

Cancellous

Month0 3

Ca

nc

ello

us

dL

S/B

S (

%)

0

3

6

9

12

15

18

†

*†

Endocortical

Month0 3

En

do

co

rtic

al d

LS

/BS

(%

)

0

10

20

30

40

50

†

*†

Intracortical

Month0 3

Intr

ac

ort

ica

l d

LS

/BS

(%

)

0

3

6

9

12

15

18

21

†

*†

–– Teriparatide

–– DenosumabPeriosteal

Month0 3

Pe

rio

ste

al d

LS

/BS

(%

)

0±¥

[1099] Odanacatib efficacy and safety in postmenopausal women with osteoporosis: 5-year data from the extension of the phase 3 long-term

odanacatib fracture trial (LOFT)

• 6,047 patients (3432 ODN, 2615 PBO) at 348 sites in 40 countries.

• Women 65+; mean age 72.8 y

• BMD T-score ≤–2.5 at TH or FN or with VFx


59

• Evaluate the efficacy and safety of ODN in postmenopausal women with osteoporosis

PARTICIPANTS

• Patients- randomized (1:1) to ODN 50 mg/week or PBO for up to 5 years

• Vitamin D3 + calcium

• Endpoints: new or worsening of morphometric VFx, hip fracture, non-VFx, clinical VFx, and safety and tolerability

METHODS

• DXA

• Radiographic vertebral assessment

• Endpoints: morphometric VFx, hip fracture, non-VFx, clinical VFx, and safety and tolerability

ANALYSES

ODN: Odanacatib; TH: total hip; FN: femoral neck; VFx: vertebral fracture; PBO: placebo; BMD: bone mineral density; DXA: dual X-ray absorptiometry

MICHAEL R. MCCLUNG, OREGON OSTEOPOROSIS CENTER, PORTLAND, USA


60

• Compared to PBOODN treatment over 5 y:

• Compared to PBO, ODN treatment led to progressive BMD increases:

• Incidence of AEs and serious AEs overall were balanced

• Deaths: ODN 383 (4.8%) PBO 334 (4.2%), HR 1.11 [95% CI: 0.96, 1.28]

RESULTS

ODN: Odanacatib; TH: total hip; FN: femoral neck; VFx: vertebral fracture; LS: lumbar spine; PBO: placebo; AEs: adverse events; HR: hazard ratio; CI: clinical interval

Treatment over 5 years Relative Risk Reduction (all p<0.001)

morphometric VFx 52%

hip fracture 48%

non-VFx 26%

clinical VFx 67%

Major fracture 42%

BMD increase at 5 years

(all p<0.001) (95% CI)

LS 10,9% (10.5, 11.2)

TH 10,3% (10.0, 10.6)

[1099] Odanacatib efficacy and safety in postmenopausal women with osteoporosis: 5-year data from the extension of the phase 3 long-term


MICHAEL R. MCCLUNG, OREGON OSTEOPOROSIS CENTER, PORTLAND, USA

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[1156] Safety of odanacatib in postmenopausal women with osteoporosis: 5-year data from the extension of the Phase 3 long-term


• Women ≥ 65 years with BMD T-score ≤ –2.5 at TH or FN, or with radiographic vertebral fracture and T-score ≤ –1.5 at TH or FN


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• Examine the safety and efficacy of ODN in postmenopausal women with osteoporosis

PARTICIPANTS

• ODN 50 mg/week or PBO

• Vit D3 (5600 IU/week) and CaMETHODS

• Adjudication of AEs: delayed fracture union, AFFs, ONJ, morphea-like skin lesions, systemic sclerosis, serious respiratory infections, and CV events

ANALYSES

TH: total hip; FN: femoral neck; AEs: adverse events; AFFs: atypical femoral shaft fractures; ONJ: osteonecrosis of the jaw; CV: cardiovascular; BMD: bone mineral density; ODN: Odanacatib; PBO: placebo;

SOCRATES PAPAPOULOS, LEIDEN UNIVERSITY MEDICAL CENTER, LEIDEN, THE NETHERLANDS


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• 6,047 patients: 3432 ODN, 2615 PBO

• 378 deaths reported

• 18 delayed fracture union in each group

• Femoral shaft fractures: 26 with ODN vs 7 PBO,

– 10 adjudicated AFF on ODN

– 0 adjudicated AFF on PBO• No ONJ observed in the study participants

• Morphea-like skin lesions observed in 13 ODN vs 3 PBO, most with onset within 2 years and 15 of 16 improved or fully recovered (unusual for this condition)

• Systemic sclerosis reported in 2 ODN vs 1 PBO

• Serious respiratory infections : balanced between groups

RESULTS

PBO: placebo; AFF: atypical femoral shaft fracture; ONJ: osteonecrosis of the jaw; ODN: Odanacatib



SOCRATES PAPAPOULOS, LEIDEN UNIVERSITY MEDICAL CENTER, LEIDEN, THE NETHERLANDS


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• More than 4300 cardiovascular events:

• 240 strokes in patients receiving ODN and a significant 32% greater risk of stroke versus placebo (HR 1.32, 95% CI 1.02-1.70, P=0.03)

• As a sensitivity analysis, the long-term extension phase of the trial (> 8,000 patients), provided 324 additional strokes, with HR 1.37 (95% CI 1.10-1.71, P=0.005)

• There was a trend towards an increased risk of atrial fibrillation or flutter, HR 1.25 (95% CI 0.98-1.60, P=0.07) in the core study and 1.22 (95% CI 0.99-1.50, P=0.06) during the extension.

• Total of 306 subjects with atrial fibrillation or flutter during the trial

• The atrial fibrillation patients did not co-localize with the stroke patients

RESULTS

ODN: Odanacatib; HR: hazard ratio; CI: confidence interval

[1155] The long-term odanacatib fracture trial (LOFT): cardiovascular safety results

MICHELLE O'DONOGHUE, BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, USA


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• ODN treatment was generally well tolerated for up to 5 years

• Femoral shaft fractures, including AFFs, and morphea-like skin lesions uncommon, but more frequent with ODN

• No confirmed cases of ONJ

AUTHOR’S

CONCLUSION

• Adverse cardiovascular risk profile will terminate clinical development of thisproduct for osteoporosis

• This study is the largest ever undertaken for postmenopausal osteoporosis and will provide a vast resource for the study of osteoporosis globally



AFF: atypical femoral shaft fracture; ONJ: osteonecrosis of the jaw; ODN: Odanacatib



SOCRATES PAPAPOULOS, LEIDEN UNIVERSITY MEDICAL CENTER, LEIDEN, THE NETHERLANDS Back to TOC

[1096] Fracture risk reduction with romosozumab: results of the Phase 3 FRAME study (FRActure study in postmenopausal woMen with

ostEoporosis)

• 7180 postmenopausal women (mean age 71) with osteoporosis (BMD T-score ≤–2.5 at TH or FN)

• Multicenter, randomized, double-blind, placebo-controlled study


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• Report the results of the FRAME study (phase 3 trial)

PARTICIPANTS

• Subjects randomized 1:1 to Pbo or 210mg Romo SC QM for 12 months

• Followed by 60mg DMAb SC Q6M for 12 months in both groupsMETHODS

• Co-primary endpoints: subject incidence of new vertebral fracture through M12 and M24

• Secondary endpoints: clinical fracture (NVT + symptomatic vertebral), NVT fracture, and BMDANALYSES

Pbo: placebo; Romo: Romosozumab; DMAb: denosumab; NVT: nonvertebral; TH: total hip, FN: Femoral neck; BMD: bone mineral density

F COSMAN, HELEN HAYES HOSPITAL, WEST HAVERSTRAW, AND COLUMBIA UNIVERSITY, NEW-YORK, USA

[1096] Fracture risk reduction with romosozumab: results of the Phase 3 FRAME study (FRActure study in postmenopausal woMen with

ostEoporosis)

• Adverse events were generally balanced between groups


66

• RRR: relative risk reduction; Pbo: placebo; Romo: Romosozumab; DMAb: denosumab; NVT: nonvertebral

• F Cosman, Helen Hayes Hospital, West Haverstraw, and Columbia University, New-York, USA

Romo % Pbo % RRR % p value

New vertebral fracture at M12

0.5 1.8 73 <0.001

vertebral fracture risk at M24 (+DMAb)

0.6 2.5 75 <0.001

clinical fracture risk at M12

1.6 2.5 36 0.008

NVT fracture incidence

through M12 1.6 2.1 25 0.096

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Dank voor Uw aandacht! • Shown speaking at press conference, left to right: Kenneth Saag, MD, NOF President and NBHA Co-Chair; Sundeep Khosla, MD, Mayo Clinic, formerASBMR President; Douglas P. Kiel, MD, MPH, ASBMR President; Andrea Singer, MD, NOF Medical Director; John Kanis, MD, IOF President

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