osteoporose teraptic update
DESCRIPTION
OSTEOPOROSE Teraptic 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. - PowerPoint PPT PresentationTRANSCRIPT
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?