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