OSTEOPOROSETeraptic update

Erik Fink Eriksen

Oslo University Hospital

AGENDA

• Osteoporose– Byrde for samfunn– Underbehandling

• Behandlings effektivitet• Østrogener og SERMS• Bisfosfonater

– Langtidsbehandling– Bivirkninger– Seponering

• PTH

Osteoporose – byrde og omkostninger i Norge

• 50% av kvinner og 15% av menn over 50 vil få en osteoporotisk fraktur

• Basert på BMD har 240,000 nordmenn osteoporose• 9000 hoftebrudd og 15000 håndleddsbrudd årlig• Behandling av hoftebrudd koster 250,000-400,000 kr• Total omkostninger 4 mia/år• Under 20% med osteoporose behandles medisinsk• Medisinomkostninger 110 mill kr/år

– RA (0,7% av befolkningen) 1,7 mia kr/år

Osteoporose og underbehandling• Helsedirektoratet og mange leger mener at osteoporose

er en livsstilssykdom som skal forebygges og behandles med endringer I kosthold og mosjon– Tvilling-studier viser at genetikk er ansvarlig for 2/3 av

bentap og brudd– Mosjon og kostholdsendringer er kun effektivt I barndom

og pubertet– Det er ikke vist at mosjon har signifikante effekter på

skjelettet hos eldre (aldrig påvist effekt på brudd), - men det er fortsatt effektivt på muskler og CV risiko

– Ca+vitamin D fortsat viktig profylakse hos eldre, men også begrenset effekt som monoterapi• Risiko for kardiovaskulær sykdom?

5

Treatment of osteoporosis

FACT StudyTetracycline Labels after 6 Months Cancellous Bone

ALN10 TPTD20

1

1

2

Tetracycline labels

Newly formed bone

Image from ME Arlot, Laboratoire d’Histodynamique Osseuse Lyon, France Meunier, et al. ECTS 2003 (Poster Presentation #P-294)

Ben resorption Ben formation

Markers:

BONE MARKERS - ORIGIN

• Pyridinium kollagen

• crosslinks • C-telopeptide (CTX)• N-telopeptide (NTX)

OsteocalcinProcollagen type I propeptides:

• C-terminal (P1CP) • N-terminal (P1NP)

Bone-specific alkaline phosphatase

8

Bone Formation and Resorption Markers after anabolics, antiresorptives and dual action agents

Resorption (NTx)Formation (PINP)

ALN - bone formation and resorption markers

Months

0 1 3 6 12

Mea

n %

cha

nge

with

SE

-100

-50

0

50

100

150

200

250

NTxPINP

*

*

Alendronate

Months

Dual action

0 1 3 6 12-100

-50

0

50

100

150

200

250

*

OCOBBal

OCOBBal

TPTD - Bone Formation Resorption Markers

Months0 1 3 6 12

Mea

n %

cha

nge

with

SE

-100

-50

0

50

100

150

200

250

NTxPINP

Teriparatide

OCOBBal

9

Classes of Pharmacologic Agents for the Treatment of Osteoporosis

– Antiresorptive agents• ET/ERT-SERMs• Calcitonin• Bisphosphonates• Anti-RANKL MAb (Denosumab)

– Dual action Agents• Cathepsin K antagonists• Chloride channel inhibitors

– Anabolic agents• Teriparatide [rhPTH(1-34), rhPTH(1-84)]]• Anti- Sclerostin MAb

– Other mechanism• Strontium ranelate

ANTI RESORPTIV BEHANDLING

11

Risiko reduksjon ved hjertesykdom og osteoporose

Month

02468

1012141618 Hazard ratio, 0.72 (95% CI, 0.56–

0.93)P = .0117

Cum

ulat

ive

Inci

denc

e (%

)

0 4 8 12 16 20 24 28 32 36

ZOL 5 mg (n = 1065)Placebo (n = 1062)

28%

Years0-1 0-30-2

Years0-1 0-30-2

Years0-1 0-30-2

Years0-1 0-30-2

19 Months

010

203040506070

60% 65

%

55%

41%

62%

48% 58

% 65%

61%

52%

65%

BP1 BP2 BP3 BP4 PTH

12

Healthy HumanIliac Crest Biopsy

Osteoporotic HumanIliac Crest Biopsy

EFFECTS OF ANTIRESORPTIVE DRUGS

X

HORMONBEHANDLING

WHI E+MPA fracture outcome

Rossouw et al. JAMA 2002

15

Østrogener beskytter mot hoftebrudd - WHI

Profile of the two WHI studies

Estrogen + MPA – 5 yrs

Estrogen only – 7 yrs

Combined – 50-59 yrs

Schierbeck et al. BMJ 2012;35:e6409

DOPS - 10 year dataRandomized cohorts

Structural Comparison of Estradiol, Raloxifene, and Other SERMs

N

OH

O

O

HO S

Raloxifene

Tamoxifen

ON

OH

HO

Estradiol

ON

Cl

ON

Cl

Toremifene Clomiphene

19Eastell R, et al. J Bone Miner Res. 2000;15(suppl 1):S229.

% In

cide

n t V

e rte

b ral

Fra

ctur

e

0

5

10

15

20

25

30

With Prevalent Vertebral Fractures

Without Prevalent Vertebral Fractures

RR 0.51(95% CI = 0.35, 0.73)

RR 0.66(95% CI = 0.55, 0.81)

Raloxifene 60 mg/d

Placebo

49%

Raloxifen reduserer fraktur risikoMORE Trial - 4 Years

-3

-2

-10123

0 6 12 18 24

-3

-2-10123

Spine

Hip0 6 12 18 24

Hip

Months

Months

BM

D %

cha

nge

BM

D %

cha

nge

Raloxifene Placebo

BISFOSFONATER

21

Actions of Bisphosphonates on Osteoclasts and Osteocytes

BP bind to bone mineral

BP = bisphosphonates

Concentrate at sites of bone resorption and inhibit osteoclasts

BP BPBPBP

BP

BPBP BP

BP

Bone

BPs may act on osteocytes and prevent apoptosis

Images by courtesy of Fraser Coxon and Mike Rogers

osteocyte

Haversian canal

Bisphosphonate (bone surface)

Osteoclast membrane

osteoclast

22

Effect of Long-term Alendronate Treatment on Total Hip BMD

0 0 5

Alendronate, n = 662 660 658 656 460† 657 642 628 599 580 553 Placebo, n = 437 435 436 432 297† 437 428 415 401 380 361

1 2 3 4 1 2 3 4

0-2

2468

10121416

Mea

n Ch

ange

from

FIT

Ba

selin

e (%

)

Time (Years)

FIT FLEX

BMD = bone mineral density; CI = confidence interval; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups; †Measured in clinical fracture arm only.Black DM, et al. JAMA. 2006;296:2927–2938.

PlaceboAlendronate (pooled)

FLEX treatment group*

Mean difference (95% CI): 2.36 (1.81, 2.90)

P < 0.001

23

Effect of Long-term Alendronate Treatment on Serum PINP

Mea

n PI

NP

(ng

/mL)

40

2010

30

0 2 3 40

1 0 2 3 4 51Time (Years)

Alendronate, n = 130 Placebo, n = 87

44†

34† 87130

87126

8713061‡

48‡

50

60

PlaceboAlendronate (pooled)

FLEX treatment group*

PINP = procollagen I N-terminal propeptide; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups; †Measured in clinical fracture arm only; ‡Measured in vertebral fracture arm only.Black DM, et al. JAMA. 2006;296:2927–2938.

FIT FLEX

24

FLEX treatment group:*

Effect of Long-term Alendronate Treatment on Clinical Fracture Risk (1)

Placebo 437 428 429 421 417 414Alendronate 662 659 657 654 650 646

No. at Risk

Clinical Vertebral Fracture Risk

Clinical Nonvertebral Fracture Risk

437 421 410 396 373 355 662 642 619 585 565 537

0

5

10

15

20

Cum

ulat

ive

Inci

denc

e (%

)

RR, 0.45 (95% CI, 0.24, 0.86)

360

5

10

15

20

0 12 24 48 60 72Time to First Fracture (Month)

RR, 1.00 (95% CI, 0.76, 1.32)

360 12 24 48 60 72Time to First Fracture (Month)

RR = relative risk; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups.Black DM, et al. JAMA. 2006;296:2927–2938.

Placebo Alendronate (pooled)

25

% P

atie

nts

Wit

h N

ew

Vert

ebra

l Fra

ctur

es

60%*(43%, 72%)

71%*(62%, 78%)

0

10

0–1 0–2 0–3Years

5

15

1.5%(42/2822)

3.7%(106/2853) 2.2%

(63/2822)

7.7%(220/2853)

3.3%(92/2822)

10.9%(310/2853)

70%*(62%, 76%)

*P < .0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.

Zoledronic Acid Reduced 3-Year Risk of Morphometric Vertebral Fractures (Stratum I) by 70%

ZOL 5 mg Placebo

26

Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = .0024; †P < .0001; ‡P = .0002; relative risk reduction vs placebo §Hip fracture was not excluded from analysis of non-vertebral fracture.Black DM, et al. N Engl J Med. 2007;356:1809-1822.

41%*(17%, 58%)

77%†(63%, 86%)

25%‡(13%, 36%)

Clinical Vertebral Fracture

HipFracture

Non-vertebral Fracture§

1.4%(52/3875) 0.5%

(19/3875)

2.5%(88/3861)

2.6%(84/3861)

8.0%(292/3875)

10.7%(388/3861)

Cum

ulat

ive

Inci

denc

e (%

) of

New

Cl

inic

al F

ract

ures

Ove

r 3

Year

s

0

10

5

15

Zoledronic Acid Reduced Cumulative 3-Year Risk of Clinical Fractures (Hip, Clinical Vertebral, Non-vertebral)

ZOL 5 mg Placebo

27

Risk

and

95%

CI

0.00

0.10

0.20

0.30

0.40

-3 1 2 3 4 5-1 0-2

6 80 100 13030 6010

Due to the non-linearity of the relationship, a quadratic model best explains the associationData on file, Novartis

Fx. Incidence and turnover changeThe Alendronate experience

T-score PINP at 1 year

PINP at 1 year ng/mL

PlaceboZOL 5 mg

6 Years of ZOL Treatment Maintains Reduction in β-CTX at a Lower Level Than 3 Years of Treatment (ITT)

• Mean values remained within the premenopausal reference range throughout

Z6 n= 44 40 39 31 41 40 44 20 21 18 19 27PBO/Z3P3 n= 46 44 37 32 38 42 46 19 25 17 22 28

*

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1 2 3 4 5 65.54.53.52.51.50.5

Mea

n β-

CTX

(ng/

mL)

Time (years)

*P < 0.05. No significant difference at any other time point in the extension study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822). ITT = intention to treat, Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years

Z6 Z3P3Start of extension trial

Core study:†P < 0.001 relative risk reduction vs placebo (PBO)*P = 0.0348, relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6 ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years1. Black DM, et al. N Engl J Med. 2007;356:1809–1822.

Continuous ZOL Treatment Resulted in Significantly Fewer New Morphometric Vertebral Fractures in Years 3-6 Than Discontinuation of Treatment (ITT)

6.2%(30/486)

3.0%(14/469)

52%*(10, 74)

% P

atie

nts

Morphometric Vertebral Fractures

3.3%(92/2822)

Core study1 Extension study

10.9%(310/2853)

70%†(62, 76)

Z3P3 Z6ZOL Core Study (Yr 0-3)PBO

0

5

10

15

Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time

Month

02468

1012141618 Hazard ratio, 0.72 (95% CI, 0.56–0.93)

P = .0117

Cum

ulat

ive

Inci

denc

e (%

)

0 4 8 12 16 20 24 28 32 36

ZOL 5 mg (n = 1065)Placebo (n = 1062)

28%

BP in CV disease in RA

Wolfe et l. JBMR 2012

• No spontaneous AE reports• AE database search of 50 MedDRA terms, with adjudication• Case definition: exposed bone in the mouth > 6 weeks• 1 in ZOL, 1 in placebo• Both cases healed with antibiotic therapy and/or debridement

Osteonecrosis of the Jaw

Frequency of ONJ – Benign indications

• Retrospective assessment– ASBMR consensus rep. 1/10,000-1/100,000– German study < 1/13,600– ADA < 1/100,000– Canadian study < 1/100,000

• Prospective assessment– ZOL (>10,000 pts) 1 BP/1 placebo – DEN 0– Extension studies: ZOL 1 ONJ case Z6, 0 in Z3P3 – DEN 1– > 1,000,000 pts used Aclasta so far

• No ONJ case reported• Risk in oncology trials 1-5%

• In oncology trials Denosumab has the same risk of ONJ than ZOL

Atypical femoral fractures

4% of hip fx. are subtrochanteric

Case reports: transversal fx. prodromal pain

focal or diffuse cort. thickening periosteal reaction fx. usually nor related to falls bilat. affection often seen Risk factors: Vitamin D deficiency, glucocorticoids, long term BP use

Atypical femoral fractures

35

• Swedish register study• Risk increases immediately• Risk decreases immediately after discontinuation• BP treatment increases risk 40X

• Study from Kaiser Permanente found increased risk with prolonged BP use (X-ray based analysis)

• 1 yr ALN 2/100,000• 12 yr ALN 250/100,000

• Risk very low 1-3 ATFF per 100 hip fractures avoided

OR = odds ratio.FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf

Predictors of Risk for Vertebral Fracture

Variable OR (95% Cl) P valueLow FN BMD T-score (≤ –2.5) atExtension baseline

3.3 (1.4, 8.0) 0.008

Low Total Hip BMD T-score (≤ –2.5) atExtension baseline

4.01 (1.8, 8.9) 0.0007

Incident vertebral fracture on ZOL during Core 4.74 (1.3, 16.7) 0.0156

Prevalent vertebral fracture atExtension baseline

1.84 (0.7, 4.4) NS

Overveie beh pause når:

BMD T-score I rygg og hofte er > -2,5Ingen nye brudd under beh,

37

Anabolicdrugs

38

osteoblast apoptosis

boneliningcells

­Wnt­ BMP­ PPAR­ IGF 1,2

­ Lining cell dedifferentiation

­ bone formation

­ bone mass/strength

PTHonce-daily Lining cells

RANKL­ OPG

PTH/ALN COMPARISONLumbar Spine Cancellous BMD - QCT

39

LS BMD DXA

Months

0 6 18

Mea

n %

cha

nge

+/=

SE

0

5

10

15

20

25

Col 1 vs Col 2 Col 1 vs Col 5

% c

hang

e (m

ean

±SE)

*P<0.05, †P<0.01 ALN10 vs.TPTD20

*

TPTD20 (n = 26)ALN10 (n = 23)

3.8

19.0

†

McClung, et al, ASBMR 2003

40

Effect of Teriparatide onSkeletal Architecture

Patient treated with 20µg Female, age 65Duration of therapy: 637 days (approx 21 mos)

BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%)

41

PER

IOST

EAL

CIR

CU

MFE

REN

CE

38

39

40

41

42

END

OC

OR

TIC

AL C

IRC

UM

FER

ENC

E

23

24

25

26

27

28

PLACEBO TPTD20 TPTD40

POLA

R M

OM

ENT

OF

INER

TIA

1900

2000

2100

2200

2300

2400

2500

2600

AXIA

L M

OM

ENT

OF

INER

TIA

660

700

740

780

820

860

PLACEBO TPTD20 TPTD40

*

†

†

†

†

†

Cortical Bone Parameters Assessed by pQCT

Zanchetta, et al. J Bone Miner Res. 2003

*P=0.005†P<0.001 †P<0.001

†P<0.001 †P<0.001

42

New VFx with Increasing Prevalent VFx Grade

Mild Moderate Severe Mild Moderate Severe14 23 27

Prevalent VFx Grade

0

5

10

15

20

25

30

Placebo Group TPTD20 GroupRR = 3.6, P<0.001

P=0.20

Fracture Prevention Trial

% o

f wom

en w

ith n

ew V

Fx

43

ANABOLIC DRUGSAntifracture efficacy over time

First Non- traumatic Non- Vertebral Fracture versus Time on Therapy

Data from Fracture Prevention TrialN: Placebo=544, TPTD20=541,TPTD40=552

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

[0,6) [6,12) [12,18) >=18

Months of Therapy

Patie

nts

with

Fra

ctur

eas

Per

cent

of P

atie

nts

at R

isk

PlaceboPTH

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

[0,6) [6,12) [12,18) >=18

Months on Therapy

Rat

io o

f Per

cent

with

Fra

ctur

e

44

Combination treatment - 68 yr oldmale

PTH 1-34 ZOL

LS-BMD (% change)

Oct 04 June 06

Behandling og alder

• 50-60– HRT og Alendronat– Intermitterende iv. Aclasta– Svær OP: Forsteo

• 60-75– Alendronat– Iv. Aclasta– Svær OP: Forsteo– (Prolia)

• > 75– Prolia– Iv. Aclasta– Svær OP: Forsteo

Nye Behandlingsregimer

Erik Fink Eriksen

Oslo Universitetssykehus

47

Agenda

– The new entrants in the market - parenteral administration• Denosumab (Prolia®)

– Dual action agents – a new MOA– New Anabolics

• Anti-Sclerostin

Osteoprotegerin (OPG) and RANK ligand (RANKL) are the principal regulators of osteoclast formation

OPG

RANKL

Osteoblast Mononuclear cell

M-CSF

1,25 Vit D

PGE2

IL-11

PTH, PTHrp

RANK

TRAF

-6 nF-B

JNK

IL-1, TNF-

E2,-IF

Osteoclast

Denusomab

Prolia® viser en rask og vedvarende reduksjon av beinresorpsjonen

1. Lewiecki EM et al. J Bone Miner Res 2007;22:1832–1841.

Gjennomsnittlig endring fra baseline i serumnivå av C-telopeptid1

49

Adapted from Lewiecki EM et al, 2007.

HISTOMORPHOMETRY FREEDOM TRIAL

Reid et al. JBMR 2010

-2

0

2

4

6

8

10

12

0 6 12 18 24 30 36

Study Month

Per

cent

Cha

nge

BMD Changes at Lumbar Spine Over 3 Years

*

**

** 9.2%

PlaceboDenosumab

*P<0.0001

Results are from the DXA substudy, N=441

BMD Changes at Total Hip Over 3 Years

**

*

*

6.0%

PlaceboDenosumab

*P<0.0001*

Results are from the DXA substudy, N=441

-2

0

2

4

6

Per

cent

Cha

nge

0 6 12 18 24 30 36Study Month

-100-80-60-40-20

020406080

0 6 12 18 24 30 36

Study Month

Per

cent

Cha

nge

Decrease in Serum CTX-I Over 3 Years

PlaceboDenosumab

** *

* *

72%

*P<0.0001

Results are from the bone marker substudy, N=160

86% relative reduction at month 1

3.1%3.1%

2.2%

1.1%

0.7%0.9%

0

0.5

1

1.5

2

2.5

3

3.5

Cru

de In

cide

nce

(%)

Vertebral Fracture Risk Reduction Year by Year

65%P<0.0001

78%P<0.0001

61%P<0.0001

Year 2Year 1 Year 3

PlaceboDenosumab

Nonvertebral Fractures

20% P=0.011 95% CI, (5 to 33%)

6.5%

8.0%

PlaceboDenosumab

0

2

4

6

8

10

0 6 12 18 24 30 360 6 12 18 24 30 36

Study Month

Cum

ulat

ive

Inci

denc

e (%

)

Total nonvertebral fractures, n = 531Rates represent Kaplan-Meier estimates at 36 months

Hip Fracture

Rates represent Kaplan-Meier estimates at 36 months

40% P=0.036

95% CI (3 to 63%)

0.7%

1.2%

PlaceboDenosumab

0.0

0.5

1.0

1.5

2.0

0 6 12 18 24 30 360 6 12 18 24 30 36

Study Month

Cum

ulat

ive

Inci

denc

e (%

)

Total hip fractures = 69

Summary of Adverse Events (AEs)

Placebo Denosumab

Any adverse event 93.1% 92.8%

Serious adverse events 25.1% 25.8%

Led to stopping the study 2.1% (81) 2.4% (93)

Led to stopping study drug 5.2% (202) 4.9% (192)Death 2.3% (90) 1.8% (70)

P=NS for all comparisons

Prespecified Adverse Events

AEs Placebo Denosumab

Malignancy 4.3% (166) 4.8% (187)

Infections 54.4% 52.9%

Delayed fracture healing or nonunion 0.1% (5) 0.1% (2)

ONJ 0% (0) 0% (0)

SAEs

Malignancy 3.2% (125) 3.7% (144)

Infections 3.4% (133) 4.1% (159)

Stroke 1.4% (54) 1.4% (56)

Coronary heart disease events 1.0% (39) 1.2% (47)

Atrial fibrillation 0.7% (29) 0.7% (29)P=NS for all comparisons

Other Adverse Events

Placebo Denosumab

AEs with ≥ 2% and P≤0.05

Eczema 1.7% (65) 3.0% (118)

Fall* 5.6% (218) 4.5% (174)

Flatulence 1.4% (53) 2.2% (84)

SAEs with ≥ 0.1% and P≤0.01

Cellulitis (includes erysipelas) <0.1% (1) 0.3% (12)

Concussion 0.3% (11) <0.1% (1)

Cumulative incidence over 3 years

Prespecified statistical criteria

*Excludes falls occurring on the same day as a fracture

Summary

• Reduced risks of vertebral, nonvertebral, and hip fractures

• Reduced bone resorption and increased BMD

• Had a safety profile similar to placebo

• Injections every 6 months may improve compliance

In the FREEDOM study, denosumab 60 mg SC every 6 months for 3 years

61

”Dual action”drugs

62

DUAL ACTION AGENTSProposed MOA

Karsdal et al. Am J Pathol 2005,166:467

63

Hypothesis: Cathepsin K-inhibiton can prevent Osteoporosis

• Osteoclastic bone resorption can be inhibited in vitro with an antisense oligonucleotide to cathepsin K or with specific inhibitors of cathepsin K

• Cathepsin K knockout mice develop osteopetrosis• Absence of cathepsin K in man leads to Pycnodysostosis

Cathepsin K is strongly expressed in osteoclasts

Cathepsin K has the strongest collagenase like activity of all enzymes secreted by osteoclasts

H+ H+

Exocytosis of Cathepsin K

Degradation of Bone matrixby Cathepsin K

H+ secretion

Cathepsin K inhibition in OPOdanacatib data

Cathepsin K inhibition in OPOdanacatib data

Anti-sclerostin

67Gardner, J. C. et al. J Clin Endocrinol Metab 2005;90:6392-6395

Lumbar spine BMD in male and female homozygous and heterozygous individuals with sclerosteosis

Homozygotes

Heterozygotes

68

Anti-sclerostin MAb

Effects of anti-sclerostin Ab in cynomolgus monkey – (3-30 mg/kg) x2/mo in 2 months

70

FUTURE TRENDS

•Antiresorptives will dominate in years to come– Generic ALN (however compliance problems with oral

drugs)– IV BPs will increase market share over orals– Denosumab will hopefully increase primary care

penetration•Antiresoptives still needed after anabolics

– Role of HRT og BPs vs. Denosumab

71

FUTURE TRENDS•Anabolics are able to increase bone mass by 30% or more

•Anabolics will have their greatest impact on non-vertebral fractures (cortical effects and dim. change)

•Anabolics need to become cheaper and more convenient

•Anti-sclerostin has advantages due to infrequent administration and potency

• Safety?