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Title: Osteoporosis: treatments


1
CHAPTER II
  • Osteoporosis treatments

2
Results of the FREEDOM study (open-label) at 5
years
Osteoporosis treatments
20
  • Effects of denosumab BMD evaluation at 5 years
  • After 3 years of treatment 2 343 "long term"
    group
  • 2 207
    "de novo" group

Incidence of new NVF
FREEDOM
Extension study
Lumbar BMD
Total hip BMD
3,5
3,1
8


3,0
14
2,7
2,6



12
6
2,3

2,5

10
2,0

1,9
4

8
2,0
Yearly incidence ofnonvertebral fractures ()


6
BMD variation (, CI95)
Variation de la DMO (, IC95)
2

4
1,5
1,2
1,1
2
0
1,0
0
-2
BL
1
2
3
4
5
BL
1
2
3
4
0,5
5
Treatment duration (years)
Treatment duration (years)
0,0
1
2
3
4
5
Yearss
Denosumab
Placebo
Placebo
Denosumab
p lt 0,002 versus placebo and baseline values
  • BMD increase continues at 5 years of treatment
  • Tolerance no ONJ or atypical fractures in
    the"long term" group 2 ONJ cases in the  de
    novo  group

ASBMR 2010 - Daprès Papapoulos (1025)
3
Denosumab different efficacy by level of renal
function ?
Osteoporosis treatments
21
  • Stratification in 4 subgroups according to
    creatinine clearance

BMD Variation within the 4 groups over 3 years
Incidence of vertebral fractures
BMD variation () 15-29ml/mn(n 73) 30-59ml/mn(n 2 817) 60-89ml/mn(n 4 069) gt 90ml/mn(n 842)
Lumbar 5.0(-0.8-10.8) 8.9(8.4-9.3) 9.0(8.6-9.4) 8.1(7.2-8.9)
Femoral neck 5.9(3.3-8.5) 5.1(4.7-5.5) 5.2(4.9-5.5) 5.6(4.9-6.3)
Total hip 5.9(3.0-8.7) 6.4(6.1-6.7) 6.4(6.2-6.7) 5.8(5.2-6.3)
Placebo (n 3 906)
Denosumab (n 3 902)
10
p lt 0.05
9.1
9
8.1
8
7.2
7.0
7.0
7
6
5
Incidence of vertebral fractures (3 years, ()



4
3.2
3.1
2.9
3
2.3

1.8
2
1
0
N1
3 691
3 702
33
31
1 309
1 332
1 962
1 924
394
413
15-29ml/mn
30-59 ml/mn
60-89 ml/mn
gt 90 ml/mn
All patients
  • Antifracture efficacity of denosumab is
    comparable with respect to renal function
  • No differences in incidence of adverse events

ASBMR 2010 - Daprès Jamal S et al., Toronto,
Canada, abstr. 1068, actualisé
4
HORIZON study 6-year extension
Osteoporosis treatments
22
  • Design at the end of 3 years of the HORIZON
    study, female patients treated with zoledronic
    acid were randomly assigned to 2 groups placebo
    (Z6 n 616) or continuation of treatment (Z3P3
    n 617)

Femoral neck BMD
New radiological vertebral fractures
2,5
15
RR 0,48IC95 (0,3 -0,9)p 0,03
PBO10,9
2
1,5
Z6
10
1
Evolution ()
6,2 (20/486)
0,5
Reduction -52
1 p lt 0,001
Female patients ()
0
3,0 (14/469)
ZOL3,3
Z3P3
5
-0,5
-1
-1,5
0
3
4,5
6
Ans
Initial study (0-3 years)Z3P3
Éxtension study(3-6 years)Z6
  • Résultats
  • Difference of femoral BMD between the Z6 group
    and the Z3P3 placebo group 1
  • No difference between the 2 groups for clinical
    fractures
  • Reduction of 52 in the number of radiologic
    vertebral fractures (n 14 versus n 30) within
    the Z6/Z3P3 group
  • Zoledronic acid long-term treatment does not
    expose to an increased risk of side effects
  • The question of the interest of prolonged
    treatment remains open

ASBMR 2010 - Daprès Black (1070)
5
What is the efficacy of a single injection of
zoledronic acid ?
Osteoporosis treatments
23
  • Post hoc analysis of antifracture efficacy after
    3 years in patients having received a single
    injection of zoledronic acid

1 single perfusion (n 1 367)
3 perfusions (n 6 904)
Zoledronic acid
Placebo
Type of fracture 1 perfusion(n 1 367) 1 perfusion(n 1 367) 1 perfusion(n 1 367) 3 perfusions(n 6 904) 3 perfusions(n 6 904) 3 perfusions(n 6 904)
nfrac. Reduction() p nfrac. Reduction() p
All fractures 105 32 0.04 466 34 lt 0.0001
Clinical vertebral fractures 14 56 0.12(NS) 64 66 lt 0.0001
Nonvertebral fractures 93 24 0.16 (NS) 414 27 lt 0.0001
20
20
15
15
Cumulated events ()
Cumulated events ()
10
10
5
5
p 0.0389
p lt 0.0001
0
0
0
10
20
30
0
10
20
30
Months
1 367
858
368
294
6 904
6 904
6 904
6 662
n
Follow-up duration 3 years
Follow-upduration 3 years
RR 0.68
p 0.04
RR 0.66
p lt 0.0001
  • A single injection induces a reduction of 32
    of the risk of new fractures at 3 years
  • The number of lost to follow-up is significant
    in this group

ASBMR 2010 - Daprès Black D et al., San
Francisco, États-Unis, abstr. 1028, actualisé
6
Bisphosphonate generics a rapid disintegration
Osteoporosis treatments
24
Comparison of disintegration rates
500
450
400
350
300
Disintégration median (in seconds)
250
200
150
100
50
0
Novo-alendronate 70 mg
Apo-alendronate 70 mg
Actonel35 mg
Fosamax70 mg
Fosavance 70 mg
  • Disintegration rate of alendronate generic
    versions is superior to the disintegration rate
    of alendronate, which raises tolerability and
    efficacy issues

ASBMR 2010 - Daprès Olszynski (FR0390)
7
Diagnostic criteria for atypical femoral fracture
Osteoporosis treatments
25
  • Major criteria
  • Fracture line in a proximal site should be under
    the lesser trochanter and , in distal site, over
    the femoral condyles
  • It should be a nontraumatic fracture, or
    following a low-energy trauma
  • Fracture line should be transversal or oblique,
    with a lt 30 angle
  • It should be a noncomminuted fracture
  • Complete fractures involve the entire
    crossection of the bone, from one cortical to the
    other, with a possible internal  thorn 
  • Incomplete fractures affect only the external
    cortical

Short-oblique configuration
Medial spine
  • Minor criteria
  • Periosteal reaction on the external cortical
  • Increase of cortical thickness
  • Dull pain prodromes in thigh s and inner thighs
  • Bilateral fracture
  • Delayed cicatrization
  • Associated comorbidities rheumatoid arthritis,
    vitamin D insufficiency, hypophosphatasia
  • Associated therapies bisphosphonates,
    corticoids, proton pump inhibitors

Noncomminuted
  • Exclusion criteria femoral neck fractures,
    intertrochanteric fractures with a
    subtrochanteric extension, periprosthetic or
    pathological fractures within the context of
    primary bone tumors or bone metastasis
  • All major criteria are required for diagnosis
  • The minor criteria are not necessary (for
    diagnosis) but sometimes (we) come across their
    association

ASBMR 2010 Task Force concernant les fractures
fémorales atypiques (16 octobre 2010)
8
Is the incidence of subtrochanteric fractures
increasing?
Osteoporosis treatments
26
  • National data base (United States) on hip
    fractures between 1996 and 2007 coupled with a
    data base on the use of bisphosphonates

Subtrochanteric fractures
Hip fractures
40
1 200
35
Women
Women
1 000
30
800
Incidence ()
Incidence
25
600
20
Men
Men
400
15
0
200
2008
2008
2002
2004
2002
2004
1995
1998
2000
1995
1998
2000
  • Hospitalizations for subtrochanteric fractures
    are rare, but they are increasing in menopausal
    women.
  • The number of menopausal patients under
    bisphosphonate treatment has been increasing
    during the same period.
  • But, at the same time, the number of classic hip
    fractures is decreasing.

ASBMR 2010 - Daprès Wang (1029)
9
Are patients who received long acting
bisphosphonates at risk for atypical fractures ?
Osteoporosis treatments
27
  • 2 retrospective monocenter 5-year studies
    radiographic analysis

New Zealand study 71 subtrochanteric and
diaphyseal fractures, of which 11 atypical
fractures
Australian study 152 subtrochanteric and
diaphyseal fractures, of which 20 atypical
fractures
Atypical (11) Typical (60)
Age (years) 81 (66-96) 81 (44-100)
Men/Women 1/10 11/49
Alendronate 4 8
Etidronate 0 5
Calcium 6 18
Vitamin D 6 14
Glucocorticoïds 2 5
IPP 0 4
Fracture background 6 28
Total Diaphyse Subtrochanter Distal
Atypical 20 15 5 0
Typical 132 15 65 52
Bisphosphonates Alendronate (median duration) Risedronate(median duration)
Atypical(n 20) 17 (85 ) 15(5.1 ans) 2(3 ans)
Typical(n 132) 3 (2.3 ) 2 (3.5 ans) 1 (1 an)
Alendronate median duration not specified All BP
RR 2.1 (0.5-8.2), p 0.16
Alendronate median duration 5.1 years All BP RR
37.4 (12.9-119), p lt 0.001
  • For these atypical femoral fractures,
  • no association with alendronate in the New
    Zealand study
  • an apparent association between BP and atypical
    fractures in the Australian study, but with a
    very weak frequency of the latter
  • treatment benefits prevail over potential risk

ASBMR 2010 - Daprès Warren (1030) et Girgis
(1071)
10
What is the incidence of subtrochanteric and
diaphyseal fractures before and after treatment
against osteoporosis ?
Osteoporosis treatments
28
  • National Danish registry, matched-centrals study
  • Each user of an antiosteoporosis treatment
    between 1996 and 2006 (n 103 562) was matched,
    after adjustment for age and sex, with 3 controls
    (n 310 683)

Subtrochanteric fractures and alendronate
20
7
After
6
16
5
Before
12
4
IRR (IC95)
IRR (IC95)
3
8
2
4
1
0
0
PTH
lt 1 year
lt 1yearn
Strontium
1-5 years
1-5 years
Étidronate
Raloxifene
gt 10 years
gt 5 yearss
Clodronate
5-10 yearss
Alendronate
Risedronate
Zoledronate
Ibandronate
Pamidronate
Before and after periods
  • There was an increased risk for subtrochanteric
    and diaphyseal fractures before starting the
    treatment against osteoporosis. This increased
    risk was especially high in the year preceding
    start of treatment.
  • With alendronate, such increased risk diminishes
    progressively with treatment.

ASBMR 2010 - Daprès Vestergaard (1072)
11
Incidence of subtrochanteric fractures in the SOF
cohort
Osteoporosis treatments
29
  • 1 396 hip fractures, 45 of which were
    subtrochanteric fractures

Femoral ? 58,1/10 000 Intertrochanteric ?
49,1/10 000 Subtrochanteric ? 3,1/10 000
  • Subtrochanteric fractures represent less than 2
    of hip fractures
  • The incidence of subtrochanteric fractures
    increases with patient age, with a same pattern
    as for hip fractures

ASBMR 2010 - Daprès Kelly (FR0355)
12
Breast cancer risk is reduced with alendronate
Osteoporosis treatments
30
  • Cohort study from a Danish national registry
  • Women gt 50 years,without cancer history that have
    been treated with alendronate from 1996 to 2005
  • 30 606 users
  • 4 centrals matched for to age and sex (n 122
    424)

3
Controls
Diagnostic of breast cancerRR 0.74 (0.66-0.84)
p lt 0.001
Alendronate
2
Combined Incidence ()
Death due to breast cancerRR 0,52 (0,40-0,68)
p lt 0,001
1
0
0
2
4
6
8
Years
  • This national registry, based on a cohort study,
    shows a significant reduction of the risk of
    developping and dying from breast cancer in
    postmenopausal women treated with alendronate

ASBMR 2010 - Daprès Abrahamsen (SU0128)
13
Effect of transdermal teriparatide on bone
remodeling
Osteoporosis treatments
31
Comparison of transdermal and subcutaneous
pharmacokinetic and pharmacodynamic profiles
Variations of bone remodeling markers
PINP
CTX
200
300
300
SC20
250
250
TD50
150
200
200
TD80


150
150
PTH mean value (pg/ml)
Variations ()
100


B

100
100
B

A



50
50
A
A

50
A

0
0

0
0
48
72
96
0
48
72
96
0
1
2
3
4
5
6
7
8
Hours
Days
Days
p lt 0,05 versus baseline Aplt 0,05 TD50 versus
TD80 Bp lt 0,01 SC20 versus TD80
  • Transdermal teriparatide has a pharmacokinetic
    and a pharmacodynamic profile on the bone
    remodeling markers comparable to subcutaneous
    teriparatide 20 ?g profile.

ASBMR 2010 - Daprès Kenan Y et al., Lod, Israël,
abstr. FR0376, actualisé
14
What is the impact of teriparatide on the
cortical bone of women with osteoporosis?
Osteoporosis treatments
32
  • In vivo study using High Resolution Cortical
    Thickness mapping
  • 65 women (median age 67.5 years) from the
    EUROFORS study, treated with teriparatide for 2
    years

Mapping and significance of cortical thickness
modifications (besides the femoral head)
Thickness variations ()
24 months - baseline
p for topographic distribution(a) p
0,00000004(b) p 0,00007 (c) p 0,00007
-2
0
2
4
6
8
0,05
0,025
0
  • At 24 months teriparatide increases the cortical
    thickness of
  • Tension zones involved in walking (muscle
    insertion sites)
  • Upper part of the cortical, critical zone for the
    susceptibility to hip fracture risk

ASBMR 2010 - Daprès Gee AH et al., Cambridge,
Royaume-Uni, abstr. 1250, actualisé
15
Are the vibrations beneficial for bone ?
Osteoporosis treatments
33
  • Randomized , placebo controlled, ITT trial, with
    evaluation on the BMD at 12 months
  • 202 menopausal women with osteopenia and controls
    (n 67)
  • Vertical acceleration 0.3 g (90 Hz n 67, 30
    Hz n 68)
  • Similar demographic parameters (age, menopause
    duration, weight, BMI, ethnics)

Densitometry data characteristics,
vitaminD-calcium contribution
Initial caracteristics Type 90 Hz 30 Hz Witnesses
Mean BMD (g/cm-2),(SD) Femoral neck 0.686 (0,049) 0.676 (0,060) 0.687 (0.054)
Total hip 0.851 (0,066) 0.836 (0,083) 0.845 (0.068)
Lumbar spince 0.904 (0,090) 0.890 (0,069) 0.902 (0.080)
Mean vBMD (mgcm-3), (SD) Trabecular tibial bone 149 (36) 144 (29) 145 (30)
Calcium (mg), mean ET (SD) Total 1 538 (677) 1 399 (656) 1 352 (642)
Vitamin D (UI), mean ET (SD) Total 866 (582) 778 (583) 808 (584)
Phisycal activity (kcal/j), mean (SD) Metabolic index 352 (224) 337 (237) 383 (227)
  • Beneficial effect in ITT vibrations on BMD has
    not been demonstrated
  • Lack of data on muscle evaluation, weight at one
    year, quality of life, etc.

ASBMR 2010 - Daprès Slatkovska (1027)
16
An explosive treatment nitroglycerin (NTG) !
Osteoporosis treatments
34
BMD variations at 24 months
Markers variations at 12 months
  • NTG seems to have beneficial effects on bone
    remodeling and BMD at 24 months

ASBMR 2010 - Daprès Jamal S et al., Toronto,
Canada, abstr. 1252, actualisé
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